CA2423919A1 - Methods of providing and using compounds (retinoids) having activity as inhibitors of cytochrome p450rai - Google Patents
Methods of providing and using compounds (retinoids) having activity as inhibitors of cytochrome p450rai Download PDFInfo
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- CA2423919A1 CA2423919A1 CA002423919A CA2423919A CA2423919A1 CA 2423919 A1 CA2423919 A1 CA 2423919A1 CA 002423919 A CA002423919 A CA 002423919A CA 2423919 A CA2423919 A CA 2423919A CA 2423919 A1 CA2423919 A1 CA 2423919A1
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
Novel compounds having the Formulas 1 through 8, wherein the symbols have the meaning defined in the specification, and certain previously known compounds have been discovered to act as inhibitors of the cytochrome P450RAI (retinoic acid inducible) enzyme, and are used for treating diseases responsive to treatment by retinoids. The compound can also be used in co-treatment with retinoids.
Description
1. Cross-Reference to Related Application This application is a continuation-in-part of application serial number 6 09/651,235, filed August 29, 2000.
7 2. Field of the Invention 8 The present invention is directed to providing, preparing and using 9 compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to selecting and preparing 11 compounds which inhibit the enzyme cytochrome P450R.AI, many of which 12 are derivatives of phenylacetic or heteroarylacetic acid, and using said 13 compounds for treatment of diseases and conditions which are normally 14 treated by retinoids.
BACKGROUND ART
16 Compounds which have retinoid-like activity are well known in the art, 17 and are described in numerous United States and other patents and in scientific 18 publications. It is generally known and accepted in the art that retinoid-like 19 activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous 21 diseases and conditions. In other words, it is generally accepted in the art that 22 pharmaceutical compositions having a retinoid-like compound or compounds 23 as the active ingredient are useful as regulators of cell proliferation and 24 differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and 26 non-inflammatory acne, psoriasis, ichthyoses and other keratinization and 27 hyperproliferative disorders of the skin, eczema, atopic dermatitis, barriers 28 disease, lichen planus, prevention and reversal of glucocorticoid damage 29 (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents 1 and to treat and reverse the effects of age and photo damage to the skin.
2 Retinoid compounds are also useful for the prevention and treatment of 3 cancerous and precancerous conditions, including, premalignant and malignant 4 hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood 6 and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and 7 papillomas of the mucous membranes and in the treatment of Kaposi's 8 sarcoma. In addition, retinoid compounds can be used as agents to treat 9 diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, 11 as well as in the treatment and prevention of various cardiovascular diseases, 12 including, without limitation, diseases associated with lipid metabolism such 13 . as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to 14 increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of 16 conditions and diseases associated with human papilloma virus (HPV), 17 including warts and genital warts, various inflammatory diseases such as I 8 pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative 19 diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, 21 modulation of apoptosis, including both the induction of apoptosis and 22 inhibition of T-Cell activated apoptosis, restoration of hair growth, including 23 combination therapies with the present compounds and other agents such as 24 MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, 26 modulation of organ transplant rejection and facilitation of wound healing, 27 including modulation of chelosis. Retinoid compounds have relatively 28 recently been also discovered to be useful for treating type II non-insulin 1 dependent diabetes mellitus (NIDDM).
2 Several compounds having retinoid-like activity are actually marketed 3 under appropriate regulatory approvals in the United States of America and 4 elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural product, 6 biosynthesized and present in a multitude of human and mammalian tissues 7 and is known to play an important rule in the regulation of gene expression, 8 tissue differentiation and other important biological processes in mammals 9 including humans. Relatively recently it has been discovered that a catabolic pathway in mammals, including humans, of natural retinoic acid includes a 11 step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI
12 (retinoic acid inducible).
13 Several inhibitors of CP450RAI have been synthesized or discovered in 14 the prior art, among the most important ones ketoconazole, liarozole and 8116010 are mentioned. The chemical structures of these prior art compounds 16 are provided below. It has also been noted in the prior art, that administration 17 to mammals, including humans, of certain inhibitors of CP-450R.AI results in 18 significant increase in endogeneous RA levels, and further that treatment with 19 CP450RAI inhibitors, for example with liarozole, gives rise to effects similar to treatment by retinoids, for example amelioration of psoriasis.
14 G ~~ocorrazoLE
1 The following publications describe or relate to the above-summarized 2 role of CP450RAI in the natural catabolism of RA, to inhibitors of CP-450RAI
3 and to ifz vitro and in vivo experiments which demonstrate that inhibition of 4 CP450RAI activity results in a increases endogeneous RA levels and potential 5 therapeutic benefits:
7 2. Field of the Invention 8 The present invention is directed to providing, preparing and using 9 compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to selecting and preparing 11 compounds which inhibit the enzyme cytochrome P450R.AI, many of which 12 are derivatives of phenylacetic or heteroarylacetic acid, and using said 13 compounds for treatment of diseases and conditions which are normally 14 treated by retinoids.
BACKGROUND ART
16 Compounds which have retinoid-like activity are well known in the art, 17 and are described in numerous United States and other patents and in scientific 18 publications. It is generally known and accepted in the art that retinoid-like 19 activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous 21 diseases and conditions. In other words, it is generally accepted in the art that 22 pharmaceutical compositions having a retinoid-like compound or compounds 23 as the active ingredient are useful as regulators of cell proliferation and 24 differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and 26 non-inflammatory acne, psoriasis, ichthyoses and other keratinization and 27 hyperproliferative disorders of the skin, eczema, atopic dermatitis, barriers 28 disease, lichen planus, prevention and reversal of glucocorticoid damage 29 (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents 1 and to treat and reverse the effects of age and photo damage to the skin.
2 Retinoid compounds are also useful for the prevention and treatment of 3 cancerous and precancerous conditions, including, premalignant and malignant 4 hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood 6 and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and 7 papillomas of the mucous membranes and in the treatment of Kaposi's 8 sarcoma. In addition, retinoid compounds can be used as agents to treat 9 diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, 11 as well as in the treatment and prevention of various cardiovascular diseases, 12 including, without limitation, diseases associated with lipid metabolism such 13 . as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to 14 increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of 16 conditions and diseases associated with human papilloma virus (HPV), 17 including warts and genital warts, various inflammatory diseases such as I 8 pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative 19 diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, 21 modulation of apoptosis, including both the induction of apoptosis and 22 inhibition of T-Cell activated apoptosis, restoration of hair growth, including 23 combination therapies with the present compounds and other agents such as 24 MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, 26 modulation of organ transplant rejection and facilitation of wound healing, 27 including modulation of chelosis. Retinoid compounds have relatively 28 recently been also discovered to be useful for treating type II non-insulin 1 dependent diabetes mellitus (NIDDM).
2 Several compounds having retinoid-like activity are actually marketed 3 under appropriate regulatory approvals in the United States of America and 4 elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural product, 6 biosynthesized and present in a multitude of human and mammalian tissues 7 and is known to play an important rule in the regulation of gene expression, 8 tissue differentiation and other important biological processes in mammals 9 including humans. Relatively recently it has been discovered that a catabolic pathway in mammals, including humans, of natural retinoic acid includes a 11 step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI
12 (retinoic acid inducible).
13 Several inhibitors of CP450RAI have been synthesized or discovered in 14 the prior art, among the most important ones ketoconazole, liarozole and 8116010 are mentioned. The chemical structures of these prior art compounds 16 are provided below. It has also been noted in the prior art, that administration 17 to mammals, including humans, of certain inhibitors of CP-450R.AI results in 18 significant increase in endogeneous RA levels, and further that treatment with 19 CP450RAI inhibitors, for example with liarozole, gives rise to effects similar to treatment by retinoids, for example amelioration of psoriasis.
14 G ~~ocorrazoLE
1 The following publications describe or relate to the above-summarized 2 role of CP450RAI in the natural catabolism of RA, to inhibitors of CP-450RAI
3 and to ifz vitro and in vivo experiments which demonstrate that inhibition of 4 CP450RAI activity results in a increases endogeneous RA levels and potential 5 therapeutic benefits:
6 Kuijpe~s, et al., "The effects of oral liarozole on epidermal proliferation and 7 differentiation in severe plaque psoriasis are comparable with those of 8 acitretin", British Journal of Dermatolo~y, (1998) 139: pp 380-389.
9 Kaug, et al., "Liarozole Inhibits Human Epidermal Retinoid Acid 4-Hydroxylase Activity and Differentially Augments Human Skin Responses to 11 Retinoic Acid and Retinol In Irivo", The Journal of Investi ate ive Dermatolo~y, 12 (August 1996) Vol.107, No. 2: pp 183-187.
13 hahWauwe, et al., "Liarozole, an Inhibitor of Retinoic Acid Metabolism, 14 Exerts Retinoid-Mimetic Effects in Vivo", The Journal of Pharmacolog~and Experimental Therapeutics, (1992) Vol. 261, No 2: pp 773-779.
16 De Po~~e, et al., "Second Generation Retinoic Acid Metabolism Blocking 17 Agent (Rumba) 8116010: Dose Finding in Healthy Male Volunteers", 18 University of Leuven, Belgium, pp 30.
19 Wauwe, et al., "Ketoconazole Inhibits the ih Vitro and in Vivo Metabolism of AlI-Ti~ahs-Retinoic Acid", The Journal of Pharmacology and Experimental 21 Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.
22 White, et al., "cDNA Cloning of Human Retinoic Acid-metabolizing Enzyme 23 (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*", The 24 Journal of Biolo_ ig'cal Chemistry, (1997) Vol. 272, No. 30, Issue of July 25 pp 18538-18541.
26 Hauzlik, et al., "Cyclopropylamines as Suicide Substrates for Cytochromes 27 P450RAI", Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-28 761.
1 O~tiz de Nlontellano, "Topics in Biology - The Inactivation of Cytochrome 2 P450RAI", Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 3 201-210.
4 Hanzlik, et al. "Suicidal Inactivation of Cytochrome P450RAI by Cyclopropylamines> Evidence for Cation-Radical Intermediates", J. Am.
6 Chem. Soc., (1982), Vol.104, No. 107, pp. 2048-2052.
7 In accordance with the present invention several previously known and 8 several new compounds are utilized as inhibitors of CP450RAI to provide 9 therapeutic benefit in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids and or which in healthy 11 mammals, including humans, are controlled by natural retinoic acid. The 12 perceived mode of action of these compounds is that by inhibiting the enzyme 13 CP450RAI that catabolyzes natural RA, endogenous RA level is elevated to a 14 level where desired therapeutic benefits are attained. The chemical structures 1 S of certain previously known compounds which have been discovered to be 16 inhibitors of the enzyme CP450RAI are provided in the descriptive portion of 17 this application for patent. The chemical structures of the novel compounds 18 which axe used in the methods of treatment in accordance with the invention 19 are summarized by Formulas 1 through 8 in the Summary Section of this application for patent. Based on these chemical structures the following art is Z I of interest as background to the novel structures.
22 U.S. Patent Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024;
23 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712;
S,I34,159;
24 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658;
5,130,335;
4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP 0 130,795;
26 DE 3316932; DE 3708060; Dawson, et al. "Chemistry and Biology of 27 Synthetic Retinoids", published by CRC Press. Inc., (I990), pages 324-356;
28 are of interest to compounds of Formula 1.
1 U.S. Patent Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744;
2 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 4,723,028;
3 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP
4 0170105;EP0286364;EP0514269;EP0617020;EP0619116;
DE 3524199; Derwent JP6072866; Dawsoh, et al. "Chemistry and Biology of 6 Synthetic Retinoids", published by CRC Press, Inc., 1990, pages 324-356; are 7 of interest to compounds of Formula 2.
8 Dawsoh, et al. "Chemistry and Biology of Synthetic Retinoids", 9 published by CRC Press, Inc., (1990), pages 324-356; is of interest to compounds of Formula 3.
11 U.S. Patent Nos. 5,965,606; 5,773,594; 5,675,024; 5,663,347;
12 5,023,341; 5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519;
4,826,969;
13 4,833,240; 5,037, 825; 5,466,861; 5,559,248; WO 85100806; WO 92/06948;
14 WO 95/04036; WO 96/05165; EP 0 098 591; EP 0 170 105; EP 0 176 034;
EP 0 253,302; EP 0 303 915; EP 0 514 269; EP 0 617 020; EP 0 619 116;
16 EP 0 661 259; DE 3316932; DE 3602473; DE 3715955; UK application 17 GB 2190378; Ey~olles et al., J. Med. Chem., (1994), 37, 1508-1517;
G~aupjzer 18 et al. Biochem. and Biophysical Research Communications, (1991), 1554-19 1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawso~a, et al. "Chemistry and Biology of Synthetic Retinoids", published by CRC Press, 21 Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.
22 U.S. Patent Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357;
23 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795;
4,992,468;
24 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051;
WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020;
26 EP 0 619 116; DE 3524199; Derwent JP6072866; Dawsoh, et al. "Chemistry 27 and Biology of Synthetic Retinoids", published by CRC Press~Inc., (1990), 28 pages 324-356; are of interest to compounds of Formula 5.
1 U.S. Patent Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357;
2 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468;
3 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051;
4 WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020;
EP 0 619 116; DE 3524199; Derwert JP6072866; Dawsoh, et al. "Chemistry 6 and Biology of Synthetic Retinoids", published by CRC Press, Inc., ( 1990), 7 pages 324-356; are of interest to compounds of Formula 6.
8 U.S. Patent Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341;
9 5,739,338; 5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 5,037,825;
EP 0 130 795; DE 3316932; Dawsoh, et al. "Chemistry and Biology of 11 Synthetic Retinoids", published by CRC Press, Inc., ( 1990), pages 324-3 56;
12 are of interest to compounds of Formula 7.
13 U.S. Patent Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024;
14 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895;
5,346,915;
5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154; 4,740,519;
16 4,826,969; 4,826,984; 4,833,240; 5,037,825; 5,466,861; 5,559,248;
17 WO 85/00806; WO 92/06948; WO 95104036; WO 96/05165; EP 0 098 591;
18 EP 0 130 795; EP 0 176 034; EP 0 253 302; EP 0 303 915; EP 0 514 269;
19 EP 0 617 020; EP 0 619 116; EP 0 661 259; DE 3316932; DE 3602473;
DE 3708060; DE 3715955; U.K, application GB 2190378; Eyrolles et al., J.
21 Med. Chem., (1994), 37 1508, 1517; Graupner et al., Biochem. and 22 Biophysical Research Communications, (1991) 1554-1561; Kagechika, et al., 23 J. Med. Chem., (1988), 31, 2182-2192; Dawsoh, et al. "Chemistry and 24 Biology of Synthetic Retinoids", published by CRC Press~Inc., (1990), pages 324-356; are of interest to compounds of Formula 8.
26 Prior art which is of interest as background to the previously known 27 compounds that have been discovered in accordance with the present invention 28 to be inhibitors of cytochrome P450RAI, is identified together with the 1 identification of these known compounds.
3 In accordance with the present invention novel compounds of 4 Formulas 1 through 8 are used as inhibitors of the enzyme cytochrome P450RAI to treat diseases and conditions which are normally responsible to 6 treatment by retinoids, or which are prevented, treated, ameliorated, or the 7 onset of which is delayed by administration of retinoid compounds or by the 8 mammalian organism's naturally occurring retinoic acid. These novel 9 compounds are shown by Formulas 1 11 (R4, s 12 ~~Z A(Rz)-(CH2)n COOR$
14 (R1)pf'f 16 Formula 1 18 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group 19 consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 21 groups being optionally substituted with one or two RZ groups;
22 X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
23 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 24 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
26 Z is -C=C-, 27 -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 28 -CO-NRl-, 1 NR~-CO-;
2 -CO-O-, 3 -O-CO-, 4 -CS-NRl-, 5 NR~-CS-, 6 -CO-S-, 7 -S-CO-, 8 -N=N-;
9 Rl is independently H or alkyl of 1 to 6 carbons;
13 hahWauwe, et al., "Liarozole, an Inhibitor of Retinoic Acid Metabolism, 14 Exerts Retinoid-Mimetic Effects in Vivo", The Journal of Pharmacolog~and Experimental Therapeutics, (1992) Vol. 261, No 2: pp 773-779.
16 De Po~~e, et al., "Second Generation Retinoic Acid Metabolism Blocking 17 Agent (Rumba) 8116010: Dose Finding in Healthy Male Volunteers", 18 University of Leuven, Belgium, pp 30.
19 Wauwe, et al., "Ketoconazole Inhibits the ih Vitro and in Vivo Metabolism of AlI-Ti~ahs-Retinoic Acid", The Journal of Pharmacology and Experimental 21 Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.
22 White, et al., "cDNA Cloning of Human Retinoic Acid-metabolizing Enzyme 23 (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*", The 24 Journal of Biolo_ ig'cal Chemistry, (1997) Vol. 272, No. 30, Issue of July 25 pp 18538-18541.
26 Hauzlik, et al., "Cyclopropylamines as Suicide Substrates for Cytochromes 27 P450RAI", Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-28 761.
1 O~tiz de Nlontellano, "Topics in Biology - The Inactivation of Cytochrome 2 P450RAI", Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 3 201-210.
4 Hanzlik, et al. "Suicidal Inactivation of Cytochrome P450RAI by Cyclopropylamines> Evidence for Cation-Radical Intermediates", J. Am.
6 Chem. Soc., (1982), Vol.104, No. 107, pp. 2048-2052.
7 In accordance with the present invention several previously known and 8 several new compounds are utilized as inhibitors of CP450RAI to provide 9 therapeutic benefit in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids and or which in healthy 11 mammals, including humans, are controlled by natural retinoic acid. The 12 perceived mode of action of these compounds is that by inhibiting the enzyme 13 CP450RAI that catabolyzes natural RA, endogenous RA level is elevated to a 14 level where desired therapeutic benefits are attained. The chemical structures 1 S of certain previously known compounds which have been discovered to be 16 inhibitors of the enzyme CP450RAI are provided in the descriptive portion of 17 this application for patent. The chemical structures of the novel compounds 18 which axe used in the methods of treatment in accordance with the invention 19 are summarized by Formulas 1 through 8 in the Summary Section of this application for patent. Based on these chemical structures the following art is Z I of interest as background to the novel structures.
22 U.S. Patent Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024;
23 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712;
S,I34,159;
24 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658;
5,130,335;
4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP 0 130,795;
26 DE 3316932; DE 3708060; Dawson, et al. "Chemistry and Biology of 27 Synthetic Retinoids", published by CRC Press. Inc., (I990), pages 324-356;
28 are of interest to compounds of Formula 1.
1 U.S. Patent Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744;
2 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 4,723,028;
3 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP
4 0170105;EP0286364;EP0514269;EP0617020;EP0619116;
DE 3524199; Derwent JP6072866; Dawsoh, et al. "Chemistry and Biology of 6 Synthetic Retinoids", published by CRC Press, Inc., 1990, pages 324-356; are 7 of interest to compounds of Formula 2.
8 Dawsoh, et al. "Chemistry and Biology of Synthetic Retinoids", 9 published by CRC Press, Inc., (1990), pages 324-356; is of interest to compounds of Formula 3.
11 U.S. Patent Nos. 5,965,606; 5,773,594; 5,675,024; 5,663,347;
12 5,023,341; 5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519;
4,826,969;
13 4,833,240; 5,037, 825; 5,466,861; 5,559,248; WO 85100806; WO 92/06948;
14 WO 95/04036; WO 96/05165; EP 0 098 591; EP 0 170 105; EP 0 176 034;
EP 0 253,302; EP 0 303 915; EP 0 514 269; EP 0 617 020; EP 0 619 116;
16 EP 0 661 259; DE 3316932; DE 3602473; DE 3715955; UK application 17 GB 2190378; Ey~olles et al., J. Med. Chem., (1994), 37, 1508-1517;
G~aupjzer 18 et al. Biochem. and Biophysical Research Communications, (1991), 1554-19 1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawso~a, et al. "Chemistry and Biology of Synthetic Retinoids", published by CRC Press, 21 Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.
22 U.S. Patent Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357;
23 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795;
4,992,468;
24 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051;
WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020;
26 EP 0 619 116; DE 3524199; Derwent JP6072866; Dawsoh, et al. "Chemistry 27 and Biology of Synthetic Retinoids", published by CRC Press~Inc., (1990), 28 pages 324-356; are of interest to compounds of Formula 5.
1 U.S. Patent Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357;
2 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468;
3 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051;
4 WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020;
EP 0 619 116; DE 3524199; Derwert JP6072866; Dawsoh, et al. "Chemistry 6 and Biology of Synthetic Retinoids", published by CRC Press, Inc., ( 1990), 7 pages 324-356; are of interest to compounds of Formula 6.
8 U.S. Patent Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341;
9 5,739,338; 5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 5,037,825;
EP 0 130 795; DE 3316932; Dawsoh, et al. "Chemistry and Biology of 11 Synthetic Retinoids", published by CRC Press, Inc., ( 1990), pages 324-3 56;
12 are of interest to compounds of Formula 7.
13 U.S. Patent Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024;
14 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895;
5,346,915;
5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154; 4,740,519;
16 4,826,969; 4,826,984; 4,833,240; 5,037,825; 5,466,861; 5,559,248;
17 WO 85/00806; WO 92/06948; WO 95104036; WO 96/05165; EP 0 098 591;
18 EP 0 130 795; EP 0 176 034; EP 0 253 302; EP 0 303 915; EP 0 514 269;
19 EP 0 617 020; EP 0 619 116; EP 0 661 259; DE 3316932; DE 3602473;
DE 3708060; DE 3715955; U.K, application GB 2190378; Eyrolles et al., J.
21 Med. Chem., (1994), 37 1508, 1517; Graupner et al., Biochem. and 22 Biophysical Research Communications, (1991) 1554-1561; Kagechika, et al., 23 J. Med. Chem., (1988), 31, 2182-2192; Dawsoh, et al. "Chemistry and 24 Biology of Synthetic Retinoids", published by CRC Press~Inc., (1990), pages 324-356; are of interest to compounds of Formula 8.
26 Prior art which is of interest as background to the previously known 27 compounds that have been discovered in accordance with the present invention 28 to be inhibitors of cytochrome P450RAI, is identified together with the 1 identification of these known compounds.
3 In accordance with the present invention novel compounds of 4 Formulas 1 through 8 are used as inhibitors of the enzyme cytochrome P450RAI to treat diseases and conditions which are normally responsible to 6 treatment by retinoids, or which are prevented, treated, ameliorated, or the 7 onset of which is delayed by administration of retinoid compounds or by the 8 mammalian organism's naturally occurring retinoic acid. These novel 9 compounds are shown by Formulas 1 11 (R4, s 12 ~~Z A(Rz)-(CH2)n COOR$
14 (R1)pf'f 16 Formula 1 18 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group 19 consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 21 groups being optionally substituted with one or two RZ groups;
22 X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
23 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 24 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
26 Z is -C=C-, 27 -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 28 -CO-NRl-, 1 NR~-CO-;
2 -CO-O-, 3 -O-CO-, 4 -CS-NRl-, 5 NR~-CS-, 6 -CO-S-, 7 -S-CO-, 8 -N=N-;
9 Rl is independently H or alkyl of 1 to 6 carbons;
10 p is an integer having the values of 0 to 4;
11 R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro 12 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to b carbons, or alkylthio of 1 13 to 6 carbons;
14 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 16 of 1 to 6 carbons or benzyl;
17 m is an integer having the values 0 to 2;
1 ~ R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 19 alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 2;
21 n is an integer having the values of 0 to 4, and 22 Rg is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a 23 pharmaceutically acceptable base.
24 The novel compounds used in the method of treatment of the present invention are also shown in Formula 2 2 (R3)m 3 ~~~ 4 4 I ~Z A(R2)-(CH2)~ COOR8 s R
7 (R~)P Formula 2 9 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 11 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 12 groups being optionally substituted with one or two RZ groups;
I3 X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
14 Z is -C=C-, -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 16 -CO-NRl-, 17 NRl-CO-, 18 -CO-O-, 19 -O-CO-, .
-CS-NRl-, 21 NR~-CS-, 22 -CO-S-, 23 -S-CO-, 24 -N-N-;
Rl is independently H or alkyl of 1 to 6 carbons;
26 p is an integer having the values of 0 to 4;
27 RZ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 28 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 1 to 6 carbons;
2 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 3 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 4 of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 4;
6 RS is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 7 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
8 n is an integer having the values of 0 to 4, and 9 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
11 The novel compounds used in the method of treatment of the present 12 invention are also shown in Formula 3 R~. ~R~
16 (R4.)o,~i 17 I I '~%~Z A(R2)-(CH2)n COORS
18 N , 19 \/
(R~)p~~ Y
21 Formula 3 22 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 23 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 24 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two RZ groups;
26 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 27 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 28 to 6 carbons, Iower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or T;
1 Z is -C=C-, 2 -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 3 -CO-NRl-, 4 ~1_CO_~
-CO-O-, 6 -O-CO-, 7 -CS-NR 1-, 8 NRl-CS-, 9 -CO-S-, -S-CO-, 11 -N=N-;
12 Rl is independently H or alkyl of 1 to 6 carbons;
13 p is an integer having the values of 0 to 5;
14 Ra is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 16 to 6 carbons;
17 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 18 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 19 of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
21 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 22 alkyl of 1 to 6 carbons, or halogen;
23 o is an integer having the values of 0 to 4;
24 n is an integer having the values of 0 to 4, and ~ R8 is H, alkyl of 1 to 6 carbons, -CH20(Cl_6-alkyl), or a cation of a 26 pharmaceutically acceptable base.
27 The novel compounds used in the method of treatment of the present 28 invention are also shown in Formula 4 R' R~ (R3)m (R4)o-z.~
~~~~Z A(R2)-(CH~)n COOR$
6 X~ Y
7 Formula 4 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 9 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 11 groups being optionally substituted with one or two RZ groups;
12 Xl is 1-imidazolyl, or lower alkyl or halogen substituted 1-imidazolyl, 13 OR, SR, NRR6 where R is H, alkyl of 1 to 6 carbons or benzyl;
14 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 16 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
17 Z is -C=C-, 18 -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 19 -CO-NRl-, NRl-CO-, 21 -CO-O-, 22 -O-CO-, 23 -CS-NRl-, 24 NRl-CS-, -CO-S-, 26 -S-CO-, 27 -N=N-;
28 Rl is independently H or alkyl of 1 to 6 carbons;
1 R2 is independently H, alkyl of 1 to 6 carbons, F, C1, Br, I, fluoro 2 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 3 to 6 carbons;
4 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 5 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 6 of 1 to 6 carbons or benzyl;
7 m is an integer having the values 0 to 2;
8 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 9 alkyl of 1 to 6 carbons, or halogen;
10 o is an integer having the values of 0 to 4;
11 R6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl 12 substituted cycloalkyl of 3 to 6 carbons;
13 n is an integer having the values of 0 to 4, and 14 R8 is H, alkyl of 1 to 6 carbons, -CH20(Cl_6-alkyl), or a cation of a 15 pharmaceutically acceptable base, with the proviso that when Y is H, A is 16 phenyl and Xl is OH then n is 1 to 4.
17 m is an integer having the values 0 to 2;
1 ~ R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 19 alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 2;
21 n is an integer having the values of 0 to 4, and 22 Rg is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a 23 pharmaceutically acceptable base.
24 The novel compounds used in the method of treatment of the present invention are also shown in Formula 2 2 (R3)m 3 ~~~ 4 4 I ~Z A(R2)-(CH2)~ COOR8 s R
7 (R~)P Formula 2 9 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 11 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 12 groups being optionally substituted with one or two RZ groups;
I3 X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
14 Z is -C=C-, -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 16 -CO-NRl-, 17 NRl-CO-, 18 -CO-O-, 19 -O-CO-, .
-CS-NRl-, 21 NR~-CS-, 22 -CO-S-, 23 -S-CO-, 24 -N-N-;
Rl is independently H or alkyl of 1 to 6 carbons;
26 p is an integer having the values of 0 to 4;
27 RZ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 28 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 1 to 6 carbons;
2 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 3 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 4 of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 4;
6 RS is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 7 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
8 n is an integer having the values of 0 to 4, and 9 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
11 The novel compounds used in the method of treatment of the present 12 invention are also shown in Formula 3 R~. ~R~
16 (R4.)o,~i 17 I I '~%~Z A(R2)-(CH2)n COORS
18 N , 19 \/
(R~)p~~ Y
21 Formula 3 22 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 23 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 24 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two RZ groups;
26 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 27 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 28 to 6 carbons, Iower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or T;
1 Z is -C=C-, 2 -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 3 -CO-NRl-, 4 ~1_CO_~
-CO-O-, 6 -O-CO-, 7 -CS-NR 1-, 8 NRl-CS-, 9 -CO-S-, -S-CO-, 11 -N=N-;
12 Rl is independently H or alkyl of 1 to 6 carbons;
13 p is an integer having the values of 0 to 5;
14 Ra is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 16 to 6 carbons;
17 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 18 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 19 of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
21 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 22 alkyl of 1 to 6 carbons, or halogen;
23 o is an integer having the values of 0 to 4;
24 n is an integer having the values of 0 to 4, and ~ R8 is H, alkyl of 1 to 6 carbons, -CH20(Cl_6-alkyl), or a cation of a 26 pharmaceutically acceptable base.
27 The novel compounds used in the method of treatment of the present 28 invention are also shown in Formula 4 R' R~ (R3)m (R4)o-z.~
~~~~Z A(R2)-(CH~)n COOR$
6 X~ Y
7 Formula 4 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 9 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 11 groups being optionally substituted with one or two RZ groups;
12 Xl is 1-imidazolyl, or lower alkyl or halogen substituted 1-imidazolyl, 13 OR, SR, NRR6 where R is H, alkyl of 1 to 6 carbons or benzyl;
14 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 16 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
17 Z is -C=C-, 18 -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 19 -CO-NRl-, NRl-CO-, 21 -CO-O-, 22 -O-CO-, 23 -CS-NRl-, 24 NRl-CS-, -CO-S-, 26 -S-CO-, 27 -N=N-;
28 Rl is independently H or alkyl of 1 to 6 carbons;
1 R2 is independently H, alkyl of 1 to 6 carbons, F, C1, Br, I, fluoro 2 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 3 to 6 carbons;
4 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 5 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 6 of 1 to 6 carbons or benzyl;
7 m is an integer having the values 0 to 2;
8 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 9 alkyl of 1 to 6 carbons, or halogen;
10 o is an integer having the values of 0 to 4;
11 R6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl 12 substituted cycloalkyl of 3 to 6 carbons;
13 n is an integer having the values of 0 to 4, and 14 R8 is H, alkyl of 1 to 6 carbons, -CH20(Cl_6-alkyl), or a cation of a 15 pharmaceutically acceptable base, with the proviso that when Y is H, A is 16 phenyl and Xl is OH then n is 1 to 4.
17 The novel compounds used in the method of treatment of the present 18 invention are also shown in Formula 5 (R3)m '~Z A(R2)-(CHZ)n COOR$
S
Y
Formula 5 1 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 2 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 3 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 4 groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C1_6-trialkylsilyl 6 or benzyl;
7 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 8 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 9 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C=C-, 11 -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 12 -CO-NRl-, 13 NRl-CO-, 14 -CO-O-, -O-CO-, 16 -CS-NRI-, 17 NRl-CS-, 18 -CO-S-, 19 -S-CO-, -N=N-;
21 Rl is independently H or alkyl of 1 to 6 carbons;
22 RZ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 23 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 24 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 26 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 27 of 1 to 6 carbons or benzyl;
28 m is an integer having the values 0 to 3;
1 R7 is H, alkyl of I to 6 carbons, cycloalkyl of 3 to 6 carbons or lower 2 alkyl substituted cycloalkyl of 1 to 6 carbons;
3 n is an integer having the values of 1 to 4, and 4 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
6 The novel compounds used in the method of treatment of the present 7 invention are also shown in Formula 6 n~Z A(R2)-(CH2)n COOR$
14 Formula 6 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 16 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 17 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl I8 groups being optionally substituted with one or two RZ groups;
19 X2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR7, SR7 or NRR7 where R is H, alkyl of I to 6 carbons or benzyl;
21 Y is H, alkyl of 1 to I O carbons, benzyl, lower alkyl or halogen 22 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 23 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
24 Z 1S -C---C-, -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 26 -CO-NRl-, 27 NRl-CO-, 28 -CO-O-, 1 -O-CO-, 2 -CS-NRI-, 3 NRl-CS-, 4 -CO-S-, -S-CO-, 6 -N=N-;
7 Rl is independently H or alkyl of 1 to 6 carbons;
8 R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 9 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
11 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 12 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 13 of 1 to 6 carbons or benzyl;
14 m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower 16 alkyl substituted cycloalkyl of 3 to 6 carbons or C1_6-trialkylsilyl.
17 n is an integer having the values of 0 to 4, and I8 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a 19 pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present 21 invention are also shown in Formula 7 24 (~)° A(RZ)-(CHZ)~ COORS
27 l~~lulula 7 28 (R') 1 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 2 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 3 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 4 groups being optionally substituted with one or two RZ groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 6 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 7 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or 8 I;
9 Z is -C---C-, -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 11 -CO-NRl-, 12 NRl-CO-, 13 -CO-O-, 14 -O-CO-, -CS-NRl-, 16 NRl-CS-, 17 -CO-S-, 18 -S-CO-, .
19 -N=N-;
Rl is independently H or alkyl of 1 to 6 carbons;
21 p is an integer having the values of 0 to 5;
22 Ra is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro 23 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 24 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CFA, fluoro 26 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 27 of 1 to 6 carbons or benzyl;
28 m is an integer having the values 0 to 2;
1 R~ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 2 alkyl of 1 to 6 carbons, or halogen;
3 o is an integer having the values of 0 to 4;
4 n is an integer having the values of 0 to 4, and 5 Rg is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a canon of a 6 pharmaceutically acceptable base.
7 The novel compounds used in the method of treatment of the present 8 invention are also shown in Formula 8 9 o d.
11 (R4)o Z A(R2)-(CH 2)n COOK $
13 y 14 Formula 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 16 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 17 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 18 groups being optionally substituted with one or two R2 groups;
19 X3 is S, or O, C(Rl)2, or CO;
Yl is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, 21 benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
22 Z is -C---C-, 23 -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 24 -CO-NRl-, NRl-CO-, 26 -CO-O-, 27 -O-CO-, 28 -CS-NRl-, 1 NR1-CS-a 2 -CO-S-, 3 -S-CO-, 4 -N=N-Rl is independently H or alkyl of 1 to 6 carbons;
6 RZ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro 7 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 8 to 6 carbons;
9 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro ZO substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 11 of 1 to 6 carbons or benzyl;
12 m is an integer having the values 0 to 2;
13 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 14 alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
16 n is an integer having the values of 0 to 4, and 17 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a 18 pharmaceutically acceptable base, the compound meeting at least one of the 19 provisos selected from the group consisting of:
Yl is cycloalkyl, 21 when Yl is not cycloalkyl then X3 is O or S and n is 1, 22 when Yl is not cycloalkyl then X3 is CO, and n is 1, 23 when Yl is not cycloalkyl then X3 is CO and the moiety A is 24 substituted with at least one F group.
In accordance with the invention the novel compounds of Formula 1 26 through Formula 8 as well as the previously known compounds disclosed 27 below in the specification axe used for the prevention or treatment of diseases 28 and conditions in mammals, including humans, those diseases or conditions 1 that are prevented, treated, ameliorated, or the onset of which is delayed by 2 administration of retinoid compounds or by the mammalian organism's 3 naturally occurring retinoic acid. Because the compounds act as inhibitors of 4 the breakdown of retinoic acid, the invention also relates to the use of the compounds of Formula 1 through Formula 8 in conjunction with retinoic 6 acid or other retinoids. In this regard it is noted that retionoids are useful for 7 the treatment of skin-related diseases, including, without limitation, actinic 8 keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, 9 psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, barriers disease, lichen planus, 11 prevention and reversal of glucocorticoid damage (steroid atrophy), as a 12 topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse 13 the effects of age and photo damage to the skin. The retinoids are also useful 14 for the prevention and treatment of metabolic diseases such as type II non-insulin dependent diabetes mellitus (NIDDM) and for prevention and 16 treatment of cancerous and precancerous conditions, including, premalignant 17 and malignant hyperproliferative diseases such as cancers of the breast, skin, 18 prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral 19 cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of 21 Kaposi's sarcoma. Retinoids can also be used as agents to treat diseases of the 22 eye, including, without limitation, proliferative vitreoretinopathy (PVR), 23 retinal detachment, dry eye and other corneopathies, as well as in the treatment 24 and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, 26 prevention of post-angioplasty restenosis and as an agent to increase the level 27 of circulating tissue plasminogen activator (TPA). Other uses for retinoids 28 include the prevention and treatment of conditions and diseases associated 1 with human papilloma virus (HPV), including warts and genital warts, various 2 inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's 3 disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's 4 disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the 6 induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration 7 of hair growth, including combination therapies with the present compounds 8 and other agents such as MinoxidilR, diseases associated with the immune 9 system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of 11 wound healing, including modulation of chelosis.
12 This invention also relates to a pharmaceutical formulation comprising 13 one or more compounds of Formula 1 through Formula 8 or one or more of 14 the previously known compounds disclosed below in the specification, in admixture with a pharmaceutically acceptable excipient, said formulation 16 being adapted for administration to a mammal , including a human being, to 17 treat or alleviate the conditions which were described above as treatable by 18 retinoids, or which are controlled by or responsive to the organism's native 19 retinoic acid. These formulations can also be co-administered with retinoids to enhance or prolong the effects of medications containing retinoids or of the 21 organism's native retinoic acid.
22 The present invention also relates to a method of providing a compound 23 which is an inhibitor of the enzyme cytochrome P450R.AI, wherein the method 24 of providing the cytochrome P450RAI inhibitory compound comprises:
identifying a compound that has activity as a retinoid in any of the art 26 recognized assays which demonstrate retinoid-like activity, the retinoid 27 compound having a formula such that it includes a benzoic acid, benzoic acid 28 ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or 1 ester moiety, with a partial structure of -A(R2)-(CH2)"-COOR8 where the 2 symbols are defined as in Formulas I through 8, and where n is 0, and 3 selecting a compound that is a homolog of the previously identified 4 retinoid compound where in the formula of the homolog n is I or 2, preferably 1. Said homolog, if it is not a previously known compound can be prepared 6 by homologation procedures well known to the synthetic organic chemist, 7 such as for example the well known A~~cdt-Eiste~t synthesis. Alternatively, 8 said homologs can be prepared by any of the applicable synthetic processes 9 illustrated below for the preparation of the novel compounds of Formulas 1 through 8 wherein the symbol n represents the integral 1 (one).
12 Figure 1 is a schematic representation of the P450RAI cell based assay 13 utilized to evaluate the ability of the compounds of the invention to inhibit the 14 Cytochrome P450RAI enzyme.
BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION
16 P450RAI-1 Cell-Based Inhibitor Assay:
17 Figure 1 shows a schematic diagram of the P450RAI-1 cell based 18 assay. P450RAI-1 stably transfected HeLa cells are maintained in 100 19 millimolar tissue culture dishes in Modified Eagle's Medium (MEM) containing 10 % Fetal Bovine Serum (FBS) and 100 p,g/ml hygromycin.
21 Exponentially growing cells are harvested by incubating in trypsin. Cells are 22 then washed with 1X Phosphate Buffered Saline (PBS) and plated in a 48-well 23 plate at 5 X105 cells in 0.2 ml MEM medium containing 10 % FBS and 0.05 24 ~.Ci [3H]-RA in the presence or absence of increasing concentrations of the test compounds. The compounds are diluted in 100% DMSO and then added in 26 triplicate wells at either 10, 1 or 0.1 ~.M final concentration. As a positive 27 control for RA metabolism inhibition, cells are also incubated with 28 ketoconazole at 100, 10 and 1 p,M. Cell are incubated for 3 hours at 37°C.
1 The retinoids are then extracted using the procedure of Bligh et al. (1959) 2 Canadian Journal of Biochemistry 37, 911-917, modified by using 3 methylenechloride instead of chloroform. The publication Bligh et al. (1959) 4 Canadian Journal of Biochemistry 37, 911-917 is specifically incorporated 5 herein by reference. The water soluble radioactivity is quantified using a ~3-6 scintillation counter. ICSO values represent the concentration of inhibitor 7 required to inhibit all-t~ahs-RA metabolism by 50 percent and are derived 8 manually from log-transformed data. The ICso values obtained in this assay 9 for several novel compounds used in accordance with the invention are 10 disclosed in Table 1 below. The ICSO values obtained in this assay for 11 several previously known compounds the cythochrome P450RAI inhibitory 12 activity of which has been discovered in accordance with the present 13 invention, are disclosed in Table 1A below.
14 Assa~rs of Retinoid-like or Retinoid Antagonist and Inverse Aaonist-like 15 Biological Activity 16 Assays described below measure the ability of a compound to bind to, 17 andlor activate various retinoid receptor subtypes. When in these assays a 18 compound binds to a given receptor subtype and activates the transcription of 19 a reporter gene through that subtype, then the compound is considered an 20 agonist of that receptor subtype. Conversely, a compound is considered an 21 antagonist of a given receptor subtype if in the below described co-tranfection 22 assays the compound does not cause significant transcriptional activation of 23 the receptor regulated reporter gene, but nevertheless binds to the receptor 24 with a Kd value of less than approximately 1 micromolar. In the below 25 described assays the ability of the compounds to bind to RARa, RARE, RAR.~, 26 RXRa, RXR~ and RXRr receptors, and the ability or inability of the 27 compounds to activate transcription of a reporter gene through these receptor 28 subtypes can be tested.
1 As far as specific assays are concerned, a chimeric receptor 2 transactivation assay which tests for agonist-like activity in the RARa, RARE, 3 and RAR.~, receptor subtypes, and which is based on work published by 4 Feigne~ P. L, and Holm M. (1989) Focus, 112 is described in detail in United States Patent No. 5,455,265. The specification of United States Patent No.
6 5,455,265 is hereby expressly incorporated by reference. The numeric results 7 obtained with several preferred novel compounds used in accordance with the 8 invention in this assay are shown below in Table 1. These data demonstrate 9 that generally speaking the compounds of Formulas 1 through 8, are not agonists (or only weak agonists) of RAR retinoic receptors, and also that they 11 do not bind, or in some cases bind only weakly to RAR retinoid receptors.
12 A holoreceptor transactivation assay and a Iigand binding assay 13 which measure the antagonist/agonist like activity of the compounds used in 14 accordance with the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application 16 No. WO W093/11755 (particularly on pages 30 - 33 and 37 - 41) published on 17 June 24, 1993, the specification of which is also incorporated herein by 18 reference. A detailed experimental procedure for holoreceptor 19 transactivations has been described by Heyman et al. Cell 68, 397 - 406, (1992); Allegretto et al. J. Biol. Chem. 268, 26625 - 26633, and Ma~zgelsdoif 21 et al. The Retinoids: Biology, Chemistry and Medicine, pp 319 - 349, Raven 22 Press Ltd., New York, which are expressly incorporated herein by reference.
23 The results obtained in this assay are expressed in ECso numbers, as they are 24 also in the chimeric receptor transactivation assay. The results of ligand binding assay are expressed in Kd numbers. (See Cheng et al. Biochemical 26 Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by 27 reference.) 28 The results if the ligand binding assay for several preferred novel 1 compounds used in accordance with the invention are included in Table 1. In 2 the holoreceptor transactivation assay, tested for RXRa, R~,~, and RXR.~
3 receptors, the novel compounds are, generally speaking, entirely devoid of 4 activity, demonstrating that the novel compounds do not act as RXR agonists.
6 TABLE ~.
7 Compound GeneralTable RAR. P450RAI
8 # Formula#1 ECso/(EFFICACY)/KdnM INHIBITION
DATA
y INTACT HELA
ICSO~M
(44) (42) > I 0 2058 409 >10K
(3 7) > 10 11 3 4 5 280 4.8 9.8 (28) (54) (52) 3 145 0.8 158 >10K >10 >10K >10K
13 108 2 3 6.6 283 141 (15) (36) (10) >10 >10 >10 >I0 >10K >10K >10K
1 2 33 1.2 6.8 (207) (126) (140) 1.7 69 1.3 363 0.19 15K 3636 >10K
0.34 21K 4272 >10K
>10 >10K >10K >10K
69 2 3 313 12 52.6 (10) (50) (31) >10 6 73 2 3 WA 22.5 91 (39) (24) >10 3.5 11K 14K >10K
0.28 14 2.2 84 9 44 1 2 49 1.7 7.5 (138) (100) (116) 0.27 37 1.9 392 >10 >10K >10K >10K
(80) (67) >10 (20) (50) (46) >10 0.95 >10K >10K >10K
2 g4 2 3 NA NA NA
>10 >10K >10K >10K
(114) (39) (SS) >10 (36) O.SS
9148 2815 >10K
S g 4 S NA 363 NA
(96) 0.4 lOK 3781 ZSK
1.4 >10K >10K >10K
7 8S 2 3 976 3.S 2.5 (60) (77) (6S) >10 0.8 9 13 4 S NA 3.2 116 (6.6) (9) 3.1 10 8 9 S7 0.3 6 (146) (86) (94) 0.7 0.033 0.025 lOK 5317 2884 0.13 61.5 15 2.5 0.4 >10K >I OK >1 OK
0.18 >10K >100K >100K
2.2 >10K >10K >10K
>10 1.1 0.18 0.05 1.6 0.1 0.4 0.09 0.03 50 0.014 0.05 0.022 >10 0.13 0.18 1.6 9 I43 Ov 145 0.2 lThe "Table #"
refers to Table through provided below where the compound is identified with reference to a corresponding specific formula of Formulas through 16.
16 Table 1A below provides data similar to those provided in Table 1, for 17 certain previously known compounds which have been discovered in 18 accordance with the present invention to be useful as inhibitors of cytochrome 19 P450RAI. These compounds are shown by Formula A through O and have compounds numbers 201 through 247.
2 Compound GeneralRAR P450RAI
3 #~ FormulaECSO/(EFFICACY)/KdnM INHIBITION
DATA
a (3 y INTACT HELA
ICSOI~M
4 201 A >10K >10K 180 0.52 300 (12) L
90 1105 (24) 202 A 0.6 6 203 C 0.62 7 204 C 0.7 9 206 C 1.8 207 D 1.2 12 209 E 1.7 (25) (122) (61) 14 211 E I.5 16 214 E 1.9 17 215 A 6.2 18 216 D 3.3 19 217 G 6.3 218 D 3.4 21 219 G 3.2 23 221 C >10 24 222 F >10 1 F >10 2 224 C 5.5 3 225 C >10 4 226 C >10 227 C 1.3 , 7 229 G 1.6 8 230 D 5.1 9 231 K 4.1 232 D 4.2 11 233 M 1.3 12 234 M 4.7 14 236 E 5.5 237 J 6.8 16 238 A 7.2 18 241 N 5.5 19 242 I 5.8 243 L 7.4 21 244 G 5.1 22 245 H 3.3 23 246 J 3.1 2 As is known the topical retinoid all-trans-retinoic acid (ATRA) and oral 3 retinoids such as 13-cis RA and etretinate are known to induce substantial skin 4 irritation in humans. This irritation is a direct result of activation of the RAR
nuclear receptors. Analysis of retinoid topical irritation is also a highly 6 reproducible method of determining iu vivo retinoid potency. The SKH1-7 h~-BR or hairless mouse provides a convenient animal model of topical 8 irritation, since retinoid-induced skin flaking and abrasion can be readily 9 scored by eye (Staudeven et al., "Specific antagonist of retinoid toxicity in mice." Toxicol. Appl. Pharmacol.,138:169-175, (1996); Tlaache~, et al., 11 "Receptor specificity of retinoid-induced hyperplasia. Effect of RXR-selective 12 agonists and correlation with topical irritation". J. Pharm. Exp. Ther., 282:528-13 534, (1997)). As is demonstrated below the topical application of P450RAI
14 inhibitors in accordance with the present invention also causes an increase in the endogenous levels of ATRA that results in ATRA-induced irritation in 16 skin of hairless mice. The attached data table discloses the retinoid-mimetic 17 effects of some P450RAI inhibitor compounds in accordance with the present 18 invention on the skin of hairless mice.
19 Methods Female hairless mice (CrI:SKH1-h~BR), S-7 weeks old, were obtained 21 from Charles River Breeding Labs (Wilmington, MA). Animals were about 6 22 weeks old at the start of the experiments. Food (Purina Rodent Chow 5001) 23 and reverse osmosis water were provided ad libitum. Mice were housed 24 individually throughout the dosing period. In some experiments, mice that fit within a defined weight range, e.g., 21-25g, were selected from the available 26 stock and then randomly assigned to the various treatment groups, using body 27 weight as the randomization variable.
28 The compounds to be tested were dissolved in acetone for application 1 to the backs of the mice.
2 Mice were treated topically on the back in a volume of 4.0 ml/kg (0.07-3 0.12m1) adjusted daily so as to deliver a fixed dose of test compound per g 4 body weight. Doses are disclosed as nmol/25g.
5 Unless indicated otherwise, mice were treated with retinoids once daily 6 on days 1 through 5 and observed on days 2, 3, 4, 5, 6, 7 and 8.
7 The mice were weighed daily and the dorsal skin was graded daily 8 using separate semi-quantitative scales to determine flaking and abrasion.
9 These flaking and abrasion scores were combined with weight change (if any) 10 to create a cutaneous toxicity score (Blackjack score).
11 Cutaneous Toxicity Score 12 A visual grading scale was used for characterizing topical irritation on a 13 daily basis. The grading scale used is as follows:
15 Flakin Abrasions 16 0 = none 0 = none 17 1 = slight (small flakes, 1 = slight (one or two abrasions <50% with 18 coverage) a light pink color) 19 2 = mild (small flakes, 50% 2 = mild (several abrasions with a 20 coverage) pink color) 21 3 = moderate (small flakes, 3 = moderate (one or two deep >50%
22 coverage & large flakes, abrasions with red color, <25% <25%
23 coverage) coverage) 24 4 = severe (small flakes, 4 = severe (multiple deep >50% abrasions 25 coverage & large flakes, with red color, >25% coverage) 25-SO%
26 coverage) 27 5 = very severe (large flakes, >50%
28 coverage) 1 Topical Toxicity Score .
2 The flaking and abrasion observations were combined with body 3 weight observations to calculate a single, semiquantitative topical or cutaneous 4 "toxicity score" as detailed below. The toxicity score (also known as "blackjack score" since the theoretical maximum is 21) takes into account the 6 maximal severity, and the time of onset of skin flaking and abrasions and the 7 extent of weight between the first and last days of the experiment. Below are 8 listed the seven numerical components of the toxicity score and an explanation 9 of how those values are combined to calculate the toxicity score. .
1. Flaking-Maximal Severity:
11 Highest flaking score attained during observation period.
12 2. Flaking-Day of Onset of grade 2 or worse:
13 0 - > 8 days 14 1-day8 2-day6or7 16 3-day4or5 17 4-day2or3 18 3. Flaking-Average Severity:
19 Flaking severity scores are summed and divided by the number of observation days.
21 4. Abrasion-Maximal Severity:
22 Highest abrasion score attained during observation period.
23 5. Abrasion-Day of Onset of grade 2 or worse:
24 Same scale as (2) above.
6. Abrasion-Average Severity:
26 Abrasion severity scores axe summed and divided by the number 27 of observation days.
28 7. Systemic Toxicity (weight loss):
1 0_<lg 2 1-lto2g 3 2-2to4g 3-4to6g 4 - >6g or dead 6 Calculation of Composite Flaking Score 7 Flaking onset score (2) and average severity score (3) are summed and 8 divided by two. The quotient is added to the maximal severity score (1).
9 Composite flaking scores are calculated for each individual animal in a group, averaged, and rounded to the nearest integer. Values can range from 0-9.
11 Calculation of Composite Abrasion Score 12 Abrasion onset score (5) and average severity score (6) are summed and 13 divided by two. The quotient is added to the maximal severity score (4).
14 Composite abrasion scores are calculated for each individual animal in a group, averaged and rounded to the nearest integer. Values can range from 0-16 8.
17 Calculation of Toxicity Score 18 Composite flaking score, composite abrasion score, and systemic 19 toxicity score are summed to give the "toxicity score." Toxicity scores are calculated for each individual animal in a group, averaged, and rounded to the 21 nearest integer. Values can range from 0-21 and are expressed in Table 1B
22 below as the mean ~ SD of the values for a group.
23 Calculation of Percentage Change in Body Weight 24 The body weight at the time of the last weighing (day 8, 1 l, or 12) was subtracted from the initial body weight. The difference was divided by the 26 initial body weight, multiplied by 100%, and rounded to the nearest integer.
27 Values were calculated for each individual animal and the mean and standard 28 deviation for each group are shown.
2 Cutaneous Toxicity Score (Blackjack Score) 3 Compound No. 100 300 1000 nmole nmole nmole 4 5 0 (~3 .
IS 1~1 5~2 6 36 1~1 110 7 38 1~1 101 g 8 5~2 8~3 121 9 22 0~0 0~0 1 ~ 1 I37 1~1 1~1 ' S~2 11 48 1~1 3~1 7~2 12 50 1~0 3~2 8~2 13 58 0~0 0~0 0~0 14 131 1~1 0~1 1~1 127 0~0 0~0 0~0 16 18 0~0 5~2 102 17 247 1~0 2~1 6~1 Modes of Administration The compounds used in the methods of treatment of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
Thus, in the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used.
Any common topical formulation such 1 as a solution, suspension, gel, ointment, or salve and the like may be used.
2 Preparation of such topical formulations are well described in the art of 3 pharmaceutical formulations as exemplified, for example, by Remington's 4 Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, the compounds could also be 6 administered as a powder or spray, particularly in aerosol form. If the drug is 7 to be administered systemically, it may be confected as a powder, pill, tablet or 8 the like or as a syrup or elixir suitable for oral administration. For intravenous 9 or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it 11 may be useful to formulate these compounds by injection. In certain cases, it 12 may be useful to formulate these compounds in suppository form or as 13 extended release formulation for deposit under the skin or intramuscular 14 inj ection.
Other medicaments can be added to such topical formulation for such 16 secondary purposes as treating skin dryness; providing protection against light;
17 other medications for treating dermatoses; medicaments for preventing 18 infection, reducing irntation, inflammation and the like.
19 Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds, or to control by 21 naturally occurring retinoic acid will be effected by administration of the 22 therapeutically effective dose of one or more compounds used in accordance 23 with the instant invention. A therapeutic concentration will be that 24 concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the compound potentially may be used in 26 prophylactic manner to prevent onset of a particular condition.
27 A useful therapeutic or prophylactic concentration will vary from 28 condition to condition and in certain instances may vary with the severity of 1 the condition being treated and the patient's susceptibility to treatment.
2 Accordingly, no single concentration will be uniformly useful, but will require 3 modification depending on the particularities of the disease being treated.
4 Such concentrations can be arnved at through routine experimentation.
5 However, it is anticipated that in the treatment of, for example, acne, or similar 6 dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per 7 milliliter of formulation will constitute a therapeutically effective 8 concentration for total application. If administered systemically, an amount 9 between 0.01 and 5 mg per kg of body weight per day would be expected to 10 effect a therapeutic result in the treatment of many diseases for which these 11 compounds are useful.
12 In some applications pharmaceutical formulations containing the CP-13 450RAI inhibitory compounds may be co-administered with formulations 14 containing retinoids. In such cases the dose of the cytochrome P450RAI
15 inhibitors compounds is in the range of 0.01 and 5 mg per kg body weight per 16 day.
18 Definitions 19 The term alkyl refers to and covers any and all groups which are known 20 as normal alkyl and branched-chain alkyl. Unless specified otherwise, Iower 21 alkyl means the above-defined broad definition of alkyl groups having 1 to 22 carbons in case of normal Iower alkyl, and 3 to 6 carbons for lower branch 23 chained alkyl groups. A pharmaceutically acceptable salt may be prepared for 24 any compound used in accordance with the invention having a functionality 25 capable of forming a salt, for example an acid functionality. A
26 pharmaceutically acceptable salt is any salt which retains the activity of the 27 parent compound and does not impart any deleterious or untoward effect on 28 the subject to which it is administered and in the context in which it is 1 administered.
2 Pharmaceutically acceptable salts may be derived from organic or 3 inorganic bases. The salt may be a mono or polyvalent ion. Of particular 4 interest are the inorganic ions, sodium, potassium, calcium, and magnesium.
Organic salts may be made with amines, particularly ammonium salts such as 6 mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed 7 with caffeine, tromethamine and similar molecules. Where there is a nitrogen 8 sufficiently basic as to be capable of forming acid addition salts, such may be 9 formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as 11 hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of 12 simple organic acids such as mono-, di- or tri- acid may also be used.
13 Some compounds used in accordance with the present invention may 14 have traps and cis (E and Z) isomers. Unless specific orientation of substituents relative to a double bond or a ring is indicated in the name of the 16 respective compound, and/or by specifically showing in the structural formula 17 the orientation of the substituents relative to the double bond or ring the 18 invention covers traps as well as cis isomers.
19 Some of the compounds used in accordance with the present invention may contain one or more chiral centers and therefore may exist in 21 enantiomeric and diastereomeric forms. The scope of the present invention is 22 intended to cover all isomers pen se, as well as mixtures of cis and tans 23 isomers, mixtures of diastereomers and racemic mixtures of enantiomers 24 (optical isomers) as well. A bond drawn with a wavy line indicates that the carbon to which the bond is attached can be in any of the applicable possible 26 configurations.
27 General Synthetic Methodology 28 The novel compounds used in accordance with the invention are 1 encompassed by the general Formulas 1 through 8 provided above. The 2 previously known compounds the cytochrome P450RAI activity of which has 3 been discovered in accordance with the present invention are identified below, 4 and references are provided which enable their preparation by one of ordinary skill in the art of synthetic organic chemistry. In each of these 6 formulas a linker or tethering group designated Z covalently connects an 7 aromatic or heteroaromatic moiety designated A(R2)-(CH2)ri COOR8 and 8 another cyclic moiety which in accordance with these formulas is a substituted 9 phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety. Generally speaking a 11 compound such as X4-A(R2)-(CH2)"COORg is commercially available, or 12 can be made in accordance with the chemical literature, or with such 13 modification of known chemical processes which are within the skill of the 14 practicing organic chemist. The group X4 represents a reactive group, which is suitable for coupling the X4 A(R2)-(CH2)ri COORg compound to a 16 derivative of the substituted phenyl, substituted tetrahydronaphthalene, 17 substituted chroman, thiochroman, tetrahydroquinoline or 18 tetrahydroisoquinoline moiety so that as a result of the coupling the linker or 19 tether moiety Z is formed. In many instances the group X4 is a leaving group such as halogen, or trifluoromethanesulfonyloxy, or a group capable of 21 participating in a Wittig or Horher Emmons reaction. In some instances the 22 group X4 is an ethynyl group capable of undergoing a coupling reaction with a 23 leaving group (such as a halogen or a trifluoromethanesulfonyloxy group) 24 attached to the substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or 26 tetrahydroisoquinoline moiety. The group X4 can also represent an OH or an 27 NH2 group that forms an ester (COO) or amide (CONH) linker, respectively, 28 when reacted with an activated carboxyl derivative of the substituted phenyl, 1 substituted tetrahydronaphthalene, substituted chroman, thiochroman, 2 tetrahydroquinoline or tetrahydroisoquinoline moiety. Examples for the 3 compounds of formula X4_A(R2)-(CH2)n COORg are provided in the specific 4 examples below. Further examples where the X4 group is halogen are ethyl S 4-iodobenzoate, ethyl 6-iodonicotinate, ethyl S-iodofuran-3-carboxylate, ethyl 6 S-iodothiophen-3-carboxylate, ethyl 5-iodofuran-2-carboxylate, ethyl 5-7 iodothiophen-2-carboxylate, and analogous halogenated derivatives of the 8 respective pyridazine, pyrazine and other heteroaryl carboxylic acid esters.
9 The analogous aryl and and heteroaryl hydroxyl compounds and amines, wherein the halogen of the above-listed compounds is replaced by OH or NH2 11 respectively, also serve as additional examples for the reagents of the formula 12 X4-A(R2)-(CH2)"-COOR8. In these examples X4 is OH or NH2, respectively.
13 Still further in accordance with the general synthetic methodology to 14 provide the compounds of Formulas 1 through 8 a derivative of the 1 S substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, 16 thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety is 17 synthesized first, having a covalently attached XS group. The X5 group reacts 18 with the X4 group of the reagent X4-A(R2)-(CH2)"COORg to form the linker 19 designated Z in Formulas 1 through 8. The XS group is one that is capable of participating in a catalyzed coupling reaction, (such as an ethynyl group when 21 X4 is a leaving group), or a leaving group (such as halogen or 22 trifluoromethanesulfonyloxy when X4 is an ethynyl group) , or an activated 23 carboxylic acid function (when X4 is OH or NH2). The XS group can also be 24 an OH, SH or NH2 group when the X4 group is an activated carboxylic acid 2S function. Specific examples for substituted phenyl, substituted 26 tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline 27 or tetrahydroisoquinoline intermediates having an XS functionality axe 28 provided below, and are also available in the chemical scientific and patent 1 literature. Generally speaking, for reagents and reactions covalently joining a 2 substituted tetrahydronaphthalene, substituted chroman, thiochroman, or 3 tetrahydroquinoline intermediate with a substituted aryl or heteroaryl group, 4 such as X4-A(R2)-(CH2)"COOR8, to form a compound including the linker designated Z, reference is made to United States Patent Nos. 5,648,503;
6 5,723,666 and 5,952,345 the specification of each of which are expressly 7 incorporated herein by reference.
8 The substituted phenyl, tetrahydronaphthalene, chroman, thiochroman, 9 tetrahydroquinoline or tetrahydroisoquinoline moiety of the novel compounds used in accordance with the invention are derivatized in a manner to include 11 the specific substituents (such as for example the cycloalkyl substituents) 12 encompassed within the scope of the invention, either before or after the -13 A(R2)-(CH2)ri COOR8 moiety has been attached and the linker Z has formed, 14 as illustrated by the below described specific examples.
The -(CH2)"COOR8 moiety of the compounds of Formulas 1 through $ can 16 be modified in order to obtain still further novel compounds. One such 17 modif cation is saponification of compounds where the R8 group is an alkyl or 18 -CHZO(C1_6-alkyl) group. Another modification is esterification of the 19 carboxylic acid function when the R8 group is H or a cation. Such saponification and esterification reactions are well known in the art and within 21 the skill of the practicing organic chemist. Still another modification of the 22 compounds used in accordance with the invention (or of the intermediates X4-23 A(R2)-(CH2)"COORg, or of precursors to these intermediates) is the 24 homologation of the (CH2)n group. The latter can be accomplished, for example, by the well known A~ndt-Eistert method of homologation, or other 26 known methods of homologation.
27 The previously known compounds which have been discovered to be 28 inhibitors of cythochrome P450RAI and which are used in accordance with 1 the present invention are made, generally speaking, pursuant to the teachings 2 of a patent or publication which is identified in connection with each of the 3 known compounds. These patents or publications are incorporated by 4 reference in the present specification.
5 The synthetic procedure of homologation that may be utilized for 6 providing a compound having the partial structure of -A(R2)-(CH2)ri COOR8 7 where n is 1, or 2 (one or two), preferably 1 (one), can be one of the several 8 known procedures of homologation of carboxylic acids or esters, such as the 9 A~hdt-Eistert procedure that is described ihte~ alia in March, Advanced 10 Organic Chemistry: Reactions, Mechanisms, and Structure, pages 809-810, 11 McGraw-Hill Publishers, 1968, incorporated herein by reference.
Alternatively 12 the homologs of the partial structure of -A(R2)-(CHz)"COOR8 are 13 synthesized in accordance with the synthetic schemes disclosed herein in 14 connection with the preparation of the novel compounds.
is SPECIFIC EMBODIMENTS
16 With reference to the symbol A in Formulas 1 through 8, the preferred 17 novel compounds used in accordance with the present invention are those 18. where A is phenyl, naphthyl, pyridyl, thienyl or furyl. Even more preferred 19 are compounds where A is phenyl. As far as substitutions on the A (phenyl) 20 and A (pyridyl) groups are concerned, compounds are preferred where the 21 phenyl group is 1,4 (pare) substituted and where the pyridine ring is 2,5 22 substituted. (Substitution in the 2,5 positions in the "pyridine"
nomenclature 23 corresponds to substitution in the 6-position in the "nicotinic acid"
24 nomenclature.) In the presently preferred novel compounds used in 25 accordance with the invention either there is no R2 substituent on the A
group, 26 or the R2 substituent is preferably a fluoro group that is preferably located on 27 the aromatic carbon adjacent (ortho) to the carbon bearing the -(CH2)ri 28 COORg group.
I As far as the -(CIi2)~ COORS is concerned the use of novel 2 compounds is preferred where n is 0, 1 or 2, and even more preferred where n 3 is 1. In Formulas 5 and 8 only compounds where n is 1 or 2 are preferred, 4 with n=1 being most preferred. For the Rg group H, lower alkyl of 1 to 3 carbons, and -CH20(C1_6-alkyl) groups are preferred, as well as the 6 pharmaceutically acceptable salts of the free acids when R8 is H. Among the 7 lower alkyl and -CH20(C1_6-alkyl) groups ethyl and OCH2CH3, respectively, 8 are presently most preferred.
9 The linker group Z in all of the novel compounds used in accordance IO with the invention is preferably ethynyl 11 (-C=C-), ester (CO-O), ethenyl, (-CRl =CRl-) or amide (CONRI). Among 12 these the ethynyl (-C=C-) and ester (CO-O) linkers are most preferred.
13 Moreover, preferably the linker Z is attached to the 6 position in Formula 1, 14 to the 4 position in Formula 2, to the 6 position in Formula 3, to the 6 position in Formula 4, to the 4 position in Formula 5, to the 4 position in 16 Formula 6, to the 6 position in Formula 7, and to the 6 position in Formula 17 8. These positions are indicated by arabic numerals in Formulas 1 through 8.
18 The Rl group substituting the non-aromatic rings in Formulas 1, 3, 4, 7 I9 and 8 is preferably alkyl, more preferably alkyl of 1 to 3 carbons, and most preferably methyl. The Rl group substituting the cyclopropane ring in 21 Formulas 1, 2, 3 and 7 is preferably non-existent (p is 0), or is alkyl of 1 to 3 22 carbons, even more preferably methyl.
23 The X group in Formulas 1 and 5 is preferably O, and in Formula 2 X
24 is preferably O or NR.
The Xl group in Formula 4 is preferably 1-imidazolyl, substituted I-26 imidazolyl, or NRR6, where R6 is preferably cyclopropyl or branched-chain 27 alkyl. The X2 group in Formula 6 is preferably I-imidazolyl or substituted 28 1-imidazolyl.
1 The X3 group in Formula 8 is preferably O or C=O.
2 The Y group is preferably H, lower alkyl of 1 to 3 carbons, cycloalkyl, 3 lower alkyl substituted cycloalkyl, or halogen. Among these, H, Cl, and 4 cyclopropyl are most preferred.
The Yl group of Formula 8 is preferably H, lower alkyl of 1 to 3 6 carbons, cycloalkyl, or lower alkyl substituted cycloalkyl. Among these H, 7 ethyl and cyclopropyl are presently most preferred.
8 The most preferred novel compounds used in accordance with the 9 invention are disclosed in Tables 2 through 9 with reference to Formulas 9 through 16. The compounds specifically shown in Tables 2 through 9 are 11 carboxylic acids, but it should be understood that the use of the corresponding 12 C1_3alkyl esters, methoxymethyl (OCH2CH3) esters and of pharmaceutically 13 acceptable salts of the acids shown in these tables is also highly preferred.
14 It should also be apparent that the preferred compounds shown in Table 2 with reference to the more specific Formula 9 are within the scope of 16 Formula 1.
17 Similarly, the preferred compounds shown in Table 3 with reference to 18 the more specific Formula 14 are within the scope of Formula 2;
19 the preferred compounds shown in Table 4 with reference to the more specific Formula 11 are within the scope of Formula 3;
21 the preferred compounds shown in Table 5 with reference to the more 22 specific Formula 12 are within the scope of Formula 4;
23 the preferred compounds shown in Table 6 with reference to the more 24 specific Formula 13 are within the scope of Formula 5;
the preferred compounds shown in Table 7 with reference to the more 26 specific Formula 14 are within the scope of Formula 6;
27 the preferred compounds shown in Table 8 with reference to the more 28 specific Formula 15 are within the scope of Formula 7, and 1 the preferred compounds shown in Table with reference to the more 2 ecific 16 Formula are s within the scope of Formula 8.
p 4 ~
1 ~,f,r(CH2)n COOH
Z
x Y
Formula 13 Compound X Y Z RZ n Position of 14 No. (CHZ)"COOH
16 40 O H -C=C- H 0 4 17 42 O H -C=C- H 1 4 18 44 O H -C=C- F 0 4 19 48 O cyclopropyl-C=C- H 1 4 50 O cyclopropyl-C=C- F 1 4 21 52 O cyclopropyl-C=C- H 0 4 22 54 O cyclopropyl-C=C- F 0 4 23 58 O cyclopropyl-CO-O- H 1 4 24 60 O cyclopropyl-CO-O- H 1 3 66 CH3N H -C=C- H 0 4 Ri roTilluia m g TABLE
Compound No. RS X Rs n 12 110 n-propyl (n-propyl)NH 0 13 112 benzyl NH H 0 14 114 benzyl (n-benzyl)NH 0 108 n-propyl NH H 0 16 116 benzyl methylN H 0 17 77 benzyl O H 0 18 78 benzyl O H 1 19 70 methyl O H 1 69 methyl O H 0 21 73 isopropyl O H 0 22 74 isopropyl O H 1 23 82 benzyl O methyl 1 24 81 benzyl O methyl 0 89 (CH3)3C-CHZ- O methyl 0 26 90 (CH3)3C-CH2- O methyl 1 27 94 benzyl O ethyl 1 28 93 benzyl O ethyl 0 1 g( isopropyl O methyl I
2 g5 isopropyl O methyl 0 3 105 ethyl O t-butyl 0 4 106 ethyl O t-butyl I
9g I isopropyl I O I ethyl ~ I
16 Formula 11 22 Compound No. Ra COOH
12 Formula 12 22 Compound No. Xz R2 n 24 3 methyl,cyclopropyl-NH 0 8 methyl,cyclopropyl-NH 1 26 13 methyl,cyclopropyl-NF 0 27 18 methyl,cyclopropyl-NF 1 28 139 1-imidazolyl H 0 29 13 7 1-imidazolyl H 1 26 methyl,isopropyl-N H 0 14 Formula 13 1 g TABLE
Compound No. R2 R~ Y R3 21 143 H methyl t-butyl t-butyl 22 145 F methyl t-butyl t-butyl R3 ~ ~ (CH2)"COOH
6 ~
12 Formula 18 Compound X2 R3 n No.
119 1-imidazolyl methyl 0 21 121 1-imidazolyl methyl 1 22 127 I-imidazolyl iso-propyl1 23 126 1-imidazolyl iso-propyl0 24 134 ethyl,cyclopropyl-N iso-propyl0 130 ethyl,cyclopropyl-N methyl 0 26 131 ethyl,cyclopropyl-N methyl 1 27 141 (1-methyl)cyclopropyl- iso- 1 oxy propyl i vaiai.,siw ~..
1 g TABLE
19 .
~ Compound R R2 n No.
22 63 Me H 1 -COOH
Z (CH2)n ' 13 Formula 21 Compound X3 YI R3 Z RZ n 22 No.
23 28 O H methyl -C=C- H 1 24 3 0 O H methyl -C = C- F 0 25 5 CO H H -C=C H 1 26 10 CO H H -C=C- F 0 27 36 O cyclopropyl methyl -C=C- H 1 28 38 O cyclopropyl methyl -C=C- F 1 29 46 O H methyl -CO-O- H 1 31 32 O H methyl -C=C- F 1 32 56 O ethyl methyl -C=C- H 1 33 34 O cyclopropyl methyl -C=C- H 0 34 15 CO H H -C=C- F 1 1 The compounds used in accordance with the invention can be 2 synthesized by applying the general synthetic methodology described above, 3 and by such modifications of the hereinafter described specific synthetic routes 4 which will become readily apparent to the practicing synthetic organic chemist in light of this disclosure and in view of general knowledge available in the 6 art. The hereinafter disclosed specific reaction schemes are directed to the 7 synthesis of exemplary and preferred compounds used in accordance with the 8 invention. Whereas each of the specific and exemplary synthetic routes shown 9 in these schemes may describe specific compounds only within the scope of one or two of the general Formulas 1 through 8, the synthetic processes and 11 methods used therein are adaptable within the skill of the practicing organic I2 chemist and can be used with such adaptation for the synthesis of compounds 13 used in accordance with the invention which are not specifically described 14 herein as examples.
Reaction Scheme 1 discloses a presently preferred synthetic route to 16 certain intermediates or reagents having the general formula X4-A(R2)-CH2)n 17 COORg, where the symbol A represents a di-, or tri-substituted phenyl 18 moiety. These intermediates are utilized in the synthesis of the novel 19 compounds used in accordance with the invention.
4 I W COOH M~O~ H2S04 I W COOCH3 I / y /
reagetu' B
~~3 NBS, A1BN, CC14 I ~ Br NaCN, EtOF4;H2_O ~ a'1 I
irate~medir~te 1 intermediate 2 EtOI~ p-TSA, PhH, Dec~t-Stcnx I ~ COpEt or 1. ROhT F~OH, refuac I reage~ C
2. EtOH, HZSOø be~ene, Dew-Stork CN KOH, EtOH;HzO ~ COOH E~H HZSOø PhH, Decor-Stank I ~ COOEf 12 ~ HO I / F HD '~ F
NO '~ F
13 iHtermediate 4 inrtermediate S
COOEt 1. Pd Ph CZ - TMS I ~ COOEt 14 T.fzO~ NEt3, CHaClZ ~ ~ .~z z~
I / F ~F
T~ Cul, NEt3, THF; 70°C
iHtermedide 6 ~. KzC03 MeOH reaget2t D
17 H9C OBut COON N~ w COOBr.~
I / H3Gi OBt~ I /
18 HO PhCH3, 80°C HO reageht E
f-/O H3C OBu~ HO
21 I ~ c°°H "3~~'--~°B~'' I ~ c°°a"~
22 PhcH,~, so°c reage,.~ F
24 REACTIDNSC~1 ~COOMe 6 ~ CHs gM~O~, H20, pyridiHe ~ COOH MeOH, HzS04 7 ~ / 1 I / F 1 / F
I~F
reagetrt' G
MeOH, p-T~S'A, PIt,F~ Dept-Strn~k I ~ C p 12 \ clu I II /~F I / F
intermedi~e 2 reageYtt H
COOH F~OH, HzS04 ~ COOEt H~F H / F
17 re ertt I
intermediate 4 REACTIDNSC13~IE1 CONTINUED
1 Reaction Scheme 2 discloses presently preferred synthetic routes to 2 obtain exemplary and preferred novel tetrahydronaphthalenone compounds 3 within the scope of Formula 8 where the the symbol X3 represents a C=O
4 group, Z represents an ethynyl moiety or a -COO- (ester) function, and A is a substituted phenyl moiety.
6 Reaction Scheme 3 discloses presently preferred synthetic routes to 7 obtain exemplary and preferred novel tetrahydronaphthalene compounds 8 within the scope of Formula 4 where Xl represents a dialkyl substituted 9 nitrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
Reaction Scheme 4 discloses presently preferred synthetic routes to 11 obtain exemplary and preferred novel isoquinoline compounds within the 12 scope of Formula 3 where the symbol Y represents hydrogen, Z is an 13 ethynyl moiety and A is a substituted phenyl moiety.
14 Reaction Scheme 5 discloses presently preferred synthetic routes to obtain exemplary and preferred novel chroman compounds within the scope of 16 Formula 8 where the symbol Yl represents hydrogen, Z is an ethynyl moiety 17 or an ester (COO) function, and A is a substituted phenyl moiety.
o poH3 TiCI~, MezZn, \ ~3 Crz03, AcOH, HZO \
\ I Ir I r cr-r ez ~c..H. r 2 2, 3 InteTntediate 8 intermediate 9 BBr3, CHzCZ2 \ OH ~3' CHZCZZ \ oTf p~Z~2~ - TMS
I r a I \ I r Crrl, NEt3, THF, 70°C
O 'N"NTfz O
intermediate 10 intermediate 11 TMS
I \ ~ gZC03~MeOH I ~ ~ 1'~l2az~ ~; NFt3 / r Cs~I, reagent A, B o~ C
intermediate 12 interntediate 13 r I 7cooR
\ j ~ 'X hOl~HaO, MeOHTHFH20 I r O
intermediate 14 n = D X =H R = CH3CHa Compound4 n=1 X =HR=CH3 Compourrd5 n=1 X=H
Compound 14 ~: =1 X = F R = CH3CH2 Compound IS n =1 X = F
/ COOEt I \ DTP P~2~z, ~ No's, ~ I \ ~ v 'F lMNaOH, EtOhl, 80°C
r COOEt /
o Ir o intermediate 11 ~ F
reagent D Compoiurd 9 \ I F
I
O Compoundl0 ~ OTf 1. Pd(OAc)Z, dppp, EDC, NEt3, CO
i w c O
DMSO o urtermedir~e 11 reagent E Compound 20 2. CF3COOH, CHZCl2 .REACTIDNSC.F~IE2 CONTINUED
~ I 7u~1. NaCNBH3, D-'NHZ
v ~X AcOH,AcCN
w I / 2. MeT, KZCO~, CH3COCH3 3 hO1ZH20, MeOI~l THFHZO
6 orIMNaDH, EtOH, THF, 80°C
intermediate 14 n = 0 X =H R = CH3CHz Compomtd 3 >? = 0 X = H
7 Compound4 n=1 X =HR=CH3 Compound8 n=1 X =H
Comporuul9 n = 0 X = FR = CH3CH2 Compound 13 n = 0 X = F
Compound 14 n =1 X = F R = CH3CH2 Comporurd 18 n =1 X = F
cooEr 9 rMS i 1. NaCNBH3, ~""NHZ ~ ~ I ~ reagent A
AcOH,AcCN
~ ' I i 2. Me,I, KZCO~, CH3COCH3 ,~N Pd~~s~z, ~ N~s,THF
11 ~ 3.ICzCO~, MeOH, EtOAc intermediate 12 intermediate 29 14 H, EtOH, THF, 80°C
Compound 25 Comporurd 26 1 g REACTIONSCI~IE3 zZ I ~ O~ Cr20~, AcOH, H
O OMe TiCI Me N, t , cHzCh, ~c~r3 /
antermediate IS
intermediate 16 NaN3, HzSO~, PkH ~ ~ LiAIfI~, THF w ~ HCOOH, EDCI, CHZCZZ
HN ~ / ~ HN
(reference 1) O
intermedide 17 ~~e~~e 18 7 ~ BBr~, CHZC22 Of-1~(ai-Ft)~, FJ.MgBr r\~OH
_ w ONC'N / OHC' I / T~ F~Iter .N /
8 . (ref~ce 2) intemtediate 19 ~~e~Jitte 20 imtennedi~de 21 N~~ ~Ti~z ~ OTf Pd(OAc)Z, ~1PPP~ CO ~ OOOEt w N I / EtOH EDC, NF~3, DMSO N
~ d- ~ ~' N~NTf2 11 intermedie~e 22 intennedicte 23 Br w Br ~O .P.Plc3, CBr~, CHZCl2 12 Z DIBAIr.T~ CH~GZ N
2. TPAP, NMO
13 cxZczZ, cx3cN
irrterneediate 25 iWermediote 26 TPAP=tetpropyl a.~nmonium penrtJsenate , NMO=N-methylmoipltolineN-oxide reference 1 Tomita et aG J. Gre»i. .S'va (c),1969,183188 16 ref~ce 2 Giap&nslai et d Angew. Cfienr. l~ Edm EigL,1996, 35, 413-414 d~EACTIDNSC~LEME~
2 . i I ~coori x / reage~:t B or C
3 n Bull, l~lF' N I ~ ~~~ 2' ~N ~ X=r~ F
iritermedi~te 27 Compound ZI X = F R = C1Y3CH2 Compound23X=H R=CH3 ~ I ' 7 ~ ~ x ~oxH2o, Nreox~H2o w' g ~N~ X=H,F
Compound 22 X = F
Compound 24 X =H
11 REACTIONSCI~IE4 CONTINUED
/ I T,~ooR
x Pd(PPk~aCGz, THF, NEt3 w ~ IMNaOH, F~OH, 80°C
Cul, reagent C or G
U. S. Patent Nos. S, 045,551 and 5, 616,597 Compomrd 29 X = F n = 0 R = CH3 Comporurd 31 X = F n =1 R = CH3CHZ
Tr~00H
/ ~ X
Compound 30 X = F n = 0 Compound 32 X = F n =1 Br I ~ ~H 1. SOCZZ, benzene ~Bnli, ether; COZ
/ / 2. pyridine, intermediate 39 reagent E
O / ~~ O / COOH
CF3COOH, CHZCl2 ~ w O~ O
Compound 45 Conrporurd 46 REACTIONSCFIFNES
1 Reaction Scheme 6 discloses presently preferred synthetic routes to 2 obtain other exemplary and preferred novel chroman compounds within the 3 scope of Formula 8 where the symbol Yl represents a cyclopropyl group, Z
4 is an ethynyl moiety and A is a substituted phenyl moiety.
Reaction Scheme 7 discloses presently preferred synthetic routes to 6 obtain exemplary and preferred novel chroman compounds within the scope of 7 Formula 1 where the symbol X represents oxygen (O), Y represents 8 hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
9 Reaction Scheme 8 discloses presently preferred synthetic routes to obtain other exemplary and preferred novel chroman compounds within the 11 scope of Formula 1 where the symbol X represents oxygen (O), Y represents 12 a cyclopropyl group, Z is an ethynyl moiety and A is a substituted phenyl 13 moiety.
4 \ &"~Clq, CIZCH(OCH~ ~ ~' CH2 F~'1t3, THF ~ Br / ~/ ~/
CHZCl2,1'hCH3 GHD
intermediate 30 intermediate 31 SiMe~
CHN OAc Ether I w ~~.~za2~ = TMS
z 2, ~ ~z, /
7 / CsI, NEt3, THF, 70°C
intermediate 32 intermediate 33 i 1 Q EZC03~ MeOH I ~ / ~~31 z~z, ~ NF~3 CuI, reagent A, B or C
13 i'ø~edir~e 34 Compound 33 X =H n = 0 R = CH3CH~
Compound 35 X =H n =1 R = CH3 14 Compound 37 X = F n =1 R = CH3CH~
IMNaOl~ EtOH, 80°C
19 Compound 34 X =H n = 0 Compound36 X=H n=1 Compound 38 X = F n =1 2~
21 REACTIONSCF~IE 6 3 ~, ~.
F~ 2 CHzCIz w 4 I ~ ~ Tebbe Reagent I % CHzIa~ z ~
-, U.S.Pr~etttNo.5,399,561~aA1~~3 it~~e~~e35 irtte~medi~te 36 Si7Vfe3 7 Pd(Pl~t~zClz, -= TMS ~ ~ RZC03, MeOH I w Cul, NEt~, THF; 70°C o intermediate 37 intermediate 38 i~00R
1 O / ~ I X IMNaDH, EtOH, 80°C
Pd(PPIt~zClz, THF, NF~'3 11 ~ re~~ A, B or G
13 Comporutd 39 X =H n = 0 R = CH3CHz Compouttd4l X=Hn=1 R=CH3 14 Conrpound43 X=F n=0 R=CH3 i ( r~ooH
x 18 Compound 40 X =H n = 0 Compowrd42 X=H n=1 19 Compound 44 X = F n = 0 21 RF,ACTIONSCIi~ISE 7 T~cc~, azcH~ocH~ ~ ~' cH2 ~t3, ~' ~ / I / o l ~-cxZa2, ~cH3 6 ~o \
7 intermedide 36 intermedi~e 40 ~erynedi~e 41 SiMe3 CHzNz, Pd(DAc)z, F~Iser ~ ~' Pd(PPk~zaz, = TMS \
I/ I/
aur, NF.t3, T~; 7o°c o 11 i,~~e~~e 42 ~~e~~e 43 14 gzCp3~ MeOH ' ~ / Pd(PPliglzaz~ THF,1VF~3 ~ ~ Cul, reagent A, B, G or intermediate 44 17 Compoui:d47 X=H n=1 R=CH3 Comporued49 X=F ~:=1 R=CH3 1 g Componrui SI X =H n = 0 R = CH3CHz Compound53 X=F n=0 R=CH3 21 IMNaOH, F~OH, 80°C
23 ~mporn~d 48 X =H n =1 24 C°~°~dSO X=F n=1 Compound S2 X =H n = 0 Compound S4 X = F n = 0 REACTIDNSCI~IEB
1 Reaction Scheme 9 discloses presently preferred synthetic routes to 2 obtain exemplary and preferred novel tetrahydroquinoline compounds within 3 the scope of Formula 1 where the symbol X represents an alkyl substituted 4 nitrogen (alkyl-N), Y represents hydrogen, Z is an ethynyl moiety and A is a 5 substituted phenyl moiety.
Reaction Schemes 10 and 11 disclose presently preferred synthetic 7 routes to obtain exemplary and preferred novel phenyl compounds within the 8 scope of Formula 2 where the symbol X represents oxygen (O), RS is alkyl or 9 benzyl, Z is an ethynyl moiety and A is a substituted phenyl moiety.
10 Reaction Scheme 12 discloses presently preferred synthetic routes to 11 obtain exemplary and preferred novel phenyl compounds within the scope of 12 Formula 2 where the symbol RS-X represents an alkyl, dialkyl, benzyl or 13 dibenzyl substituted nitrogen, Z is an ethynyl moiety and A is a substituted 14 phenyl moiety.
15 Reaction Schemes 13 and 14 disclose presently preferred synthetic 16 routes to obtain exemplary and preferred novel phenyl compounds within the 17 scope of Formula 6 where the symbol X2 represents a (1-imidazolyl) moiety, 18 Z is an ethynyl moiety and A is a substituted phenyl moiety.
w Br 3 ~ er- ~~ ~ y'' atct3, x4o°c I
Nlt CH Q
4 HN a~ 2 2 I
intermediate 54 intermediate 55 sin~3 6 ~~o~)~ ~ga, I ~ ~' PdlPn~~zct2, ._-_ Tnns I w 7 THF; F~her N C~l, NEt3, THI; 70°C
intermediate 56 intermedirte 57 g / CODEt 1) KZC03, MeOH j \ IMNaOH, EtOH, THF; 80°C
1 O Z) 4 I C6H4-COOEt, Pd(PPk~~, N I /
NEt3, Carl, THF I
Cvmpourrd 65 13 ~ I
~I i 14 ~ nr~
I
Compormd 66 REACTIDNSCF~IE9 2 ~G'~,v~aa3 3 ~I~SO~, R'OH R ~ ~' ~~ ~~s or R ~ ~KzCOz, acetone, Rx' R.~O ~ ~
(.( I ~ or~ a TebbeReage~
SOCIZ; R'Ohl, pysidiase intermedirteG2 R=H R'=i~ropyl intermediate 67 R=H R'=benzyl R=I~ Me, F~ uedirte 72 R=Me R'=benzyl intermedir~e 77 R=Me R'=i propyl 6 ir~teimedir~e 82 R=Me R'=neopentyl u~terneedir~e SG R=El' R'=benzyl 7 urtermedi~e 91 R=Ft R'=i~ropyl R ~, 1. Pcl(Pl~t~ZCl2, - TMs R Br CHzIZ, F~22n, CH2Clz I W
R~~~ ~ R,~~ ~ Cul, NEt3, THF, 70°C
ir~teimediate SS R=H R'=Me 2. KZC03, MeOH
iatertnedirte 63 R=H R'=i~ropyl i~ermediate59 R=H R'=Me i~termedicte 68 R=H R'=benzyl irrtermedide Gø R=H R'=ipropyl intermedir~e 73 R=Me R'=beyyl intermedir~e G9 R=H R'=ber~zyl 11 intermediate 78 R=Me R'=ipropyl ioterneedirte 74 R=Me R'=benZyl intermediate 83 R=Me R'=neopeHtyl intermediate 79 R=Me R'=ipropyl 12 intermediate 87 R=Ft R'=beryl ihte~medir~e 84 R=Me R'=neopentyl irrtermediafe 92 R = Fl R'= i-propyl intermediate 88 R =F~ R'= benzyl intermedi~e 93 R=F~ R'=i propyl REACTIONSCI~ME10 2 ~ % 1. .Pd(PPh~zCdz~ THF, NF~~, Gal, I . ~..,..,..
R
R,~ ~ I ~ reagent A or reagent B R
3 2. NaDH R~~~
intermediate 61 R=H R'=Me intermediate 66 R =H R'=i propyl intermediate 71 R =H R'=beaazyl Compound 69 n = 0 R =H R'=methyl iaatermediate 76 R=Me R'=benZyl Compound 70 s:=1 R=H R'=metlryl inteamediate 81 R =Me R'= i pabpyl Compound 73 n = 0 R =H R'= i propyl intermediate 85 R =Me R'= neopeaatyl Compoauad 74 n =1 R = H R'= i propyl iartermediate 90 R = Et R'= beaazyl Compoauad 77 n = 0 R =H R'= benzyl 7 irateamedis>xe95 R=Et R'=i~ropyl Compound 78 aa=1 R=H R'=benzyl Compoauad 81 as = 0 R = Me R'= benzyl Compound 82 n =1 R =Me R'= benzyl Compoauad 85 n = 0 R = Me R'= i~a»pyl Compound 86 n=1 R=Me R'=i~ropyl Comporuad 89 n = 0 R = Me R'=neopeadyl Compoaurd 90 n=1 R=Me R'=aaeopeartyl Compound 93 n = 0 R = F~ R'= benzyl Compoauad 94 n =1 R = Et R'= beaazyl Compoauad 97 n = 0 R = EC R'=i propyl Compound 98 as =1 R = F~ R'= i panpyl 12 g~C~ONSCII~I~ElO CONTINtTFD
2 pMe 1, NBS, CCI~, reflrr~c OH
2. B81'g, ~Z~Z
3. separate isomers by column 4 intermediate 104 ~~ALCHs R ~ OTIPS .~.Cf ~ CH3 R ~ OH 1. TII'SCI, DMF, imidazo~
~-0.
2. ~Buh, Et20; ClCOOEt y Tebbe Reagerrt R = i~ropyl intermediate 97 R = i propyl 7 irrtermediate104 R=t-butyl intermedirde106 R=tbutyl R OTIPS R ~ OTIPS
g ~ ~ CHiI2, F~2Zn, CHZCIz TBAF, THF
i ~o ~ i intermediate 98 R = i propyl intermediate 99 R = i propyl intermediate 107 R =t butyl irrtermedirte 108 R =t butyl 11 1. 5 C~C3HS1V 2 NT f2, NEt3, G'IIZCl2 12 ~ R ~ ~ ~ 2.1'd~=~1 z~z, - TMS R w ~O
13 ate; Ness, Tip; 7o°c 3. KZC03, MeOH i~.~e~~e 103 R = i propyl 14 intermediate 100 R = i~ropyl intermediate 112 R = t butyl intermediate 109 R =t butyl 1. Pd(PPJt~2Cl2, THF, NEt3, Cut, R
1 ( reagent A or reagent B
2. NaOH
Compound 101 n = 0 R =i propyl 17 Compound 102 n =1 R = i propyl TIPS tri-iso propylsilyl Compound 105 n = 0 R =t butyl Compound 106 n =1 R =t butyl 18 TBAF=teGrarr~ brdyl ammonium fluoride 19 d ~ w o i 5 C~C3HS1V 2 lVT~f'z = ~ 'O
o=s=o x~c~oNSC~m I
2 ~ 1. KOH, OH(CH~~OH, w ~Br(CH~~Br, NaOH NC ~ / re~
3 N~ I / 2. NF.~3, t BuOH, P(O)(OPh)ZN3 3. 3MHCl intermediate 113 5 ~ gnBr~ R ~ Br HpN / °r ' R'~N
1. CH3CHZCOCI, pyridine intermediate 116 2. BH3:MexS iy~~erliate 118 R =1'~ R'= n propyl 7 or intermediate 121 R = n propyl, R'= n propyl CH3CH2CHO, NaCNBH3 iy~~edi~e 124 R=H, R'=beryl irderrnediate IZS R=beryl, R'=beryl w ~ Mel, R'ZC03, acetone ~,,~fi~ / ~N /
intermediate 130 11 .-w ~ 1.1'd~~z~z~ - TMS
R~.-N I / RN
Gsl, Nl~g, TIH;
2. IC2C03, MeOH
~~e~~e R=H, R'= n-propyl intermediate R=l~ R'= n propyl ~~e~~e R=nZnnropy~ R'=n 118 123 propyl 14 intermediate R =n propyl, R'=n intermediate R=H, R'=beryl 121 propyl 127 intermediate R=H, R'=beryl intermediate R = beryl R'=
124 129 beryl intermediate R = beryly R'= u~ern:ediate R=methyl R'=beryl 125 beryl 132 IS intermediate R=ntethy~ R'=beryl I7 / cooH
Z Pd(PPIa~2Cl2, THF, NF~3, GrI, w 1 g ø r CbH4COOF~
R ~ ~ Comporurd 108 R=H, R'=n~ropyl 2. NaOH R..N / Compound I10 R =n propy, R'=r:~ropyl 19 Compound 112 R=- H, R'= beryl Compound 114 R=beryl; R'=berz~yl Compourrd 116 R = met&y~ R'= beryl ~C~ONSC~12 &'~turø ~ w B''TMSC~ NF~3, T~ ~ % er 1. Pa~,~2c~Z,._-_ rnns F~x~,~ Grl, NFt~, THF, 70°C
2. If2C0~, MeOH
isrter~ediate 133 intermediate 134 S
/ COOEt 7 % / w I NBS, PPls3, CHZCZ2 P~1 z~Z~ ~; NF13 i ~
Gel, reagerst A
Comporuul117 irrtermedirte 136 cooEt ~ i 11 ~ ~ / v ~ % v 1. Imidsrzole, NsrFl, DMF
2. NaOH
13 Br irrtermedirste 137 ~ ~ ComPoiussl119 1 S ~ ~ ~W ~~ ~ZGZ I ~ ~ Isxid~nle, Nahl DMF
16 OH Br u~~~~e 138 ~N intennedirtte 139 17 irrtermedirte 133 1. P~,~actZ, = runs ~ i 1. Pd(PPIs~ZCIz, THF, NF~3 Gsl, NBt~, THF, 70°C
Grl, reagerst B
2 ~ 2. KaCO~, MeOH ~ ) ~ NCH
M
istterrtsedirte 141 H
23 REACTIONSC1~1~E13 ZS
~ 1. MeT, IC2C03, acetone ~ ~ 1. BBr~, CHZCl2 ~ OTSS
4 I '~ 2. NBS, CCZ4 I '~ 2. T~SCl, Imidrr~ole OH
3. t Bali; DMF
irdemtediate 143 intermediate 146 7 1. TBAF, THF ~ OTf 1 ~C~t~2~a~ = TMS
I
2. 5 CL-C~IS1V 2 iVT~f'a, R'F~~, CHZCZZ ('~ CuI, NF~3, Tf~; 70°C
8 3. NaBH~ O
4. TBSCZ, Irrrida~ole, DMF 2~ ~2C~3~ MeOH
intermediate 150 ~R
11 ~ \ d~~a~a' ~ NF~3 1. TB 4F, THF _ 2. NB~S, PPh3, CHZCZ2 Cu.~ reagerrtA orreagent~
OTBS
intermediate 152 intermediate 153 n = 0 R = ethyl 13 intermediate 154 n =1 R = ~netlryl 14 . , i Tri ooH
~R
1 S ~ I , 1,1_~~yl imidagole, CH3CN
r r 16 I , 2. NaOH ~ Co orurd 12b n = 0 N
Con:porard 127 r: =1 intermediate ISS n ~ 0 R = ethyl 1 g irrterneediate 156 n =1 R = methyl TBS=t brrtylrJimethylsilyl 19 a w °~s.cF3 5 C~C~ISN 2 NTfz =
o=s=o cF~ RFACTIDNSCIi~1E14 1 Reaction Scheme 15 disclose presently preferred synthetic routes to 2 obtain exemplary and preferred novel phenyl compounds within the scope of 3 Formula 6 where X2 represents an alkyl and cyclopropyl substituted n ztrogen 4 (X2 = (alkyl,cycloalkyl)N) , Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
6 Reaction Scheme 16 discloses presently preferred synthetic routes to 7 obtain exemplary and preferred novel tetrahydronaphthalene compounds 8 within the scope of Formula 4 where the symbol Xl represents a ( 1-9 imidazolyl) moiety, Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
11 Reaction Scheme 17 discloses presently preferred synthetic routes to 12 obtain exemplary and preferred novel phenyl compounds within the scope of 13 Formula 6 where the symbol X2 represents a 1-methyl-cyclopropoxy moiety, 14 Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
16 Reaction Scheme 18 discloses presently preferred synthetic routes to 17 obtain exemplary and preferred novel phenyl compounds within the scope of 18 Formula 5 where the symbol X represents oxygen (O), Y represents a 19 tertiary-butyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.
~v-2 I ~ ~Z SOClz; PYndine, cyclopropyl amine ~ I ~ Fl'T, KZCO3, acetone 2. BH3:MezS
u~te~mediote 158 4 _ ~~~~~~~
8f' 1. Pd~l~2a2~"_ TICS ~ ~ ~ ~2~r ~NEtS
N I / N I /
G~l; reagent A or reagent B
a~; NFt3, ~; ~o°C ~' Z. .K2C03, MeOH
irrtermedi~e 159 intermedirte 161 I ~CppR
9 ~N I / NaOH
~mpo~d 128 n = 0 R = F.1 Compound 130 s: = 0 / ~t Compound 129 n =1 R =Me Compound 131 n =1 11 cooEt i cyclopropyl marine, EtOH I / ~ xzCOs v 12 ~ ./ HN acetone I/
it~tetmedide ISS
14 _____ Compound132 _____ \ r ~' \ i 16 ~ ComPo~d 133 .~ I / Compound 134 17 ' v v RF4CTIDNSCI~IE15 $0 1'~~zaz~ ~ 1VF1'3 3'~, MeOHlEtOH
$ ~ r CSuI, reagentff or B
O
intermediate 13 n=0 R=Et 1 O Comporu~d 4 s: =1 R =Me 11 ~ ~ ~cooR
12 ~ ~ Y 1. N,N'-car~5nr~yl,~liimid~nle, THF
2. NaOH
13 ot~
14 n=o R=.~
Comporuid 135 n --__ 1 R =Me Compound 137 n =1 Compom:1139 n = 0 RF~1 CTION,SCI~l~El6 3 \ OH ~ OTf ~'ebbe reagent HOHz~ I r 4 CHsCOC~ pyridine OAc irdermedid'e 149 it~ermediate 162 6 O l % OT~zizr ~'zZn I \ OTf I. Pd(PI~'c~aClzr = TMS
C5~1, NF~~, THF, 70°C
intermediate 163 2. IfZC03, MeOH
intermediate 164 intermediate 166 cOOH
I. Pd~t3~2~2r ~ ~3 \
1~ \
CuY, reagent B ~ ~~, I I 2. NaOH
12 Comporuid Id1 13 r~cTroNSCx~x~
IS
1. ~'C~~z~a~ = TMS I ~ ~ Pd(P.~c~aCla, THF, NF~3 3 _ HO ~ ~ N~ ~, ~~ H3 ~ Cul, reagent B or reagent H
2. MeI, KZC03, acetone 3. R'ZC03, MeOH intermediate 169 xOH
12 Compound 142 R =H Compound 143 R =H
Compound 144 R = F Compound I4S R = F
REACTIDNSC~IE18 1 Certain known compounds which have been discovered in accordance 2 with the present invention to be useful as inhibitors of cytochrome P450RAI
3 are shown by Formula A where R8 generally represents H, alkyl of I to 6 4 carbons, -CH20(C~_6-alkyl), or a canon of a pharmaceutically acceptable base, and where the other variables have the following specific values:
I8 In Compound 201 X5 = O, X6 = CH, n = 0, Rg = H or a canon of a 19 pharmaceutically acceptable base and R1Q = CH3.
In Compound 202 XS = S, X6 = CH, n = l, R8 = H or a canon of a 21 pharmaceutically acceptable base and Rlo = H.
22 In Compound 210 XS = S, X6 = CH, n = 2, R$ = H or a canon of a 23 pharmaceutically acceptable base and R~o = H.
24 InCompound215X5=S, X6=CH,n=O, R8=Horacationofa pharmaceutically acceptable base and Rlo = H.
26 In Compound 238 XS = S, X6 = N, n = 0, R8 = H or a cation of a 27 pharmaceutically acceptable base, Rlo = H.
28 Compound 201 is described as compound 4 in United States Patent 1 No. 4,980,369 incorporated herein by reference. Compounds 202, 21D, and 2 215 are described in United States Patent No. 4,810,804 incorporated herein 3 by reference. Compound 215 is example 12 of Patent No. ,4810,804.
4 Compound 238 is described in United States Patent No. 5,089,509 incorporated herein by reference (see Claim S of Patent No. 5,089,509).
6 Other known compounds which have been discovered in accordance 7 with the present invention to be useful as inhibitors of cytochrome P450RAI
8 are shown by Formula B where R8 generally represents H, alkyl of 1 to 6 9 carbons, -CHzO(C1_6-alkyl), or a canon of a pharmaceutically acceptable base.
21 Specifically in Compound 240 Rg is H ox a cation of a pharmaceutically 22 acceptable base. Compound 240 is described and can be made in accordance 23 with the teachings of United States Patent Nos. 5,089,509, ,5,602,130 or 24 5,348,972 all of which are incorporated herein by reference.
1 Still other known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula C where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(Ci_6-alkyl), or a ration of a pharmaceutically 5 acceptable base, and whexe the other variables have the following specific 6 values:
10 N ~ ~ COORS
H
11 Roc Xs 12 ula C Rs2 16 In Compound 203 Rg is H or a ration of a pharmaceutically acceptable base, 17 Rlo = CH3, Rll = Cl, Rl~ = F and X6 = CH.
18 In Compound 204 R8 is H or a ration of a pharmaceutically acceptable base, 19 Rlo = CH3, Rll = cyclopropyl, R12 = F and X6 = CH.
In Compound 205 R8 is H or a ration of a pharmaceutically acceptable base, 21 Rlo = CH3, Rll - CF3, R12 = F and X6 = CH.
22 In Compound 206 Rg is H or a ration of a pharmaceutically acceptable base, 23 Rlo = CH3CH2, Rll = Br, R12 = F and X6 = CH.
24 In Compound 220 Rg is H or a ration of a pharmaceutically acceptable base, 2S Rlo = CH3, Rll = CH3, R12 = F and X6 = CH.
26 In Compound 221 Rg is H or a ration of a pharmaceutically acceptable base, 27 Rlo = CH3, Rll = CI, R12 = F and X6 = N.
28 In Compound 224 Rg is H or a ration of a pharmaceutically acceptable base, 1 Rlo = CH3, Rll = phenyl, R12 = F and X6 = CH.
2 In Compound 225 R8 is H or a ration of a pharmaceutically acceptable base, 3 RIO = H, Rll = Br, R12 = F and X6 = CH.
4 Tn Compound 226 R8 is H or a ration of a pharmaceutically acceptable base, Rlo = CH3, RI1 = OCH3, R12 = F and X6 = CH.
6 In Compound 227 R8 is H or a ration of a pharmaceutically acceptable base, 7 Rlo = CH3, Rll = CH3, R12 = H and X6 = CH.
8 Tn Compound 228 R8 is H or a ration of a pharmaceutically acceptable base, 9 Rla = CH3, Rll = H, R12 = F and X6 = CH.
Tn Compound 247 Rg is H or a ration of a pharmaceutically acceptable base, I I Rlo = CH3, Rll = Br, Rl2 = F and Xb = CH.
12 In Compound 248 R8 is H or a canon of a pharmaceutically acceptable base, 13 Rlo = CH3, Rll =- CF3CF2, R12 = F and X6 = CH.
14 In Compound 249 R8 is H or a ration of a pharmaceutically acceptable base, Rio = CH3, Rll = CH3,CH2, R12 = F and X6 = CH.
16 In Compound 250 Rg is H or a ration of a pharmaceutically acceptable base, 17 Rlo = CH3, Rll ' iso-propyl, R12 = F and X6 = CH.
18 In Compound 25~ Rg is H or a ration of a pharmaceutically acceptable base, 19 Rlo = CH3, Rll = (1-methyl)cyclopropyl, R12 = F and X6 = CH.
Tn Compound 252 R8 is H ox a ration of a pharmaceutically acceptable base, 21 Rla = CH3, Rll = tertiary-butyl, R12 = F and X6 = CH.
22 In Compound 253 R8 is H ox a ration of a pharmaceutically acceptable base, 23 Rio = CH3, Rll = (2,2-difluoro)cyclopropyl R12 = F and X6 = CH.
24 In Compound 254 Rg is H or a ration of a pharmaceutically acceptable base, Rlo = CH3, Rll = (cyclopropyl)methyl, R12 = F and X6 = CH.
26 Compounds 203 - 206, 220, 221, 224 - 228 and 247 - 254 are 27 described and can be made in accordance with the teachings of United States 28 Patent No. 5,675,024 which is incorporated herein by reference. (Compound 1 205 is compound or example 14, Compound 225 is compound or example 10, 2 and Compound 228 is compound or example 32 in Patent No. 5,675,024.
3 Compound 220 is also described in United States Patent No. 5,965,606, 4 incorporated herein by reference.
Still other known compounds which have been discovered in 6 accordance with the present invention to be useful as inhibitors of cytochrome 7 P450RA.I are shown by Formula D where R8 generally represents H, alkyl of 8 1 to 6 carbons, -CH20(C1_6-alkyl), or a canon of a pharmaceutically 9 acceptable base, and where the other variables have the following specific values:
R1a R14 13 ~ ~ ~----COORB
1 s ~ ,/ R12 Fo~rnulaD
16 ~
"13 R13 21 In Compound 207 R8 is H or a ration of a pharmaceutically acceptable base, 22 R12 = H, the two R13 groups jointly represent an oxo (=O) function and R14 =
23 CH3.
24 In Compound 208 R8 is H or a ration of a pharmaceutically acceptable base, R12 = H, R13 = H and R14 = CH3.
2b In Compound 216 R8 is H or a canon of a pharmaceutically acceptable base, 27 R12 = H, R13 = CH3 and R14 = CH3.
28 In Compound 21$ ,R8 is H or a ration of a pharmaceutically acceptable base, 1 R12 = H, R13 = CH3 and R14 = H.
2 In Compound 230 R8 is H or a canon of a pharmaceutically acceptable base, 3 R12 = F, R13 = CH3 and R14 = CH3.
4 In Compound 232 Rs is H or a cation of a pharmaceutically acceptable base, R12 = H, one of the R13 groups is H, the other is OH and R14 = CH3.
6 Compound 207 is described (as compound 7) in United States Patent 7 No. 5,489,584 incorporated herein by reference. Compound 232 is described 8 (as compound 42) in United States Patent No. 5,654,469 incorporated herein 9 by reference. Compounds 208, 216 and 218 are described in the publication by Cha~d~a~atna el al. J. Eur. J. Med. Chem., Suppl. to Vol. 30, 1995, 506s-11 517s. Compound 230 can also be made in accordance with the teachings of 12 the publication by Cha~cd~a~atna el al. J. Eur. J. Med. Chem., Suppl to VoI.
13 30, 1995, 506s-517s, incorporated herein by reference, or by such modification 14 of the synthetic procedures of this reference which will be readily apparent to those skilled in the art.
16 StiII further known compounds which have been discovered in 17 accordance with the present invention to be useful as inhibitors of cytochrome 18 P450RAI are shown by Formula E where R8 generally represents H, alkyl of 19 1 to 6 carbons, -CH2O(C1_6-alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific 21 values:
R~5 ~ n ~ ~-- COORS
27 R~s 1 In Compound 209 Rg is H or a cation of a pharmaceutically acceptable base, 2 R12 = H, Rls = tertiary-butyl, R16 = OH and R17 = Cl.
3 In Compound 211 Rs is H or a canon of a pharmaceutically acceptable base, 4 R12 = H, R15 = tertiary-butyl, R16 = OCH3 and R17 = tertiary-butyl.
In Compound 214 R8 is H or a canon of a pharmaceutically acceptable base, 6 R12 = H, Rls = 1-adamantyl, R16 = OCH3 and R17 = H.
7 In Compound 235 Rg is H or a cation of a pharmaceutically acceptable base, $ R12 = H, Rls = tertiary-butyl, R16 = OH and R17 = tertiary-butyl.
9 In Compound 236 R8 is H or a cation of a pharmaceutically acceptable base, R12 = F, R15 = tertiary-butyl, R16 = OH and R17 = H.
11 Compound 211 is described and can be made in accordance with the 12 teachings of United States Patent No. 5,202,471, and Compound 235 is 13 described and can be made in accordance with the teachings of United States 14 Patent No. 5,498,795. The specification of Patent Nos. 5,202,471 and 5,498,795 are incorporated herein by reference. Compounds 209, 214 and 16 236 can also be made in accordance with the teachings of United States Patent 17 Nos. 5,202,471 and 5,498,795 with such modifications of the synthetic 18 procedures which will be readily apparent to those skilled in the art.
19 Still more known compounds which have been discovered in accordance with the present invention to be useful as inhibitors of cytochrome 21 P450RAI are shown by Foxmula F where Rg generally represents H, alkyl of 22 1 to 6 carbons, -CH20(Cl_~-alkyl), or a cation of a pharmaceutically 23 acceptable base, and where the other variables have the following specific 24 values:
O
,' NH ~ ~ CODRg 7 R~2 nula F
11 Tn Compound 222 Rg is H or a cation of a pharmaceutically acceptable base, 12 R12 = F, R15 = tertiary-butyl, R16 = CH3CH20 and R17 = I.
13 In Compound 223 R8 is H or a cation of a pharmaceutically acceptable base, 14 R12 = F, Rls = tertiary-butyl, R16 = CH3CH20 and R17 = Br.
Compounds 222 and 223 are described and can be made in accordance 16 with the teachings of United States Patent Nos. 5,663,357 and 5,917,048, the .
17 specifications of which are incorporated herein by reference.
18 Yet more known compounds which have been discovered in 19 accordance with the present invention to be useful as inhibitors of cytochrome P450RAI are shown by Formula G where R8 generally represents H, alkyl of 21 1 to 6 carbons, -CHzO(C~_6-alkyl), or a cation of a pharmaceutically 22 acceptable base, and where the other variables have the following specific 23 values:
' CODRB
6 ~s 7 R~z r Fo~nula G
s 11 In Compound 212 R8 is H or a cation of a pharmaceutically acceptable base, 12 R12 = H, X6 = CH and X7 = (CH3)~C.
13 In Compound 217 Rg is H or a cation of a pharmaceutically acceptable base, 14 R12 = H, X6 = CH and X7 = CH2.
1 S In Compound 219 R8 is H or a cation of a pharmaceutically acceptable base, I6 R12=H, X6=CH and X7=S.
17 In Compound 229 R8 is H or a cation of a pharmaceutically acceptable base, 18 R12 = F, X6 = CH and X7 = CHI.
19 In Compound 244 R8 is H or a cation of a pharmaceutically acceptable base, R12 = H, X6 = N and X7 = CH2.
21 Compounds 217 is described (as example or compound 4) and can be 22 made in accordance with the teachings of United States Patent Nos.
4,739,098 23 the specification of which is incorporated herein by reference. Compounds 24 219 is described (as compound 2) and can be made in accordance with the 2S teachings of United States Patent Nos. 5,688,957, the specification of which is 26 incorporated herein by reference. Compound 212 and Compound 229 can be 27 made in accordance with the teachings of United States Patent Nos.
4,739,098 28 and in case of Compound 212 also in accordance with United States Patent 1 No. 5,426,118, with such modifications of the synthetic procedures which will 2 be readily apparent to those skilled in the art. The specification of United 3 States Patent No. 5,426,118 is incorporated herein by reference. Compound 4 244 is described (as compound or example 7) and can be made in accordance with the teachings of United States Patent Nos. 4,923,884, the specification of 6 which is incorporated herein by reference.
7 Still more known compounds which have been discovered in 8 accordance with the present invention to be useful as inhibitors of cytochrome 9 P450R.AI are shown by Formula H where R8 generally represents H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a canon of a pharmaceutically 11 acceptable base.
16 _ ~ ~ ~~--OOORB
Formula H
23 Specifically in Compound 245 R8 is H or a canon of a pharmaceutically 24 acceptable base.
Compounds 245 is described and can be made in accordance with the 26 teachings of United States Patent Nos. 4,923,884.
1 Further known compounds which have been discovered in accordance 2 with the present invention to be useful as inhibitors of cytochrome P450R.AI
3 are shown by Formula T where Rg generally represents H, alkyl of 1 to 6 4 carbons, -CH20(C1_6-alkyl), or a ration of a pharmaceutically acceptable base.
COOf~8 14 ~'o~raulal 17 Specifically in Compound 242 R8 is H or a ration of a pharmaceutically 18 acceptable base.
19 Compound 242 is described in the publication by Befn2a~d et al.
Biochem. Biophys. Res. Commun., 1992, Vol. 186, 977-9~3, incorporated 21 herein by reference.
1 Still more known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula J where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific 6 values:
NH ~ ~ COORS
12 ~'~2 14 Form~rla J
18 In Compound 237 Rg is H or a cation of a pharmaceutically acceptable base, 19 Rlz = F, Rl$ = H and R19 = H.
In Compound 246 R8 is H or a canon of a pharmaceutically acceptable base, 21 R12=H,RIg=OH andRl9=F.
22 Compounds 237 and 246 are described and can be made in accordance 23 with the teachings of United States Patent Nos. 5,675,024 and 5,856,490.
24 Compound 237 is compound or example 2 of Patent No. 5,675,024. The specification of United States Patent No. 5,856,490 is incorporated herein by 26 reference.
1 Additional known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula K where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(C~_6-alkyl), or a cation of a pharmaceutically 5 acceptable base.
11 ~ ~ ~ COORS
13 s.....~ulal~
17 Specifically in Compound 231 R8 is H or a cation of a pharmaceutically 18 acceptable base.
19 Compound 231 is described (as compound 2) in United States Patent No, 5,006,550, the specification of which is incorporated herein by reference.
1 Still more known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula L where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically S acceptable base.
l0 0 ~ ~ COORS
12 ;ula L
16 Specifically in Compound 243 R8 is H or a cation of a pharmaceutically 17 acceptable base.
~ 8 Compound 243 is described (as example or compound 7) in United 19 States Patent No. 5,130,335, the specification of which is incorporated herein 20 by reference.
1 Still more known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P4SORAI axe shown by Formula M where Rg generally represents H, alkyl of 4 1 to 6 carbons, -CH20(Cl_6-alkyl), or a cation of a pharmaceutically S acceptable base, and where the other variables have the following specific 6 values:
16 In Compound 233 R$ is H or a cation of a pharmaceutically acceptable base, 17 Rls = I-adamantyl and R16 = OH.
I8 In Compound 234 R8 is H or a cation of a pharmaceutically acceptable base, 19 R15 = 1-adamantyl and R16 = OCH3.
Compounds 233 and 234 are described in the publication by Shoot et 21 al. J. M. EP 199636 (1986) incorporated herein by reference.
1 Further known compounds which have been discovered in accordance 2 with the present invention to be useful as inhibitors of cytochrome P450RAI
3 are shown by Formula N where R8 generally represents H, alkyl of 1 to 6 4 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
COOR$
17 Specif cally in Compound 241 R$ is H or a cation of a pharmaceutically 18 acceptable base. .
19 Compound 241 is described in the publieation by Dawsoh et al. J.
Med. Chem., 1983, Vol. 26, 1653-1656. incorporated herein by reference.
1 Still further compounds which have been discovered in accordance with 2 the present invention to be useful as inhibitors of cytochrome P450RAI are 3 shown by Formula 4 where R8 generally represents H, alkyl of 1 to 6 4 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
\ \ \ \
v ~' ~' V 'COOK 8 8 \
lFormula O
12 Specifically in Compound 247 Rg is H or a cation of a 13 pharmaceutically acceptable base. Compound 247 is described in the 14 publication by Wiuum et al. I1 Farmaco, 1997, Vol. 52, l, p39-42, incorporated herein by reference.
16 The P450RAI inhibition data of this compound are provided in Table 17 1A, and the cutaneous toxicity score (blackjack score) of the compound in the 18 topical skin irritation tests provided above, are disclosed in Table 1B.
2 4-Hydroxy phenyl acetic acid-t-bu 1 ester (Reagent E) 3 A stirred suspension of 4-hydroxy-phenyl acetic acid (0. Z S2g, l mmol) 4 in anhydrous toluene (SmL) was heated at 80°C and N,N-dimethyl formamide-S di-t-butyl acetal (lmL, 4.17mmol) was added when the solution became 6 homogenous. After O.Sh, the reaction mixture was cooled to ambient 7 temperature and the volatiles were distilled off in vacuo. The residue was 8 diluted with water and extracted with diethyl ether (x2). The combined 9 organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column 11 chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in 12 hexane as the eluent to afford the title compound as a solid (0.1 1g, S6%).
13 1H-NMR (300 MHz, CDCl3):8 1.44(s, 9H), 3.45(s, 2H), 6.SS(s, 1H), 6.69(d, J
14 = 8.8Hz, 2H), 7.06(d, J = B.SHz, 2H).
3-H drox~phenKl acetic acid-t-butyl ester (Reagent F) 16 A stirred suspension of 3-hydroxy-phenyl acetic acid (1.52g, l Ommol) 17 in anhydrous toluene (20mL) was heated at 80°C and N,N-dimethyl 18 formamide-di-t-butyl acetal (9.6mL, 40mmol) was added when the solution 19 became homogenous. After O.Sh, the reaction mixture was cooled to ambient temperature and the volatiles were distilled off in vacuo. Th residue was 21 diluted with water and extracted with diethyl ether (x2). The combined 22 organic extract was dried over anhydrous sodium sulfate, filtered and 23 evaporated in vacuo to afford an oil which was subjected to flash column 24 chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in 2S hexane as the eluent to afford the title compound as a solid (1.17g, S6%).
26 'H-NMR (300 MHz, CDCl3):8 1.47(s, 9H), 3.49(s, 2H), 6.30(s, 1H), 6.70-6.79 27 (m, 2H), 6.81(d, J = 7.6Hz, 1H), 7.16(t, J = 7.7Hz, 1H).
28 Methyl-2-fluoxo-4-iodo benzoate (Reagent G) 1 A solution of 2-fluoro-4-iodo toluene (5g, 26.6mmo1) in pyridine (2mL) 2 and water (20mL) was treated with potassium permanganate ( I 6.6g, 3 lOSmmol) and heated at 150°C overnight. The reaction mixture was then 4 cooled to room temperature and filtered and the filtrate was extracted with hexane. The aqueous phase was acidified with 10% hydrochloric acid and 6 extracted with ethyl acetate. The organic phase was dried over anhydrous 7 sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved 8 in 20mL of methanol, treated with concentrated sulfuric acid (1mL) and 9 refluxed overnight. The volatiles were distilled off in vacuo and the residue was dissolved in diethyl ether, washed with brine, dried over anhydrous 11 sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column 12 chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in 13 hexane as the eluent afforded the title compound as an oil (0.26g, 5%).
14 'H NMR (300 MHz, CDCl3): ~ 7.60 (m, 4H), 3.93 (s, 3H).
Eth.1-Toro-4-hydroxy benzoate (Reagent I) 16 A solution of 2-fluoro-4-hydroxy benzoic acid (Intermediate 4, 3g, 17 19.2mmol) in ethanol (65mL) and benzene (90mL) was treated with 18 concentrated sulfuric acid (l.SmL) and heated at reflux overnight using a 19 Dean-Stark water trap. The volatiles were distilled off in vacuo and the residue was diluted with water and diethyl ether. The phases were separated 21 and the organic phase was washed with saturated aqueous sodium bicarbonate 22 (x1), water (x1) and brine (x1), dried over anhydrous magnesium sulfate, 23 filtered and evaporated in vacuo to afford the title compound as a solid (3.07g, 24 86%).
'H-NMR (300 MHz, CD3COCD3): 8 1.34 (t, J= 7.lHz, 3H), 4.32 (q, J=
26 7.lHz, 2H), 6.66(dd, J = 2.6, 10.9Hz, 1H), 6.76 (dd, J= 2.3, 8.SHz, 1H), 27 7.83(d, J= 8.4Hz, 1H), 9.91 (s, 1H).
28 Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6) 29 A stirred, cooled (ice bath) solution of ethyl-2-fluoro-4-hydroxy-1 benzoate (Intermediate 5, 0.368g, 2mmol) and 2,6-di-tert-butyl-4-methyl-2 pyridine (0.81 g, 8mmo1) in 8mL of dichloromethane was treated with 3 trifluoromethanesulfonic anhydride (0.1g, 4mmo1). The reaction mixture was 4 allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-6 400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title 7 compound (0.53g, 85%).
8 1H-NMR (300 MHz, CDCl3): ~ 1.41 (t, J= 7.3Hz, 3H), 4.42 (q, J= 7.lHz, 9 2H), 7.12-7.20(m, 2H), 8.08(t, J= 8.3Hz, 1H).
Eth~l-2-fluoro-4-trimeth,~lsilanylethynyl-benzoate (Intermediate 7) 11 A solution of ethyl-2-fluoro-4- trifluoromethylsulfonyloxy-benzoate 12 (Intermediate 6, 1.82g, 6mmol) in triethyl amine ( l2mL) and anhydrous 13 tetrahydrofuran (30mL) was treated with copper(I)iodide (0.12g, 0.6mmol) 14 and sparged with argon. Dichlorobis(triphenylphosphine)palladium(II) (0.43g, 0.6mmo1) was added followed by (trimethylsilyl)acetylene (3.6mL, 24mmol) 16 and the resulting reaction mixture was heated at 70°C overnight. It was then 17 cooled to ambient temperature, diluted with diethyl ether and filtered over a 18 bed of celite. The filtrate was evaporated in vacuo to an oil which was 19 subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as 21 an orange oil (1.5g, quantitative).
22 rH-NMR (300 MHz, CDC13):8 0.011 (s, 9H), 1.13(t, J= 7.lHz, 3H), 4.13 (q, J
23 = 7.lHz, 2H), 6.93-7.02(m, 2H), 7.07 (s, 1H), 7.61(t, J= 7.9Hz, 1H).
24 Ethyl-4-eth~nyl-2-fluoro benzoate (Reagent D) A solution of ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate 26 (Intermediate 7, 1.5g, 6mmo1) in ethanol (l6mL) was treated with potassium 27 carbonate (1.485g, 10.74mmo1) and stirred overnight at room temperature.
28 The reaction mixture was then diluted with water and extracted with diethyl 29 ether (x2). The combined organic phase was dried over anhydrous magnesium 1 sulfate, filtered and evaporated in vacuo to afford an orange oil. Flash column 2 chromatography over silica gel (230-400 mesh) using S% ethyl acetate in 3 hexane as the eluent afforded the title compound (1g, 86%).
4 1H-NMR (300 MHz, CDC13):8 1.39 (t, J= 7.lHz, 3H), 3.26 (s, 1H), 4.39 (q, J
= 7.lHz, 2H), 7.22-7.33 (m, 2H), 7.88(t, J= 7.7Hz, 1H).
6 Methyl-4-iodo-phenyl acetate (Reagent B) 7 A solution of 4-iodo phenyl acetic acid (Sg, l9mmol) in methanol was 8 treated with concentrated sulfuric acid (O.SmL) and refluxed overnight. The 9 volatiles were distilled off in vacuo and the residue was dissolved in ethyl 010 acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and 11 evaporated in vacuo to an oil which was subjected to flash column 12 chromatography over silica gel (230-400 mesh) using S% ethyl acetate in 13 hexane as the eluent to afford the title compound as a clear oil (Sg, 9S%).
14 'H NMR (300 MHz, CDC13): ~ 7.63 (d, 2H, J= 8.SHz), 7.01 (d, 2H, J=
1S B.OHz), 3.67 (s, 3H), 3.SS (s, 2H).
16 2-Fluoro-4-iodo-phenyl acetonitrile (Intermediate 2) 17 A solution of 2-fluoro-4-iodo-benzyl bromide (Intermediate 1, 2.S6g, 18 8.1 Smmol) in ethanol (SSmL and water (lOmL) was treated with sodium 19 cyanide (2.1 Sg, 43.86mmo1) and refluxed for O.Sh. The volatiles were distilled 20 off in vacuo and the residue was diluted with water and extracted with diethyl 21 ether (x2). The combined organic extract was washed with water (x1) and 22 brine (x1), dried over anhydrous magnesium sulfate, filtered and evaporated in 23 vacuo to afford the title compound as a pale yellow solid (2.OSg, 96%).
24 'H-NMR (300 MHz, CDC13): 8 3.71(s, 3H), 7.16(t, J= 8.2Hz, 1H), 7.45(dd, J
2S = 1.7, 9.lHz, 1H), 7.51(dd, J= 1.5, 8.2Hz, 1H).
26 2-Fluoro-4-iodo-phenyl acetic acid (Intermediate 3) 27 A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 28 2.OSg, 7.83mmo1) in ethanol (SOmL and water (lSmL) was treated with 29 potassium hydroxide (3.4g, 60.7mmol) and refluxed for 4h. The volatiles were 1 distilled off in vacuo and the residue was diluted with water and poured into 2 cold, dilute hydrochloric acid and the precipitated solid was filtered. The solid 3 was dissolved in diethyl ether, and the organic solution was dried over 4 anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound a pale yellow solid (I.75g, 79%).
6 'H-NMR (300 MHz, CDCl3):8 3.64 (s, 2H), 6.98(t, J= 7.9Hz, 1H), 7.25-7.46 7 (m, 2H), 9.60-10.40(br s, 1H).
8 Ethyl-2-fluoro-4-iodo-phenyl acetate (Reagent C) 9 A solution of 2-fluoro-iodo-phenyl acetic acid (Intermediate 3, 1.75g, 6.22mmol) in ethanol (SOmL) and benzene (100mL) was treated with 11 concentrated sulfuric acid ( 1.4mL) and heated at reflux overnight using a 12 Dean-Stark water trap. The volatiles were distilled off in vacuo and the 13 residue was diluted with water and diethyl ether. The phases were separated 14 and the organic phase was washed with saturated aqueous sodium bicarbonate (x1), water (xI) and brine (x1), dried over anhydrous magnesium sulfate, 16 filtered and evaporated in vacuo to afford an oil which was subjected to flash 17 column chromatography over silica gel (230-400 mesh) using 5%-10% ethyl 18 acetate in hexane as the eluent to afford the title compound as a pale yellow 19 solid (1.4g, 73%).
'H-NMR (300 MHz, CDC13): 8 1.25 (t, J= 7.lHz, 3H), 3.60 (s, 2H), 4.I6 (q, J
21 = 7.lHz, 2H), 6.99(t, J = B.OHz, IH), 7.39-7.44(m, 2H).
22 Methyl-2-fluoro-4-iodo-phenyl acetate (Reagent H) 23 A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 3g, 24 1 I .4Smmo1) in methanol (SOmL) and benzene (SOmL) was treated with p-toluene sulfonic acid (2.5g, 13.1 Smmol) and heated at reflux overnight using a 26 Dean-Stark water trap. The volatiles were distilled off in vacuo and the 27 residue was diluted with water and diethyl ether. The phases were separated 28 and the organic phase was washed with saturated aqueous sodium bicarbonate 29 (x1), water (x1) and brine (xI), dried over anhydrous magnesium sulfate, 1 filtered and evaporated in vacuo to afford an oil which was subjected to flash 2 column chromatography over silica gel (230-400 mesh) using 6% ethyl acetate 3 in hexane as the eluent to afford the title compound as a colorless oil (2.7g, 4 80%).
1H-NMR (300 MHz, CDCl3): 8 3.62 (s, 2H), 3.70 (s, 3H), 6.99(t, J = 7.9Hz, 6 1H), 7.39-7.45(m, 2H).
7 GENERAL PROCEDURE A: 7-Methoxy-1 1-dimethyl-1,2,3,4-8 tetrah~dronaphthalene (Intermediate 8) 9 A stirred, cooled (-40°C) solution of titanium tetrachloride in anhydrous dichloromethane (1M, 20mL) under argon, was treated with a solution of 11 dimethyl zinc (2M, 40mL) in toluene. After 0.5h, a solution of 7-methoxy-1-12 tetralone (1.76g, lOmmol) in anhydrous dichloromethane (5mL) was 13 cannulated into the reaction mixture and the resulting solution was allowed to 14 warm to ambient temperature and stirred overnight. The reaction mixture was then cooled to -40°C and cautiously quenched with methanol (llmL). It was 16 diluted with dichloromethane and saturated aqueous ammonium chloride 17 solution. The phases were separated and the aqueous phase was extracted with 18 dichloromethane (x2mL). The combined organic phase was dried over 19 anhydrous sodium sulfate, filtered and evaporated in vacuo to the title compound (1.75g, 92%) as an oil.
21 1H-NMR (300 MHz, CDC13):8 1.33(s, 6H), 1.67-1.71(m, 2H), 1.79-1.90(m, 22 ZH), 2.75(t, J = 6.2Hz, 2H), 3.83(s, 3H), 6.72(dd, J = 2.6, 8.3Hz, 1H), 6.93(d, 23 J = 2.6Hz, 1 H), 7.02(d, J = 8.3Hz, 1 H).
24 GENERAL PROCEDURE B: 6-Methox~-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 9) 26 A solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene 27 (Intermediate 8, 1.658, 8.7 mmol) in 7.5mL of glacial acetic acid was cooled 28 to 0°C and treated with a solution of chromium trioxide (2ga 20mmo1) in 8mL
29 of acetic acid and 7mL of water. The reaction mixture was then allowed to 1 warm to ambient temperature and stirred overnight. It was diluted with water 2 and extracted with diethyl ether (x2). The combined organic phase was 3 washed with water (x1), saturated aqueous sodium bicarbonate (x1) and brine 4 (x1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (1.64g, 93%) as a yellow oil.
6 IH-NMR (300 MHz, CDCl3):8 1.34(s, 6H), 1.96(t, J = 7.lHz, 2H), 2.64(t, J =
7 7.1 Hz, 2H), 3 . 83 (s, 3 H), 6.77(dd, J = 2.6, 8.7Hz, 1 H), 6. 83 (d, J =
2. SHz, 1 H), 8 7.98(d, J = 8.7Hz, 1H).
9 6-H,~xy-4~4-dimethXl-1~2 3 4-tetrah~drOnaphthalene-1-one (Intermediate 10) 11 A stirred, cooled (-78°C) solution of 6-methoxy-4,4-dimethyl-1,2,3,4-12 tetrahydronaphthalene-1-one (Intermediate 9, 0.8, 3mmo1) under argon was 13 treated with a 1M solution of boron tribromide (lOmL). The reaction mixture 14 was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to -78°C, quenched and diluted with saturated 16 aqueous sodium bicarbonate solution and the aqueous phase was extracted 17 with dichloromethane (x2). The combined organic phase was dried over 18 anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash 19 column chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent afforded the title compound (0.3g, 52%) as a 21 yellow viscous oil.
22 iH-NMR (300 MHz, CDC13):8 1.33(s, bH), 1.97(t, J = 6.8Hz, 2H), 2.71 (t, J =
23 6.7Hz, 2H), 6.81(dd, J = 2.3, 8.SHz, 1H), 6.94(d, J = 2.3Hz, 1H), 7.98(d, J
=
24 8.7Hz, 1H), 9.35(s, 1H).
GENERAL PROCEDURE C: 4 4-Dimethyl-6-trifluorometh~lsulfonyloxy-26 1,2~3,4-tetrahvdronaphthalene-1-one (Intermediate 11) 27 A stirred, cooled (0°C) solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-28 terahydronaphthalene-1-one (Intermediate 10, 0.3g, l.6mmo1) in anhydrous 29 dichloromethane (lOmL) was treated with 4-(dimethylamino)pyridine (0.36g, 1 3.27mmo1) followed by 2-~N,N'-bis(trifluoromethylsulfonyl)amino]-5-2 chloropyridine (0.798, 2mmo1). After stirring at ambient temperature for 3 0.75h, the reaction mixture was diluted with dichloromethane and washed with 4 water (x1). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over 6 silica gel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluent 7 afforded the title compound (0.462g, 90%) as an off white solid.
8 1H-NMR (300 MHz, CDC13): 8 1.36(s, 6H), 2.01 (t, J = 6.8Hz, 2H), 2.70(t, J =
9 6.7Hz, 2H), 7.15(dd, J = 2.5, 8.7Hz, 1H), 7.28(d, J = 2.4Hz, 1H), 8.06(d, J
=
8.7Hz, 1H).
11 GENERAL PROCEDURE D: 4~4-Dimethyl-6-trimethylsilanyl-eth~yl-12 1 2 3 4-tetrah~dronaphthalene-1-one (Intermediate 12) 13 A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-14 tetrahydronaphthalene-1-one (Intermediate 11, 0.46g, 1.43mmo1) in triethyl amine (3mL) and anhydrous tetrahydrofuran (8mL) was treated with 16 copper(I)iodide (0.1g, 0.53mmo1) and sparged with argon for 5 minutes.
17 Trimethylsilyl acetylene (0.85mL, 6mmo1) was then added followed by 18 dichlorobis(triphenylphosphine)palladium(II) (0.25g, 0.36mmol). The 19 resulting reaction mixture was heated at 70°C for 17h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of 21 celite. The filtrate was evaporated vacuo to an oil which was subjected to 22 flash column chromatography over silica gel (230-400 mesh) using 5% ethyl 23 acetate in hexane as the eluent to afford the title compound (0.28g, 72%).
24 tH-NMR (300 MHz, CDC13): 8 0.26(s, 9H), 1.36(s, 6H), 1.99(t, J = 6.8Hz, 2H), 2.69(t, J = 6.7Hz, 2H), 7.35(dd, J = 1.7, 8.2Hz, 1H), 7.49 (unresolved d, 26 1H), 7.93(d, J = 8.lHz, 1H).
27 GENERAL PROCEDURE E: 6-Eth~Xl-4,4-dimeth~l-1,2,3,4-28 tetrah.~phthalene-1-one (Intermediate 13) 1 A solution of 4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-2 tetrahydronaphthalene-1-one (Intermediate 12, 0.28g, 1.03mmol) in methanol 3 (1 OmL) was treated with potassium carbonate (0.74g, 5.35mmo1) and stirred at 4 ambient temperature for 4h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with diethyl ether (x2). The 6 combined organic extract was dried over anhydrous magnesium sulfate, 7 filtered and evaporated in vacuo to afford the title compound (0.19g, 89%) as 8 an oil that solidified on standing.
9 1H-NMR (300 MHz, CDCl3):8 1.33(s, 6H), I .96(t, J = 6.8Hz, 2H), 2.67(t, J =
6.8Hz, 2H), 3.25(S, 1H), 7.33(dd, J = 1.5, 8.lHz, 1H), 7.49 (d, J = I .SHz, 11 1H), 7.13(d, J = 8.lHz, 1H).
12 GENERAL PROCEDURE F: 4~8 8-Dimeth~l-5-oxo-5 6 7 8-tetrahydro-13 naphthalene-2 ~1-ethyn~)-benzoic acid eth 1y ester (Intermediate 14) 14 A solution of 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.23g, l.lmmol) and ethyl-4-iodo benzoate (Reagent 16 A, 0.36g, I.3mmo1) in triethyl amine (7mL) and anhydrous tetrahydrofuran 17 (3mL) was treated with copper(I)iodide (0.114g, 0.6mmol) and sparged with 18 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 19 0.33mmo1) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite.
21 The filtrate was evaporated in vacuo to a brown oil that was subjected to flash 22 column chromatography over silica gel (230-400 mesh) using 6-7% ethyl 23 acetate in hexane as the eluent to afford the title compound (0.29g, 72%) as a 24 pale brown solid.
'H-NMR (300 MHz, CDC13): 8 I.3(t, J = 7. lHz, 3H), 1.37(s, 6H), 1.80 (t, J =
26 6.8Hz, 2H), 2.69(t, J = 6.8Hz, 2H), 4.35(q, J = 7.lHz, 2H), 7.40(dd, J =
1.5, 27 8.2Hz, 1H), 7.51 (d, J = 1.6Hz, 1H), 7.57 (d, J = 8.3Hz, 2H), 7.96(d, J =
28 8,2Hz, 1H), 7.99(d, J = 8.SHz, 2H).
1 GENERAL PROCEDURE G 4 (5 Cyclopropylamino-8 8-dimethyl-5,6,7,8-2 tetrahy~phthalene 2y1-ethyn~)-benzoic acid ethyl ester (Compound 1, 3 General Formula 4) 4 A solution of 4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Intermediate 14, 0.148, 0.4mmo1) in 3mL
6 of dichloromethane and 2mL of acetonitrile was treated with cyclopropyl 7 amine(lmL, 14.45mmo1). After 5 minutes, acetic acid (1mL) was added 8 followed by sodium cyanoborohydride (0.13g, 2mmo1). The reaction was 9 stirred overnight at ambient temperature. It was then diluted with water and saturated aqueous sodium carbonate solution and extracted with 11 dichloromethane (x2). The combined organic extract was dried over 12 anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash 13~ column chromatography over silica gel (230-400 mesh) using 20% ethyl 14 acetate in hexane as the eluent afforded the title compound (0.1 g, 62%) as a pale yellow solid.
16 1H-NMR (300 MHz, CDCl3): 8 0.30-0.60(m, 4H), 1.28(s, 3H), 1.35 (s, 3H), 17 1.30(t, J = 7.lHz, 3H), 1.55-1.61(m, 1H), 1.83-2.05(m, 3H), 2.25 (quintet, J=
18 3 .0 Hz, 1 H), 3 .80 (t, J = 4.9Hz, 1 H), 4.39(q, J =. 7.1 Hz, 2H), 7.27-7.3 6(m, 19 2H), 7.52 (s, 1H), 7.55(d, J= 8.3Hz, 2H), 8:03(d, J= 8.5Hz, 2H).
GENERAL PROCEDURE H 4-[(5-Cycloprop, 1-Y meth-amino-8 8-dimethyl=
21 5 6 7 8-tetrah~dro-naphthalene-2-~ynyll-benzoic acid ethyl ester 22 (Compound 2, General Formula 4) 23 A solution of 4-(5-cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro-24 naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Compound 1, 0.064g, 0.16mmo1) in acetone (2mL) was treated with potassium carbonate (0.6g, 26 4.34mmo1) and methyl iodide (lmL, l6mmol) and stirred overnight at ambient 27 temperature. The volatiles were distilled off in vacuo and the residue was 28 diluted with water and extracted with dichloromethane (x2). The combined 1 organic extract was dried over anhydrous sodium sulfate, filtexed and 2 evaporated in vacuo to afford the title compound (0.06S8, 99%).
3 1H-NMR (300 MHz, CDCl3): ~ 0.28-0.49 (m, 4H), 1.21(s, 3H), 1.26 (s, 3H), 4 1.33 (t, J = 7.lHz, 3H), 1.58-1.73 (m, 2H), 1.83-1.89 (m, 2H), 2.02-2.08 (m, 1H), 2.06 (s, 3H), 3.88 (t, J = 8.lHz, 1H), 4.32(q, J = 7.lHz, 2H), 7.20(d, J
=
6 7.8Hz, 1H), 7.41 (s, 1H), 7.46 (d, J = 7.8Hz, 1H), 7.52(d, J = 8.4Hz, 2H), 7 8.03(d, J = 8.3Hz, 2H).
8 GENERAL PROCEDURE I: 4-[( -S-Cyclonrouyl-methyl-aminol-8,8-dimethyl-9 S 6 7 8-tetrahydro-naphthalene-2y1-ethynyll-benzoic acid (Compound 3, General Formula 4) A solution of 4-[(S-cyclopropyl-methyl-amino)-8,8-11 dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoic acid ethyl ester 12 (Compound 2, 0.06S8, O.lS8mmol) in ethanol (1mL) and tetrahydrofuran 13 (1mL) was treated with 1M aqueous sodium hydroxide solution (1mL) and 14 heated at 80°C for 1h. The volatiles were distilled off in vacuo and the residue 1 S was diluted with saturated aqueous ammonium chloride solution and extracted 16 with ethyl acetate (x2). The combined organic extract was dried over 17 anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid 18 that was washed with dichoromethane and dried to afford the title compound 19 (0.0298, 38%) as a white solid.
'H-NMR (300 MHz, CD3COCD3): 8 0.35-O.S1(m, 4H), 1.26(s, 3H), 1.29 (s, 21 3H), 1.60-1.82(m, 2H), 1.88-2.02(m, 2H), 2.02-2.15 (m, 1H), 2.10 (s, 3H), 22 3.93 (t, J = B.OHz, 1H), 7.26(dd, J = 1.5, 8.2Hz, 1H), 7.S 1 (d, J = l.SHz, 1H), 23 7.52(d, J = 8.2Hz, 1H), 7.62(d, J = 8.SHz, 2H), 8.02(d, J = 8.2Hz, 2H).
24 4-[(8 8-Dimeth~oxo-5,6,7,8-tetrah d~aphthalene-2-~l-eth~yl)-phenyl]-2S acetic acid methyl ester (Compound 4, General Formula 8) 26 Following general procedure F and using 6-ethynyl-4,4-dimethyl-27 1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.3128, l.Smmol), 4-28 iodo phenyl acetic acid methyl ester (Reagent B, O.SOg, l.8mmo1), triethyl 29 amine (7mL), anhydrous tetrahydrofuran (3mL), copper(I)iodide (0.048, 1 0.2mmo1) and dichlorobis(triphenylphosphine)palladium(II) (O.lSg, 2 0.213mmo1) followed by flash column chromatography over silica gel (230-3 400 mesh) using 16-20% ethyl acetate in hexane as the eluent, the title 4 compound was obtained as a pale yellow solid (0.42g, 76%).
'H-NMR (300 MHz, CDC13):8 1.42(s, 6H), 2.04(t, J = 6.7Hz, 2H), 2.74(t, J =
6 6.7Hz, 2H), 3.66(s, 2H), 3.71(x, 3H), 7.29 (d, J = 8.2Hz, 2H), 7.43(dd, J =
1.5, 7 7.9Hz, 1H), 7.52 (d, J = 8.2Hz, 2H), 7.57 (d, J = l.SHz, 1H), 8.00(d, J =
8 8.2Hz, 1H).
9 GENERAL PROCEDURE J: 4-[(8~8-Dimethyl-5-oxo-5 6,7,8-tetrahydro-naphthalene-2-~1-eth~nyll-phenyl]-acetic acid (Compound 5, General 11 Formula 8) 12 A solution of 4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-13 2-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 4, O.lg, 0.28mmo1) 14 in a mixture of methanol (2mL), tetrahydrofuran (3.SmL) and water (I.SmL) was treated with lithium hydroxide monohydrate (0.11 g, 2.62mmo1) and the 16 resulting reaction mixture was stirred at ambient temperature for 3h. The I7 volatiles were distilled off in vacuo and the residue was diluted with water and 18 dilute hydrochloric acid and extracted with ethyl acetate (x3). The combined 19 organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a pale yellow solid 21 (0.088g, 92%).
22 1H-NMR (300 MHz, CDC13): 8 1.41(s, 6H), 2.02(t, J = 6.7Hz, 2H), 2.74(t, J =
23 6.8Hz, 2H), 3.68(s, 2H), 7.28 (d, J = 8.2Hz, 2H), 7.42(dd, J = 1.5, 8.2Hz, 1H), 24 7.52 (d, J= 8.2Hz, 2H), 7.56 (d, J= l.SHz, 1H), 7.99(d, J= 8.2Hz, 1H).
4-f(5 ~CXclopropyl-amine-8 8-dimethxl- 5 6 7~8-tetrahydro-naphthalene-2-yl-26 eth~~)-phenyl]-acetic acid meth 1 e~ster_ (Compound 6, General Formula 27 4) 28 Following general procedure G and using 4-[(8,8-dimethyl-5-oxo-29 5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-acetic acid methyl ester 1 (Compound 4, 0.2g, 0.54mmo1), dichloromethane (4mL), acetonitrile(2mL), 2 cyclopropyl amine(lmL, 14.45mmol), acetic acid (1mL)and sodium 3 cyanoborohydride (0.168, 2.54mmol) followed by flash column 4 chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent the title compound was obtained as a pale yellow oil 6 (0.22g, 99%).
7 'H-NMR (300 MHz, CDC13): 8 0.38-0.60 (m, 4H), 1.26(s, 3H), 1.33(s, 3H), 8 1.50-1.59(m, 1H), 1.79-2.10 (m, 3H), 2.25(m, 1H), 3.63(s, 2H), 3.69(s, 3H), 9 3.79(t, J = 4.8Hz, 1H), 7.20-7.32 (m, 4H), 7.47(s, 1H), 7.58(d, J = 8.2Hz, 2H).
4 [~5 (Cyclopropyl-methyl-amino)-8 8-dimethyl- 5 6 7 8-tetrahydro-11 naphthalene-2-xl-eth~yll-phenxl]-acetic acid methyl ester (Compound 7, 12 General Formula 4) 13 Following general procedure H and using 4-[(5-(cyclopropyl-amino)-14 8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 6, 0.15g, 0.37mmo1), acetone (5mL), potassium 16 carbonate ().)g, 7.95mmo1) and methyl iodide (lmL, l6mmol), the following 17 work-up was used. The volatiles were distilled off in vacuo and the residue 18 was diluted with water and extracted with dichloromethane (x2). The 19 combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound (0.148g, 97%).
21 1H-NMR (300 MHz, CDCl3): 8 0.38-0.58(m, 4H), 1.27(s, 3H), 1.31 (s, 3H), 22 1.68-1.81(m, 2H), 1.85-1.98(m, 2H), 2.08-2.15 (m, 1H), 2.12 (s, 3H), 3.62(s, 23 2H), 3.69(s, 3H), 3.94 (t, J = 7.9Hz, 1H), 7.24(d, J = 8.2Hz, 1H), 7.24 (d, J =
24 8.2Hz, 2H), 7.44-7.51(m, 4H).
4-[(5-(Cyclopropyl-methyl-amino)-8 8-dimethyl- 5 6 7 8-tetrah~dro-26 naphthalene-2-~~n~l-phenyl'-acetic acid (Compound 8, General 27 Formula 4) 28 Following general procedure J and using 4-[(5-(cyclopropyl-methyl-29 amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-phenyl]-1 acetic acid methyl ester (Compound 7, 0.148g, 0.357mmo1), methanol (2mL), 2 tetrahydrofuran (4mL), water (1mL) and lithium hydroxide monohydrate 3 (0.25g, 5.95mmol) followed by flash column chromatography over silica gel 4 (230-400 mesh) using 30-75% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.08g, 56%).
6 'H-NMR (300 MHz, CDCl3): 8 0.52-0.54(m, 2H), 0.68-0.70(m, 2H), 1.27(s, 7 3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H), 2.19-2.24(m, 1H), 8 2.24(s, 3H), 3.60(s, 2H), 4.18(t, J = 7.7Hz, 1H), 7.24(dd, J = 1.5, 8.2Hz, 1H), 9 7.26 (d, J = 8.2Hz, 2H), 7.43 (d, J = 8.2Hz, 1H), 7.47(s, 1H), 7.47(d, J _ 8.2Hz, 2H), 10.37(br s, 1H).
11 2-Fluoro-4-C($ 8-dimethX,l-5-oxo-5 6 7~8-tetrah d~phthalen-2-yl-12 eth~nyl]benzoic acid eth 1y ester (Compound 9, General Formula 8) 13 A solution of 4,4-dimethyl-6-trifluromethylsulfonyloxy-1,2,3,4-14 tetrahydronaphthalene-1-one (Intermediate 11, 0.3g, 0.9mmo1), copper(I)iodide (0.057g, 0.3mmo1) and ethyl-2-fluoro-4-ethynyl-benzoate 16 (Reagent D, 0.44g, 2.27mmol) in triethyl amine (2mL) and tetrahydrofuran 17 (3mL) was sparged with argon for 5 minutes and treated with 18 dichlorobis(triphenylphosphine)palladium(II) (0.135g, 0.192mmo1) and stirred 19 at room temperature overnight and then refluxed for 2h. It was then cooled to ambient temperature, diluted with diethyl ether and f ltered over a bed of 21 celite. The filtrate was evaporated in vacuo to an oil which was subjected to 22 flash column chromatography over silica gel (230-400 mesh) using 10-15%
23 ethyl acetate in hexane as the eluent to afford the title compound as a yellow 24 solid (0.228, 67%).
1H-NMR (300 MHz, CDC13): 8 1.38 (t, J = 7.OHz, 3H), 1.39(s, 6H), 2.01(t, J
26 = 6.7Hz, 2H), 2.71(t, J = 6.7Hz, 2H), 4.37(q, J= 7Hz, 2H), 7.28(dd, J= 0.9, 27 lOHz, IH), 7.34(dd, J= 0.9, 8.2Hz, 1H), 7.41 (dd, J = 1.5, 8.2Hz, 1H), 7.57(d, 28 J = 0.9Hz), 7.90(t, J= 7.9Hz, 1H), 7.93 (d, J= 7.9Hz, 1H).
1 2 Fluoro 4 (8 8 dimethyl 5 oxo 5 6 7 8 tetrahydro-naphthalen-2yl-ethynyl~-2 benzoic acid (Compound 10, General Formula 8) 3 A solution of 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-4 naphthalen-2-ylethynyl)benzoic acid ethyl ester (Compound 9, 0.1 g, 0.274mmol) in ethanol(4mL), methanol (2mL) and tetrahydrofuran (2mL) was 6 treated with 1M aqueous sodium hydroxide solution and heated at 70°C
for 7 1h. The volatiles were distilled off in vacuo and the residue was diluted with 8 water and dilute hydrochloric acid and extracted with ethyl acetate (x2).
The 9 combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from hot 11 aqueous acetonitrile to afford the title compound (0.025g, 27%).
12 1H-NMR (300 MHz, CDCl3): b 1.43(s, 6H), 2.05(t, J = 6.9Hz, 2H), 2.76(t, J =
13 6.9Hz, 2H), 7.26-7.47(m, 3H), 7.60(d, J = l.lHz, 1H), 7.99-8.05(m, 2H).
14 4-f 5- Cyclopropyl-aminol-8 8-dimethyl- 5,6 7,8-tetrah dy ro-naphthalene-2-yl-eth~Xl]-2-fluoro-benzoic acid ethyl ester (Compound 11, General Formula 16 4) 17 Following general procedure G and using 2-fluoro-4-(8,8-dimethyl-5-18 oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester 19 (Compound 9, 0.132g, 0.3mmol), dichloromethane (4mL), acetonitrile(2mL), cyclopropyl amine(lmL, 14.45mmol), acetic acid (1mL)and sodium 21 cyanoborohydride (0.18g, 2.86mmo1) followed by flash column 22 chromatography over silica gel (230-400 mesh) using 16-20% ethyl acetate in 23 hexane as the eluent, the title compound was obtained as a pale yellow oil 24 (0.1 g, 82%).
1H-NMR (300 MHz, CDC13):8 0.36-0.54 (m, 4H), 1.27(s, 3H), 1.33(s, 3H), 26 1.40(t, J= 7.OHz, 3H), 1.54-1.61(m, 2H), 1.82-2.05 (m, 2H), 2.26(m, 1H), 27 3.79 (t, J = 4.9Hz, 1H), 4.39(q, J= 7.lHz, 2H), 7.26-7.50(m, 4H), 7.87(s, 1H), 28 7.92 (t, J= 7.9Hz, 1H).
1 4 f 5 (Cyclopropyl methyl amino 8,8-dimethyl- 5 6 7 8-tetrahvdro-2 naphthalene 2 y1 -ethynyll-2-fluoro benzoic acid ethyl ester (Compound 12, 3 General Formula 4) 4 Following general procedure H and using 4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-6 benzoic acid ethyl ester (Compound 11, 0.18, 0.246mmo1), acetone (4mL), 7 potassium carbonate (0.9178, 6.63mmol) and methyl iodide (0.8mL, 1 lmmol), 8 the following work-up was used. The volatiles were distilled off in vacuo and 9 the residue was diluted with water and extracted with dichloromethane (x2).
The combined organic extract was dried over anhydrous sodium sulfate, 11 filtered and evaporated in vacuo to an oil. Flash column chromatography over 12 silica gel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluent 13 afforded the title compound as a pale yellow oil (0.1028, 98%).
14 'H-NMR (300 MHz, CDC13): 8 0.39-0.62 (m, 4H), 1.29(s, 3H), 1.34(s, 3H), 1.42(t, J= 6.9Hz, 3H), 1.65-1.82(m, 2H), 1.85-2.02 (m, 2H), 2.02-2.10(m, 16 1H), 2.15(s, 3H), 3.97(t, J = 7.7Hz, 1H), 4.42(q, J= 7.OHz, 2H), 7.28-7.36 (m, 17 3H), 7.59(s, 1H), 7.55(d, J = 7.9Hz, 2H), 7.92 (t, J= 7.SHz, 1H).
18 4-[5-(Cyclo~ropyl-meth,~l-amino)-8Y8-dimethyl- 5 6 7 8-tetrahydro-19 naphthalene-2-yl-ethynvl]-2-fluoro benzoic acid (Compound 13, General Formula 4) 21 Following general procedure I and using 4-[(5-cyclopropyl-methyl-22 amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-23 benzoic acid ethyl ester (Compound 12, 0.1028, 0.23mmol), ethanol (4mL) 24 and 1 M aqueous sodium hydroxide solution (2mL) followed by flash column chromatography over silica gel (230-400 mesh) 30% ethyl acetate in hexane as 26 the eluent, the title compound was obtained as an off white solid(0.015g, 27 16%).
28 IH-NMR (300 MHz, CDC13): 8 0.54-0.65 (m, 4H), 1.29 (s, 3H), 1.32 (s, 3H), 29 1.68-1.83 (m, 2H), 1.97-2.05 (m, 2H), 2.18-2.25 (m, 1H), 2.25 (s, 3H), 4.13 (t, 1 J = 6.7Hz, 1H), 7.26-7.30 (m, 2H), 7.34 (dd, J = 1.5, 7.9Hz, 1H), 7.48 (d, J
=
2 1.8Hz, IH), 7.60 (d, J = 8.5Hz, 1H), 7.95 (t, J = 7.9Hz, 1H).
3 ~2 Fluoro 4 (8 8 dimethyl-5-oxo-5 6 7 8-tetrahydro-naphthalene-2-yl-4 ethvnyllsphen~]acetic acid ethyl ester (Compound 14, General Formula 8) Following general procedure F and using 6-ethynyl-4,4-dimethyl-6 1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.2988, 1.43mmo1), 7 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.448, 1.43mmo1), 8 triethyl amine (Intermediate 13, 3mL), anhydrous tetrahydrofuran (7mL), 9 copper(I)iodide (0.048, 0.2mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.158, 0.2I3mmo1) followed by 11 flash column chromatography over silica gel (230-400 mesh) using 14-16%
12 ethyl acetate in hexane as the eluent, the title compound was obtained as an oil 13 (0.438, 77%).
14 IH-NMR (300 MHz, CDC13): 8 1.26(t, J= 7.2Hz, 3H), 1.41(s, 6H), 2.04(t, J =
6.7Hz, 2H), 2.74(t, J = 6.7Hz, 2H), 3.68(s, 2H), 4.18(q, J= 7.lHz, 2H), 7.23-16 7.57(m, 4H), 7.59 (d, J = l.SHz, 1H), 7.99(d, J = 7.9Hz, 1H).
17 [2-Fluoro-4-~(8 8-dimethyl-5-oxo-5~6 7 8-tetrahydro-naphthalene-2- ~~1-18 ethynyl)nhen,1~1-acetic acid (Compound 15, General Formula 8) I9 Following general procedure J and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]acetic acid methyl 21 ester (Compound 14, 0.188, 0.48mmol), methanol (4mL), tetrahydrofuran 22 (8mL), water (2mL) and lithium hydroxide monohydrate (0.28, 4.76mmo1) 23 followed by flash column chromatography over silica gel (230-400 mesh) 24 using 50- 100% ethyl acetate in hexane as the eluent, the title compound was obtained as a dirty white solid (0.0688, 41%).
26 1H-NMR (300 MHz, CDCI3): 8 I.41(s, 6H), 2.03(t, J= 6.7Hz, 2H), 2.74(t, J=
27 6.8Hz, 2H), 3.73(s, 2H), 7.24-7.32(m, 3H), 7.42(dd, J= 1.5, 7.9Hz, 1H), 7.56 28 (s, 1H), 7.99(d, J = 7.9Hz, 1H), 9.40-10.00 (br s, 1H).
1 [4~~Cyc~lonrooyl aminol 8 8 dimethyl 5 6 7 8-tetrahydro-na-ahthalene-2-vl-2 eth~nyll-2-fluoro-phenyll acetic acid ethyl ester (Compound 16, General 3 Formula 4) 4 Following general procedure G and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl) phenyl]acetic acid ethyl ester 6 (Compound 14, 0.258g, 0.68mmol), dichloromethane (4mL), 7 acetonitrile(2mL), cyclopropyl amine(lmL, 14.45mmo1), acetic acid (1mL)and 8 sodium cyanoborohydride (0.266g, 4.23mmo1) followed by flash column 9 chromatography over silica gel (230-400 mesh) using 16-20-25% ethyl acetate in hexane as the eluent , the title compound was obtained as a pale yellow oil 11 (0.21g, 73%).
12 1H-NMR (300 MHz, CDC13):8 0.35-0.54 (m, 4H), 1.25(t, J= 7.lHz, 3H), 13 1.26(s, 3H), 1.32(s, 3H), 1.53-1.64(m, 1H), 1.82-2.05 (m, 3H), 2.21-2.28(m, 14 1H), 3.65(s, 2H), 3.78(t, J = S.OHz, 1H), 4.17(q, J= 7.lHz, 2H), 7.19-7.41 (m, 5H), 7.47(d, J = 1.SHz, 1H).
16 f4-(5-~Cyclopropyl-methyl-amino)-8 8-dimethyl~5 6 7 8-tetrah~dro-17 naphthalene-2-yl-eth~n~l-2-fluoro-phenyl]-acetic acid eth l~r 18 (Compound 17, General Formula 8) 19 Following general procedure H and using [4-((5-cyclopropyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-2-fluoro-21 phenyl]acetic acid ethyl ester (Compound 16, 0.21g, 0.5mmo1), acetone 22 (5mL), potassium carbonate (1.13g, 8.17mmo1) and methyl iodide (0.5mL, 23 8mmo1), the following work-up was used. The volatiles were distilled off in 24 vacuo and the residue was diluted with water and extracted with dichloromethane (x2). The combined organic extract was dried over 26 anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil.
27 Flash column chromatography over silica gel (230-400 mesh) using 8% ethyl 28 acetate in hexane as the eluent afforded the title compound (0.158, 69%).
1 'H-NMR (300 MHz, CDC13): 8 0.39-0.53(m, 4H), 1.27(s, 3H), 1.31 (s, 3H), 2 1.66-1.81(m, 2H), 1.89-2.05(m, 2H), 2.08-2.13 (m, 1H), 2.13 (s, 3H), 3.62(s, 3 2H), 3.94 (t, J = 8.OHz, 1H), 4.16(q, J= 7.lHz, 2H), 7.20-7.29(m, 4H), 7.44(d, 4 J = 1.SHz, 1H), 7.51 (d, J = 8.2Hz, 1H).
f4 (S~Cvclopropyl methyl aminol-~ 8-dimethyl- 5 6 7 8-tetrahydro-6 naphthalene-2-yl-ethynXl)-2-r fluoro-phenyll-acetic acid (Compound 18, 7 General Formula 4) 8 Following general procedure J and using [4-(5-(cyclopropyl-methyl-9 amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 17, 0.0258, 0.059mmol), methanol 11 (1mL), tetrahydrofuran (1mL), water (O.SmL) and lithium hydroxide 12 monohydrate (0.0608, 1.43mmol), the title compound was obtained as a white 13 solid (0.0238, 95%).
14 'H-NMR (300 MHz, CDC13):8 0.52-0.54(m, 2H), 0.68-0.70(m, 2H), 1.27(s, 3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H), 2.19-2.24(m, IH), 16 2.24(s, 3H), 3.60(s, 2H), 4.18(t, J = 7.7Hz, 1H), 7.19-7.28(m, 4H), 7.45 (d, J
17 = l.SHz, 1H), 7.49(d, J = 8.2Hz, 1H), 8.80-9.20(br s, 1H).
18 GENERAL PROCEDURE K: 8 8-Dimeth~l-5 6 7 8-tetrahydro-naphthalene-1-19 one-2-carboxxlic acid-4-(tent-butoxycarbon l~meth~lphenyl ester Compound 19, General Formula 8) 21 A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-I,2,3,4-22 tetrahydronaphthalene-I-one (Intermediate I1, 0.148, 0.434mmol), t-butyl-4-23 hydroxy-phenyl acetate (Reagent E, 0.148, 0.673mmol), palladium acetate 24 (0.0548, 0.24mmo1) and 1,3-bis(diphenylphosphino)propane (0.0828, 0.2mmol) in a mixture of dimethylsulfoxide (1mL), 1,2-dichloroethane 26 (l.SmL) and triethyl amine (1mL) was heated at 70°C under an atmosphere of 27 carbon monoxide overnight. The volatiles were distilled of in vacuo and the 28 residue was diluted with water and extracted with diethyl ether (x3). The 29 combined organic extract was dried over anhydrous magnesium sulfate, 1 filtered and evaporated in vacuo to an oil which was subjected to flash column 2 chromatography over silica gel (230-400 mesh) using 15% ethyl acetate in 3 hexane as the eluent to afford the title compound (0.1 1g, 53%).
4 1H-NMR (300 MHz, CDCI3): ~ 1.44(s, 3H), 1.44(s, 9H), 1.46 (s, 3H), 2.07(t, J
= 6.9Hz, 2H), 2.76(t, J = 6.8Hz, 2H), 3.55(s, 2H), 7.17 (d, J = 8.5Hz, 2H), 6 7.35(d, J = 8.5Hz, 2H), 8.05-8.13(m, 2H), 8.25 (d, J = l.SHz, 1H).
7 8 8 Dimeth~ 5-oxo-5~6 7 8-tetrahydro-naphthalene-2-carboxylic acid-4-8 (carbox~meth~)phen 1y ester (Compound 20, General Formula 8) 9 A solution of 8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4-(tent-butoxycarbonylmethyl)phenyl ester (Compound 19, 11 0.11 g, 0.229mmol) in dichloromethane (2mL) was treated with trifluoroacetic 12 acid (0.85mL and stirred at ambient temperature for 2.5h. The volatiles were 13 distilled off in vacuo and the residue was diluted with water and extracted with 14 ethyl acetate (x3). The combined organic phase was dried over anhydrous sodium sulfate, f Itered and evaporated in vacuo to afford a solid which was 16 subjected to flash column chromatography over silica gel (230-400 mesh) 17 using ethyl acetate as the eluent to afford the title compound (0.024g, 25%).
18 1H-NMR (300 MHz, CDCl3): S 1.46 (s, 6H), 2.08(t, J = 6.7Hz, 2H), 2.80(t, J
19 = 6.7Hz, 2H), 3.70(s, 2H), 7.20(d, J = 8.5Hz, 2H), 7.37(d, J = 8.SHz, 2H), 8.08(dd, J = 1.4, 8.2Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 8.24 (d, J = 1.2Hz, 1H).
21 5-Methox~3,3-dimethyl-indane (Intermediate 15) 22 Following general procedure A and using titanium tetrachloride 23 (5.5mL,50mmoL), anhydrous dichloromethane (80mL), 2M solution dimethyl 24 zinc (50mL) in toluene and a solution of 6-methoxy-indane-1-one (4.05g, 25mmo1) in dichloromethane (lOmL) the title compound was obtained as an 26 oil (3.13g, 71%).
27 'H-NMR (300 MHz, CDC13):8 1.37 (s, 6H), 2.04(t, J = 7.2Hz, 2H), 2.94(t, J =
28 7.2Hz, 2H), 3.89(s, 3H), 6.82(d, J= 2.lHz, 1H), 7.28(dd, J= 2.1, 7.OHz, 1H), 29 7.35 (d, J = 7.OHz, 1H).
1 5-Methoxy-3~3-dimethyl-indane-1-one (Intermediate 16) 2 Following general procedure B and using 5-methoxy-3,3-dimethyl 3 indane (Intermediate 15, 3.13g, 17.78mmol) in 20mL of glacial acetic acid 4 and a solution of chromium trioxide (3.91g, 39.1mmo1) in 20mL of acetic acid and 20mL of water the title compound was obtained as a viscous yellow oil 6 (3.3g, 97%).
7 iH-NMR (300 MHz, CDC13):8 1.37 (s, 6H), 2.54 (s, 2H), 3.87(s, 3H), 6.86-8 6.87 (m, 2H), 7.60 (d, J = 7.OHz, 1H).
9 6-Methoxy-4 4-dimethxl-1 2 3 4-tetrahXdro-isoquinoline-1-one (Intermediate 17) 11 A solution of 5-methoxy-3,3-dimethyl-indane-1-one (Intermediate 16, 12 3.3g, 17.4mmo1) in benzene (SOmL) was treated with concentrated sulfuric 13 acid (lOmL) and heated to 60°C. Sodium azide (1.95g, 30mmo1) was added in 14 small portions and after the addition was complete, the reaction mixture was heated further for 4h. It was then cooled, diluted with water and extracted with 16 chloroform (x3). The combined organic phase was dried over anhydrous 17 magnesium sulfate, filtered and evaporated in vacuo to afford the title 18 compound as a brown solid (3.5g, quantitative by weight).
19 1H-NMR (300 MHz, CDC13): b 1.31 (s, 6H), 3.28 (s, 2H), 3.83(s, 3H), 6.78 (d, J = 2.6Hz, 1H), 6.82(dd, J = 2.6Hz, 8.SHz, 1H), 7.59 (s, 1H), 8.02 (d, J=
21 8.2Hz, 1H).
22 6-Methoxy-4,4-dimethyl-1,2,3 4-tetrahydro-isoquinoline (Intermediate 18) 23 A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-24 1-one (Intermediate 17, 3.5g, l7mmol) in 100mL of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (1.3g, 26 34.ZSmmol) in small portions and the resulting suspension was refluxed for 27 hours under argon. The reaction mixture was then cooled in an ice bath and 28 cautiously quenched with saturated aqueous sodium sulfate solution and the 29 resulting slurry was filtered and the filter-cake washed well with ethyl acetate.
1 The filtrate and washings were evaporated in vacuo to a brown oil which was 2 dissolved in chloroform, the solution was dried over anhydrous magnesium 3 sulfate, filtered and evaporated in vacuo to afford the title compound (3.2g, 4 100%).
1H-NMR (300 MHz, CDCl3): 8 1.27 (s, 6H), 2.22 (s, 1H), 2.84 (s, 2H), 3.79 (s, 6 3H), 3.95 (s, 2H), 6.68(dd, J = 2.4Hz, 8.3Hz,1H), 6.86(d, J = 2.4Hz, 1H), 6.91 7 (d, J= 8.3Hz, 1H).
8 6 Methoxy-4 4-dimethyl-1 2 3 4-tetrahydro-isoc~uinoline-2-carbaldehyde 9 (Intermediate 19) A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline 11 (Intermediate 18, 3.2g, 16.7mmol) in anhydrous dichloromethane (40mL) 12 was treated with formic acid (lmL, 26.5mmo1) followed 1-(3-13 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9g, 20.34mmo1) 14 and the resulting solution was stirred at ambient temperature overnight. It was then diluted with chloroform and washed with water (x 1 ) and brine (x 1 ), dried 16 over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 17 the title compound as pale brown viscous oil (3.26g, 90%).
18 'H-NMR (300 MHz, CDC13): 8 1.28 (s, 6H), 3.32 (s, 0.7H), 3.54 (s, 0.3H), 19 3.79(s, 3H), 4.54 (s, 0.3H), 4.66(s, 0.7H), 6.71(dd, J= 2.6Hz, 8.2Hz, 1H), 6.85-6.97(m, 1H), 7.02-7.27(m, 1H), 8.15(s, 0.7H), 8.34(s, 0.3H), 8.40-8.80 21 (br s, 1H).
22 6-Hydrox~-4 4-dimethyl-11 2 3 4-tetrahydro-isoquinoline-2-carbaldehyde 23 (Intermediate 20) A stirred, cooled (-78°C) solution of 6-methoxy-4,4-24 dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 19, 3 .26g, 15mmol) in anhydrous dichloromethane ( 15mL) was treated with 1 M
26 solution of boron tribromide in dichloromethane (50mL) stirred at ambient 27 temperature for 3h. It was then cooled again to 78°C and quenched carefully 28 with saturated aqueous sodium carbonate solution, diluted with water and the 29 aqueous phase was extracted with ethyl acetate (x2). The combined organic 1 extract was dried over anhydrous sodium sulfate, filtered and evaporated in 2 vacuo to afford the title compound as a solid foam (3g, 99%).
3 IH-NMR (300 MHz, CDC13): 8 1.23 (s, 6H), 3.31 (s, 0.7H), 3.54 (s, 0.3H), 4 4.51 (s, 0.3H), 4.64 (s, 0.7H), 6.70-6.75(m, 1H), 6.84-6.90(m, 2H), 7.50 7.80(br s, 1H), 8.12(s, 0.7H), 8.32(s, 0.3H).
6 2 C, cly opropyl 6-h~drox~-4~4-dimethyl -1 2 3 4-tetrahydro-isoauinoline 7 (Intermediate 21) 8 A stirred, cooled (0°C)solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-9 tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3g, 11.21mmo1) in anhydrous tetrahydrofuran (40mL) under argon was treated with titanium 11 tetra-iso-propoxide (8.28mL, 28mmo1) followed by 3M solution of ethyl 12 magnesium bromide in diethyl ether ( 18.7mL) and the reaction mixture was 13 then heated at 55°C overnight. It was then cooled in an ice-bath, quenched 14 with saturated aqueous ammonium chloride solution and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous sodium 16 sulfate, filtered and evaporated in vacuo to afford a yellow oily solid.
Flash 17 column chromatography over silica gel (230-400 mesh) using 10-20% ethyl 18 acetate in hexane as the eluent afforded the title compound as a pale yellow 19 solid (l.SSg, 63%).
1H-NMR (300 MHz, CD3COCD3): 8 0.016-O.I6(m, 4H), 0.847 (s, 6H), 1.37 21 (m, 1H), 2.20(s, 2H), 3.25 (s, 2H), 6.22(dd, J= 2.4, 8.2Hz, 1H), 6.41(d, J=
22 2.6Hz, 1H), 6.47(d, J= 8.2Hz, 1H), 7.62(s, 1H).
23 2-Cycloprop~-4 4-dimethyl-6-trifluorometh~sulfon~~1,2,3,4-tetrahydro-24 isoc~uinoline (Intermediate 22) Following general procedure C and using 2-cyclopropyl-6-hydroxy-4,4-26 dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 21, 1.5g, 6.9mmo1) in 27 anhydrous dichloromethane (30mL), triethyl amine (l.SmL, 10.39mmo1) and 28 [N,N'-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (2.758, 7mmo1) 29 followed by flash column chromatography over silica gel (230-400 mesh) 1 using 8% ethyl acetate in hexane as the eluent the title compound was obtained 2 (2.23g, 92%) as oil. 'H-NMR (300 MHz, CDC13): 8 0.42-0.54(m, 4H), 1.25(s, 3 6H), 1.76(m, 1H), 2.62(s, 2H), 3.74(s, 2H), 6.98(dd, J= 2.3, 8.4Hz, 1H), 4 7.16(d, J = 8.2Hz, 1H), 7.I4(d, J = 2.3Hz, 1H).
EthXl 2 cvclopropyl 4 4-dimeth~ 2 3 4-tetrahydroisoauinoline-6-6 carbox~ate (Intermediate 23) 7 Following general procedure K and using 2-cyclopropyl-4,4-dimethyl-8 6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline (Intermediate 9 22, 1.6g, 4.6mmo1), palladium acetate (0.127g, 0.56mmo1), 1,3-bis(diphenylphosphino)propane (0.160g, 0.39mmo1), dimethylsulfoxide 11 (2mL), 1,2-dichloroethane (SmL), triethyl amine (2mL) , ethanol (SmL) and an 12 atmosphere of carbon monoxide followed by flash column chromatography 13 over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent 14 the title compound was obtained as an oil (1g, 79%).
'H-NMR (300 MHz, CDCl3):8 0.44-0.54(m, 4H), 1.27(s, 6H), 1.38 (t, J =
16 7Hz, 3H), 1.73(m, 1H), 2.62(s, 2H), 3.76(s, 2H), 4.35 (q, J = 7.lHz, 2H), 17 7.04(d, J = 7.9Hz, 1H), 7.74 (dd, J = 1.7, 7.9Hz, 1H), 7.97(d, J = l.BHz, 1H).
18 2-Cyclopro~yl-6-h~drox n~~-4 4-dimeth~-1 2 3 4-tetrahydroisoquinoline 19 (Intermediate 24) A stirred cooled (-78°C)solution of ethyl-2-cyclopropyl-4,4-dimethyl-21 1,2,3,4-tetrahydro isoquinoline-6-carboxylate (Intermediate 23, 1g, 22 3.66mmo1) in anhydrous dichloromethane (20mL) under argon was treated 23 with a 1M solution of di-iso-butyl aluminum hydride in dichloromethane 24 (lOmL) and the reaction mixture was warmed to -20°C over 1h. It was then quenched with saturated aqueous ammonium chloride solution and diluted 26 with dichloromethane and filtered over a bed of celite. The phases were 27 separated and the aqueous phase was extracted with dichloromethane (x1).
28 The combined organic extract was dried over anhydrous sodium sulfate, 1 filtered and evaporated in vacuo to afford the title compound as a viscous oil 2 (0.74g, 87%).
3 iH-NMR (300 MHz, CDCl3): 8 0.45-0.53(m, 4H), 1.25(s, 6H), 1.72-1.82(m, 4 2H), 2.61(s, 2H), 3.73(s, 2H), 4.61 (d, J = SHz, 2H), 6.98(d, J = 7.9Hz, 1H), 7.07 (dd, J = 1.5, 7.6Hz, 1H), 7.27(s, 1H).
6 2 Cyclopropyl 4 4 dimethvl-I 2 3 4-tetrahydroisoquinoline-6-carbaldehyde 7 (Intermediate 25) 8 A solution of 2-cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-9 tetrahydroisoquinoline (Intermediate 24, 0.74g, 3.2mmo1) in dichloromethane (lOmL) and acetonitrile (2.SmL) was treated sequentially with 4A°
molecular 11 sieves powder (1.06g), tetra-h-propyl ammonium perruthenate (O.OSOg, 12 0. l4mmol) and N-methyl morpholine N-oxide ( 1.1 g, 9.8mmo1). After stirring 13 at ambient temperature for O.Sh, it was diluted with SmL of hexane and 14 subjected to flash column chromatography over silica gel (230-400 mesh) using IO% ethyl acetate in hexane as the eluent to afford the title compound as 16 an oil (0.278, 37%).
17 1H-NMR (300 MHz, CDC13):8 0.44-0.56(m, 4H), 1.30(s, 6H), 1.79(m, 1H), 18 2.66(s, 2H), 3.82(s, 2H), 7.17(d, J = 7.9Hz, 1H), 7.60 (dd, J = 1.6, 7.9Hz, 1H), 19 7.82(d, J = I .BHz, 1H), 9.95 (s, 1H).
6-(2 2-Dibromo-vinxll-2-cycloprop~l-4,4-dimethyl-1,2,3,4-21 tetrahydroisoquinoline (Intermediate 26) 22 A stirred, cooled (ice-bath) solution of triphenyl phosphine (0.53g, 23 2mmo1) in anhydrous dichloromethane was treated with carbon tetrabromide 24 (0.35g, lmmol) under argon. After O.Sh, a solution of 2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 25, 26 0.13g, 0.57mmo1) in dichloromethane (2mL) was cannulated into the reaction 27 mixture. After 1.5h between 0°C and 10°C, the reaction mixture was subjected 28 to flash column chromatography over silica gel (230-400 mesh) using 3-5%
1 ethyl acetate in hexane as the eluent to afford the title compound as a viscous, 2 pale yellow oil (0.18g, 82%).
3 'H-NMR (300 MHz, CDC13):8 0.49-O.S7(m, 4H), 1.31(s, 6H), 1.80(m, 1H), 4 2.67(s, 2H), 3.77(s, 2H), 7.04(d, J = 7.9Hz, 1H), 7.29 (dd, J = 1.7, 7.9Hz, 1H), S 7.49 (s, 1H), 7.50(d, J = l.7Hz, 1H).
6 2 Cxcloprop~-6-eth~n~l-4~4-dimethyl-1 2 3 4-tetrahydroisoauinoline 7 (Intermediate 27) 8 A stirred, cooled (-78°C) solution of 6-(2,2-dibromo-vinyl)-2-9 cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 26, 0.18g, 0.47mmo1) in tetrahydrofuran (2mL) was treated 11 with 1.6M solution of h-butyl lithium (0.6mL, 0.96mmo1) under argon. The 12 reaction mixture was allowed to warm to -20°C over l.Sh, quenched with 13 saturated aqueous ammonium chloride solution and extracted with diethyl 14 ether (x2). The combined organic phase was dried over anhydrous magnesium 1 S sulfate, filtered and evaporated in vacuo to afford the title compound as an oil 16 (0.1 g, 94%).
17 'H-NMR (300 MHz, CDC13):~ 0.47-O.SS(m, 4H), 1.28(s, 6H), 1.77(m, 1H), 18 2.63(s, 2H), 3.OS(s, 1H), 3.67(s, 2H), 6.98(d, J = 7.6Hz, 1H), 7.26 (dd, J
=
19 1.5, 7.9Hz, 1H), 7.46(d, J = l.SHz, 1H).
[4-(2-Cyclopropyl-4s4-dimethyl-1 2~3 4-tetrahydro-isoquinolin-6-yl-ethynyl)-21 2-fluoro-phenyll-acetic acid eth 1y ester (Compound 21, General Formula 3) 22 Following general procedure F and using 2-cyclopropyl-6-ethynyl-4,4-23 dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13g, 24 O.S71mmo1), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.16g, 2S O.S2mmol), triethyl amine (0.8mL), anhydrous tetrahydrofuran (2mL), 26 copper(I)iodide (0.0S 1 g, 0.27mmo1) and 27 dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0. l4mmol) followed by 28 flash column chromatography over silica gel (230-400 mesh) using 10% ethyl 29 acetate in hexane as the eluent, O.lg of the title compound was obtained as an 1 oil. It was further purified by preparative normal phase HPLC on a partisil-2 silica column using 10% ethyl acetate in hexane as the mobile phase (0.055g, 3 24%).
4 1H-NMR (300 MHz, CDCl3):8 0.42-0.51(m, 4H), 1.26(t, J= 7.3Hz, 3H), 1.27(s, 6H), 1.75(m, 1H), 2.6I(s, 2H), 3.66(x, 2H), 3.74(s, 2H), 4.18 (q, J=
6 7.3Hz, 2H), 6.97 (d, J = 7.9Hz, 1H), 7.20-7.29(m, 4H), 7.45(d, J = 1.SHz, 7 1H).
8 f4 (2 Cyclopro~rl-4 4-dimethyl-1 2 3,4-tetrah~dro-isoquinolin-6-yl-ethynyll-9 2-fluoro-phenvl]-acetic acid (Compound 22, General Formula 3) Following general procedure J and using [4-(2-cyclopropyl-4,4-I1 dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-acetic 12 acid ethyl ester (Compound 21, 0.055g, 0.135mmol), methanol (2mL), 13 tetrahydrofuran (4mL), water (1mL) and lithium hydroxide monohydrate 14 (0.117g, 2.97mmo1) the title compound was obtained as a pale yellow solid foam (0.040g, 78%).
16 1H-NMR (300 MHz, CDCl3): 8 0.52-0.65(m, 4H), 1.27(s, 6H), 1.84(m, 1H), 17 2.71(s, 2H), 3.61(s, 2H), 3.85(s, 2H), 6.98(d, J = 7.9Hz, 1H), 7.06 (t, J =
18 7.6Hz, 1H), 7.17-7.25(m, 3H), 7.43(d, J= l.2Hz, 1H), 8.60-9.00(br s, 1H).
19 [~2-C cly opropyl-4 4-dimethyl-1 2,3 4-tetrah_ydro-isoquinolin-6-yl-ethynyll-phenyll-acetic acid meth.1~ (Compound 23, General Formula 3) 21 Following general procedure F and using 2-cyclopropyl-4,4-dimethyl-22 6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13g, 23 0.571mmol), 4-iodo phenyl acetic acid methyl ester (Reagent B, 0.168, 24 0.58mmol), triethyl amine (0.5mL), anhydrous tetrahydrofuran (2mL), copper(I)iodide (0.04g, 0.21mmo1) and 26 dichlorobis(triphenylphosphine)palladium(II) (0.12g, 0.17mmo1) followed by 27 flash column chromatography over silica gel (230-400 mesh) using 10% ethyl 28 acetate in hexane as the eluent, 0.05g of the title compound was obtained as an 29 oil. It was further purified by preparative normal phase HPLC on a partisil-1 silica column using 10% ethyl acetate in hexane as the mobile phase (0.01 g, 2 6%).
3 'H-NMR (300 MHz, CDC13): ~ 0.42-0.58(m, 4H), 1.29(m, 6H), 1.79(m, 1H), 4 2.64(s, 2H), 3.67(s, 3H), 3.72(s, 2H), 3.77(s, 2H), 7.09 (d, J = 7.9Hz, 1H), 7.28(dd, J = 1.5, 7.9Hz, 1H), 7.36 (d, J = 7.9Hz, 2H), 7.50 (d, J = 1.6Hz, 1H), 6 7.51 (d, J = 7.9Hz, 2H).
7 ~4 (2 C~clo~ropyl 4 4-dimethyl-1 2 3 4-tetrahydro-isoquinolin-6-yl-ethynyl)-8 phenvll-acetic acid (Compound 24, General Formula 3) 9 Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-acetic acid 11 methyl ester (Compound 23, O.OIg, 0.027mmo1), methanol (1mL), 12 tetrahydrofuran (1mL), water (O.SmL) and lithium hydroxide monohydrate 13 (0.042g, lmmol) the title compound was obtained as a pale yellow solid foam 14 (0.0065g, 68%).
1H-NMR (300 MHz, CDC13): S 0.35-0.52(m, 4H), 1.24(s, 6H), 1.74(m, 1H), 16 2.59(s, 2H), 3.64(s, 2H), 3.71(s, 2H), 7.03 (d, J = 8.2Hz, 1H), 7.22(dd, J
=
17 1.4, 7.9Hz, 1H), 7.33 (d, J = 8.2Hz, 2H), 7.46 (d, J = 8.2Hz, 2H), 7.47(s, 1H).
18 1-(Iso-prowl-meth-aminol-6-trimethylsilan 1y eth~nyl-4 4-dimethyl-1,2,3,4-19 tetrahydro-naphthalene (Intermediate 28) Following general procedure G and using a solution of 4,4-dimethyl-6-21 trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene 2-one (Intermediate 22 12, 0.2g, 0.78mmo1), dichloromethane (4mL), acetonitrile (2mL), acetic acid 23 (1mL), isopropyl amine (lmL, 11.74mmo1) and sodium cyanoborohydride 24 (0.19g, 3.02mmo1), after l5days of reaction time and work up afforded an intermediate (0.148, 60%, 0.47mmo1) which was used following general 26 procedure H along with acetone (2mL), potassium carbonate (0.6g, 4.34mmol) 27 and methyl iodide (O.SmL, 8mmol). The crude product after work up was 28 subjected to flash column chromatography over silica gel (230-400 mesh) 1 using 15% ethyl acetate in hexane as the eluent to afford the title compound as 2 a pale yellow oil (0.14g, 95%).
3 1H-NMR (300 MHz, CDC13): 8 0.001(s, 9H), 0.85 (d, J= 6.4Hz, 6H), 0.98 (s, 4 3H), 1.03 (s, 3H), 1.32-1.60 (m, 4H), 1.81(s, 3H), 2.64(heptet, J= 6.4Hz, 1H), 3.65 (dd, J = 6.1, 9.4Hz, 1H), 6.97 (dd, J = 1.7, 7.9Hz, 1H), 7.13 (d, J=
6 1.7Hz, 1 H), 7.82 (d, J = 7.9Hz, 1 H).
7 6 Ethynxl 1 (iso pro 1-y methyl-amino 4 4-dimeth~-1 2 3 4-tetrahydro-8 naphthalene (Intermediate 29) 9 Following general procedure E and using 1-(methyl-iso-propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene 11 (Intermediate 28, 0.14g, 0.45mmo1), methanol (SmL), potassium carbonate 12 (0.61g, 4.41mmol) and ethyl acetate the title compound (0.092g, 80%) was 13 obtained as an oil.
14 'H-NMR (300 MHz, CDCl3):8 1.11(d, J= 6.4Hz, 6H), 1.23(s, 3H), 1.28(s, 3H), 1.51-1.87 (m, 4H), 2.09(s, 3H), 2.90 (heptet, J = 6.4Hz, 1H), 3.00(s, 1H), 16 3.91 (dd, J= 5.8, lO.OHz, 1H), 7.25(dd, J = 1.7, 8.2Hz, 1H), 7.41 (d, J =
17 1.7Hz, 1 H), 7.70(d, J = 8.2Hz, 1 H).
18 4-jS~Iso-propyl-methyl-aminol-8 8-dimeth~l-5,6 7~8-tetrahydro-naphthalene-19 2-.yl-ethyn~ll-benzoic acid ethyl ester (Compound 25, General Formula 4) Following general procedure F and 6-ethynyl-1-(iso-propyl-methyl-21 amino)-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 29, 22 0.092g, 0.36mmol), ethyl-4-iodo benzoate (Reagent A, 0.12g, 0.48mmo1), 23 triethyl amine (1mL), tetrahydrofuran (2mL), copper(I)iodide (0.028g, 24 0.14mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.075g, 0.1 lmmol) followed by flash column chromatography over silica gel (230-400 26 mesh) using 10-15% ethyl acetate in hexane as the eluent the title compound 27 was obtained (0.04g, 27%).
28 iH-NMR (300 MHz, CDCl3): 8 1.12 (d, J= 6.SHz, 6H), 1.27 (s, 3H), I.31 (s, 29 3H), 1.40 (t, J = 7.OHz, 3H), 1.62-1.89 (m, 4H), 2.10(s, 3H), 2.92 (heptet, J =
1 6.4Hz, 1H), 3.94(dd, J = 6.1, 9.7Hz, 1H), 4.38(q, J = 7.lHz, 2H), 7.31(dd, J
=
2 1.4, 8.2Hz, 1H), 7.46 (d, J = 1.7Hz, 1H), 7.58 (d, J = 8.2Hz, 2H), 7.75(d, J
=
3 8.2Hz, 1 H), 8.01 (d, J = 8.2Hz, 2H).
4 4 [S~Iso propyl methyl-amino)-8 8-dimethyl-55 6 7 8-tetrahydro-naphthalene-2-vl-eth~nyl)]-benzoic acid (Compound 26, General Formula 4) 6 Following general procedure I and using 4-[5-(iso-propyl-methyl-7 amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)]-benzoic 8 acid ethyl ester (Compound 25, 0.048, O.Olmmol), ethanol (2mL), 9 tetrahydrofuran (ImL) and 1M aqueous sodium hydroxide solution (lxnL) followed by recrystallization from diethylether-hexane, the title compound 11 was obtained as an off white solid (0.0)08, 27%).
12 'H-NMR (300 MHz, CDC13): b 1.30(d, J= 6.OHz, 6H), 1.31(s, 9H), 1.67-13 1.98(m, 4H), 2.35 (s, 3H), 3.19 (heptet, J= 6.4Hz, 1H), 4.36 (t, J = 7.6Hz, 14 1H), 7.28(dd, J= 1.4, 8.2Hz, 1H), 7.48 (d, J = l.4Hz, 1H), 7.55 (d, J =
8.2Hz, 2H), 7.81 (d, J = 8.2Hz, 1H), 8.05 (d, J = 8.2Hz, 2H).
16 f 4 ~2 2 4 4-Tetrameth~l-chroman-6-xI-eth~n~l phen~] acetic acid methyl 17 ester (Compound 27, General Formula 8) 18 Following general procedure F and using 6-ethynyl-2,2,4,4-19 tetramethylchroman (synthesis described in U.S. Patent Nos. 5,045,551 and 5,616,597 incorporated herein by reference) (0.0608, 0.28mmo1), methyl-4-21 iodo phenyl acetate (Reagent B, 0.0788, 0.28mmo1), triethyl amine (4mL), 22 tetrahydrofuran (4mL), copper(I)iodide (0.0308, 0.16mmol) and 23 dichlorobis(triphenylphosphine)palladium(II) (0.11 g, 0.16mmol) followed by 24 flash column chromatography over silica gel (230-400 mesh) using 5-10 ethyl acetate in hexane as the eluent the title compound was obtained (0.0478, 26 46%).
27 1H NMR (300 MHz, CDC13): S 7.48-7.45 (m, 3H), 7.25-7.23 (m, 3H), 6.75 (d, 28 1H, J= 8.2Hz), 3.70 (s, 3H), 3.62 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35 (s, 29 6H).
1 GENERAL PROCEDURE L: f 4-(2 2 4 4-Tetramethyl-chroman-6-yl-ethynyll 2 phenyll acetic acid (Compound 28, General Formula 8) 3 A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl]
4 acetic acid methyl ester (Compound 27, 0.0478, 0.13mmol) in 5mL of methanol was treated with 1M sodium hydroxide solution (2mL) and heated at 6 55°C for 2h. The volatiles were distilled off in vacuo and the residue was 7 acidified with 10% hydrochloric acid and extracted with ethyl acetate (x2).
8 The combined organic phase was washed with brine (x1), dried over 9 anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in 11 acetonitrile as the mobile phase to afford the title compound (0.0348, 82%). 'H
12 NMR (300 MHz, CDC13): ~ 7.49-7.45 (m, 3H), 7.26-7.22 (m, 3H), 6.75 (d, 13 1H, J= 8.2Hz), 3.65 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35 (s, 6H).
14 2-Fluoro-4-(2 2 4 4-tetramethyl-chroman-6-~yn~l~ benzoic acid meth ester (Compound 29, General Formula 8) 16 Following general procedure F and using 6-ethynyl-2,2,4,4-17 tetramethylchroman (0.118, O.Slmmol), methyl-2-fluoro-4-iodo-benzoate 18 (Reagent G, 0.148, 0.51mmo1), triethyl amine (5mL), tetrahydrofuran(lOmL), 19 copper(I)iodide(0.030g, 0.16mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 10g, 0.16mmo1) followed by 21 flash column chromatography over silica gel (230-400 mesh) using 5-10 22 ethyl acetate in hexane as the eluent, the title compound was obtained (0.148, 23 79%).
24 'H NMR (300 MHz, CDC13): 8 7.82 (t, 1H, J= 7.9Hz), 7.39 (d, 1H, J=
l.BHz), 7.25-7.16 (m, 3H), 6.69 (d, 1H, J= 8.2Hz), 3.85 (s, 3H), 1.77 (s, 2H), 26 1.29 (s, 6H), 1.28 (s, 6H).
27 2-Fluoro-4-(2,2 4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid 28 (Compound 30, General Formula 8) 1 Following general procedure L and using 2-fluoro-4-(2,2,4,4-2 tetramethyl-chroman-6-yl-ethynyl)-benzoic acid methyl ester (Compound 29, 3 0.14g, 0.4mmo1), 5mL of methanol and 1M sodium hydroxide solution (2mL) 4 followed by recrystallization from ethyl acetate, the title compound was obtained (0.083g, 58%).
6 'H NMR (300 MHz, CD3COCD3): 8 8.00 (t, 1H, J= 7.8Hz), 7.63 (d, 1H, J=
7 2.lHz), 7.45 (dd, 1H, J= 1.5, 7.9Hz), 7.38 (dd, 1H, J= 1.5, 11.4Hz), 7.32 (dd, 8 1H, J= 2.1, 8.2Hz), 6.81 (d, 1H, J= 8.SHz), 1.92 (s, 2H), 1.41 (s, 6H), 1.38 (s, 9 6H).
[2-Fluoro-4-f2 2 4 4-tetramethyl-chroman-6-yl-eth~nyl~phenyll acetic acid I 1 ethyl ester (Compound 31, General Formula 8) 12 . Following general procedure F and using 6-ethynyl-2,2,4,4-13 tetramethylchroman (0.204g, 0.95mmo1), ethyl-2-fluoro-4-iodo phenyl acetate 14 (Reagent C, 0.263g, 0.86mmo1), triethyl amine, tetrahydrofuran, 1 S copper(I)iodide (0.025g, 0. l3mmol) and 16 dichlorobis(triphenylphosphine)palladium(II) (0.075g, 0.1 lmmol) followed by 17 flash column chromatography over silica gel (230-400 mesh) using 5-10 18 ethyl acetate in hexane as the eluent, the title compound was obtained (0.2I g, 19 ~ 62%).
IH NMR (300 MHz, CDC13): 8 7.46 (d, 1H, J= 2.IHz), 7.25-7.21 (m, 4H), 21 6.69 (d, 1 H, J = 8. SHz), 4.16 (q, 2H, J = 7.1 Hz), 3.65 (s, 2H), 1. 82 (s, 2H), 22 1.35 (s, 6H), 1.35 (s, 6H), 1.24 (t, 3H, J= 7.2Hz).
23 2-Fluoro-4- 2 2 4 4-tetramethyl-chxoman-6-yl-ethyn~ phenyl] acetic acid 24 (Compound 32, General Formula 8) Following general procedure L and using [2-fluoro-4-(2,2,4,4-26 tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid ethyl ester (Compound 27 31, 0.21g, 0.58mmo1), 5mL of methanol and 1M sodium hydroxide solution 28 (2mL) followed by flash column chromatography over silica gel (230-400 1 mesh) using SO% ethyl acetate in hexane, the title compound was obtained as a 2 solid (0.184g, 93%).
3 'H NMR (300 MHz, CDC13): 8 11.40 (br s, 1H), 7.48 (d, 1H, J= l.BHz), 7.46-4 7.16 (m, 4H), 6.76 (d, 1H, J= 8.2Hz), 3.69 (s, 2H), 1.82 (s, 2H), 1.34 (s, 12H).
S 3-MethXl-but-2-enoic acid 4-bromo-phen 1y ester:
6 To a stirred, cooled (ice bath) suspension of sodium hydride (2.4g, 7 100mmo1) in anhydrous tetrahydrofuran (200mL), 4-bromo phenol (17.3g, 8 100mmo1) was added followed by 3,3,-dimethyl acryloyl chloride (11.14mL, 9 100mmol). After 4hours at ambient temperature, the reaction mixture was poured into brine and extracted with diethyl ether (x2). The combined organic I 1 phase was dried over anhydrous sodium sulfate, filtered and evaporated in 12 vacuo to afford an oil which was subjected to flash column chromatography 13 over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent 14 to afford the title compound (1 Sg, S9%).
1S. 'H-NMR (300 MHz, CDCl3):S 2.00(s, 3H), 2.23(s, 3H), 5.89(s, 1H), 7.00(d, J
16 = 8.8Hz, 2H), 7.49(d, J = 8.8Hz, 2H).
17 6-Bromo-4.4-dimethyl-chroman-2-one:
18 A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7g, 19 27.6mmo1) in anhydrous dichloromethane (200mL) was cooled (ice bath) and treated with aluminum chloride (6.6g, 49.6mmol) and the reaction mixture was 21 stirred overnight at ambient temperature. The reaction mixture was quenched 22 with saturated aqueous sodium bicarbonate solution and extracted with diethyl 23 ether (x2). The combined organic extract was washed woth brine (x1), dried 24 over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an 2S oil which was purified by flash column chromatography over silica gel (230-26 400 mesh) using Z.S% ethyl acetate in hexane as the eluent to afford the title 27 compound (4.2g, 57%).
28 'H-NMR (300 MHz, CDC13):8 1.36(s, 6H), 2.62(s, 2H), 6.95(d, J = 8.SHz, 29 1H), 7.37(dd, J = 2.4, B.SHz, 1H), 7.43(d, J = 2.3Hz, 1H).
1 4-Bromo-2-f 3-h d~ roxX-1 1 3-trimethyl-butyll-phenol:
2 A solution of 6-bromo-4,4-dimethyl-chroman-2-one (1g, 3.92mmol) in 3 anhydrous tetrahydrofuran (20mL) was treated with 3M solution of ethyl 4 magnesium bromide (2.6mL) and stirred at ambient temperature for 2hours.
The reaction mixture was poured into cold dilute hydrochloric acid and 6 extracted with ethyl acetate (x2). The combined organic extract was dried 7 over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a 8 residue which was subjected to flash column chromatography over silica gel 9 (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow solid (1.1g, 100%).
11 1H-NMR (300 MHz, CDC13):b 1.14(s, 6H), 1.44(s, 6H), 2.20(s, 2H), 6.49(d, J
12 = 8.4Hz,lH), 7.15(dd, J = 2.4, 8.SHz, 1H), 7.37(d, J = 2.4Hz, 1H).
13 6-Bromo-2,2,414-tetrameth~-chroman:
14 A solution of 4-bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol (1.1g, 3.92mmo1) andp-toluene sulfonic acid (0.744g, 3.92mmol) in benzene 16 (20mL) was refluxed overnight. The reaction mixture cooled to ambient 17 temperature, filtered on silica gel and washed with 10% ethyl acetate in 18 hexane. The filtrate and washings were evaporated in vacuo to an oil which 19 was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a 2I pale yellow oil (0.848, 80%).
22 'H-NMR (300 MHz, CDCl3):8 1.34(s, 6H), 1.35(s, 6H), 1.82(s, 2H), 6.68(d, J
23 = 8.4Hz, 1 H), 7.16(dd, J = 2.7, 8.7Hz, 1 H), 7.3 7(d, J = 2.6Hz, 1 H).
24 The synthesis of this compound, as described here, is in close analogy to the synthesis of 6-bromo-2,2,4,4-tetramethylthiochroman, as described in 26 United States Patent No. 5,045,551 27 2 2 4 4-tetramethyl-6-f2-trimeth~ l~)eth~nyl chroman:
28 Following general procedure D and using 6-bromo-2,2,4,4-tetramethyl 29 chroman (0.5g, 1.87mmo1), triethyl amine (5mL), anhydrous tetrahydrofuran 1 (lSmL),copper(I)iodide (0.1078, 0.156mmo1), trimethylsilyl acetylene (1.848, 2 18.7mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.398, 3 0.56mmol) the title compound was obtained as a brown oil (0.618, 100%).
4 1H NMR (300 MHz, CDCl3): 8 7.43 (d, 1H, J= 2.lHz), 7.23 (dd, 1H, J= 7.9, 2.lHz), 6.73 (d, 1H, J= 8.2Hz), 1.83 (s, 2H), 1.36 (s, 12H), 0.28 (s, 9H).
6 6-Eth,~nyl-2,2,4,4-tetramethyl chroman:
7 Following general procedure E and using 2,2,4,4-tetramethyl-6-(2-8 trimethylsilyl)ethynyl chroman (0.618, 1.87mmo1), potassium carbonate ( 1.98, 9 13.74mmo1) and methanol the title compound was obtained (0.48, 90%).
I0 'H NMR (300 MHz, CDCI3): 8 7.47 (d, 1H, J= 2.lHz), 7.24 (dd, 1H, J= 7.9, 11 2.lHz), 6.76 (d, 1H, J= 8.2Hz), 3.01 (s, 1H), 1.85 (s, 2H), 1.37 (s, 6H), 1.36 12 (s, 6H).
13 An alternative synthesis for this compound is described in United States 14 Patent Nos. 5,045,551 and 5,616,597 GENERAL PROCEDURE M: 6-Bromo-2,2,4 4-tetramethyl-chroman-8-16 carbaldehyde (Intermediate 30) 17 A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl 18 chroman, (0.5g, 1.865mmol) in anhydrous dichloromethane (SmL) was treated 19 with a 1M solution (1.86mL, 1.86mmo1) of titanium tetrachloride in dichloromethane followed by a,a,-dichloro methyl ether (0.2148, 1.865mmol).
21 The reaction mixture was allowed to warm to ambient temperature for 4h. The 22 reaction mixture was diluted with diethyl ether, washed with brine (x1) and 23 dried over anhydrous sodium sulfate, filtered and evaporated in vczcuo to a 24 residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane to afford the title compound 26 as a yellow solid (0.528, 94%).
27 1H NMR (300 MHz, CDCl3): 810.38 (s, 1H), 7.72 (d, 1H, J= 2.6Hz), 7.57 (d, 28 1 H, J = 2. 6Hz), 1. 8 8 (s, 2H), 1.41 (s, 6H), 1.3 6 (s, 6H).
1 GENERAL PROCEDURE N: 6-Bromo-8-vinyl -2 2 4 4-tetramethyl- chroman 2 (Intermediate 31) 3 A solution of methylidene triphenyl phosphorane [generated from 4 methyl triphenylphosphonium bromide (7g, 20mmo1) and ( 11.BmL, 19mmo1) S of a 1.6M solution of h-butyl lithium in hexanes ] was added 6-bromo-2,2,4,4-6 tetramethyl chroman-8-carbaldehyde (Intermediate 30, O.S2g, 1.75mmo1).
7 After 1 h the reaction mixture was diluted with hexane, washed with brine (x 1 ), 8 dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a 9 clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the 11 title compound as a clear oil (0.378, 72%).
12 1H NMR (300 MHz, CDC13): 8 7.46 (d, 1H, J= 2.SHz), 7.33 (d, 1H, J=
13 2.SHz), 7.03 (dd, 1H, J= 11.3, 17.9Hz), 5.75 (dd, 1H, J= 1.4, 17.9Hz), 5.30 14 (dd, 1H, J= 1.4, 11.3Hz), 1.8S (s, 2H), 1.39 (s, 6H), 1.37 (s, 6H).
1 S GENERAL PROCEDURE O: 6-Bromo-8-c~propxl-2,2,4,4-tetramethyl 16 chroman (Intermediate 32) 17 A stirred, cooled (-30°C) solution of 6-bromo-8-vinyl-2,2,4,4-18 tetramethyl chroman (Intermediate 31, 0.37g, 1.26mmo1) in diethyl ether was 19 treated with a solution of diazomethane in diethyl ether and catalytic amount of palladium (II)acetate (~30mg). The reaction mixture was allowed to warm 21 to ambient temperature and subjected to flash column chromatography over 22 silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to 23 afford the title compound as a clear, pale yellow oil (0.376g, 97%).
24 1H NMR (300 MHz, CDC13): 8 7.17 (d, 1H, J= 2.3Hz), 6.73 (d, 1H, J=
2S 2.6Hz), 2.19-2.16 (m, 1H), 1.83 (s, 2H), 1.37 (s, 6H), 1.33 (s, 6H), 0.94-0.88 26 (m, 2H), 0.64-0.59 (m, 2H).
27 8-C cly opro~yl-6-trimeth 1y silan 1y eth,~~l-2 2 4 4-tetramethyl chroman 28 (Intermediate 33) 1 Following general procedure D and using 6-bxomo-8-cyclopropyl-2 2,2,4,4-tetramethyl chroman (Intermediate 32, 0.3768, 1.22mmo1), 3 (trimethylsilyl)acetylene (4mL, 2$mmol), triethyl amine (3mL), anhydrous 4 tetrahydrofuran (SmL), copper(I)iodide (0.0258, 0.13mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.11mmo1), the title 6 compound was obtained as an oil (0.1738, 43%).
7 1H NMR (300 MHz, CDC13): 8 7.36 (d, 1H, J= 2.2Hz), 6.90 (d, 1H, J=
8 l.9Hz), 2.31-2.22 (m, 1H), 1.96 (s, 2H), 1.49 (s, 6H), I.46 (s, 6H), 1.05-0.88 9 (m, 2H), 0.78-0.72 (m, 2H), 0.37 (s, 9H).
8-Cxclopro~yl-6-eth~nyl-2 2 4~4-tetrameth~l chroman (Intermediate 34) 11 Following general procedure E and using 8-cyclopropyl-6-12 trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 33, 0.178, 13 0.68mmol), methanol and potassium carbonate (0.28, 1.47mmol) the title 14 compound was obtained as an oil (0.0648, 47%).
1H NMR (300 MHz, CDCl3): ~ 7.38 (d, 1H, J= l.9Hz), 6.92 (d, 1H, J=
16 l.9Hz), 3.08 (s, 1H), 2.32-2.23 (m, 1H), 1.96 (s, 2H), 1.50 (s, 6H), 1.46 (s, 17 6H), 1.05-0.99 (m, 2H), 0.77-0.72 (m, 2H).
18 4~8-CXcloprop~-2~2 4 4 tetrameth~hroman-6-yl-eth~~ll-benzoic acid 19 ethyl ester (Compound 33, General Formula 8) Following general procedure F and using 8-cyclopropyl-6-ethynyl-21 2,2,4,4-tetramethylchroman (Intermediate 34, O.lg, 0.38mmol), ethyl-4-iodo-22 benzoate (Reagent A, O.lg, 0.34mmol), triethyl amine (SmL), 23 tetrahydrofuran(lOmL), copper(I)iodide(0.025g, 0.13mmo1) and 24 dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.1 lmmol) followed by flash column chromatography over silica gel (230-400 mesh) using S-10 26 ethyl acetate in hexane as the eluent, the title compound was obtained (0.1358, 27 89%).
28 1H NMR (300 MHz, CDCl3): ~ 8.00 (d, 2H, J= 8.2Hz), 7.55 (d, 2H, J=
29 8.2Hz), 7.30 (d, 1H, J= l.BHz), 6.84 (d, IH, J= 2.OHz), 4.38 (q, 2H, J=
1 6.9Hz), 2.22-2.12 (m, 1H), 1.85 (s, 2H), 1.40 (t, 3H, J= 6.9Hz), 1.38 (s, 6H), 2 1.36 (s, 6H), 0.92-0.88 (m, 2H), 0.67-0.62 (m, 2H).
3 4 ~~clopropyl-2 2 4 4-tetramethyl-chroman-6-yl-ethynyll-benzoic acid 4 (Compound 34, General Formula 8) S Following general procedure L and using 4-(8-cyclopropyl-2,2,4,4-6 tetramethyl-chroman-6-yl-ethynyl)-benzoic acid ethyl ester (Compound 33, 7 0.13Sg, 0.34mmol), SmL of methanol and IM sodium hydroxide solution 8 (2mL) followed by preparative reverse phase HPLC using 10% water in 9 acetonitrile as the mobile phase, the title compound was obtained as a solid IO (0.093g, 73%).
11 1H NMR (300 MHz, CDC13): 8 1 I.26 (br s, 1H), 8.08 (d, 2H, J= 8.2Hz), 7.59 12 (d, 2H, J = 8.2Hz), 7.31 (d, 1 H, J = 1.BHz), 6.8 S (d, 1 H, J = 2.1 Hz), 2.22-2.13 13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.95-0.87 (m, 2H), 0.68-0.63 14 (m, 2H).
1 S f 4-(8-Cyclopropyl-s2 4 4-tetramethyl-chroman-6-~yn~2phen~] acetic 16 acid methyl ester (Compound 35, General Formula 8) 17 Following general procedure F and using 8-cyclopropyl-6-ethynyl-18 2,2,4,4-tetramethylchroman (Intermediate 34, 0.096g, 0.38mmo1), methyl-4-19 iodo phenyl acetate (Reagent B, 0.094g, 0.34mmo1), triethyl amine (3mL), 20 tetrahydrofuran (3mL), copper(I)iodide (0.025g; 0.13mmo1) and 21 dichlorobis(triphenylphosphine)palladium(II) (0.07Sg, 0.11mmol) the title 22 compound was obtained (0.137g, 90%). 1H NMR (300 MHz, CDCl3): b 7.47 23 (d, 2H, J= 7.9Hz), 7.29 (d, 1H, J= l.BHz), 7.24 (d, 2H, J= 7.9 Hz), 6.82 (d, 24 1H, J= 2.lHz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.I3 (m, 1H), I.BS (s, 2H), 2S 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63 (m, 2H).
26 [4-(8-C.yclopropyl-2 2 4 4-tetrameth~-chroman-6-yl-ethynyl~phen~] acetic 27 acid (Compound 36, General Formula 8) 28 Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-29 tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid methyl ester I (Compound 35, 0.137g, 0.30mmo1), SmL of methanol and 1M sodium 2 hydroxide solution (2mL) followed by preparative reverse phase HPLC using 3 10% water in acetonitrile as the mobile phase, the title compound was 4 obtained as a solid (0.11g, 80%).
1H NMR (300 MHz, CDCl3): 8 I 1.56 (br s, 1H), 7.47 (d, 2H, J= 8.9Hz), 7.28 6 (d, 1H, J= l.9Hz), 7.23 (d, 2H, J= 8.SHz), 6.82 (d, 1H, J= l.9Hz), 3.62 (s, 7 2H), 2.21-2.12 (m, 1H), 1.83 (s, 2H), 1.36 (s, 6H), 1.34 (s, 6H), 0.93-0.82 (m, 8 2H), 0.72-0.62 (m, 2H).
9 f4-(8-Cyclopropyl-2 2 4 4-tetramethyl-chroman-6-~-eth~nyl)-2-fluorophenyll acetic acid ether ester (Compound 37, General Formula 8) 1 I Following general procedure F and using 8-cyclopropyl-6-ethynyl-12 2,2,4,4-tetramethylchroman (Intermediate 34, 0.096g, 0.38mmol), ethyl-2-13 fluoro-4-iodo phenyl acetate (Reagent C, 0.104g, 0.34mmo1), triethyl amine 14 (3mL), tetrahydrofuran (3mL), copper(I)iodide (0.020g, O.lmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.085mmo1) the title 16 compound was obtained (0.14g, 8S%).
17 'H NMR (300 MHz, CDC13): 8 7.31 (d, 1.H, J= l.9Hz), 7.29-7.21 (m, 3H), 18 6.85 (d, 1H, J= l.9Hz), 4.20 (q, 2H, J= 7.lHz), 3.68 (s, 2H), 2.24-2.14 (m, 19 1H), 1.87 (s, 2H), 1.40 (s, 6H), 1.38 (s, 6H), 1.28 (t, 3H, J= 7.lHz), 0.96-0.85 (m, 2H), 0.70-0.64 (m, 2H).
21 f4-(8-C~propyl-2 2 4 4-tetramethXl-chroman-6-yl-eth~n~)-2-fluorophenyll 22 acetic acid (Compound 38, General Formula 8) 23 Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-24 tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl] acetic acid ethyl ester (Compound 37, 0.14g, 0.323mmo1), SmL of methanol and 1M sodium 26 hydroxide solution (2mL) followed by reverse phase HPLC using 10% water 27 in acetonitrile as the mobile phase, the title compound was obtained as a solid 28 (0.110g, 80%).
1 1H NMR (300 MHz, CDC13): ~ 7.28 (d, 1H, J= 2.lHz), 7.27-7.17 (m, 3H), 2 6.82 (d, 1H, J= l.BHz), 3.70 (s, 2H), 2.21-2.11 (m, 1H), 1.84 (s, 2H), 1.37 (s, 3 6H), 1.35 (s, 6H), 0.94-0.87 (m, 2H), 0.67-0.62 (m, ZH).
4 GENERAL PROCEDURE P: 6-Bromo-4 4-dimeth~methylene chroman (Intermediate 3S) 6 A stirred, cooled (ice bath) solution of 6-bromo-4,4-dimethyl-chroman-7 2-one available in accordance with U.S. Patent No. 5,399,561 incorporated 8 herein by reference ( 1 g, 3.92mmo1) in SmL of anhydrous tetrahydrofuran was 9 treated with a 0.5 M solution of p.-chloro-~.-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminum (Tebbe reagent) in toluene 11 (8.23mL, 4.12mmo1). After 10 minutes, the reaction mixture was poured into 12 ice-water mixture containing SOmL of 1M sodium hydroxide and extracted I 3 with hexane. The hexane extract was washed with brine (x 1 ), filtered over a 14 bed of celite and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the 16 eluent to afford the title compound (0.74g, 74%) as a clear oil.
17 1H NMR (300 MHz, CDC13): b 7.34 (d, 1H, J= 2.3Hz), 7.23 (dd, 1H, J=
18 2.3,8.SHz), 6.77 (d, 1H, J= 8.OHz), 4.61 (d, 1H, J= 0.73Hz), 4.17 (d, 1H, J=
19 0.73Hz), 2.33 (s, 2H), 1.27 (s, 6H).
GENERAL PROCEDURE Q: 6-Bromo-3 4-dihydro-4,4-dimeth ls~ piro'[2H 1-21 benzop r~,1'-c~propanel (Intermediate 36) 22 A solution of diethyl zinc in hexane (1M, 7.lmL) was treated with 23 diiodomethane (1.89g, 7.lmmol). After 5 minutes, a solution of 6-bromo-4,4-24 dimethyl-2-methylene chroman (Intermediate 35, 0.448, 1.77mmol) in 3mL
of hexane was added and the solution was refluxed for 1h. The reaction 26 mixture was then cooled to ambient temperature, diluted with hexane, washed 27 with brine (x1), dried over anhydrous sodium sulfate, filtered and evaporated 28 in vacuo to a residue which was subjected to flash column chromatography 1 over silica gel (230-400 mesh) using hexane as the eluent to obtain the title 2 compound (0.44g, 93%).
3 1H NMR (300 MHz, CDC13): 8 7.47 (d, 1H, J= 2.3Hz), 7.23 (dd, 1H, J=
4 2.3, 8.SHz), 6.70 (d, 1H, J= 8.OHz), 1.96 (s, 2H), 1.47 (s, 6H), 1.09-1.05 (m, 2H), 0.74-0.70 (m, 2H).
6 3 4-Dih d~ 4-dimethyl-6-~trimethylsilanyl eth~~piro[2H 1-benzopyran-7 2,1'-c~propanel (Intermediate 37) 8 Following general procedure D and using 6-bromo-3,4-dihydro-4,4-9 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 36, 0.44g, I.65mmo1), triethyl amine (4mL), anhydrous tetrahydrofuran (SmL), 11 copper(I)iodide (0.95g, O.Smmol), trimethylsilyl acetylene (1.62g, l6.Smmol) 12 and dichlorobis(triphenylphosphine)palladium(II) (0.4g, 0.56mmol), the title 13 compound was obtained as a brown oil (0.4g, 86%).
14 1H NMR (300 MHz, CDCl3): 8 7.44 (d, 1 H, J = 2. I Hz), 7.18 (dd, 1 H, J =
2.1,8.SHz), 6.65 (d, 1H, J= B.SHz), 1.87 (s, 2H), 1.37 (s, 6H), 1.01-0.97 (m, 16 2H), 0.65-0.61 (m, 2H), 0.26 (s, 9H).
17 6-Eth m~,4-dih~dro-4,4-dimeth~piro[2H 1-benzopyran-2,1'-18 cvclopropanel (Intermediate 38) 19 Following general procedure E and using 3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H 1-benzopyran-2,1'-cyclopropane]
21 (Intermediate 37, 0.4g, 1.42mmo1), potassium carbonate (0.98g, 7.lmmol) 22 and methanol, the title compound was obtained as a yellow oil (0.3g, 100%).
23 'H NMR (300 MHz, CDCl3): 8 7.44 (d, 1H, J= 2.lHz), 7.18 (dd, 1H, J= 2.1, 24 8.SHz), 6.65 (d, 1H, J= 8.SHz), 2.97 (s, 1H), 1.86 (s, 2H), 1.37 (s, 6H), 1.00-0.95 (m, 2H), 0.64-0.59 (m, 2H).
26 Benzoic acid, 4-[(3~4-dih~dro-4 4-dimethy-ls~iro[2H 1-benzopyran-2,1'-27 c.~clopro~pane~ 6=yl~eth~,~]-ethyl ester (Compound 39, General Formula 1) 28 Following general procedure F and using 6-ethynyl-3,4-dihydro-4,4-29 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 38, 0.06g, 1 0.28mmo1), ethyl-4-iodo-benzoate (Reagent A, 0.0868, 0.31mmo1), triethyl 2 amine (4mL), tetrahydrofuran(4mL), copper(I)iodide(0.032g, 0.17mmo1) and 3 dichlorobis(triphenylphosphine)palladium(II) (0.1188, 0.17mmol) followed by 4 flash column chromatography over silica gel (230-400 mesh) using 5-10 ethyl acetate in hexane as the eluent, the title compound was obtained (0.078, 6 70%).
7 1H NMR (300 MHz, CDC13): 8 8.01 (d, 2H, J= 8.2Hz), 7.56 (d, 2H, J=
8 B.SHz), 7.49 (d, 1H, J= 2.lHz), 7.24 (dd, 1H, J= 2.1,8.SHz), 6.70 (d, 1H, J=
9 8.SHz), 4.38 (q, 2H, J= 7.lHz), 1.89 (s, 2H), 1.40 (s, 6H), 1.40 (t, 3H, J=
7.OHz), 1.02-0.98 (m, 2H), 0.67-0.62 (m, 2H).
11 Benzoic acid~4-~(3 4-dih~dro-4 4-dimethXlsniro[2H 1-benzopyran-2,1'-12 cyclopropane]-6-,1~)eth~~]~ (Compound 40, General Formula 1) 13 Following general procedure L and using benzoic acid, 4-[(3,4-dihydro-4,4-14 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-ethyl ester (Compound 39, 0.078, 0.196mmol), SmL of ethanol and 1M sodium 16 hydroxide solution (2mL) followed by preparative reverse phase HPLC using 17 10% water in acetonitrile as the mobile phase, the title compound was 18 obtained as a solid (0.0348, 52%).
19 'H NMR (300 MHz, CD3COCD3): 8 8.05 (d, 2H, J= 8.2Hz), 7.64 (d, 2H, J=
8.2Hz), 7.60 (d, 1H, J= 2.lHz), 7.28 (dd, 1H, J= 2.1, 8.SHz), 6.73 (d, 1H, J=
21 8.SHz), 1.95 (s, ZH), 1.43 (s, 6H), 0.96-0.92 (m, 2H), 0.74-0.71 (m, 2H).
22 Benzeneacetic acid, 4-x(3,4-dih,~,4-dimethvlspiro[2H 1-benzopyran-2,1'-23 cyclopropane]-6;Ylleth~rn 1y 1-meth.~I ester (Compound 41, General Formula 24 1) Following general procedure F and using 6-ethynyl-3,4-dihydro-4,4-26 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 3$, , 27 0.0608, 0.28mmo1), methyl-4-iodo phenyl acetate (Reagent B, 0.0788, 28 0.28mmol), triethyl amine (4mL), tetrahydrofuran (4mL), copper(I)iodide 29 (0.0328, 0.17mmo1) and dichlorobis(triphenylphosphine)palladium(II) 1 (0.118g, 0.17mmo1) followed by flash column chromatography over silica gel 2 (230-400 mesh) using 5 % ethyl acetate in hexane as the eluent, the title 3 compound was obtained (0.084g, 84%).
4 1H NMR (300 MHz, CDCl3): 8 7.48-7.45 (m, 3H), 7.26-7.20 (m, 3H), 6.67 (d, 1H, J= B.SHz), 3.70 (s, 3H), 3.63 (s, 2H), 1.89 (s, 2H), 1.40 (s, 3H), 1.40 (s, 6 3H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).
7 Benzeneacetic acid~4-[C3 4-dihydro-4~4-dimethylspiro[2H 1-benzopyran-2,1'-8 c~clopropane]-6-~)ethyn~l]- (Compound 42, Formula 1) 9 A solution of benzeneacetic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-methyl 11 ester (Compound 41, 0.084g, 0.24mmo1) in SmL of methanol was treated 12 with 1M sodium hydroxide solution (2mL) and heated at 55°C for 2h.
The 13 volatiles were distilled off in vacuo and the residue was acidified with 10%
14 hydrochloric acid and extracted with ethyl acetate (x2). The combined organic phase was washed with brine (x1), dried over anhydrous sodium sulfate, 16 filtered and evaporated in vacuo to a residue which was purified by preparative 17 reverse phase HPLC using 10% water in acetonitrile as the mobile phase to 18 afford the title compound (0.080g, 100%).
19 1H NMR (300 MHz, CD3COCD3): b 7.49-7.46 (m, 3H), 7.25 (d, 2H, J=
8.2Hz), 7.22 (dd, 1H J= 2.1,8.SHz), 6.68 (d, 1H, J= 8.SHz), 3.66 (s, 2H), 1.88 21 (s, 2H), 1.44 (s, 6H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).
22 2-Fluoro-benzoic acid, 4-[(3 4-dih d~~4-dimeth~pirof2H 1-benzopyran-23 2,1'-c,~clopr~ane]-6-, l~lethyny~-methyl ester (Compound 43, General 24 Formula 1) Following general procedure F and 6-ethynyl-3,4-dihydro-4,4 26 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 38, 27 O.OSOg, 0.23mmo1), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.069g, 28 0.24mmol), triethyl amine (SmL), tetrahydrofuran(SmL), 29 copper(I)iodide(0.013g, 0.07mmo1) and 1 dichlorobis(triphenylphosphine)palladium(II) (0.0498, 0.07mmol) followed by 2 flash column chromatography over silica gel (230-400 mesh) using S-10 3 ethyl acetate in hexane as the eluent, the title compound was obtained (0.0808, 4 100%).
S 1H NMR (300 MHz, CDC13): 8 7.90 (t, 1H, J= 7.9Hz), 7.63 (d, 1H, J=
6 l.BHz), 7.32 (dd, 1H, J=1.5, 8.2Hz), 7.26 (dd, 1H, J= 1.5,11.4Hz), 7.24 (dd, 7 1H, J= 2.1, B.SHz), 6.7I (d, 1H, J= B.SHz), 1.97 (s, ZH), 1.44 (s, 6H), 0.98-8 0.94 (m, 2H), 0.76-0.71 (m, 2H).
9 2-Fluoro-benzoic acid 4-j(3 4-dih~dro-4 4-dimethylspiro[2H 1-benzopyran-2,1'-c~lopropane]-6-yl ethynyll' (Compound 44, General~Formula 1) 11 Following general procedure L and using 2-fluoro-benzoic acid, 4-12 [(3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-13 yI)ethynyl]-methyl ester (Compound 43, 0.088, 0.23mmol), SmL of methanol 14 and 2M sodium hydroxide solution (1mL) followed by flash column 1 S chromatography over silica gel (230-400 mesh) using ethyl acetate as the 16 eluent, the title compound was obtained (0.0208, 2S%).
17 1H NMR (300 MHz, CD3COCD3): 8 7.99 (t, 1H, J= 7.9Hz), 7.63 (d, 1H, J=
18 2.lHz), 7.44 (dd, 1H, J= 1..5, 7.9Hz), 7.37 (dd, 1H, J= 1.5, 11.4Hz), 7.31 (dd, 19 1H, J= 2.1, 8.SHz), 6.75 (d, 1H, J= 8.2Hz), 1.97 (s, 2H), 1.44 (s, 6H), 0.98-0.94 (m, 2H), 0.76-0.71 (m, 2H).
21 GENERAL PROCEDURE R: 2,2 4,4-Tetramethyl-chroman-6-carboxylic acid 22 (Intermediate 39) 23 A stirred, cooled (-78°C) solution of 6-bromo-2,2,4,4-tetramethyl 24 chroman ( 1.28, 4.47mmo1) in 1 SmL of anhydrous tetrahydrofuran was treated 2S with a 1.7M solution of tent-butyl lithium solution in pentane ( S.27mL, 26 8.9mmo1). After 10 minutes at -78°C, carbon dioxide (generated from dry ice) 27 was bubbled into the reaction mixture. The reaction mixture was allowed to 28 warm to ambient temperature. The reaction mixture was diluted with ethyl 29 acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and 1 evaporated in vacuo to a residue which was subjected to flash column 2 chromatography over silica gel (230-400 mesh) using ethyl acetate as the 3 eluent to afford the title compound as a white solid (1.1g, 92%).
4 'H NMR (300 MHz, CDCl3): 8 12.17 (br s, 1H), 8.09 (d, 1H, J= 2.lHz), 7.85 (dd, 1H, J= 2.1, 8.5Hz), 6.83 (d, 1H, J= 8.2Hz), 1.87 (s, 2H), 1.39 (s, 6H), 6 1.37 (s, 6H).
7 2 2 4 4-Tetramethyl-chxoman-6-carboxylic acid 4-(te~t-8 butoxycarbonylmethyl_lphen l~ (Compound 45, General Formula 8) 9 A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43mmo1) in thionyl chloride (lOmL) was refluxed for 2h. The thionyl 11 chloride was evaporated under reduced pressure and the residue was dissolved 12 in 5mL of dichloromethane and treated with triethyl amine (5mL) followed by 13 test-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088g, 0.427mmol). After I4 0.5h, the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to 16 afford the title compound (0.1g, 55%).
17 'H NMR (300 MHz, CDC13): b 8.15 (d, 1H, J= 2.lHz), 7.93 (dd, 1H, J= 2.1, I8 8.5Hz), 7.33 (d, 2H, J= 8.8Hz), 7.16 (d, 2H, J= 8.8Hz), 6.88 (d, 1H, J=
19 8.5Hz), 3.54 (s, 2H), 1.89 (s, 2H), 1.45 (s, 9H), 1.41 (s, 6H), 1.40 (s, 6H).
2,2,4,4-Tetramethyl-chroman-6-carbox~c acid 4-(carbox~methyl)phenyl 21 ester (Compound 46, General Formula 8) 22 A solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(tert-23 butoxycarbonylmethyl)phenyl ester (Compound 45, 0.1 g, 0.23mmo1) was 24 treated with 5mL of trifluoroacetic acid and stirred at ambient temperature for 1 h. The trifluoroacetic acid was distilled off under reduced pressure and the 26 residue was subjected to preparative reverse phase HPLC using 10% water in 27 acetonitrile as the mobile phase to afford the title compound as a white solid 28 (0.045g, 50%).
1 1H NMR (300 MHz, CDC13): 8 8.13 (d, 1H, J= 2.lHz), 7.92 (dd, 1H, J= 2.3, 2 8.SHz), 7.35 (d, 2H, J= 8.8Hz), 7.17 (d, 2H, J= B.SHz), 6.87 (d, IH, J=
3 8.SHz), 3.68 (s, 2H), 1.89 (s, 2H), 1.41 (s, 6H), 1.39 (s, 6H).
4 6-Bromo-8-carbaldehyde-3 4-dih~dro-4 4-dimethvls~iro[2H 1-benzop ry an-y 2,1'-cyclopropanel (Intermediate 40) 6 Following general procedure M and using 6-bromo-3,4-dihydro-4,4-7 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane](Intermediate 36, 2.3g, 8 8.65mmo1), anhydrous dichloromethane (25mL), 1M solution (8.65mL, 9 8.65mmo1) of titanium tetrachloride in dichloromethane and a,a-dichloro methyl ether (1.09g, 9.52mmol) followed by flash column chromatography 11 using 10% ethyl acetate in hexane as the eluent, the title compound was 12 obtained as a yellow solid (2.06g, 81 %).
13 IH NMR (300 MHz, CDC13): 8 10.20 (s, 1H), 7.69 (d, 1H, J= 2.6Hz), 7.58 (d, 14 1 H, J= 2.6Hz), I .92 (s, 2H), 1.40 (s, 6H), 1.09-1.04 (m, 2H), 0.73-0.69 (m, 2H).
16 6-Bromo-3 4-dihydro-4,4-dimethyl-8-vinXlspiro[2H 1-benzopyran-2,1'-17 cvclopropanel (Intermediate 41) 18 Following general procedure N and using A solution of methylidene 19 triphenyl phosphorane [generated from methyl triphenylphosphonium 'bromide (7g, 20mmo1) and 1.6M solution of h-butyl lithium in hexanes (11.8mL, 21 l9mmol) ], 6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H 1-22 benzopyran-2,1'-cyclopropane](Intermediate 40, 2.06g, 7mmol) followed by 23 flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl 24 acetate in hexane as the eluent, the title compound was obtained as a clear oil (1.36g, 66%).
26 'H NMR (300 MHz, CDC13): 8 7.36 (d, 1H, J= 2.3Hz), 7.28 (d, 1H, J=
27 2.6Hz), 6. 80 (dd, 1 H, J = 11.1, 17.9Hz), 5.63 (dd, 1 H, J = 1.2, 17.9Hz), 5.19 28 (dd, 1H, J=1.2, 11.1Hz), 1.84 (s, 2H), 1.35 (s, 6H), 0.97 (t, 2H, J=
6.3Hz), 29 0.62 (d, 1H, J= 5.3Hz), 0.60 (d, 1H, J= 6.2Hz).
1 6-Bromo-8-c,~lopropyl-3~4-dihydro-4 4-dimeth ~~lspiro[2H 1-benzot?Vran-2 2.1'-c~propanel (Intermediate 42) 3 Following general procedure O and using A 6-bromo-3,4-dihydro-4,4 4 dimethyl-8-vinylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 41, 1.36g, 4.6mmol), a solution of diazomethane in diethyl ether and 6 palladium (II)acetate (~30mg) followed by flash column chromatography over 7 silica gel (230-400 mesh) using hexane as the eluent, the title compound was 8 obtained as a clear oil (1.388, 100%).
9 1H NMR (300 MHz, CDC13): 8 7.19 (d, 1H, J= 2.2Hz), 6.71 (d, 1H, J=
2.2Hz), 1.99-1.92 (m, 1H), 1.87 (s, 2H), 1.35 (s, 6H), 1.00-0.95 (m, 2H), 0.90-11 0.82 (m, 2H), 0.65-0.54 (m, 4H).
12 8-C,~prop,~-3,4-dihydro-4 4-dimethyl-6-(trimethXlsilanylleth~nylspiro[2H
13 1-benzop~ran-2~1'-c~lopropanel (Intermediate 43) 14 Following general procedure D and 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
16 (Intermediate 42, 0.74g, 2.4mmol), (trimethylsilyl)acetylene (4mL, 28mmo1), 17 triethyl amine (8mL), anhydrous tetrahydrofuran , copper(I)iodide (O.OSOg, 18 0.26mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.15g, 19 0.22mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound 21 was obtained as an oil (0.62g, 80%).
22 'H NMR (300 MHz, CDCl3): b 7.28 (d, 1H, J= l.9Hz), 6.77 (d, 1H, J=
23 l.9Hz), 2.03-1.94 (m, 1H), 1.91 (s, 2H), 1.40 (s, 6H), 1.05-0.98 (m, 2H), 0.95-24 0.83 (m, 2H), 0.69-0.59 (m, 4H), 0.27 (s, 9H).
8-C~lopropXl-6-ethyn~ 4-dihydro-4.4-dimethylspiro[2H 1-benzop~ran-26 2,1'-c~propanel (Intermediate 44) 27 Following general procedure E, and 8-cyclopropyl-3,4-dihydro-4,4-28 dimethyl-6-(trimethylsilanyl)ethynylspiro[2H 1-benzopyran-2,1'-29 cyclopropane] (Intermediate 43, 0.628, 1.9mmol), methanol and potassium 1 carbonate (0.58, 3.6mmol) followed by flash column chromatography over 2 silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the 3 title compound was obtained as an oil (0.58, 100%).
4 'H NMR (300 MHz, CDCl3): 8 7.30 (d, 1H, J= l.BHz), 6.80 (d, 1H, J=
2.OHz), 2.97 (s, 1H), 2.04-1.95 (m, 1H), 1.9I (s, 2H), 1.39 (s, 6H), 1.20-0.90 6 (m, 2H), 0.90-0.84 (m, 2H), 0.75-0.58 (m, 4H).
7 Benzeneacetic acid 4-~(8-cyclopropyl-3 4-dih~dro-4 4-dimethy-piro[2H 1-8 benzo~~-2 1'-c~clopropane]-6-~leth~~]-methfester (Compound 47, 9 General Formula I) Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-11 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
12 (Intermediate 44, 0.118, 0.43mmo1), methyl-4-iodo phenyl acetate (Reagent 13 B, 0.1148, 0.41mmo1), triethyl amine (5mL), tetrahydrofuran (3mL), I4 copper(I)iodide (0.0258, 0.13mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.1 lmmol), the title 16 compound was obtained as a clear oil (0.0968, 56%).
17 'H NMR (300 MHz, CDC13): 8 7.46 (d, 2H, J= 8.OHz), 7.31 (d, 1H, J=
18 l.9Hz), 7.24 (d, 2H, J= ~.2Hz), 6.81 (d, 1H, J= I.9Hz), 3.69 (s, 3H), 3.62 (s, 19 2H), 2.04-1.95 (m, 1H), 1.90 (s, 2H), 1.39 (s, 6H), 1.03-0.99 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).
21 Benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethy-piro'[2H 1-22 benzopyran-2,1'-cyclopropane]-6-ylleth~~]- (Compound 48, General 23 Formula 1) 24 Following general procedure L and using benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-26 cyclopropane]-6-yl)ethynyl]-methyl ester (Compound 47, 0.968, 0.24mmo1), 27 5mL of methanol and 1M sodium hydroxide solution (2mL) followed by flash 28 column chromatography over silica gel (230-400 mesh) using 15% methanol 1 in dichloromethane as the eluent, the title compound was obtained as a solid 2 (0.0848, 91%).
3 iH NMR (300 MHz, CDC13): 8 10.27 (br s, 1H), 7.46 (d, 2H, J= 8.2Hz), 7.30 4 (d, 1H, J= l.BHz), 7.23 (d, 2H, J= 8.2Hz), 6.80 (d, 1H, J= l.SHz), 3.63 (s, 2H), 2.07-1.94 (m, 1H), 1.89 (s, 2H), 1.39 (s, 6H), 1.03-0.98 (m, 2H), 0.89-6 0.82 (m, 2H), 0.73-0.59 (m, 4H).
7 4-[(8-C~cloprop~-3 4-dihydro-4 4-dimethylspiro[2H 1-benzopyran-2,1'-8 c c~~ane]-6-~)eth~ l~l-2-fluoro-benzeneacetic acid meth 1y ester 9 (Compound 49, General Formula 1) Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-11 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
12 (Intermediate 44, 0.1258, O.Smmol), methyl-2-fluoro-4-iodo phenyl acetate 13 (Reagent H, 0.148, O.Smmol), triethyl amine (3mL), tetrahydrofuran (3mL), 14 copper(I)iodide (0.0208, O.lmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.0608, 0.085mmo1) followed 16 by preparative normal phase HPLC using 10% ethyl acetate in hexane as the 17 mobile phase, the title compound was obtained (0.0968, 46%).
18 1H NMR (300 MHz, CDC13): 8 7.30 (d, 1H, J= 2.lHz), 7.26-7.18 (m, 3H), 19 6.80 (d, 1H, J= l.BHz), 3.71 (s, 3H), 3.67 (s, 2H), 2.04-1.94 (m, 1H), 1.90 (s, 2H), 1.40 (s, 6H), 1.18-0.99 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).
21 4-[(8-Cyclopropyl-3 4-dihydro-4,4-dimethylspiro[2H 1-benzop~ran-2,1'-22 cyclopropane]-6-, l~leth,~yl]-2-fluoro-benzeneacetic acid (Compound 50, 23 General Formula 1) 24 Following general procedure L and using 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-26 yl)ethynyl]-2-fluoro-benzeneacetic acid methyl ester (Compound 49, 0.0968, 27 0.23mmol), SmL of methanol and 1M sodium hydroxide solution (2mL) 28 followed by flash column chromatography over silica gel (230-400 mesh) 1 ~ using 15% methanol in dichloromethane as the eluent, the title compound was 2 obtained as a solid (0.093g, 100%).
3 1H NMR (300 MHz, CDC13): b 9.50 (br s, 1H), 7.27 (d, 1H, J= 2.lHz), 7.24-4 7.15 (m, 3H), 6.77 (d, 1H, J= l.SHz), 3.67 (s, 2H), 2.01-1.91 (m, 1H), 1.87 (s, 2H), 1.36 (s, 6H), 1.01-0.96 (m, 2H), 0.87-0.80 (m, 2H), 0.65-0.56 (m, 4H).
6 Benzoic acid 4-[(8-c~loprop~l-3~4-dihydro-4 4-dimethy-piro[2H 1-7 benzoR ry an-2 1'-c cy lonropane]-6-~lethynyll-ethyl ester (Compound 51, 8 General Formula 1) 9 Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
I I (Intermediate 44, O.OSg, 0.2mmo1), ethyl-4-iodo-benzoate (Reagent A, 12 O.OSSg, 0.2mmo1), triethyl amine (3mL), tetrahydrofuran(3mL), 13 copper(I)iodide(0.020g, 0.1 mmol) and 14 dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.085mmol), the title compound was obtained (0.06g, 75%).
16 'H NMR (300 MHz, CDC13): 8 8.00 (d, 2H, J= 8.2Hz), 7.55 (d, 2H, J=
17 8.2Hz), 7.33 (d, 1H, J= l.BHz), 6.83 (d, 1H, J= 2.lHz), 4.38 (q, 2H, J=
18 7.1 Hz), 2.04-1.95 (m, 1 H), 1.91 (s, 2H), 1.40 (s, 6H), 1.40 (t, 3 H, J =
7. OHz), 19 1.05-0.95 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.61 (m, 4H).
Benzoic acid, 4-[(8-c cly opropyl-3,4-dih dy ro-4,4-dimethylspiro[2H 1-21 benzop roan-2,1'-c~lopropane]-6-~leth~n~]- (Compound 52, General 22 Formula 1) 23 Following general procedure L and using benzoic acid, 4-[(8-24 cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-ethyl ester (Compound 51, 0.06g, O.lSmmol), 26 SmL of methanol and 1M sodium hydroxide solution (2mL) followed by 27 preparative reverse phase HPLC using 10% water in acetonitrile as the mobile 28 phase, the title compound was obtained as a solid (0.040g, 72%).
1 'H NMR (300 MHz, CDC13): ~ 8.08 (d, 2H, J= 8.8Hz), 7.60 (d, 2H, J=
2 8.8Hz), 7.34 (d, 1H, J= l.9Hz), 6.84 (d, 1H, J= l.9Hz), 2.05-1.96 (m, 1H), 3 1.92 (s, 2H), 1.41 (s, 6H), 1.05-0.95 (m, 2H), 0.92-0.83 (m, 2H), 0.75-0.60 (m, 4 4H).
4-[(8-C~loproi~yl-3 4-dihydro-4~4-dimethylsuiro[2H 1-benzop~ran-2,1'-6 cyclopropane]-6-,~~ethyny_1]-2-fluoro-benzoic acid meth 1y ester (Compound 7 53, General Formula 1) 8 Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-9 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
(Intermediate 44, 0.038, 0.1 lmmol), methyl-2-fluoro-4-iodo-benzoate 11 (Reagent G, 0.025g, 0.09mmol), triethyl amine (3mL), tetrahydrofuran(3mL), 12 copper(I)iodide(0.020g, O.lmmol) and 13 dichlorobis(triphenylphosphine)palladium(II) (0.068, 0.085mmo1) followed by 14 preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a white solid (0.019g, 40%).
16 1H NMR (300 MHz, CDC13): 8 7.97 (t, 1H, J= 7.8Hz), 7.34 (d, 1H, J=
17 1.9Hz), 7.32-7.25 (m, 2H), 6.83 (d, 1H, J= l.9Hz), 3.95 (s, 3H), 2.06-1.96 (m, 18 1H), 1.93 (s, 2H), 1.42 (s, 6H), 1.06-1.02 (m, 2H), 0.91-0.86 (m, 2H), 0.71-19 0.61 (m, 4H).
4-[(8-C cloprop~,4-dihydro-4,4-dimeth ls~[2H 1-benzop r~,l'-21 cyclopropane]-6-~leth~nyl]-2-fluoro-benzoic acid (Compound 54, General 22 Formula 1) 23 Following general procedure L and using 4-[(8-cyclopropyl-3,4-24 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoic acid methyl ester (Compound 53, 0.019g, 26 0.047mmo1), SmL of methanol and 1M sodium hydroxide solution (2mL) 27 followed by preparative reverse phase HPLC using 10% water in acetonitrile 28 as the mobile phase, the title compound was obtained as a solid (0.01 g, 56%).
1 'H NMR (300 MHz, CDC13): 8 7.99 (t, IH, J= 8.OHz), 7.36 -7.28 (m, 3H), 2 6.83 (d, 1H, J= l.9Hz), 2.18-1.95 (m, 1H), 1.92 (s, 2H), 1.41 (s, 6H), 1.06-3 1.01 (m, 2H), 0.96-0.83 (m, 2H), 0.76-0.60 (m, 4H).
4 8-Acetyl-6-bromo-2 2 4 4-tetramethyl chroman (Intermediate 45) A stirred, cooled (ice bath) suspension of aluminum chloride (0.998, 6 7.46mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl 7 chloride (0.58g, 7.46mmo1). After 5 minutes, a solution of 6-bromo-2,2,4,4-8 tetramethyl chroman ( I g, 3.73mmol)in dichloromethane was added. The 9 reaction was allowed to warm to ambient temperature and stirred for 2h. The reaction mixture was then poured into ice containing 10% hydrochloric acid 11 and extracted with diethyl ether (x2). The combined organic phase was 12 washed with saturated aqueous sodium bicarbonate solution, dried over 13 anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which 14 was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a 16 pale yellow oiI (0.95g, 83%). It was used as such for the next step without any 17 characterization.
18 6-promo-8-eth.~2,2,4 4 tetramethyl chroman (Intermediate 46) 19 A stirred, cooled (ice bath) solution of 8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 45, 0.958, 3.lmmol) in trifluoroacetic 21 acid (lOmL) was treated with triethylsilane (l4mL) and the resulting reaction 22 mixture was allowed to warm to ambient temperature and stirred overnight.
23 The volatiles were distilled off in vacuo and the residue was diluted with water 24 and extracted with hexane (x2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil which 26 was subjected to flash column chromatography over silica gel (230-400 mesh) 27 using hexane as the eluent to afford the title compound as a clear oil, 28 contaminated with a small amount to triethylsilane (O.Slg, 56%).
1 'H NMR (300 MHz, CDC13): 8 7.23 (d, 1H, J= 2.3Hz), 7.08 (d, 1H, J=
2 2.3Hz), 2.58 (q, 2H, J= 7.6Hz), 1.81 (s, 2H), 1.34 (s, 6H), 1.33 (s, 6H), 1.17 3 (t, 3H, J= 7.6Hz).
4 8-Ethyl-6-trimethylsilanXlethynyl-2~2 4 4-tetramethyl chroman (Intermediate S 47) 6 Following general procedure D and using 6-bromo-8-ethyl-2,2,4,4-7 tetramethyl chroman (Intermediate 46, O.Sg, 1.61mmo1), 8 (trimethylsilyl)acetylene (l.S7g, l6.lmmol), triethyl amine (8mL), anhydrous 9 tetrahydrofuran (lOmL), copper(I)iodide (0.02Sg, 0.13mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07Sg, 0.llmmol), followed 11 by flash column chromatography over silica gel (230-400 mesh) using S%
12 ethyl acetate in hexane as the eluent, the title compound was obtained as an oil 13 (0.137g, 27%).
14 ~H NMR (300 MHz, CDC13): 8 7.27 (d, 1H, J= 2.lHz), 7.10 (d, 1H, J=
2.lHz), 2.SS (q, 2H, J= 7.6Hz), 1.81 (s, 2H), 1.33 (s, 6H), 1.32 (s, 6H), 1.15 16 (t, 3H, J= 7.6Hz), 0.24 (s, 9H).
17 8-Ethyl-6-ethyn~,2,4.4-tetramethyl chroman (Intermediate 48) 18 Following general procedure E and using 8-ethyl-6-19 trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 47, 0.137g, 0.44mmol), methanol and potassium carbonate (0.1g, 0.72mmo1) 21 followed by flash column chromatography over silica gel (230-400 mesh) 22 using S% ethyl acetate in hexane as the eluent, the title compound was 23 obtained as an oil (0.066g, 62%).
24 'H NMR (300 MHz, CDC13): 8 7.33 (d, 1H, J= 2.2Hz), 7.15 (d, 1H, J=
2S l.6Hz), 2.99 (s, 1H), 2.59 (q, 2H, J= 7.6Hz), 1.84 (s, 2H), 1.37 (s, 6H), 1.35 26 (s, 6H), 1.19 (t, 3H, J= 7.6Hz).
27 ~4-~8-Ether 2 4 4-tetramethvl-chroman-6-yl-ethynyl) phen~] acetic acid 28 meth,1~ (Compound S5, General Formula 8) 1 Following general procedure F and using 8-ethyl-6-ethynyl-2,2,4,4-2 tetramethylchroman (Intermediate 48, 0.0338, 0.136mmol), methyl-4-iodo 3 phenyl acetate (Reagent B, 0.0348, 0.12mmol), triethyl amine (2mL), 4 tetrahydrofuran (2mL), copper(I)iodide (0.0258, 0.13mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.1 lmmol) the title 6 compound was obtained (0.0358, 73%).
7 1H NMR (300 MHz, CDC13): 8 7.49 (d, 2H, J= 7.9Hz), 7.35 (d, 1H, J=
8 l.BHz), 7.26 (d, 2H, J= 7.9Hz), 7.18 (d, 1H, J= l.9Hz), 3.72 (s, 3H), 3.65 (s, 9 2H), 2.61 (q, 2H, J= 7.SHz), 1.85 (s, 2H), 1.38 (s, 12H), 1.21 (t, 3H, J=
7.SHz).
11 [4-(8-Ethyl-2~2 4 4-tetrameth~-chroman-6-xl-ethyn~) phenyl] acetic acid 12 (Compound 56, General Formula 8) 13 Following general procedure L and using [4-(8-ethyl-2,2,4,4-14 tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid methyl ester (Compound 55, 0.0358, O.lmmol), SmL of methanol and 1M sodium 16 hydroxide solution (1mL) followed by preparative reverse phase HPLC using 17 10% water in acetonitrile as the mobile phase, the title compound was 18 obtained as a solid (0.118, 25%).
19 1H NMR (300 MHz, CDC13): 8 7.48 (d, 2H, J= 8.OHz), 7.33 (d, 1H, J=
l.9Hz), 7.25 (d, 2H, J= B.OHz), 7.15 (d, 1H, J= l.9Hz), 3.65 (s, 2H), 2.59 (q, 21 2H, J= 7.SHz), 1.83 (s, 2H), 1.35 (s, 12H), 1.18 (t, 3H, J= 7.4Hz).
22 Sairo[2H 1-benzop~-2 1'-cyclopropane]-6-carboxylic acid, 8-c~prop~
23 3,4-dihydro-4,4-dimethyl- (Intermediate 49) 24 Following general procedure R and using 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H I-benzopyran-2,1'-cyclopropane]
26 (Intermediate 42, 0.458, 1.48mmol), anhydrous tetrahydrofuran (SmL), 1.7M
27 solution of tent-butyl lithium solution in pentane ( 1.74mL, 2.96mmo1) and 28 carbon dioxide generated from dry ice, followed by flash column 29 chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in 1 hexane as the eluent, the title compound was obtained as a white solid (0.34g, 2 85%).
3 1H NMR (300 MHz, CDCl3): 8 12.43 (br s, 1H), 7.94 (d, 1H, J= 2.lHz), 7.42 4 (d, 1H, J= l.BHz), 2.06-1.96 (m, 1H), 1.92 (s, 2H), 1.42 (s, 6H), 1.12-0.97 (m, 2H), 0.95-0.81 (m, 2H), 0.77-0.60 (m, 4H).
6 Spiro[2H 1-benzopyran-2~1'-cyclopronane~-6-carboxylic acid, 8-cyclopropyl-7 3 4-dihXdro-4~4-dimeth ~~1- 4-(tart-butoxxcarbon 1Y meth~lphenyl ester 8 (Compound 57, General Formula 1) 9 A solution of spiro[2H 1-benzopyran-2,1'-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 0.06g, 11 0.22mmol) in anhydrous dichloromethane (SmL) was treated with test-butyl-4-12 hydroxy phenyl acetate (Reagent E, O.OSg, 0.22mmo1) followed by 1-(3-13 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.22mmo1) 14 and 4-dimethylaminopyridine (0.028g, 0.22mmo1). The resulting solution was stirred at ambient temperature overnight. The reaction mixture was subj acted 16 to flash column chromatography over silica gel (230-400 mesh) using 7%
17 ethyl acetate in hexane as the eluent to afford the title compound as a clear oil 18 that solidified on standing (0.048g, 48%).
19 1H NMR (300 MHz, CDC13): 8 7.91 (d, 1H, J= 2.lHz), 7.41 (d, 1H, J=
l.BHz), 7.24 (d, 2H, J= 8.8Hz), 7.05 (d, 2H, J= 8.SHz), 3.46 (s, 2H), 1.97-21 1.90 (m, 1H), 1.87 (s, 2H), 1.37 (s, 9H), 1.36 (s, 6H), 1.04-0.90 (m, 2H), 0.87-22 0.75 (m, 2H), 0.65-0.56 (m, 4H).
23 Spiro[2H 1-benzop rr~2 1'-c~propane]-6-carbox~ic acid, 8-c~loprop ~~l-24 3,4-dihydro-4,4-dimeth~l~ 4-(carboxymeth~lphenyl ester (Compound 58, General Formula 1) 26 A solution of spiro[2H 1-benzopyran-2,1'-cyclopropane]-6-carboxylic 27 acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 4-(te~t-28 butoxycarbonylmethyl)phenyl ester (Compound 57, 0.048g, O.lO5mmo1) was 29 treated with 2mL of trifluoroacetic acid and stirred at ambient temperature for 1 2h. The trifluoroacetic acid was distilled off under reduced pressure and the 2 residue was subjected to preparative reverse phase HPLC using 10% water in 3 acetonitrile as the mobile phase to afford the title compound as a white solid 4 (0.029g, 55%).
1H NMR (300 MHz, CDC13): 8 7.99 (d, 1H, J= 2.2Hz), 7.48 (d, 1H, J=
6 1.9Hz), 7.34 (d, 2H, J= 8.5Hz), 7.16 (d, 2H, J= 8.5Hz), 3.67 (s, 2H), 2.07-7 1.97 (m, 1H), 1.95 (s, 2H), 1.44 (s, 6H), 1.09-1.04 (m, 2H), 0.93-0.85 (m, 2H), 8 0.79-0.64 (m, 4H).
9 S i~ro[2H 1-benzopyran-2 1'-c~propane]-6-carboxylic acid, 8-c~clopropyl-3 4-dihydro-4 4-dimeth ~~l-, 3-(tent-butox~carbonylmeth~llphen 1~~ ester 11 (Compound 59, General Formula 1) 12 A solution of spiro[2H 1-benzopyran-2, I'-cyclopropane]-6-carboxylic 13 acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, O.OSg, 14 0.18mmo1) in anhydrous dichloromethane (SmL) was treated with tent-butyl-3-hydroxy phenyl acetate (Reagent F, 0.04g, 0.18mmo1) followed by 1-(3-16 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.029g, O.lmmol) 17 and 4-dimethylaminopyridine (0.022g, 0. l8mmol). The resulting solution was 18 stirred at ambient temperature overnight. The reaction mixture was subj ected 19 to flash column chromatography over silica gel (230-400 mesh) using 7%
ethyl acetate in hexane as the eluent to afford the title compound as a clear oil 21 that solidified on standing (0.020g, 23%).
22 1H NMR (300 MHz, CDC13): 8 7.98 (d, 1H, J= l.9Hz), 7.48 (d, 1H, J=
23 2.2Hz), 7.38 (t, 1H, J= 7.7Hz), 7.19-7.11 (m, 3H), 3.68 (s, 2H), 2.05-1.94 (m, 24 1H), 1.95 (s, 2H), 1.44 (s, 15H), 1.09-1.04 (m, 2H), 0.96-0.82 (m, 2H), 0.73-0.64 (m, 4H).
26 Spirof2H 1-benzop rah_n-2,1'-c~propane]-6-carboxylic acid, 8-c~cloprop ~~1-27 3,4-dih dro-4,4-dimethyl-, 3-(carboxymethyl)phen 1',~ ester (Compound 60, 28 General Formula 1) 1 A solution of spiro[2H 1-benzopyran-2,1'-cyclopropane]-6-carboxylic 2 acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 3-(te~t-3 butoxycarbonylmethyl)phenyl ester (Compound 59, 0.0208, 0.04mmol) was 4 treated with 2mL of trifluoroacetic acid and stirred at ambient temperature for - 2h. The trifluoroacetic acid was distilled off under reduced pressure and the 6 residue was subjected to preparative reverse phase HPLC using 10% water in 7 acetonitrile as the mobile phase to afford the title compound as a white solid 8 (0.01258, 62%).
9 1H NMR (300 MHz, CDC13): ~ 7.99 (d, 1H, J= 2.lHz), 7.49 (d, 1H, J=
2.lHz), 7.36 (t, 1H, J= 7.8Hz), 7.18-7.08 (m, 3H), 3.56 (s, ZH), 2.06-1.95 (m, 11 1H), 1.95 (s, 2H), 1.45 (s, 6H), 1.09-1.05 (m, 2H), 0.96-0.84 (m, 2H), 0.74-12 0.65 (m, 4H).
13 6-Bromo-4 4-dimeth~ 2 3 4-tetrah d~quinoline-1-carbaldeh~
14 (Intermediate 50) A solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline, 16 available in accordance with United States Patent No. 5,089,509, the 17 specification of which is incorporated herein by reference (1.88, 7.5mmol) in 18 lOmL of formic acid was refluxed for 3h. The reaction mixture was then 19 cooled to ambient temperature and poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (x2). The 21 combined organic phase was dried over anhydrous sodium sulfate, filtered and 22 evaporated in vacuo to a residue which was subjected to flash column 23 chromatography over silica gel (230-400 mesh) using 15-25% ethyl acetate in 24 hexane as the eluent to afford the title compound as a pale yellow solid (1.88, 90%).
26 iH NMR (300 MHz, CDC13): b 8.71 (s, 1H), 7.45 (d, 1H, J= 2.2Hz), 7.28 (dd, 27 1H, J= 2.2, 8.5Hz), 6.98 (d, 1H, J= 8.5Hz), 3.78 (t, 2H, J= 6.3Hz), 1.74 (t, 28 2H, J= 6.3Hz), 1.28 (s, 6H).
1 6-Bromo-1-c~clopropyl-4 4-dimethXl-1 2 3 4-tetrahydroauinoline 2 (Intermediate 51) 3 A stirred, cooled (0°C) solution of 6-bromo-4,4-dimethyl-1,2,3,4-4 tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7mmol) in anhydrous tetrahydrofuran (20mL) under argon was treated with titanium 6 tetra-iso-propoxide (2.15mL, 7.39mmo1) followed by 3M solution of ethyl 7 magnesium bromide in diethyl ether (5.6mL, 16.8mmol) and the reaction 8 mixture was then heated at 50°C overnight. It was then cooled in an ice-bath, 9 quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous 11 sodium sulfate, filtered over celite and evaporated in vacuo to residue which 12 was subjected to flash column chromatography over silica gel (230-400 mesh) 13 using 5% ethyl acetate in hexane as the eluent to afford the title compound as 14 an oil (1.2g, 64%).
1H NMR (300 MHz, CDC13): 8 7.24 (d, 1H, J= 2.SHz), 7.12 (dd, 1H, J= 2.2, 16 8.8Hz), 7.01 (d, 1H, J= 8.8Hz), 3.20 (t, 2H, J= 6.OHz), 2.27-2.20 (m, 1H), 17 1.68 (t, 2H, J= 5.9Hz), 1.24 (s, 3H), 1.23 (s, 3H), 0.83-0.77 (m, 2H), 0.60-18 0.55 (m, 2H).
19 1-C.~lopro~~l-6-trimethylsilanyleth~.~,4-dimeth~,2.3,4-tetrah~dro-eluinoline (Intermediate 52) 21 Following general procedure D and using 6-bromo-1-cyclopropyl-4,4-22 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8g, 2.86mmo1), 23 (trimethylsilyl)acetylene (SmL, 35mmo1), triethyl amine (lOmL), anhydrous 24 tetrahydrofuran, copper(I)iodide (0.080g, 0.42mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.240g, 0.34mmo1), the title 26 compound was obtained as an oil (0.678, 79%).
27 'H NMR (300 MHz, CDC13): 8 7.33 (d, 1H, J= l.BHz), 7.22 (dd, 1H, J= 2.1, 28 8.SHz), 7.06 (d, 1H, J= B.SHz), 3.27 (t, 2H, J= 5.9Hz), 2.37-2.31 (m, 1H), 1 1.70 (t, 2H, J= 6.OHz), 1.28 (s, 6H), 0.89-0.82 (m, 2H), 0.66-0.60 (m, 2H), 2 0.28 (s, 9H).
3 1-C~pro~yl-6-ethynyl-4 4-dimeth~-1 2 3L4-tetrahydroauinoline:
4 (Intermediate 53) Following general procedure E and using 1-cyclopropyl-6-6 trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline 7 (Intermediate 52, 0.40g, 1.34mmol), methanol and potassium carbonate 8 (0.2g, 1.47mmol) followed by flash column chromatography over silica gel 9 (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.17g, 56%).
11 1H NMR (300 MHz, CDC13): 8 7.38 (d, 1H, J= 2.lHz), 7.27 (dd, 1H, J= 2.1, 12 8.5Hz), 7.11 (d, 1H, J= 8.5Hz), 3.30 (t, 2H, J= 6.OHz), 3.02 (s, 1H), 2.40-13 2.34 (m, 1H), 1.74 (t, 2H, J= 6.OHz), 1.30 (s, 6H), 0.93-0.85 (m, 2H), 0.70-14 0.63 (m, 2H).
4-(1-C cly opro~yl~4,4-dimeth~~2 3 4-tetrah d~quinolin-6-yl-ethynyl)-16 benzoic acid eth. l ester (Compound 61, General Formula 7) 17 Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-18 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.118, 0.43mmo1), 19 ethyl-4-iodo-benzoate (Reagent A, 0.11g, 0.9mmo1), triethyl amine (3mL), tetrahydrofuran(3mL), copper(I)iodide(0.02g, O.lmmol) and 21 dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.085mmol) followed 22 by flash column chromatography over silica gel (230-400 mesh) using 5-10%
23 ethyl acetate in hexane as the eluent, the title compound was obtained (0.05g, 24 31%).
'H NMR (300 MHz, CDC13): 8 7.99 (d, 2H, J= 8.2Hz), 7.54 (d, 2H, J=
26 8.2Hz), 7.37 (d, 1H, J= 2.lHz), 7.26 (dd, 1H, J= 2.1, 8.5Hz), 7.10 (d, 1H, J=
27 8.8Hz), 4.37 (q, 2H, J= 7.lHz), 3.28 (t, 2H, J= 6.OHz), 2.40-2.33 (m, 1H), 28 1.71 (t, 2H, J= 5.8Hz), 1.40 (t, 3H, J= 7.OHz), 1.27 (s, 6H), 0.94-0.82 (m, 29 2H), 0.65-0.60 (m, 2H).
1 4 (1 C cl~prop~,4-dimethyl-1 2 3 4-tetrah~droquinolin-6-yl-ethynyll-2 benzoic acid (Compound 62, General Formula 7) 3 Following general procedure L and using 4-(1-cyclopropyl-4,4-4 dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester (Compound 61, O.OSg, 0.13mmo1), SmL of ethanol and SM sodium hydroxide 6 solution (2mL) followed by recrystallization fiom hot ethyl acetate, the title 7 compound was obtained as a solid (0.0308, 64%).
8 'H NMR (300 MHz, DMSO-d6): b 7.92 (d, 2H, J= 8.2Hz), 7.57 (d, 2H, J=
9 8.2Hz), 7.33 (d, 1H, J= l.9Hz), 7.23 (dd, 1H, J= 1.9, B.SHz), 7.06 (d, 1H, J=
8.8Hz), 3.25 (t, 2H, J= 5.8Hz), 2.41-2.34 (m, 1H), 1.64 (t, 2H, J= 5.6Hz), 11 1.21 (s, 6H), 0.87-0.81 (m, 2H), 0.59-0.54 (m, 2H).
12 j4-(1-Cyclopropyl-4 4-dimethyl-1 2 3 4-tetrah d~quinolin-6-13 eth ~nvl)phenyl] acetic acid meth l~ ester (Compound 63, General Formula 14 7) Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-16 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, O.OSg, 0.22mmol), 17 methyl-4-iodo-phenyl acetate (Reagent B, O.OSSg, 0.2mmo1), triethyl amine 18 (SmL), tetrahydrofuran, copper(I)iodide(0.025g, 0.13mmo1) and 19 dichlorobis(triphenylphosphine)palladium(II) (0.758, 0.llmmol) followed preparative normal phase HPLC using 10 % ethyl acetate in hexane as the 21 mobile phase, the title compound was obtained (0.0898, 100%).
22 'H NMR (300 MHz, CDCl3): b 7.47 (d, 2H, J= 8.8Hz), 7.45 (d, 1H, J=
23 l.BHz), 7.35-7.22 (m, 2H), 7.10 (d, 2H, J= 8.8Hz), 3.70 (s, 3H), 3.63 (s, 2H), 24 3 .27 (t, 2H, J = 6.OHz), 2.3 7-2.31 (m, 1 H), 1.71 (t, 2H, J = 6.OHz), 1.27 (s, 6H), 0.89-0.81 (m, 2H), 0.65-0.60 (m, 2H).
26 [4=(1-C~clopropyl-4 4-dimeth~ 2 3 4-tetrahydro-quinolin-6-~yn~l-2-27 fluoro ~hen,~~l] acetic acid eth,~ster (Compound 64, General Formula 7) 28 Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-29 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.118, 0.49mmo1), 1 ethyl-2-fluoro-4-iodo-phenyl acetate (Reagent C, 0.11 g, 0.9mmo1), triethyl 2 amine (3mL), tetrahydrofuran(3mL), copper(I)iodide(0.06g, 0.32mmol) and 3 dichlorobis(triphenylphosphine)palladium(II) (0.258, 0.36mmo1) followed by 4 flash column chromatography over silica gel (230-400 mesh) using 10 % ethyl acetate in hexane as the eluent, the title compound was obtained (0.1 g, 51 %).
6 IH NMR (300 MHz, CDCl3): 8 7.34 (d, 1H, J= 2.lHz), 7.25-7.17 (m, 3H), 7 7.09 (d, 2H, J= 8.8Hz), 4.17 (q, 2H, J= 7.lHz), 3.65 (s, 2H), 3.27 (t, 2H, J=
8 6.OHz), 2.38-2.31 (m, 1H), 1.69 (t, 2H, J= 6.OHz), 1.27 (s, 6H), 1.25 (t, 3H, J
9 = 7.lHz), 0.88-0.81 (m, 2H), 0.65-0.59 (m, 2H).
N-(4-Bromophen~l-N-methyl-3-methyl-2-butenamide (Intermediate 54) 11 3,3-Dimethylacryloyl chloride (3mL, 27mmo1) was added to a solution 12 of 4-bromo-N-methyl-aniline (4.55g, 25mmo1) in 150mL of dichloromethane 13 followed after 5 minutes by triethyl amine (SmL, 33mmol). After 2.5h at 14 ambient temperature, the reaction mixture was washed with water and the organic phase was dried over anhydrous sodium sulfate and evaporated in 16 vacuo to afford the title product as a brown oil in quantitative yield.
17 'H-NMR (300 MHz, CDC13): d 1.71 (s, 3H), 2.11(s, 3H), 3.28(s, 3H), 5.47(s, 1 ~ 1H), 7.05(d, J = 8.5Hz, 2H), 7.50(d; J = 8.2Hz, 2H).
19 6-Bromo-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrah~quinoline (Intermediate 55) N-(4-bromophenyl)-N-methyl-3-methyl-2-butenamide 21 (Intermediate 54, 6.428, 24mmo1) was heated to 130°C and aluminum 22 chloride (5g, 37.4mmol) was added in portions over 0.5h. The reaction 23 mixture was stirred for 1 hour at the same temperature and then cooled to 24 room temperature. Ice was added cautiously to the solid, followed by ~200mL
of iced water. The reaction mixture was then extracted with ether (x2) and 26 dichloromethane (x1) and the combined organic phase was dried over 27 anhydrous magnesium sulfate and evaporated in vacuo to yield a brown solid.
28 The solid was treated with hexane-dichloromethane and filtered to afford 1.7g 29 of product. The mother liquor was evaporated and purified by flash column 1 chromatography on silica gel (230-400 mesh) to afford 2.9g of the title 2 compound as a solid (total 72%).
3 1H-NMR (300 MHz, CDC13): 81.29(s, 6H), 2.49(s, 2H), 3.36(s, 3H), 6.87(d, J
4 = 8.2Hz, 1H), 7.36(dd, J = 2.0, 8.SHz, 1H), 7.39(d, J = 2.OHz, 1H).
6-Bromo-1 4 4-trimethylspiro[2H I-I 2 3 4-tetrahydroquinoline-2,1'-6 c~propanel (Intermediate 56) 7 A stirred, cooled (-78°C) 3M solution of ethyl magnesium bromide in 8 ether (8.lmL, 24.25mmol) under argon was treated with anhydrous 9 tetrahydrofuran (20mL) followed by a solution of titanium tetra-iso-propoxide (3.15mL, 10.2mmo1) in tetrahydrofuran (lOmL). A solution of 6-bromo-I,4,4-11 trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (Intermediate 55, 2.6g, 12 9.7mmo1) was cannulated into the reaction mixture and the solution was 13 allowed to warm to room temperature overnight. It was then cooled in an ice-14 bath, quenched with saturated aqueous ammonium chloride solution, filtered over celite and the aqueous phase was extracted with diethyl ether (x2). The 16 combined organic phase was dried over anhydrous magnesium sulfate, filtered 17 and evaporated in vacuo to afford an orange oil. Flash column 18 chromatography over silica gel (230-400 mesh) using 2-4% ethyl acetate in 19 hexane as the eluent afforded the title compound as an oil which was ~70%
pure (1.7g, 63%) and O.Sg of recovered starting material.
21 1H-NMR (300 MHz, CDCl3): 8 0.58(t, J= 6.OHz, 2H), 0.91(t, J= 6.OHz, 2H), 22 1.35 (s, 6H), 1.70(s, 2H), 2.68 (s, 3H), 6.59 (d, J= 8.8Hz, 1H), 7.16(dd, J=
23 2.3, 8.8Hz, 1H), 7.33(d, J= 2.3Hz, 1H).
24 1,4,4-TrimethXl-6-(trimeth, ls~~ eth~~piro[2H 1-1,2,3,4-tetrahydxoquinoline-2x1'-cyclopropanel (Intermediate 57) 26 Following general procedure D and using 6-bromo-1,4,4-27 trimethylspiro[2H 1-1,2,3,4-tetrahydroquinoline-2,1'-cyclopropane]
28 (Intermediate 56, 0.56g, 2mmol), (trimethylsilyl)acetylene (1.13mL, 8mmol), 29 triethyl amine (4mL), anhydrous tetrahydrofuran (SmL), copper(I)iodide 1 (0.088, 0.4mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.288, 2 0.4mmo1), followed by flash column chromatography over silica gel (230-400 3 mesh) using hexane-2% ethyl acetate in hexane as the eluent, the title 4 compound was obtained as an oil (0.428, 70%).
'H NMR (300 MHz, CDCl3): 8 0.023(s, 9H), 0.33(t, J= 6.lHz, 2H), 0.71(t, J
6 = 6.lHz, 2H), 1.10(s, 6H), 1.45(s, 2H), 2.41 (s, 3H), 6.31(d, J= B.SHz, 1H), 7 6.96 (dd, J= 2.1, 8.SHz, 1H), 7.10(d, J= 2.lHz, 1H).
8 Benzoic acid 4-[~1 4 4-trimeth lspiro[2H 1-1 2 3 4-tetrah~~uinoline-2 1'-9 c~lopropane]-6-ylleth ~n~]-eth 1 ester (Compound 65, General Formula 1) Following general procedure E and using a solution of 1,4,4-trimethyl-11 6-(trimethylsilanyl)ethynylspiro[2H 1-1,2,3,4-tetrahydroquinoline-2,1'-12 cyclopropane] (Intermediate 57, 0.4168, l.4mmol), methanol (lOmL), ethyl 13 acetate (2mL) and potassium carbonate (1.088, mmol) a silyl deprotected 14 acetylenic intermediate was obtained which was used directly for the next step (0.258, 79%). Following general procedure F and using part of the acetylenic 16 intermediate obtained as above (0.118, O.Smmol), ethyl-4-iodo benzoate 17 (Reagent A, 0.1128, 0.4mmo1), triethyl amine (1mL), tetrahydrofuran 18 (2.SmL), copper(I)iodide (0.0508, 0.26mmo1) and 19 tetrakis(triphenylphosphine)palladium(0)(0.096g, 0.17mmo1) followed by flash column chromatography over silica gel (230-400 mesh) using 8% ethyl 2I acetate in hexane as the eluent and preparative HPLC on Partisil 10 silica 22 column using 10% ethyl acetate in hexane as the mobile phase, the title 23 compound was obtained as a yellow oil (0.0488, 26%).
24 1H-NMR (300 MHz, CDC13): 8 0.60 (t, J= 6.lHz, 2H), 0.99(t, J= 6.lHz, 2H), 1.37(s, 6H), I.42(t, J= 7.OHz, 3H), 1.73(s, 2H), 2.68(s, 3H), 4.40 (q, J =
26 7.OHz, ZH), 6.61(d, J = 8.8Hz, 1H), 7.28 (dd, J = 2.1, B.SHz, 1H), 7.42 (d, J =
27 2.1 Hz, 1 H), 7.57(d, J = 8.2Hz, 2H), 8.0I (d, J = 8.2Hz, 2H).
28 Benzoic acid, 4-[(1,4,4-trimeth lspiro[2H 1-1,2,3,4-tetrah~quinoline-2,I'-29 c.~pronane~ 6-, l~leth nv vllT (Compound 66, General Formula 1) 1 Following general procedure I and using benzoic acid, 4-[(1,4,4-2 trimethylspiro[2H 1-1,2,3,4-tetrahydroqunoline-2,1'-cyclopropane]-6-3 yl)ethynyl]-ethyl ester (Compound 65, 0.03g, 0.08mmo1), ethanol (2mL), 4 tetrahydrofuran (2mL) and 1M aqueous sodium hydroxide solution (1mL), the title compound was obtained as a yellow solid (0.020g, 67%).
6 1H-NMR (300 MHz, CD3COCD3): 8 0.60 (t, J= 5.8Hz, 2H), 1.03(t, J= 5.8Hz, 7 2H), 1.34(s, 6H), 1.74(s, 2H), 2.69(s, 3H), 6.60(d, J = 8.SHz, 1H), 7.23 (dd, J
8 = 2.0, 8.4Hz, 1H), 7.39 (d, J = 2.OHz, 1H), 7.58(d, J = 8.2Hz, 2H), 8.01(d, J
9 = 8.2Hz, 2H).
Esterification Methods:
11 Method A:
12 The carboxylic acid was combined with a solution of the desired 13 alcohol and concentrated sulfuric acid (20 to 1 v/v) and the resulting mixture 14 or solution (0.75 to 1.0 M) heated to reflux overnight. The solution was cooled to room temperature, diluted with Et~O, and washed with H20, 16 saturated aqueous NaHC03, and saturated aqueous NaCl before being dried 17 over MgS04. Concentration of the dry solution under reduced pressure 18 afforded the desired carboxylic ester of sufficient purity to be used directly in 19 the next reaction.
Method i3:
21 To a solution (0.67 to l .OM) of the carboxylic acid in acetone was 22 added 1.1 equivalents of the desired alkyl halide and 1.0 equivalents of solid 23 potassium carbonate. The resulting mixture was heated to reflux for 2h and 24 then allowed to stir at room temperature overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The product was isolated 26 from the residue by column chromatography using silica gel as the solid phase.
27 Method C:
28 A solution (1M) of the carboxylic acid in thionyl chloride was heated at 1 reflux until analysis of a reaction aliquot by IR spectroscopy showed the 2 absence of the aryl carboxylic acid carbonyl band ( 1705 - 1680 cm 1). The 3 solution was cooled to room temperature and concentrated under reduced 4 pressure to give the crude acyl chloride.
The acyl chloride was dissolved in CHZC12 and the resulting solution 6 (0.5 to 0.75M) treated with 1.1 equivalents the desired alcohol and 2.0 7 equivalents of pyridine. After stirring overnight at room temperature the 8 solution was diluted with Et~O and washed with H20, 10% aqueous HCl, 9 saturated aqueous NaHC03, and saturated aqueous NaCl before being dried over NaZS04. Concentration of the dry solution under reduced pressure 11 followed by column chromatography afforded the desired ester.
12 GENERAL PROCEDURE l .(preparation of Enol ethers):
13 A solution (0.35 M) of the aryl ester in anhydrous THF was cooled to 0 14 °C and treated with 1.0 equivalents of Tebbe's Reagent ([~,-chloro-~-methylene[bis(cyclopentadieny))titanium]-dimethylaluminum] 0.5 M in 16 toluene). After 30 minutes the solution was warmed to room temperature and 17 stirred for 30 minutes before being carefully added to a 0.1 N NaOH
solution 18 at 0 °C. This mixture was treated with hexanes and the solids removed by 19 filtration through a pad of Celite. The solids were washed with hexanes and the filtrate passed through a second pad of Celite to remove any newly formed 21 solids. The organic layer was dried (Na2S04) and concentrated under reduced 22 pressure. The desired enol ether was isolated from the residue by column 23 chromatography using 1-2% of Et3N added to the eluant. (note: prolonged 24 exposure of the product to the column can result in hydrolysis and formation of the corresponding methyl ketone.) 26 GENERAL PROCEDURE 2 (cyclopropanation of the enol ethers):
27 To a solution (0.3 M) of the enol ether in anhydrous Et20 was added 28 2.0 equivalent of Et2Zn (as a solution in hexanes) and 2.0 equivalents of CHZTZ.
1 The resulting solution was heated to reflux until analysis of a reaction aliquot 2 (by TLC or 1H NMR) indicated that all of the starting enol ether had been 3 consumed. (note: Additional equal amounts of EtzZn and CH2I2 can be added 4 to drive the reaction to completion.) Upon cooling to room temperature the reaction was carefully quenched by the addition of saturated aqueous NH4Cl.
6 The resulting mixture is extracted with Et20 and the combined organic layers 7 washed with HBO and saturated aqueous NaCl before being dried over Na2S04 8 and concentrated under reduced pressure. The product is isolated from the 9 residue by column chromatography.
1-Bromo-4-(1-methoxyvin~)-benzene: (Intermediate 58) 11 Using General Procedure 1; methyl 4-bromo-benzoate (600.0 mg, 2.78 12 mmols), and 5.6 mL of Tebbe's Reagent (794.0 mg, 2.78 mmols) afforded 13 420.0 mg (70%) of the title compound as a colorless oil after column 14 chromatography (100% hexanes).
1H NMR (CDCl3) 8: 7.48 - 7.45 (4H, m), 4.64 (1H, d, J = 2.9 Hz), 4.23 (1H, d, 16 J = 2.9 Hz), 3.73 (3H, s).
17 1-Bromo-4-(1-methoxycycloprop, l~l~benzene (Intermediate 59) 18 Using General Procedure 2; 1-bromo-4-( 1-methoxyvinyl)-benzene 19 (Intermediate 58, 410. 0 mg, 1.92 mmols), EtzZn (711.3 mg, 5.76 mmols), and CHaI2 (1.54 g, 5.76 mmols) in 4.0 mL Et20 afforded 300.0 mg (69%) of 21 the title compound as a colorless oil after chromatography (0-3% EtOAc -22 hexanes).
23 1H NMR (CDC13) 8: 7,46 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 3.21 24 (3H, s), 1.19 (2H, m), 0.94 (2H, m).
f4-(1-Methoxyc~cloprou~)-phen~h~yl]-trimeth ls~ ilane (Intermediate 26 60) 27 Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-28 benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and 1 anhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide (93.0 mg, 2 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl 3 acetylene (1.39 g, 14.2 mmols) was then added followed by 4 dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The S resulting reaction mixture was heated to 70 °C for 60h. The title compound 6 (286.0 mg, 90%) was isolated by chromatography (0 - 3% EtOAc - hexanes).
7 'H NMR (CDC13) ~: 7.35 (2H, d, J = 7.2 Hz), 7.14 (2H, d, J = 7.2 Hz), 3.14 8 (3H, s), 1.14 (2H, m), 0.88 (2H, m), 0.17 (9H, s).
9 1-Ethynyl-4-( 1-methox~~clopropyl)-benzene (Intermediate 61) Using General Procedure E; [4-(1-methoxycyclopropyl)-11 phenylethynyl]-trimethylsilane (Intermediate 60, 285.0 mg, 1.18 mmols) in 12 methanol (lOmL) was treated with potassium carbonate (I00.0 mg, 0.72 13 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 14 mg, 100%) was used directly in the next reaction.
1H NMR (CDC13) 8: 7.46 (2H, d, J = 8.2 Hz), 7.24 (2H, d, J = 8.2 Hz), 3.23 16 (3H, s), 3.06 (1H, s), 1.22 (2H, m), 0.98 (2H, m).
17 Ether 4-[4-(1-methox~~prop~)-phenyleth~~]-benzoate (Compound 67, 18 General Formula 2) 19 Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate 21 (Reagent A, 141.0 mg, O.S 1 mmol) in triethyl amine (6 mL) was treated with 22 copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon fox S minutes.
23 Dichlorobis(triphenylphosphine)palladium(II) ( 109 mg, 0.16 mmol) was added 24 and the reaction mixture was stirred overnight at zoom temperature. Column 2S chromatography (2-S% EtOAc - hexanes) afforded 135.0 mg (90%) of the title 26 compound as an orange solid.
27 'H NMR (CDCl3) 8: 8.02 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.52 28 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.8 Hz), 4.39 (2H, q, J = 7.1 Hz), 3.25 1 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.23 (2H, m), 1.00 (2H, m).
~nyll-phenyll -acetate 2 Methyl 14 f 4 ( 1 methoxycyclopropyl)-phen 3 (Compound 68, General Formula 2) 4 Using General Procedure F; 1-ethynyl-4-( 1-methoxycyclopropyl)-benzene (Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodophenyl)-6 acetate (Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was 7 treated with copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 8 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19 9 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc - hexanes) afforded 11 140.0 mg (78%) of the title compound as an orange solid.
12 'H NMR (CDC13) b: 7.50 (4H, d, J = 8.1 Hz), 7.28 (4H, d, J = 8.1 Hz), 3.76 13 (3H, s), 3.64 (2H, s), 3.25 (3H, s), 1.22 (2H, m), 0.99 (2H, m).
14 4-[4-(1-Methox~yclopropyl~phenylethynyl]-benzoic acid (Compound 69, General Formula 2) 16 Using General Procedure I; a solution of ethyl 4-[4-(1-17 methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0 mg, 18 0.34 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 19 NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 85.0 mg (86%) of the title 21 compound as an orange solid.
22 'H NMR (CDC13) ~: 8.05 (2H), 7.66 (2H), 7.56 (2H, d, J = 8.5 Hz), 7.35 (2H, 23 d, J = 8.6 Hz), 3.22 (3H, s), 1.21 (2H, m), 1.01 (2H, m).
24 ~4-[4-(1-Methox~cycl~ro~yll-phen 1y eth~nyll-phen~~acetic acid (Compound 70, General Formula 2) 26 Using General Procedure I; a solution of methyl ~4-[4-(1-27 methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 68, 100.0 28 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 1 with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and 2 stirred overnight at room temperature. Work-up afforded 80.0 mg (84%) of 3 the title compound as an orange solid.
4 1H NMR (CDCl3) 8: 7.49 (4H), 7.27 (4H), 3.66 (2H, s), 3.25 (3H, s), 1.22 (2H, m), 0.99 (2H, m).
6 Isoprop~I 4-bromobenzoate (Intermediate 62) 7 Using General Esterification Procedure A; 4-bromobenzoic acid (1.50 8 g, 7.46 mmols) was combined with isopropyl alcohol to give 1.76 g (97%) of 9 the title compound as a colorless oil.
1H NMR (CDC13) 8: 7.90 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 11 5.24 (1H, septet, J = 6.2 Hz), 1.37 (6H, d, J = 6.2 Hz).
12 1-Bromo-4-~1-isopropoxyvinyll-benzene (Intermediate 63) 13 Using General Procedure l; isopropyl 4-bromobenzoate (Intermediate 14 62, 780.0 mg, 3.20 mmols) and 6.4 mL of Tebbe's Reagent (910.7 mg, 3.20 mmols) afforded 328.0 mg (43%) of the title compound as a colorless oil after 16 column chromatography (100% hexanes).
17 1H NMR (CDC13) 8: 7.46 (4H, m), 4.66 (1H, d, J = 2.6 Hz), 4.40 (1H, septet, J
18 = 6.2 Hz), 4.21 (1H, d, J = 2.6 Hz), 1.34 (6H, d, J = 6.2 Hz).
19 1-Bromo-4 ~1-isopropox cy yclopro~yl~benzene (Intermediate 64) Using General Procedure 2; 1-bromo-4-(1-isopropoxyvinyl)-benzene 21 (Intermediate 63, 328. 0 mg, 1.36 mmols), Et2Zn (335.9 mg, 2.72 mmols), 22 and CHzI2 (728.0 mg, 2.72 mmols) in 4.0 mL Et20 afforded 240.0 mg (70%) 23 of the title compound as a colorless oil after chromatography (3% EtOAc 24 hexanes).
'H NMR (CDC13) 8: 7.43 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 3.70 26 (1H, septet, J = 6.2 Hz), 1.18 (2H, m), 1.06 (6H, d, J = 6.2 Hz), 0.91 (2H, m).
27 ~~1-Isopropox c~ycloprop~l~phenyleth~n~]-trimeth~lsilane (Intermediate 28 65) 1 Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-2 benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) was 3 treated with copper(I)iodide ( 18.0 mg, 0.094 mmol) and then sparged with 4 argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 6 0.094 mmol). The resulting reaction mixture was heated to 70 °C for 5 days.
7 The title compound (250.0 mg, 98%) was isolated by chromatography (0 - 3%
8 EtOAc - hexanes) as an orange oil.
9 'H NMR (CDCI~) 8: 7.41 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 7.9 Hz), 3.70 ( 1 H, septet, J = 6.2 Hz), 1.18 (2H, m), 1.05 (6H, d, J = 6.2 Hz), 0.93 (2H, m), 11 0.94 (9H, s).
12 1-Eth~~-4-~(1-iso~ropox~~prop~l-benzene (Intermediate 66) 13 Using General Procedure E; [4-(1-isopropoxycyclopropyl)-14 phenylethynyl]-trimethylsilane (Intermediate 65, 260.0 mg, 0.96 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 16 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 17 mg, 100%) was used directly in the next reaction.
18 1H NMR (CDCl3) 8: 7.45 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz), 3.72 19 ( 1 H, septet, J = 6.2 Hz), 3.06 ( 1 H, s), 1.20 (2H, m), 1.07 (6H, d, J =
6.2 Hz), 0.95 (2H, m).
21 Ethyl4-[4-(1-isopropoxycyclopropyll-~hen~ynyl]-benzoate (Compound 22 71, General Formula 2) 23 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-24 benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with 26 copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes.
27 Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added 28 and the reaction mixture was stirred overnight at room temperature. Column 1 chromatography (2-4% EtOAc - hexanes) afforded 1 S 1.0 mg (76%) of the title 2 compound as an orange solid.
3 'H NMR (CDC13) 8: 8.02 (2H, d, J = 7.6 Hz), 7.58 (2H, d, J = 7.6 Hz), 7.50 4 (2H, d, J = 7.8 Hz), 7.39 (2H, d, J = 7.8 Hz), 4:39 (2H, q, J = 7.1 Hz), 3.74 (1H, septet, J = 6.2 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.22 (2H, m), 1.08 (6H, d, J =
6 6.2 Hz), 0.97 (2H, m).
7 MethX114-[4-(1-isopropoxycyclo~ropyll-phen~yn~l-phenyll-acetate 8 (Compound 72, General Formula 2) 9 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)-11 acetate (Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated 12 with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon fox 5 13 minutes. Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16 mmol) 14 was added and the reaction mixture was stirred overnight at room temperature.
Column chromatography (2-8% EtOAc - hexanes) afforded 110.0 mg (70%) 16 of the title compound as an orange oil.
17 'H NMR (CDCl3) 8: 7.20 (4H), 7.08 (2H, d, J = 7.0 Hz), 6.97 (2H, d, J = 7.9 18 Hz), 3.45 (1H, septet, J = 6.2 Hz), 3.41 (3H, s), 3.35 (2H, s), 0.91 (2H, m), 19 0.79 (6H, d, J = 6.2 Hz), 0.68 (2H, m).
4-[4-(1-Isobropoxyc~cloprop~l-phenYleth~yl]-benzoic acid (Compound 21 73, General Formula 2) 22 Using General Procedure I; a solution of ethyl 4-[4-(1-23 isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71, 110.0 mg, 24 0.32 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred 26 overnight at room temperature. Work-up afforded 89.0 mg (88%) of the title 27 compound as a yellow solid.
28 1H NMR (CDCl3) ~: 8.06 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 7.55 1 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 3.73 (1H, septet, J = 6.2 Hz), 1.18 2 (2H, m), 1.04 (6H, d, J = 6.2 Hz), 0.99 (2H, m).
3 d4 ~j4 f 1 Iso~ropoxycyclonropyll-phenylethynyll-phenyl~-acetic acid 4 (Compound 74, General Formula 2) Using General Procedure I; a solution of methyl {4-[4-(1-6 isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 72, 80.0 7 mg, 0.23 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 8 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and 9 stirred overnight at room temperature. Work-up afforded 48.0 mg (56%) of the title compound as a solid.
11 'H NMR (CDC13) 8: 7.20 (2H, d, J = 8.2 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.09 12 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.2 Hz), 3.46 (1H, septet, J = 6.2 Hz), 3.37 13 (2H, s), 0.92 (2H, m), 0.79 (6H, d, J = 6.2 Hz), 0.67 (2H, m).
14 Benzxl 4-bromobenzoate (Intermediate 67) Using General Esterification Method B; 4-bromobenzoic acid (2.01 g, 16 10.0 mmols), benzyl bromide (1.89 g, 11.1 mmols), and KZCO3 (1.40 g, 10.0 17 mmols) afforded 2.33 g (80%) of the title compound as a colorless solid after 18 column chromatography (3-10% EtOAc - hexanes).
19 1H NMR (CDCl3) 8: 7.89 (2H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.43 -7.31 (5H), 5.33 (2H, s).
21 1-Bromo-4-(1-benz.~xyvin~l-benzene (Intermediate 68) 22 Using General Procedure 1; benzyl 4-bromobenzoate (Intermediate 23 67, 920.0 mg, 3.16 mmols) and 6.3 mL of Tebbe's Reagent (897.0 mg, 3.16 24 mmols) afforded 640.0 mg (70%) of the title compound after column chromatography (100% hexanes).
26 1H NMR (CDCl3) 8: 7.55 - 7.35 (9H), 4.95 (2H, s), 4.73 (1H, d, J = 2.9 Hz), 27 4.34 (1H, d, J = 2.9 Hz).
28 1-Bromo-4-(1-~enz~yc~clopropyl -benzene (Intermediate 69) 1 Using General Procedure 2; 1-bromo-4-(1-benzyloxyvinyl)-benzene 2 (Intermediate 68, 280. 0 mg, 0.97 mmol), Et2Zn (247.0 mg, 2.0 mmols), and 3 CHZIZ (536.0 mg, 2.0 mmols) in 2.0 mL Et2O afforded 159.0 mg (53%) of the 4 title compound as a colorless solid after chromatography (2-5% EtOAc -hexanes).
6 1H NMR (CDC13) 8: 7.49 - 7.24 (9H), 4.41 (2H, s), 1.29 (2H, m), 1.00 (2H, 7 m).
8 [4-(1-Benzylox c~yclopro~yll-phen~~nyl]-trimethylsilane (Intermediate 9 70) Using General Procedure D; 1-bromo-4-(1-benzyloxycyclopropyl)-11 benzene (Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamine (5 mL) was 12 treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with 13 argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then 14 added followed by dichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C for Sd.
The 16 title compound (150.0 mg, 83%) was isolated by chromatography (0 - 3%
17 EtOAc - hexanes) as a pale-yellow oil.
18 'H NMR (CDCl3) 8: 7.21 (3H, m), 7.09 - 7.01 (6H, m), 4.18 (2H, s), 1.07 (2H, 19 m), 0.79 (2H, m), 0.02 (9H, s).
1-Eth~.~l-4-(1-benzXlox, c~yclopropyll-benzene (Intermediate 71) 21 Using General Procedure E; [4-(1-benzyloxycyclopropyl)-22 phenylethynyl]-trimethylsilane (Intermediate 70, 150.0 mg, 0.47 mmols) in 23 methanol (6 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) 24 and stirred overnight at ambient temperature. The crude allcyne (115 mg, 100%) was used directly in the next reaction.
26 1H NMR (CDC13) 8: 7.67 - 7.50 (2H, d, J = 8.2 Hz), 7.34 - 7.26 (7H, m), 4.43 27 (2H, s), 3.07 (1H, s), 1.32 (2H, m), 1.04 (2H, m).
28 Ethyl4-~4-(1-benzXlox~cyclopro~yll-phenxlethynyl]-benzoate (Compound 1 75, General Formula 2) 2 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3 benzene (Intermediate 71, 60.0 mg, 0.24 mmol) and ethyl-4-iodo benzoate 4 (Reagent A, 72.0 mg, 0.26 mmol) in triethylamine (4 mL) was treated with copper(I)iodide (17.0 mg, 0.09 mmol) and sparged with argon for 5 minutes.
6 Dichlorobis(triphenylphosphine)palladium(II) (61 mg, 0.09 mmol) was added 7 and the reaction mixture was stirred overnight at room temperature. Column 8 chromatography (2-4% EtOAc - hexanes) afforded 85.0 mg (91 %) of the title 9 compound as an orange oil.
IH NMR (CDC13) 8: 8.03 (2H, d, J = 8.2 Hz), 7.62-7.54 (4H, m), 7.39-7.26 11 (7H, m), 4.47 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz), 1.36 12 (2H, m), 1.07 (2H, m).
13 Methyl f 4-[4-( 1-benzylox c~yclopro~~-_phen 1~~~]-phen~~ -acetate 14 (Compound 76, General Formula 2) Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-16 benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-17 acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated 18 with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 19 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature.
21 Column chromatography (2-7% EtOAc - hexanes) afforded 64.0 mg (81 %) of 22 the title compound as a yellow oil.
23 'H NMR (CDC13) ~: 7.52-7.47 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H, s), 3.70 24 (3H, s), 3.64 (2H, s), 1.32 (2H, m), 1.06 (2H, m).
4-[4-(1-Benzylox~c~prop~l-phen~yn~]-benzoic acid (Compound 77, 26 General Formula 2) 27 Using General Procedure I; a solution of ethyl 4-[4-(1-28 benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0 mg, 1 0.20 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 2 NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred 3 overnight at room temperature. Work-up afforded 65.0 mg (89%) of the title 4 compound as a solid.
1H NMR (CDC13) 8: 7.97 (2H, d, J = 8.5 Hz), 7.67 (2H, d, J = 8.7 Hz), 7.58 6 (2H, d, J = 8.5 Hz), 7.41-7.28 (7H, m), 4.44 (2H, s), 1.33 (2H, m), 1.12 (2H, 7 m).
8 ~4-[4-(1-BenzyloxycYclo~ropyll-phenylethyn~l]-phenyl~-acetic acid 9 (Compound 78, General Formula 2) Using General Procedure I; a solution of methyl f 4-[4-(1-11 benzyloxycyclopropyl)-phenylethynyl]-phenyl-acetate (Compound 76, 45.0 12 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 13 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and 14 stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
16 1H NMR (CDC13) ~: 7.49 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H, s), 3.66 (2H, 17 s), 1.32 (2H, m), 1.05 (2H, m).
18 Benzyl 4-bromo-2-methylbenzoate (Intermediate 72) 19 Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3h with 10 mL SOCl2. The 21 resulting solution concentrated under reduced pressure and the crude acyl 22 chloride was combined with benzyl alcohol (1.08 g, lO.Ommols) and pyridine 23 ( 1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up 24 and column chromatography (2-5% EtOAc - hexanes) as a colorless oil.
1H NMR (CDC13) ~: 7.81 (1H, d, J = 8.5 Hz), 7.41-7.33 (7H, m), 5.32 (2H, s), 26 2.57 (3H, s).
27 4-Bromo-1-(1-benzylox v~inyll-2-meth~benzene (Intermediate 73) 28 Using General Procedure 1; benzyl 4-bromo-2-methylbenzoate 1 (Intermediate 72, 840.0 mg, 2.77 mmols) and 5.4 mL of Tebbe's Reagent 2 (788.0 mg, 2.77 mmols) afforded 640.0 mg (76%) of the title compound after 3 column chromatography (100% hexanes).
4 1H NMR (CDC13) 8: 7.38-7.19 (8H, m), 4.88 (2H, s), 4.45 (1H, d, J = 2.6 Hz), 4.25 (2H, d, J = 2.6 Hz), 2.35 (3H, s).
6 4-Bromo-1-(1-benzXloxxcyclo~ro~yll-2-methyl-benzene (Intermediate 74) 7 Using General Procedure 2; 4-bromo-1-(1-benzyloxyvinyl)-2-methyl-8 benzene (Intermediate 73, 400. 0 mg, 1.32 mmols), Et2Zn (325.0 mg, 2.63 9 mmols), and CH2I2 (704.0 mg, 2.63 mmols) in 4 mL Et20 afforded 380.0 mg (90%) of the title compound as a colorless oil after chromatography (2-5%
I 1 EtOAc - hexanes).
12 1H NMR (CDC13) 8: 7.42-7.20 (8H, m), 4.31 (2H, s), 2.58 (3H, s), I .25 (2H, 13 m), 0.94 (2H, m).
14 [4-(1-Benzyloxycycloprop~l-3-meth ~~1-phenylethynyl]-trimeth lsy'lane (Intermediate 75) 16 Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-17 methyl-benzene (Intermediate 74, 320.0 mg, 1.00 mmol) in triethylamine (8 I 8 mL) was treated with copper(I)iodide ( 19.0 mg, 0.1 mmol) and then sparged 19 with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 21 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
22 The title compound (300.0 mg, 89%) was isolated by chromatography (0 - 2%
23 EtOAc - hexanes).
24 'H NMR (CDC13) 8: 7.34-7.13 (8H, m), 4.24 (2H, s), 2.52 (3H, s), 1.20 (2H, m), 0.88 (2H, m), 0.25 (9H, s).
26 4- Eth,~.~(1-benz~lox, c~yclopropyl)-2-methyl-benzene (Intermediate 76) 27 Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-methyl-28 phenylethynyl]-trimethylsilane (Intermediate 75, 300.0 mg, 0.95 mmols) in 1 methanol (6 mL) was treated with potassium carbonate (120.0 mg, 0.87 mmol) 2 and stirred overnight at ambient temperature. The crude alkyne (185 mg, 3 79%) was used directly in the next reaction.
4 1H NMR (CDC13) 8: 7.37-7.16 (8H, m), 4.27 (2H, s), 3.07 (1H, s), 2.55 (3H, s), 1.21 (2H, m), 0.92 (2H, m).
6 Ether[4 (1-benz~yc~propyll-T 3-meth~phenylethynyll-benzoate 7 (Compound 79, General Formula 2) 8 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-9 methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was 11 treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 12 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) 13 was added and the reaction mixture was stirred overnight at room temperature.
14 Column chromatography (2-4% EtOAc - hexanes) afforded 68.0 mg (54%) of the title compound.
16 1H NMR (CDCl3) 8: 8.03 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.33-17 7.16 (8H, m), 4.39 (2H, q, J = 7.1 Hz), 4.29 (2H, s), 2.57 (3H, s), 1.40 (3H, t, J
18 = 7.1 Hz), 1.22 (2H, m), 0.93 (2H, m).
19 Methyl ~4-f4-(1-benz~~yclopropyll-3-meth~phenvlethynyl]-phenyll-acetate (Compound 80, General Formula 2) 21 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-22 methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and methyl- (4-23 iodophenyl)-acetate (Reagent B, 95.0 mg, 0.34 mmol) in triethylamine (5 mL) 24 was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 26 mmol) was added and the reaction mixture was stirred overnight at room 27 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 90.0 28 mg (71%) of the title compound as a pale-yellow oil.
1 1H NMR (CDC13) ~: 7.49 (2H, d, J = 8.2 Hz), 7.32-7.16 (10H, m), 4.28 (2H, 2 s), 3.70 (3H, s), 3.64 (2H, s), 2.56 (3H, s), 1.22 (2H, m), 0.92 (2H, m).
3 4 f4 (1 Benzxlox cy yclopropyl~-3-methyl-phenylethynyll-benzoic acid 4 (Compound 81, General Formula 2) Using General Procedure I; a solution of ethyl 4-[4-(1-6 benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 79, 7 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 8 treated with NaOH (360.0 mg, 9.0 rnmols, 3.0 mL of a 3N aqueous solution) 9 and stirred overnight at room temperature. Work-up afforded 48.0 mg (76%) of the title compound as a solid.
11 1H NMR (CDC13) ~: 8.10 (2H, d, J = 8.1 Hz), 7.63 (2H, d, J = 8.1 Hz), 7.44-12 7.16 (8H, m), 4.29 (2H, m), 2.58 (3H, s), 1.24 (2H, m), 0.94 (2H, m).
13 ~4-[4-(1-Benzylox~yclo_propel)-3-methyl-phenylethynyl]-phen~~ acetic acid 14 (Compound 82, General Formula 2) Using General Procedure I; a solution of methyl {4-[4-(1-16 benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 17 80, 75.0 mg, O.I 8 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 18 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 19 and stirred overnight at room temperature. Work-up afforded 30.0 mg (40%) of the title compound.
21 'H NMR (CDC13) S: 7.51 (2H, d, J = 8.2 Hz), 7.42 (1H, s), 7.33-7.17 (9H, m), 22 4.36 (2H, s), 3.67 (2H, s), 2.57 (3H, s), 1.23 (2H, m), 0.94 (2H, m).
23 Isopropyl 3-methyl-4-bromobenzoate (Intermediate 77) 24 Using General Esterification Procedure A; 4-bromo-2-methylbenzoic acid ( 1.6 g, 7.4 mmols) was combined with isopropyl alcohol to give 1.5 g 26 (79%) of the title compound as a colorless oil.
27 1H NMR (CDCl3) 8: 7.76 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 7.4 Hz), 7.37 28 (1H, dd, J = 1.4, 8.2 Hz), 5.23 (1H, septet, J = 6.2 Hz), 2.57 (3H, s), 1.37 (6H, 1 d, J = 6.2 Hz).
2 4 Bromo-1-(1-isopropoxyvinxl~-2-methyl-benzene (Intermediate 78) 3 Using General Procedure 1; isopropyl 2-methyl-4-bromobenzoate 4 (Intermediate 77, 800.0 mg, 3.11 mmols) and 6.2 mL of Tebbe's Reagent (885.2 mg, 3.11 mmols) afforded 595.0 mg (75%) of the title compound as a 6 colorless oil after column chromatography (100% hexanes).
7 'H NMR (CDC13) 8: 7.31-7.25 (2H, m), 7.16 (1H, d, J = 8.2 Hz), 4.34 (1H, 8 septet, J = 6.0 Hz), 4.31 (1H, d, J = 2.1 Hz), 4.18 (1H, d, J = 2.1 Hz), 2.33 (3H, 9 s), 1.31 (6H, d, J = 6.0 Hz).
4-Bromo-1-(1-isopro~oxycycloprop~l-2-meth-benzene (Intermediate 79) 11 Using General Procedure 2; 4-bromo-1-(1-isopropoxyvinyl)-2-methyl-12 benzene (Intermediate 78, 389. 0 mg, 1.53 mmols), EtZZn (376.6 mg, 3.05 13 mmols), and CH2I2 (817.0 mg, 3.05 mmols) in 3.0 mL EtzO afforded 340.0 mg 14 (84%) of the title compound as a colorless oil after chromatography (3%
EtOAc - hexanes).
16 1H NMR (CDCl3) 8: 7.33 (1H, d, J = 2.3 Hz), 7.24 (1H, dd, J = 2.3, 8.2 Hz), 17 7.13 (1H, d, J = 8.2 Hz), 3.57 (1H, septet, J = 6.1 Hz), 2.49 (3H, s), 1.00 (2H, 18 m), 0.97 (6H, d, J = 6. I Hz), 0.82 (2H, m).
19 [4-(1-Isopropoxycyclopropxll-3-meth ~~1-phenyleth~yl]-trimethylsilane (Intermediate 80) 21 Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-22 methyl-benzene (Intermediate 79, 250.0 mg, 0.95 mmol) in triethylamine (8 23 mL) was treated with copper(I)iodide (19.0 mg, 0.10 mmol) and then sparged 24 with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 26 mg, 0.1 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
27 The title compound (250.0 mg, 91%) was isolated by chromatography (0 - 3%
28 EtOAc - hexanes).
1 1H NMR (CDC13) 8: 7.32-7.17 (3H, m), 3.56 (1H, septet, J = 6.2 Hz), 2.48 2 (3H, s), 1.00 (2H, m), 0.95 (6H, d, J = 6.2 Hz), 0.83 (2H, m), 0.24 (9H, s).
3 4 Eth nyl-1- 1-isopropoxycyclopropyl -2-methyl-benzene (Intermediate 81) 4 Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 80, 250.0 mg, 0.87 mmol) in 6 methanol ( 10 mL) was treated with potassium carbonate ( 100.0 mg, 0.72 7 mmol) and stirred overnight at ambient temperature. The crude alkyne (180 8 mg, 98%) was used directly in the next reaction.
9 1H NMR (CDCl3) ~: 7.32 (1H, s), 7.23 (2H, m), 3.57 (1H, septet, J = 6.2 Hz), 3.05 (1H, s), 2.50 (3H, s), 1.11 (2H, m), 0.96 (6H, d, J = 6.2 Hz), 0.83 (2H, m).
11 Ethyl 4-j4 ~1-iso,.pro~ox c~yclopropyl)-3-methyl-phen 1~~~]-benzoate 12 (Compound 83, General Formula 2) 13 Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-14 methyl-benzene (Intermediate 81, 80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was 16 treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 17 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (91 mg, 0.13 18 mmol) was added and the reaction mixture was stirred overnight at room 19 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 75.0 mg (56%) of the title compound as an orange solid.
21 1H NMR (CDC13) 8: 8.02 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.39 22 (1H, s), 7.29-7.20 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 3.60 (1H, septet, J =
6.2 23 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.13 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0.87 (2H, 24 m).
Methy~4-f4-(1-isopropoxycycloprop~)-3-meth ~~l-phen~~nyll-phenyl~-26 acetate (Compound 84, General Formula 2) 27 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-3-28 methyl-benzene (Intermediate 81, 100.0 mg, 0.47 mmol) and methyl-(4-1 iodophenyl)-acetate (Reagent B, 129.0 mg, 0.45 mmol) in triethylamine (6 2 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with 3 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) ( 110 mg, 4 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 6 120.0 mg (71 %) of the title compound.
7 1H NMR (CDC13) ~: 7.48 (2H, d, J = 8.5 Hz), 7.36 (1H, s), 7.29-7.22 (4H, m), 8 3.70 (3H, s), 3.63 (2H, s), 3.60 (1H, septet, J = 6.2 Hz), 2.52 (3H, s), 1.09 (2H, 9 m), 0.97 (6H, d, J = 6.2 Hz), 0.86 (2H, m).
I0 4-(4-(1-Isopropox cy yclopropyll-3-meth ~~1-phen l~ethyn_~l-benzoic acid 11 (Compound 85, General Formula 2) 12 Using General Procedure I; a solution of ethyl 4-[4-(1-13 isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 83, 14 60.0 mg, 0.17 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) 16 and stirred overnight at room temperature. Work-up afforded 38.0 mg (69%) 17 of the title compound as a colorless solid.
18 1H NMR (d6-acetone) 8: 8.06 (2H, d, J = 8.5 Hz), 7.66 (2H, d, J = 8.5 Hz), 19 7.42 ( 1 H, s), 7.3 5 (2H, m), 3 .59 ( 1 H, septet, J = 6.2 Hz), 2.52 (3H, s), 1.07 (2H, m), 0.93 (6H, d, J = 6.2 Hz), 0.88 (2H, m).
21 ~4-(4-(1-Isopropoxycycloprop~l-3-methyl-phenylethyn~]_phenyl -acetic 22 acid (Compound 86, General Formula 2) 23 Using General Procedure I; a solution of methyl ~4-[4-(1-24 isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran 26 (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N
27 aqueous solution) and stirred overnight at room temperature. Work-up 28 afforded 60.0 mg (62%) of the title compound as a colorless solid.
1 1H NMR (CDC13) 8: 7.48 (2H, d, J = 7.6 Hz), 7.36 (1H, s), 7.25 (4H, m), 3.65 2 (2H, s), 3.60 (1H, septet, J = 6.2 Hz), 2.51 (3H, s), 1.12 (2H, m), 0.97 (6H, d, J
3 = 6.2 Hz), 0.86 (2H, m).
4 2 2-Dimethylpronyl 2-methyl-4-bromobenzoate (Intermediate 82) Using General Esterification Method C; 2-methyl-4-bromo-benzoic 6 acid (1.82 g, 8.47 mmols) was refluxed for 3h with 10 mL SOC12. The 7 resulting solution was concentrated under reduced pressure and the crude acyl 8 chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols) and 9 pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g, 68%) after work-up and column chromatography (2-S% EtOAc - hexanes) as a colorless 11 oil.
12 'H NMR (CDC13) &: 7.81 (1H, d, J = 8.2 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.39 13 (1H, dd, J = 2.0, 8.2 Hz), 3.99 (2H, s), 2.60 (3H, s), 1.03 (9H, s).
14 4-Bromo-1-f 1 ~2 2-dimethXl~rop~loxy -vine]-2-methyl-benzene (Intermediate 83) 16 Using General Procedure 1; 2,2-dimethylpropyl 2-methyl-4-17 bromobenzoate (Intermediate 82, 820.0 mg, 2.87 mmols) and 5.8 rnL of 18 Tebbe's Reagent (817.0 mg, 2.87 mmols) afforded 800.0 mg (98%) of the title 19 compound as a colorless oil after column chromatography (100% hexanes).
'H NMR (CDCl3) 8: 7.32 ( 1 H, d, J = 2.0 Hz), 7.28 ( 1 H, dd, J = 2.0, 8.2 Hz), 21 7.18 (1H, d, J = 8.2 Hz), 4.27 (1H, d, J = 2.1 Hz), 4.10 (1H, d, J = 2.1 Hz), 22 3.43 (2H, s), 2.33 (3H, s), 0.98 (9H, s).
23 4-Bromo-1-[~2 2-dimeth~propyloxx~cyclopropyl]-2-methyl-benzene 24 (Intermediate 84) Using General Procedure 2; 4-bromo-1-[1-(2,2-dimethylpropyloxy)-26 cyclopropyl]-2-methyl-benzene (Intermediate 83, 400. 0 mg, 1.43 mmols), 27 Et2Zn (353.2 mg, 2.86 mmols), and CH2I2 (760.0 mg, 2.86 mmols) in 3.0 mL
28 Et20 afforded 370.0 mg (87%) of the title compound as a colorless oil after 1 chromatography (3% EtOAc - hexanes).
2 'H NMR (CDC13) 8: 7.36 (1H, s),7.27 (1H, d, J = 8.5 Hz), 7.09 (1H, d, J =
7.9 3 Hz), 2.86 (2H, s), 2.52 (3H, s), 1.08 (2H, m), 0.83 (2H, m), 0.80 (9H, s).
4 f4 f 1 f 1 (2 2 Dimethylpro~yloxyl-cyclopronyll-3-methyl-phenylethvnvlll-trimethylsilane (Intermediate 84a) 6 Using General Procedure D; 4-bromo-1-[1-(2,2-dimethylpropyloxy)-7 cyclopropyl]-2-methyl-benzene (Intermediate 84, 255.0 mg, 0.86 mmol) in 8 triethylamine (8 mL) was treated with copper(I)iodide (17.0 mg, 0.09 mmol) 9 and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-I 1 (triphenylphosphine)palladium(II) (63.0 mg, 0.09 mmol). The resulting 12 reaction mixture was heated to 70 °C for 5d. The title compound (220.0 mg, 13 81%) was isolated by chromatography (1-2% EtOAc - hexanes).
14 'H NMR (CDCl3) 8: 7.30 (1H, s), 7.21 (1H, d, J = 7.6 Hz), 7.12 (1H, d, J =
8.6 Hz), 2.80 (2H, s), 2.47 (3H, s), 1.05 (2H, m), 0.82 (2H, m), 0.75 (9H, s), 0.24 I6 (9H, s).
17 4-Eth3myl-1-~-(2 2-dimeth~lurop~oxyl-cycloprop~l]-2-meth-benzene 18 (Intermediate 85) 19 Using General Procedure E; [4-[1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]]-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 84a, 21 220.0 mg, 0.83 mmol) in methanol (10 mL) was treated with potassium 22 carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature.
23 The crude alkyne (155 mg, 76%) was used directly in the next reaction.
24 'H NMR (CDC13) 8: 7.32 (1H, s), 7.24 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J =
7.1 Hz), 3.04 (1H, s), 2.83 (2H, s), 2.49 (3H, s), 1.06 (2H, m), 0.83 (2H, m), 0.76 26 (9H, s).
27 Ethyl 4-[4-[1-(2 2-dimethxlnropyloxK -cycloprop~]-3-methyl-phenylethynyll-28 benzoate (Compound 87, General Formula 2) 1 Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-2 cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and 3 ethyl-4-iodo benzoate (Reagent A, 86.0 mg, 0.31 mmol) in triethylamine (5 4 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (78 mg, 6 0.11 mmol) was added and the reaction mixture was stirred overnight at room 7 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 60.0 8 mg (50%) of the title compound as an orange solid.
9 1H NMR (CDCl3) 8: 8.02 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.38 (lH,s),7.30(lH,dd,J=1.1,8.OHz),7.20(lH,d,J=8.OHz),4.38(2H,q,J
11 = 7.1 Hz), 2.84 (2H, s), 2.52 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.07 (2H, m), 12 0.84 (2H, m), 0.77 (9H, s).
13 Methxl ~4-j4-f 1-(2 2-dimethylpropyloxyl-cyclopropyl]-3-methyl-14 phenyleth~nvl]-phen~)-acetate (Compound 88, General Formula 2) Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-16 cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and I7 methyl-(4-iodophenyl)-acetate (Reagent B, 86.0 mg, 0.31 mmol) in 18 triethylamine (6 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) 19 and sparged with argon for 5 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (78 mg, 0.11 mmol) was added 21 and the reaction mixture was stirred overnight at room temperature. Column 22 chromatography (2-4% EtOAc - hexanes) afforded 100.0 mg (83%) of the title 23 compound.
24 'H NMR (CDC13) 8: 7.48 (2H, d, J = 7.9 Hz), 7.36-7.24 (4H, m), 7.18 (1H, d, J
= 7.9 Hz), 3.70 (3H, s), 3.63 (2H, s), 2.84 (2H, s), 2.5I (3H, s), 1.07 (2H, m), 26 0.83 (2H, m), 0.77 (9H, s).
27 4-f4-[1-~2 2-Dimeth l~pro~~oxy~-cyclopronyll-3-methyl-phen~lethYnyll-28 benzoic acid (Compound 89, -General Formula 2) 1 Using General Procedure I; a solution of ethyl 4-[4-[1-(2,2-2 dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate 3 (Compound 87, 60.0 mg, 0.1 S mmol) in ethanol (3 mL) and tetrahydrofuran 4 (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N
aqueous solution) and stirred overnight at room temperature. Work-up 6 afforded 24.0 mg (43%) of the title compound as a colorless solid.
7 IH NMR (CDC13) 8: 8.06 (2H, d, J = 7.9 Hz), 7.65 (2H, d, J = 7.9 Hz), 7.42 8 (1H, s), 7.33 (2H, m), 2.89 (2H, s), 2.53 (3H, s), 1.07 (2H, m), 0.90 (2H, m), 9 0.77 (9H, s).
~4-f4-f 1-(2 2-Dimethylpropyloxyl.Tcyclopropyl]''-3-methyl-phenylethynyll-11 phenxl~ acetic acid (Compound 90, General Formula 2) 12 Using General Procedure I; a solution of methyl {4-[4-[1-(2,2-13 dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate 14 (Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N
16 aqueous solution) and stirred overnight at room temperature. Work-up 17 afforded 49.0 mg (53%) of the title compound as a colorless solid.
18 'H NMR (CDC13) 8: 7.49 (2H, d, J = 8.2 Hz), 7.36 (1H, s), 7.27 (3H, m), 7.18 19 (1H, d, J = 7.9 Hz), 3.66 (2H, s), 2.84 (2H, s), Z.SI (3H, s), 1.07 (2H, m), 0.83 (2H, m), 0.77 (9H, s).
21 Benzyl 4-bromo-2-ethyl-benzoate (Intermediate 86) 22 Using General Esterification Method B; 4-bromo-2-ethyl-benzoic acid 23 (0.98 g, 4.25 rnmols), benzyl bromide (0.80 g, 4.68 mmols), and KZC03 (0.64 24 g, 4.68 mmols) afforded 1.0 g (74%) of the title compound after column chromatography (0-3% EtOAc - hexanes).
26 1H NMR (CDC13) 8: 7.76 (1H, d, J = 8.5 Hz), 7.41-7.33 (7H, m), 5.32 (2H, s), 27 2.95 (2H, q,a J = 7.6 Hz), 1.20 (3H, t, J = 7.6 Hz).
28 4-Bromo-1-(1-benzyloxXvin~l-2-ethyl-benzene. (Intermediate 87) 1 Using General Procedure 1; benzyl 4-bromo-2-ethylbenzoate 2 (Intermediate 86, 1.20 g, 3.78 mmols) and 7.6 mL of Tebbe's Reagent (1.08 3 g, 3.78 mmols) afforded 800.0 mg (66%) of the title compound after column 4 chromatography (100% hexanes).
1H NMR (CDC13) 8: 7.37-7.17 (8H, m), 4.88 (2H, s), 4.43 (1H, d, J = 2.1 Hz), 6~ 4.25 (1H, d, J = 2.1 Hz), 2.71 (2H, q, J = 7.6 Hz), 1.18 (3H, t, J = 7.6 Hz).
7 4-Bromo-1-(1-benz~loxycyclopropXll-2-ethyl-benzene (Intermediate 88) 8 Using General Procedure 2; 4-bromo-1-(1-benzyloxyvinyl)-2-ethyl-9 benzene (Intermediate 87, 330. 0 mg, 1.04 mmols), EtzZn (257.0 mg, 2.08 mmols), and CHaIz (557.0 mg, 2.08 mmols) in 4 mL Et20 afforded 241.0 mg 11 (70%) of the title compound as a colorless oil after chromatography (2-5%
12 EtOAc - hexanes).
13 'H NMR (CDCl3) 8: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.00 (2H, q, J = 7.6 Hz), 14 1.29-1.21 (5H, m), 0.90 (2H, m).
[4-(1-Benzyloxycyclopropyll-3-ethyl-phen l~~nyl]-trimethylsilane 16 (Intermediate 89) 17 Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-18 ethyl-benzene (Intermediate 88, 220.0 mg, 0.66 mmol) in triethylamine (8 19 mL) was treated with copper(I)iodide ( 14.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was 21 then added followed by dichlorobis-(triphenylphosphine)palladium(II) (50.0 22 mg, 0.07 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
23 The title compound was isolated by chromatography (0 - 2% EtOAc -24 hexanes).
1H NMR (CDCl3) b: 7.41-7.13 (8H, m), 4.24 (2H, s), 2.98 (2H, q, J = 7.6 Hz), 26 1.25 (3H, t, J = 7.6 Hz), 1.20 (2H, m), 0.90 (2H, m), 0.26 (9H, s).
27 4-Ethynyl-1-(1-benzyloxycyclopropyll-2-ethyl-benzene (Intermediate 90) 28 Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-ethyl-1 phenylethynyl]-trimethylsilane (Intermediate 89, 240 mg, 0.69 mmol) in 2 methanol (6 mL) was treated with potassium carbonate (10.0 mg, 0.72 mmol) 3 and stirred overnight at ambient temperature. The crude alkyne (190 mg, 4 99%) was used directly in the next reaction. 1H NMR (CDC13) 8: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.08 (IH, s), 3.0I (2H, q, J = 7.6 Hz), 1.26 (3H, t, J
=
6 7.6 Hz), 1.22 (2H, m), 0.92 (2H, m).
7 Ethxl4 [4 (1 benzyloxycyclopropyll-3-ethyl-phenylethynyll-benzoate 8 (Compound 91, General Formula 2) 9 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo 11 benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was 12 treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 13 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) 14 was added and the reaction mixture was stirred overnight at room temperature.
Column chromatography (2-4% EtOAc - hexanes) afforded 100.0 mg (72%) 16 of the title compound.
17 'H NMR (CDC13) 8: 8.03 (2H, d, J = 7.9 Hz), 7.59 (2H, d, J = 7.9 Hz), 7.49 18 (1H, s), 7.36-7.16 (7H, m), 4.38 (2H, q, J = 7.1 Hz), 4.28 (2H, s), 3.04 (2H, q, 19 J = 7.6 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.23 (2H, m), 0.94 (2H, m).
21 Methyl (4-[4-(1-benzXloxycyclopro~~l-3-ethyl-phenylethyn~l]-phenyl~-22 acetate (Compound 92, General Formula 2) 23 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-24 ethyl-benzene (Intermediate 90, 107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0 mg, 0.39 mmol) in triethylamine (5 26 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with 27 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 28 0.13 mmol) was added and the reaction mixture was stirred overnight at room 1 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 2 130.0 mg (79%) of the title compound as a pale-yellow oil.
3 'H NMR (CDC13) 8: 7.49 (3H, m), 7.32-7.16 (9H, m), 4.28 (2H, s), 3.7I (3H, 4 s), 3.64 (2H, s), 3.03 (2H, q, J = 7.6 Hz), I.32-1.23 (5H, m), 0.94 (2H, m).
4 [4 (1 Benzyloxycyclopropyll-3-ethyl-phenylethynyll-benzoic acid 6 (Compound 93, General Formula 2) 7 Using General Procedure I; a solution of ethyl 4-[4-(1-8 benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 91, 9 100.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 11 and stirred overnight at room temperature. Work-up and purification by 12 HPLC (Partisil 10-pac, 10% HZO/CH3CN) afforded the title compound as a 13 colorless solid.
14 'H NMR (CDC13) 8: 8.10 (2H, d, J = 8.5 Hz), 7.64 (2H, d, J = 8.5 Hz), 7.50 (1H, s), 7.35-7.16 (7H, m), 4.29 (2H, s), 3.04 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J
16 = 7.6 Hz), 1.25 (2H, m), 0.95 (2H, m).
17 ~4-f4~1-Benzylox~yclopro»yl)-3-ethy-1-phenylethyn~]-phen~, -acetic acid 18 (Compound 94, General Formula 2) 19 Using General Procedure I; a solution of methyl ~4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl)-acetate (Compound 21 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 22 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 23 and stirred overnight at room temperature. Work-up and purification by 24 HPLC (Partisil IO-pac, 10% H20/CH3CN) afforded the title compound.
'H NMR (CDCl3) ~: 7.49 (3H, m), 7.31-7.16 (9H, m), 4.28 (2H, s), 3.66 (2H, 26 s), 3.02 (2H, q, J = 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.23 (2H, m), 0.94 (2H, 27 m).
28 Isopropvl 2-ethXl-4-bromobenzoate (Intermediate 91) 1 Using General Esterification Procedure A; 4-bromo-2-ethyl-benzoic 2 acid (2.25 g, 9.9 mmols) was combined with isopropyl alcohol to give the title 3 compound as a colorless oil after column chromatography (2% EtOAc-4 hexanes).
1H NMR (CDC13) 8: 7.69 (1H, d, J = 8.5 Hz), 7.41 (1H, s), 7.36 (1H, d, J = 8.5 6 Hz), 5.23 (1H, septet, J = 6.2 Hz), 2.95 (2H, q, J = 7.6 Hz), 1.37 (6H, d, J
= 6.2 7 Hz), 1.23 (3H, t, J = 7.6 Hz).
8 4-Bromo-1-(1-isopropoxwinxl~2-ether-benzene (Intermediate 92) 9 Using General Procedure 1; isopropyl 2-ethyl-4-bromobenzoate (Intermediate 91, 1.21 g, 4.46 mmols) and 8.9 mL of Tebbe's Reagent ( 1.27 11 g, 4.46 mmols) afforded 570.0 mg (75%) of the title compound after column 12 chromatography (100% hexanes).
13 1H NMR (CDC13) b: 7.36 (1H, d, J = 2.0 Hz), 7.28 (1H, dd, J = 2.0, 8.0 Hz), 14 7. I 7 ( I H, d, J = 8.0 Hz), 4.39 ( 1 H, septet, J = 6.2 Hz), 4.31 ( 1 H, d, J = 2.1 Hz), 4.26 (1H, d, J = 2.1 Hz), 2.73 (2H, q, J = 7.6 Hz), 1.35 (6H, d, J = 6.2 Hz), 16 1.24 (3H, t, J = 7.6 Hz).
17 4-Bromo-1-(1-isopro~oxYcycloprop~ -2-ethyl-benzene (Intermediate 93) 18 Using General Procedure 2; 4-bromo-1-(1-isopropoxyvinyl)-2-ethyl-19 benzene (Intermediate 92, 570. 0 mg, 2.11 mmols), EtZZn (521.0 mg, 4.22 mmols), and CH2Iz (1.13 g, 4.22 mmols) in 7.0 mL Et20 afforded 500.0 mg 21 (85%) of the title compound as a colorless oil after chromatography (3%
22 EtOAc - hexanes).
23 1H NMR (CDC13) 8: 7.39 (1H, d, J = 2.1 Hz), 7.25 (1H, dd, J = 2.1, 8.1 Hz), 24 7.1 S ( 1 H, d, J = 8.1 Hz), 3.59 ( 1 H, septet, J = 6.2 Hz), 2.97 (2H, q, J = 7.6 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.11 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0:83 (2H, m).
26 [4-(1-Tsopropox ~cXclopropyll-3-ethyl-phenyleth~nyl)-trimethylsilane 27 (Intermediate 94) 28 Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-1 ethyl-benzene (Intermediate 93, 300.0 mg, 1.07 mmol) in triethylamine (8 2 mL) was treated with copper(I)iodide (20.0 mg, 0.11 mmol) and then sparged 3 with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was 4 then added followed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 S mg, 0.11 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
6 The title compound (320.0 mg, 99%) was isolated by chromatography (0 - 2%
7 EtOAc - hexanes) as an orange oil.
8 'H NMR (CDCl3) 8: 7.37-7.21 (3H, m), 3.56 (1H, septet, J = 6.2 Hz), 2.96 9 (2H, q, J = 7.6 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.10 (2H, m), 0.94 (6H, d, J
= 6.2 Hz), 0.84 (2H, m), 0.25 (9H, s).
11 4-Eth~nyl-1-f 1-isopropox c~yclopropyll-2-ethyl-benzene (Intermediate 95) 12 Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-ethyl-13 phenylethynyl]-trimethylsilane (Intermediate 94, 330.0 mg, 1.10 mmols) in 14 methanol (10 mL) was treated with potassium carbonate (150.0 mg, 1.10 1 S mmol) and stirred overnight at ambient temperature. The crude alkyne (23 8 16 mg, 9S%) was used directly in the next reaction.
17 1H NMR (CDC13) 8: 7.40-7.22 (3H, m), 3.59 (1H, septet, J = 6.2 Hz), 3.07 18 (1H, s), 2.97 (2H, q, J = 7.6 Hz), 1.28 (3H, t, J = 7.6 Hz), 1.12 (2H, m), 0.96 19 (6H, d, J = 6.2 Hz), 0.85 (2H, m).
Ether[~1-isopropox~cyclopropyll-3-ethyl-phenylethynyl]-benzoate 21 (Compound 95, General Formula 2) 22 Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-23 ethyl-benzene (Intermediate 95, 108.0 mg, 0.47 mmol) and ethyl-4-iodo 24 benzoate (Reagent A, 130.0 mg, 047 mmol) in triethylamine (S mL) was 2S treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 26 S minutes. Dichlorobis(triphenylphosphine)-palladium(II) (110 mg, 0.16 27 mmol) was added and the reaction mixture was stirred overnight at room 28 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 1 125.0 mg (71%) of the title compound as an oil.
2 1H NMR (CDC13) 8: 8.02 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.46 3 (1H, s), 7.33-7.26 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 3.62 (1H, septet, J =
6.2 4 Hz), 3.01 (2H, q, J = 7.6 Hz), 1.41 (3H, t, J = 7.1 Hz), 1.31 (3H, t, J =
7.1 Hz), 1.14 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0.88 (2H, m).
6 Methyl 144 (1 iso~ropox~~clopropyll-3-ethyl-phen~ethynyll-phenyl~-7 acetate (Compound 96, General Formula 2) 8 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-3-9 ethyl-benzene (intermediate 95, 130.0 mg, 0.57 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 157.0 mg, 0.57 mmol) in triethylamine (5 11 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with 12 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 13 0.19 mmol) was added and the reaction mixture was stirred overnight at room 14 temperature. Column chromatography (2-5% EtOAc - hexanes) afforded 150.0 mg (70%) of the title compound as an orange oil.
16 'H NMR (CDCl3) 8: 7.50-7.44 (3H, m), 7.27 (4H, m), 3.70 (3H, s), 3.64 (2H, 17 s), 3.62 (1H, septet, J = 6.2 Hz), 3.00 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J
= 7.6 18 Hz), 1.13 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0.87 (2H, m).
19 4-~4-(1-Isopropoxycyclopro~yll-3-eth ~~-1-phenylethXnyll-benzoic acid (Compound 97, General Formula 2) 21 Using General Procedure I; a solution of ethyl 4-[4-( 1-22 isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 95, 23 110.0 mg, 0.29 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 24 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC
26 (partisil 10-pac, 10% H20/CH3CN) afforded the title compound as a colorless 27 solid.
28 1H NMR (d6-acetone) S: 8.06 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 1 7.49 (1H, s), 7.40-7.34 (2H, m), 3.61 (1H, septet, J = 6.2 Hz), 3.01 (2H, q, J =
2 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.08 (2H, m), 0.93 (6H, d, J = 6.2 Hz), 0.88 3 (2H, m).
4 ~4 f4 (I Isonropoxycyclopropyll 3 ethyl-phenylethynyll-phenyl~-acetic acid (Compound 98, General Formula 2) 6 Using General Procedure I; a solution of methyl {4-[4-(1-7 isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 8 96, 156.0 mg, 0.41 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 9 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC
11 (partisil 10-pac, 10% HZO/CH3CN) afforded 85.0 mg (57%) of the title 12 compound.
13 'H NMR (CDC13) 8: 7.54-7.48 (3H, m), 7.34-7.27 (4H, m), 3.68 (2H, s), 3.66 14 (1H, septet, J = 6.2 Hz), 3.03 (2H, q, J = 7.6 Hz), 1.33 (2H, t, J = 7.6 Hz), 1.17 (2H, m), 1.01 (6H, d, J = 6.2 Hz), 0.90 (2H, m).
16 (4-Bromo-3-iso~rop.~~l-phenoxyl-triiso~ropyl-silane (Intermediate 96) 17 To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols) 18 and imidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was added chloro-19 triisopropylsilane (946.0 mg, 4.90 mmols). After stirring overnight at room temperature the solution was diluted with H20 and extracted with EtOAc. The 21 combined organic layers were washed with H2O and saturated aqueous NaCl 22 before being dried (MgS04) and concentrated under reduced pressure. The 23 title compound, 1.30 g (92%), was isolated by column chromatography (1-2%
24 EtOAc-hexanes) as a colorless oil.
'H NMR (CDCI3) ~: 7.34 (1H, d, J = 8.5 Hz), 6.8I (1H, d, J = 2.9 Hz), 6.59 26 (1H, dd, J = 2.9, 8.5 Hz), 3.31 (1H, septet, J = 7.0 Hz), 1.33-1.21 (3H, m), 1.24 27 (6H, d, J = 7.0 Hz), 1.13 (18H, d, J = 7.0 Hz).
28 Ethxl 2-isouropy_I_4-triiso~prop lsy ilanyloxy-benzoate (Intermediate 97) 1 To a solution of (4-bromo-3-isopropyl-phenoxy)-triisopropyl-silane 2 (Intermediate 96, 1.3 g, 3.8 mmols) in 15 mL Et20 cooled to -78 °C
was 3 added 4.9 mL of tent-butyllithium in pentane (532.0 mg, 8.3 mmols; 1.7 M).
4 After stirring for 30 minutes ethyl chloroformate (832.0 mg, 7.8 mmols) was added. The resulting solution was warmed to room temperature and quenched 6 by the addition of saturated aqueous NH4C1. The mixture was extracted with 7 EtOAc and the combined organic layers dried (MgS04) concentrated under 8 reduced pressure and the residue chromatographed (4% EtOAc-hexanes) to 9 give 1.09 g (85%) of the title compound as a colorless oil.
1H NMR (CDC13) ~: 7.72 (1H, d, J = 8.5 Hz), 6.87 (1H, d, J = 2.3 Hz), 6.69 11 (1H, dd, J = 2.3, 8.5 Hz), 3.88 (1H, septet; J = 7.1 Hz), 4.30 (2H, q, J =
7.1 12 Hz), 1.36 (3H, t, J = 7.1 Hz), 1.31-1.17 (9H, m), 1.09 (18H).
13 f4-(1-Ethoxwin~l-3-isopropyl-phenoxy]-triisopropyl-silane (Intermediate 14 98) Using General Procedure 1; ethyl 2-isopropyl-4-triisopropylsilanyloxy-16 benzoate (Intermediate 97, 450.0 mg, 1.34 mmols) and 2.0 mL of Tebbe's 17 Reagent (398.0 mg, 1.40 mmols) afforded the title compound after column 18 chromatography (100% hexanes).
19 'H NMR (CDC13) b: 7.11 (1H, d, J = 8.2 Hz), 6.78 (1H, d, J = 2.3 Hz), 6.63 (1H, dd, J = 2.3, 8.2 Hz), 4.23 (1H, d, J = 1.7 Hz), 4.10 (1H, d, J = 1.7 Hz), 21 3.86 (2H, q, J = 7.0 Hz), 3.16 (1H, septet, J = 7.0 Hz), 1.35 (3H, t, J =
7.1 Hz), 22 1.28-1.19 (3H, m), 1.19 (6H, d, J = 7.0 Hz), 1.11 (18H).
23 [4-(1-Ethox~cyclopropyll-3-isopropyl-phenox'~]-triisopropyl-silane 24 (Intermediate 99) Using General Procedure 2; [4-(1-ethoxyvinyl)-3-isopropyl-phenoxy]-26 triisopropyl-silane (Intermediate 98, 300. 0 mg, 0.83 mmols), Et2Zn (325.0 27 mg, 2.63 mmols), and CH2I2 (704.0 mg, 2.63 mmols) in 5.0 mL EtzO afforded 28 270.0 mg (86%) of the title compound as a colorless oil after chromatography 1 (O.S-2.S% EtOAc - hexanes).
2 'H NMR (CDC13) b: 7.06 (1H, d, J = 8.2 Hz), 6.81 (1H, d, J = 2.6 Hz), 6.59 3 ~ (1H, dd, J = 2.6, 8.2 Hz), 3.76 (1H, septet, J = 7.0 Hz), 3.25 (2H, q, J =
7.0 4 Hz), 1.30-1.20 (3H, m), 1.19 (6H, d, J = 7.0 Hz), 1.15 (2H, m), 1.10 (18H), S 1.02 (2H, t, J = 7.0 Hz), 0.82 (2H, m).
6 4-(1-Ethoxyc~propyll-3-isopropyl-phenol (Intermediate 100) 7 To a solution of [4-(1-ethoxycyclopropyl)-3-isopropyl-phenoxy]-8 triisopropyl-silane (Intermediate 99, 360.0 mg, 0.96mmo1) in 3 mL THF at 0 9 °C was added tetrabutylammonium fluoride (625.0 mg, 2.39 mmols, 2.4 mL of a 1 M solution in THF). The solution was stirred at 0 °C for 30 minutes and 11 then quenched by the addition of HZO. The mixture was extracted with EtOAc 12 and the combined organic layers were washed with HZO and saturated aqueous 13 NaCI before being dried (MgS04) and concentrated under reduced pressure.
14 The title compound ( 180 mg, 86%) was isolated from the residue by column 1S chromatography (4-10% EtOAc-hexanes) as a colorless solid.
16 'H NMR (CDC13) 8: 7.13 (1H, d, J = 8.2 Hz), 6.79 (1H, d, J = 2.6 H), 6.57 17 (1H, dd, J = 2.6, 8.2 Hz), 5.48 (1H, s), 3.79 (1H, septet, J = 7.0 Hz), 3.32 (2H, 18 q, J= 7.0 Hz), 1.21 (6H, d, J = 7.0 Hz), 1.12 (2H, m), 1.0S (3H, t, J = 7.0 Hz), 19 0.84 (2H, m).
~1-Ethox~~propyll-3-isopropyl-phenv1111-trifluoromethansulfonate 21 (Intermediate 101) 22 A solution of 4-(1-ethoxycyclopropyl)-3-isopropyl-phenol 23 (Intermediate 100, 172.0 mg, 0.78 mmol) in S mL of CHzCl2 was cooled to 0 24 °C and to it was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-S-2S chloropyridine (321.0 mg, 0.82 mmol) and triethylamine (240.0 mg, 2.4 26 mmols). The resulting solution was warmed to room temperature and stirred 27 overnight. The reaction was quenched by the addition of HZO and the mixture 28 extracted with EtOAc and the combined organic layers were washed with 10%
1 aqueous HCI, saturated aqueous NaHCO3, H20, and saturated aqueous NaCl.
2 The solution was dried (MgS04) and concentrated under reduced pressure.
3 The title compound was isolated by column chromatography (2-4% EtOAc-4 hexanes) as a colorless oil, 240.0 mg, 87%.
1 H NMR (CDCl3) b: 7.31 ( 1 H, d, J = 8.6 Hz), 7.18 ( 1 H, d, J = 2. 6 Hz), 7.00 6 (1H, dd, J = 2.6, 8.6 Hz), 3.87 (1H, septet, J = 7.0 Hz), 2.38 (2H, q, J =
7.0 7 Hz), 1.24 (6H, d, J = 7.0 Hz), 1.15 (2H, m), 1.04 (3H, t, J = 7.0 Hz), 0.86 (2H, 8 m).
9 f4 (1-Ethox~cyclopropyl)-3-iso~ro~y-1-phen~ethyn_~l-trimethylsilane (Intermediate 102) 11 Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropyl-12 phenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 13 mmol) in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5 14 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 16 mmol). The resulting reaction mixture was heated to 95 °C for Sd.
The title 17 compound, 200.0 mg (99%), was isolated by chromatography (0 - 2% EtOAc -18 hexanes) as an orange oil.
19 'H NMR (CDC13) 8: 7.43 (1H, d, J = 1.7 Hz), 7.25 (1H, dd, J = 1.7, 7.9 Hz), 7.16 ( 1 H, d, J = 7.9 Hz), 3.80 ( 1 H, septet, J =' 6. 8 Hz), 3.26 (2H, q, J
= 7.0 Hz), 21 1.24 (6H, d, J = 6.8 Hz), 1.24-1.10 (2H, m), 1.03 (3H, t, J = 7.0 Hz), 0.87 (2H, 22 s), 0.26 (9H, s).
23 ~1-Ethoxyc~prop~l)-4-ethvnyl-2-isopropylbenzene (Intermediate 103) 24 Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane (Intermediate 102, 210.0 mg, 0.70 mmol) in 26 methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 27 mmol) and stirred overnight at ambient temperature. The crude alkyne was 28 used directly in the next reaction.
1 ' H NMR (CDC13) 8: 7.47 ( 1 H, d, J = 1.7 Hz), 7.23 ( 1 H, dd, J = 1.7, 7.6 Hz), 2 7. I 9 ( 1 H, d, J = 7.6 Hz), 3 .80 ( 1 H, septet, J = 7.0 Hz), 3.27 ( 1 H, q, J = 7.0 Hz), 3 3.07 (1H, s), 1.23 (6H, d, J = 7.0 Hz), 1.13 (2H, m), 1.03 (3H, t, J = 7.0 Hz), 4 0.85 (2H, m).
Ethyl 4 f4 ~I ethox c~yclopropyll-3-isopropy-1-phenylethynyll-benzoate 6 (Compound 99, General Formula 2) 7 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-8 isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo 9 benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 11 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 12 mmol) was added and the reaction mixture was stirred overnight at room 13 temperature. Column chromatography (1-2% EtOAc - hexanes) afforded 28.0 14 mg (34%) of the title compound.
1H NMR (CDC13) b: 8.01 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.51 16 ( 1 H, d J = 1.7 Hz), 7.2 8 ( 1 H, dd, J = 1.7, 7.9 Hz), 7.21 ( 1 H, d, J =
7.9 Hz), 17 4.38 (2H, q, J = 7.1 Hz), 3.83 (1H, septet, J = 6.7 Hz), 3.29 (2H, q, J =
7.0 Hz), 18 1.40 (3H, t, J = 7.1 Hz), 1.26 (6H, d, J = 6.7 Hz), 1.14 (2H, m), 1.04 (3H, t, J =
19 7.0 Hz), 0.87 (2H, m).
Methyl ~4-[4-(1-ethox~cyclopropyl)-3-isonropyl-phen~ethynyll-phenyl~-21 acetate (Compound 100, General Formula 2) 22 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-23 isopropylbenzene (Intermediate I03, 120.0 mg, 0.52 mmol) arid methyl-(4-24 iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with 26 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 27 0.17 mmol) was added and the reaction mixture was stirred overnight at room 28 temperature. Column chromatography (2-5% EtOAc - hexanes) afforded 1 140.0 mg (71 %) of the title compound as a pale-yellow oil.
2 1H NMR (CDCI3) 8: 7.53 (3H, m), 7.31-7.23 (4H, m), 3.86 (1H, septet, J = 6.7 3 Hz), 3.73 (3H, s), 3.67 (2H, s), 3.33 (2H, q, J = 7.0 Hz), 1.30 (6H, d, J =
6.7 4 Hz), 1.15 (2H, m), 1.08 (3H, t, J = 7.0 Hz), 0.90 (2H, m).
S 4 f4 (1 EthoxXcyclonropyll-3-isopropyl-phenylethynyll-benzoic acid 6 (Compound 101, General Formula 2) 7 Using General Procedure I; A solution of ethyl 4-[4-(1-8 ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound 99, 9 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) 11 and stirred overnight at room temperature. Work-up afforded 24 mg (92%) 12 the title compound as a pale-yellow solid.
13 1H NMR (d6-acetone) 8: 8.06 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 14 7.58 (1H, s), 7.33 (2H, m), 3.87 (1H, m), 2.27 (2H, q, J = 7.0 Hz), 1.26 (6H, d, J = 6.7 Hz), 1.09 (2H, m), 0.99 (3H, t, J = 7.0 Hz), 0.88 (2H, m).
16 ~4-[4-(1-Ethox c~ycloprop~)-3-isoprop_y-1-phenylethyn~l-phenyl~-acetic acid 17 (Compound 102, General Formula 2) 18 Using General Procedure I; a solution of methyl f 4-[4-(1-19 ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl-acetate (Compound 100, 130.0 mg, 0.35 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was 21 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 22 and stirred at 50 °C for 4h. Work-up and isolation by HPLC (Partisil 10-pac, 23 10% H20/CH3CN) afforded 88.0 mg (70%) of the title compound.
24 1H NMR (CDC13) 8: 7.50 (3H, m), 7.28-7.19 (4H, m), 3.82 (1H, m), 3.65 (2H, s), 3.29 (2H, q, J = 7.0 Hz), 1.25 (6H, d, J = 6.7 Hz), 1.14 (2H, rn), 1.04 (3H, t, 26 J = 7.0 Hz), 0.86 (2H, m).
27 4-Bromo-3-tent-but~phenol (Intermediate 104) 28 To a mixture of 3-tent-butyl-methoxy benzene (1.00 g, 6.09 mmols) in 1 CC14 (20 mL), molecular sieves, and silica gel was added N bromosuccinimide 2 (1.19 g, 6.70 mmols). This mixture was stirred at 55 °C for 48h. The resulting 3 mixture was cooled to room temperature, filtered to remove the solids, and the 4 filtrate diluted with EtOAc. This solution was washed with HZO, 10%
aqueous HCl, HaO, saturated aqueous NaHC03 and saturated aqueous NaCl 6 before being dried (MgS04) and concentrated under reduced pressure.
7 Column chromatography (2.5% EtOAc-hexanes) afforded 1.15 g (78%) of a 3 8 to 1 mixture of 1-bromo-2-tent-butyl methoxy benzene and 1-bromo-2-9 methoxy-4-tent-butyl benzene as a colorless oil.
A solution of the isomeric methoxy compounds in 10 mL of CHZC12 11 was cooled to 0 °C and treated with a solution (18.5 mL) of BBr3 in 12 (4.63 g, 18.5 mmols). After I O minutes the solution was warmed to room 13 temperature, stirred for 1h, and then quenched with HZO. The mixture was 14 extracted with EtOAc and the combined organic layers washed with saturated aqueous NaCI, dried (MgS04), and concentrated under reduced pressure. The 16 title compound was isolated, 1.17 g (59%), by column chromatography (2.5-17 5% EtOAc-hexanes).
18 'H NMR (CDC13) ~: 7.39 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 2.9 Hz), 6.54 19 ( 1 H, dd, J = 2.9, 8. S Hz), 1.46 (9H, s).
~4-Bromo-3-test-butyl-phenoxyl-triisopropyl-silane (Intermediate I05) 21 To a solution of 4-bromo-3-tent-butylphenol (Intermediate 104, 1.17 g, 22 5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMF was added 23 chloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirring overnight at 24 room temperature the solution was diluted wirth H20 and extracted with EtOAc. The combined organic layers were washed with H20 and saturated 26 aqueous NaCl before being dried (MgS04) and concentrated under reduced 27 pressure. The title compound, 1.80 g (92%), was isolated by column 28 chromatography (0-1.5% EtOAc-hexanes) as a colorless oil.
1 'H NMR (CDC13) 8: 7.38 (1H, d, J = 8.0 Hz), 6.97 (1H, d, J = 2.9 Hz), 6.56 2 (1H, dd, J = 2.9, 8.5 Hz), 1.47 (9H, s), 1.29-1.24 (3H, m), 1.09 (18H, d, J
= 6.7 3 Hz).
4 Eth~l 2 tent-butyl-4-triisopropylsilanyloxv-benzoate (Intermediate 106) To a solution of (4-bromo-3-tent-butyl-phenoxy)-triisopropyl-silane b (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et20 cooled to -78 °C
was 7 added 3.6 mL of test-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols).
8 After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was 9 added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with 11 EtOAc and the combined organic layers dried (MgS04) concentrated under 12 reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) 13 to give 1.23 g (88%) of the title compound as a colorless oil.
14 'H NMR (CDC13) b: 7.24 (1H, d, J = 8.2 Hz), 6.97 (1H, d, J = 2.6 Hz), 6.69 I S (1H, dd, J = 2.6, 8.2 Hz), 4.33 (2H, q, J = 7.1 Hz), 1.39 (9H, s), 1.37 (3H, t, J =
16 7.1 Hz), 1.29-1.21 (3H, m), 1.10 (18H, d, J = 6.7 Hz).
17 [4-(1-Ethox~vin~l-3-test-butyl-phenoxy]-triisopropyl-silane (Intermediate 18 107) I9 Using General Procedure 1; ethyl 2-test-butyl-4-triisopropylsilanyloxy-benzoate (Intermediate 106, 1.30 g, 3.44 mmols) and 7.2 mL of Tebbe's 21 Reagent (1.03 g, 3.61 mmols) were reacted. The reaction required 7 days at 22 room temperature to go to completion. The standard work-up afforded 1.29 g 23 (78%) of the title compound after column chromatography (1-2% EtOAc-24 hexanes).
1H NMR (CDC13) 8: 7.05 (1H, d, J = 8.2 Hz), 6.94 (1H, d, J = 2.6 Hz), 6.63 26 (1H, dd, J = 2.6, 8.2 Hz), 4.20 (1H, d, J = 1.7 Hz), 4.08 (IH, d, J = 1.7 Hz), 27 3.83 (2H, q, J = 7.1 Hz), 1.37 (9H, s), 1.36 (3H, t, J = 7.1 Hz), 1.27-1.20 (3H, 28 m), 1.10 (18H, d, J = 6.7 Hz).
1 ~4 (1 Ethoxycyclonropyll 3 tent butyl-phenoxyl-triisoprobyl-silane 2 (Intermediate 108) 3 Using General Procedure 2; [4-(1-ethoxyvinyl)-3-tent-butyl-phenoxy]-4 triisopropyl-silane (Intermediate 107, 320. 0 mg, 0.85 mmols), Et2Zn (325.0 mg, 2.63 mmols), and CHzI2 (704.0 mg, 2.63 mmols) in 5.0 mL EtZO afforded 6 257.0 mg (66%) of the title compound as a colorless oil after chromatography 7 (1-2.5% EtOAc - hexanes).
8 1H NMR (CDC13) 8: 7.24 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 2.6 Hz), 6.60 9 (1H, dd, J = 2.6, 8.5 Hz), 3.24 (2H, q, J = 7.1 Hz), 1.50 (9H, s), 1.29-1.21 (3H, m), 1.11 (18H, d, J = 6.7 Hz), 1.04 (3H, t, J = 7.1 Hz).
11 4-(1-Ethoxyc~lo~ro~~ -3-test-butxl-phenol (Intermediate 109) 12 To a solution of [4-(1-ethoxycyclopropyl)-3-tent-butyl-phenoxy]-13 triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 14 0 °C was added tetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols;
3.1 mL of a 1 M solution in THF). The solution was stirred at 0 °C for 30 16 minutes and then quenched by the addition of HZO. The mixture was extracted 17 with EtOAc and the combined organic layers were washed with HZO and 18 saturated aqueous NaCl before being dried (MgSOø) and concentrated under 19 reduced pressure. The title compound (400 mg, 88%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless 21 solid.
22 'H NMR (CDC13) 8: 7.29 (1H, d, J = 8.2 Hz), 7.01 (1H, d, J = 2.6 Hz), 6.57 23 (1H, dd, J = 2.6, 8.2 Hz), 3.29 (2H, q, J = 7.1 Hz), 1.59 (9H, s), 1.08-1.04 (7H, 24 m).
4-(1-Ethox cyclopropyll-3-tent-butt'-1-phenyl 1 1 1-trifluoromethansulfonate 26 (Intermediate 110) 27 A solution of 4-(1-ethoxycyclopropyl)-3-tent-butyl-phenol 28 (Intermediate 109, 400.0 mg, 1.71 mmol) in 10 mL of CH2C12 was cooled to 1 0 °C and to it was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-2 chloropyridine (705.0 mg, 1.79 mmol) and triethylamine (522.0 mg, 5.1 3 mmols). The resulting solution was warmed to room temperature and stirred 4 overnight. The reaction was quenched by the addition of H20 and the mixture extracted with EtOAc and the combined organic layers were washed with 10%
6 aqueous HCl, saturated aqueous NaHC03, H20, and saturated aqueous NaCI.
7 The solution was dried (MgS04) and concentrated under reduced pressure.
8 The title compound was isolated by column chromatography (2-4% EtOAc-9 hexanes) as a colorless oil, 542.0 mg (87%).
'H NMR (CDC13) 8: 7.48 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 2.6 Hz), 7.01 11 (1H, dd, J = 2.6, 8.5 Hz), 3.26 (2H, q, J = 7.1 hz), 1.52 (9H, s), 1.12 (2H, bs), 12 1.08-1.04 (5H, m).
13 [~1-Ethox~~prop~l-3-test-butyl-phen~eth~yl-1-trimethylsilane 14 (Intermediate 111) Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tent-butyl-16 phenyl 1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 17 mmol) in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5 18 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added 19 followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 95 °C for 18 hours.
The 21 title compound, 215.0 mg (96%), was isolated by chromatography (0 - 2%
22 EtOAc - hexanes) as an orange oil.
23 1H NMR (CDC13) 8: 7.63 (1H, d, J = 1.7 Hz), 7.32 (1H, d, J = 7.9 Hz), 7.19 24 (1H, dd, J = 1.7, 7.9 Hz), 3.24 (2H, q, J = 7.1 Hz), 1.51 (9H, s), 1.10 (2H, bs), 1.06-1.01 (5H, m), 0.25 (9H, s).
26 1- 1-Ethox~~prop~~4-eth~yl-2-tent-butylbenzene (Intermediate 112) 27 Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-tent-butyl-28 phenylethynyl]-trimethylsilane (Intermediate 1l1, 215.0 mg, 0.69 mmol) in 1 methanol (10 mL) was treated with potassium carbonate (80.0 mg, 0.58 mmol) 2 and stirred overnight at ambient temperature. The crude alkyne, 169 mg, was 3 used directly in the next reaction.
4 1H NMR (CDC13) 8: 7.68 (1H, d, J =1.8 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.23 ( 1 H, dd, J = 1.8, 7.9 Hz), 3 .26 (2H, q, J = 7.1 Hz), 3 .06 ( 1 H, s), 1.51 (9H, s), 6 1.11 (2H, bs), 1.07-1.02 (5H, m).
7 Ether 4 f 4 ( 1 ethoxXcyclopropyll-3-tent-butyl-phen~ethynyll-benzoate 8 (Compound 103, General Formula 2) 9 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tey°t-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo 11 benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was 12 treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 13 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 14 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc - hexanes) afforded 70.0 16 mg (73%) of the title compound.
17 'H NMR (CDC13) 8: 8.02 (2H, d, J = 8.8 Hz), 7.72 (1H, d, J = 1.7 Hz), 7.59 18 (2H, d, J = 8. 8 Hz), 7.40 ( 1 H, d, J = 7.9 Hz), 7.2 8 ( 1 H, dd, J = 1.7, 7.9 Hz), 19 4.39 ( 2H, q, J = 7.1 Hz), 3.28 (2H, q, J = 7.1 Hz), 1.55 (9H, s), 1.40 (3H, t, J =
7.1 Hz), 1.12 (2H, bs), 1.08-1.04 (5H, m).
21 Meth~l~4-[4-(1-ethoxxcyclopropyll-3-tent-butyl-phenylethynyll-phenyll-22 acetate (Compound 104, General Formula 2) 23 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tef°t-24 butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylamine (8 26 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with 27 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 28 0.13 mmol) was added and the reaction mixture was stirred overnight at room 1 temperature. Column chromatography (2-5% EtOAc - hexanes) afforded 2 100.0 mg (72%) of the title compound.
3 'H NMR (CDCl3) 8: 7.70 (1H, d, J = 1.5 Hz), 7.50 (2H, d, J = 7.9 Hz), 7.38 4 (1H, d, J = 7.9 Hz), 7.27 (3H, m), 3.70 (3H, s), 3.64 (2H, s), 3.28 (2H, q, J =
7.1 Hz), 1.54 (9H, s), 1.12 (2H, bs), 1.08-1.03 (5H, m).
6 4 f 4 ( 1 EthoxXcvclonropyl~ 3-teat-butyl-nhenylethynyll-benzoic acid 7 (Compound 105, General Formula 2) 8 Using General Procedure I; a solution of ethyl 4-[4-(1-9 ethoxycyclopropyl)-3-tent-butyl-phenylethynyl]-benzoate (Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 11 treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) 12 and stirred overnight at room temperature. Work-up afforded 40 mg (62%) 13 the title compound as a pale-yellow solid.
14 1H NMR (d6-acetone) ~: 8.06 (2H, d, J = 8.7 Hz), 7.76 (1H, d, J =1.8 Hz), 7.67(2H,d,J=8.7Hz),7.50(lH,d,J=7.9Hz),7.33(lH,dd,J=1.8,7.9 16 Hz), 3.28 (2H, q, J = 7.3 Hz), 1.54 (9H, s), 1.13 (2H, bs), 1.10 (2H, m), I
.02 17 (3H, t, J = 7.3 Hz).
18 ~4-[4-(1-Ethox cv yclopropyll-3-test-butyl-phenylethynyl]-phen~~acetic acid 19 (Compound 106, General Formula 2) Using General Procedure I; a solution of methyl f 4-[4-(1-21 ethoxycyclopropyl)-3-tent-butyl-phenylethynyl]-phenyl-acetate (Compound 22 104, 100.0 mg, 0.26 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) was 23 treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) 24 and stirred at 50 °C for 4h. Work-up and isolation by HPLC (Partisil 10-pac, 10% H20/CH3CN) afforded 70.0 mg (73%) of the title compound.
26 'H NMR (CDCl3) 8: 7.73 (1H, d, J = I .3 Hz), 7.53 (2H, d, J = 7.9 Hz), 7.41 27 (1H, d, J = 7.9 Hz), 7.28 (3H, m), 3.69 (2H, s), 3.31 (2H, q, J = 7.1 Hz), 1.56 28 (9H, s), 1.15 (2H, bs), 1.11-1.05 (5H, m).
1 1 (4 Bromophenyll-cyclopropanecarbonitrile (Intermediate 113) 2 To a 50% aqueous NaOH solution (40.0 g, wt/wt) was added benzyl 3 triethylammonium chloride ( 1.0 g, 4.4 mrnols), 4-bromobenzonitrile ( 19.6 g, 4 0.10 mol), and 1,2-dibromoethane (56.4 g, 0.30 mol). The mixture was stirred overnight at room temperature and then diluted with 100 mL of H20. This 6 mixture was extracted with EtOAc and the combined extracts were washed 7 with saturated aqueous NaHS203, HZO, and saturated aqueous NaCl before 8 being dried (MgS04) and concentrated under reduced pressure. Bulb-to-bulb 9 distillation afforded 18.8 g (85%) of the title compound as a colorless solid.
1H NMR (CDCl3) 8: 7.48 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 1.75 11 (2H, dd, J = 5.2, 7.6 Hz), 1.39 (2H, dd, J = 5.2, 7.6 Hz).
12 1-(4-Bromophenyl~c~lopropanecarbox~ic acid (Intermediate 114) 13 To a solution of KOH (6.06 g, 0.11 mol) in 10 mL of HZO was added 14 40 mL of ethylene glycol and 1-(4-bromophenyl)-cyclopropanecarbonitrile (Intermediate 113, 10.0 g, 0.45 mol). This solution was heated to 135-140 °C
16 for 4h, cooled to room temperature, and then poured into a mixture of 100 mL
I7 ice and I O% aqueous HCl. The resulting mixture was allowed to stand 18 overnight at 5 °C, the solid was collected by filtration and washed with HZO.
19 The colorless solid was dried under reduced pressure to give 10.6 g (97%) of the title compound.
21 1H NMR (CDC13) 8: 7.43 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 1.68 22 (2H, dd, J = 4.0, 7.1 Hz), I .24 (2H, dd, J = 4.0, 7.1 Hz).
23 Test-butt(I-~4-bromo~henyll-cycloprop~]'-carbamate (Intermediate 115) 24 A solution of 1-(4-bromophenyl)-cyclopropanecarboxylic acid (Intermediate 114, 2.32 g, 9.62 mmols), diphenylphosphoryl azide (2.65 g, 26 9.62 mmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL teYt-BuOH
27 (distilled from Na°) was heated to reflux for 17h. The solution was 28 concentrated under reduced pressure and the residue dissolved in EtOAc and 1 washed with 5% aqueous HC1, H20, saturated aqueous NaHC03, and saturated 2 aqueous NaCI before being dried over MgS04. Concentration of the dry 3 solution under reduced pressure and column chromatography (5-10% EtOAc -4 hexanes) afforded 2.01 g (67%) of the title compound as a colorless solid.
1H NMR (CDCl3) 8: 7.39 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.3 Hz), 5.35 6 (1H, bs), 1.43 (9H, s), 1.26 (2H, m), 1.17 (2H, m).
7 1-~4-Bromophen l~yclopropylamine (Intermediate 116) 8 To a solution of test-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate 9 (Intermediate 115, 1.08 g, 3.40 mmols) in 20 mL MeOH and 20 mL THF was added 20 mL of 3M aqueous HCl. The solution was warmed to 35 °C for 3 11 hours and then stirred for 17h at 25 °C. The reaction was quenched by 12 adjusting the pH of the solution to 12 with 3M aqueous NaOH. The mixture 13 was extracted with EtzO and the combined organic layers were washed with 14 HZO and saturated aqueous NaCl before being dried (MgS04) and concentrated under reduced pressure. The title compound 613 mg (85%) was 16 used without further purification.
17 1H NMR (CDCl3) 8: 7.43 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz), 1.89 18 (2H, bs), 1.07 (2H, m), 0.95 (2H, m).
19 N [ 1 ~4-bromophenyl~cyclopropyl]-propionamide (Intermediate 117) To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 21 116, 84 mg, 0.4 mmol) in 4 mL CH2Cl2 at room temperature was added 22 propionyl chloride (43.0 mg, 0.47 mmol) and pyridine (5.6.0 mg, 0.71 mmol).
23 After stirring 17 hours at room temperature the reaction was quenched by the 24 addition of H20 and extracted with EtOAc. The combined extracts were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and saturated 26 aqueous NaCl before being dried (MgS04) and concentrated under reduced 27 pressure. The title compound 85.0 mg (67%), was isolated by column 28 chromatography (20-50% EtOAc-hexanes) as a colorless solid.
1 1H NMR (CDC13) ~: 7.48 (2H, d, J = 8.S Hz), 7.09 (2H, d, J = 8.S Hz), 6.40 2 (1H, s), 2.19 (2H, q, J = 7.2 Hz), 1.18-1.24 (4H, m), 1.12 (3H, t, J = 7.2 Hz).
3 j1 (4 Bromophenxll-c~clopropyll-~ famine (Intermediate 118) 4 To a solution of N [1-(4-bromophenyl)-cyclopropyl]-propionamide S (Intermediate 117, 85.0 mg, 0.32 mmol) in THF (S mL) at 0 °C was added 6 BH3-Me2S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). The 7 solution was heated to SS °C for 17 hours, cooled to room temperature, 8 saturated aqueous NaHC03 was added and the resulting mixture was stirred 9 for 2 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with HZO and saturated aqueous NaCI before being dried 11 (MgS04) and concentrated under reduced pressure. The title compound was 12 isolated by column chromatography (10-30% EtOAc-hexanes).
13 1H NMR (CDC13) 8: 7.42 (2H, d, J = 8.S Hz), 7.19 (2H, d, J = 8.S Hz), 2.46 14 (2H, t, J = 7.3 Hz), 1.40 (2H, m), 0.98 (2H, m), 0.86 (SH, m).
1 S Pronyl-f 1- 4-trimeth ls~~ethynyl-phenyl-c~propyl_]-amine 16 (Intermediate 119) 17 Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-18 propylamine (Intermediate 118, 100.0 mg, 0.39 mmol) in triethylamine (8 19 mL) was treated with copper(I)iodide ( 13.0 mg, 0.06 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was 21 then added followed by dichlorobis(triphenylphosphine)palladium(II) (48.0 22 mg, 0.06 mmol). The resulting reaction mixture was heated to 70 °C
for 23 Sdays. The title compound (80.0 mg, 7S%) was isolated by chromatography 24 (0 - 10% EtOAc - hexanes) as an orange oil.
1H NMR (CDCl3) 8: 7.41 (2H, d, J = 8.S Hz), 7.21 (2H, d, J = 8.S Hz), 2.45 26 (2H, t, J = 7.3 Hz), 1.39 (2H, m), 0.98 (2H, m), 0.87 (2H, m), 0.84 (3H, t, J =
27 7.3 Hz), 0.24 (9H, s).
28 j~4-Ethyn~phenyll-cycloaropyll-nro~wlamine (Intermediate 120) 1 Using General Procedure E; propyl-[1-(4-trimethylsilanylethynyl-2 phenyl)-cyclopropyl]-amine (Intermediate 119, 80.0 mg, 0.30 mmols) in 3 methanol (8 mL) was treated with potassium carbonate (80.0 mg, 0.59 mmol) 4 and stirred overnight at ambient temperature. The crude alkyne (58 mg, 100%) was used directly in the next reaction.
6 1H NMR (CDC13) ~: 7.44 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 3.05 7 ( 1 H, s), 2.46 (2H, t, J = 7.3 Hz), 1.41 (2H, m), 1.00 (2H, m), 0.90 (2H, m), 8 0.86 (3H, t, J = 7.3 Hz).
9 Eth~l4-~4-(1-propylamino-c~cloprop~2phenylethynyll-benzoate (Compound 107, General Formula 2) 11 Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-12 propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo 13 benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was 14 treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) 16 was added and the reaction mixture was stirred overnight at room temperature.
17 Column chromatography (5-15% EtOAc - hexanes) afforded 40.0 mg (61%) 18 of the title compound as an orange oil.
19 'H NMR (CDCl3) 8: 8.01 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz), 4.39 (2H, q, J = 7.1 Hz), 2.49 21 (2H, t, J = 7.3 Hz), 1.46 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 1.0l (2H, m), 0.89 22 (2H, m), 0.87 (3H, t, J = 7.3 Hz).
23 4-(4-~(1-Propylamino-e.~prop,~phen,~eth~,Yll-benzoic acid (Compound 24 108, General Formula 2) Using General Procedure I; a solution of ethyl 4-[4-(1-propylamino-26 cyclopropyl)-phenylethynyl]-benzoate (Compound 107, 40.0 mg, 0.12 mmol) 27 in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 28 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at 1 room temperature. Work-up afforded 25.0 mg (69%) of the title compound as 2 a solid.
3 'H NMR (d6-DMSO) ~: 7.97 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.50 4 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.37 (2H, m), 1.00 (2H, m), 0.93 (2H, m), 0.84 (3H, t, J = 7.3 Hz).
6 ~1 (4 Bromophenvl)-cyclonrop~]-dipropylamine (Intermediate 121) 7 To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 8 116) in CH3CN / HOAc (5 mL, 9:1, v/v) and THF 3 mL at 0 °C was added 9 propionaldehyde (277.0 mg, 4.95 mmols) and NaCNBH3 (153.0 mg, 2.47 mmols). The reaction was warmed to room temperature and after Shours 11 quenched with HZO. The pH of the solution was adjusted to 8-9 using aqueous 12 NaOH and extracted with EtOAc. The combined extracts were washed with 13 H20 and saturated aqueous NaCl, dried (MgS04) and concentrated under 14 reduced pressure. The title compound, 190.0 mg (56%), was isolated by column chromatography (2-5% EtOAc-hexanes).
16 'H NMR (CDC13) ~: 7.42 (2H, d, J = 8.3 Hz), 7.18 (2H, d, J = 8.3 Hz), 2.39 17 (4H, t, J = 7.3 Hz), 1.62-1.40 (4H, m), 0.96 (2H, m), 0.86 (6H, t, J = 7.3 Hz), 18 0.80 (2H, m).
19 Dipropyl-f 1-(4-trimeth lsy ilan~lethynyl-phenyll-cycloarop~l]-amine (Intermediate 122) 21 Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-22 dipropylamine (Intermediate 121, 150.0 mg, 0.50 mmol) in triethylamine (5 23 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged 24 with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 26 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
27 The title compound was isolated by chromatography (0 - 3% EtOAc -28 hexanes).
1 'H NMR (CDC13) 8: 7.35 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 2.39 2 (4H, t, J = 7.3 Hz), 1.55-1.42 (4H, m), 0.96 (2H, m), 0.88-0.79 (8H, m), 0.25 3 (9H, s).
4 [1 (4 Ethynvlphenyll-cyclonropYll-dipropylamine (Intermediate 123) Using General Procedure E; dipropyl-[1-(4-trimethylsilanylethynyl-6 phenyl)-cyclopropyl]-amine (Intermediate 122, 45.0 mg, 0.14 inmols) in 7 methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) 8 and. stirred overnight at ambient temperature. The crude alkyne (34 mg, 9 100%) was used directly in the next reaction.
1H NMR (CDCl3) 8: 7.42 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 11 2.40(4H, t, J = 7.3 Hz), 1.53-1.40 (4H, m), 0.96 (2H, m), 0.90-0.79 (8H, m).
12 Eth 1Y 4-f4-(1-dipropylamino-cycloprop~l~phenylethynyll-benzoate 13 (Compound 109, General Formula 2) 14 Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0 mg, 0.16 mmol) and ethyl-4-iodo 16 benzoate (Reagent A, 59.0 mg, 0.21 mmol) in triethyl amine (6 mL) was 17 treated with copper(I)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 18 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) 19 was added and the reaction mixture was stirred overnight at room temperature.
Column chromatography (2-4% EtOAc - hexanes) afforded the title compound 21 as a yellow oil.
22 'H NMR (CDCl3) 8: 8.03 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.49 23 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 4.39 (2H, q, J = 7.1 Hz), 2.43 24 (4H, t, J = 7.3 Hz), 1.52-1.42 (4H, m), 1.41 (3H, t, J = 7.1 Hz), 0.99 (2H, m), 0.88-0.83 (8H, m). .
26 4-[4-(1-Dipropylamino-c~lo~ropyll-phenylethyn~]-benzoic acid 27 (Compound 110, General Formula 2) 28 Using General Procedure I; a solution of ethyl 4-[4-(1-dipropylamino-1 cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) 2 in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 3 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at 4 room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
6 1H NMR (d6-DMSO) 8: 7.98 (2H, d, J = 8.3 Hz), 7.67 (6H, m), 3.05-2.89 (4H, 7 m), 1.98 (2H, m), 1.72 (4H, m), 1.23 (2H, m), 0.88 (6H, t, J = 7.3 Hz).
8 Benzxl f 1 t4 bromobhen~)-c~propyl]-amine Intermediate 124) and 9 Dibenzyl-[ 1-f 4-bromophenyll-cyclopropyl]-amine (Intermediate 125) A solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116, 11 244.0 mg, 1.15 mmols) and benzyl bromide (255.0 mg, 1.50 mmols) in 4 mL
12 DMF was stirred at 85 °C for 6 hours, cooled to room temperature and stirred 13 overnight. The solution was diluted with H20 and the pH adjusted to 8-9 with I4 aqueous NaOH. The solution was extracted with EtOAc and the combined organic layers were washed with H20 and saturated aqueous NaCI, dried 16 (MgS04) and concentrated under reduced pressure. Column chromatography 17 (5-10% EtOAc-Hexanes) afforded 110 mg (32%) of the N benzyl amine.
I8 1H NMR (CDC13) 8: 7.48 (2H, d, J = 8.4 Hz), 7.30-7.23 (7H, m), 3.68 (2H, s), 19 1.07 (2H, m), 0.93 (2H, m); and 100 mg (22%) of the N,N dibenzyl amine, 1H
NMR (CDC13) 8: 7.55 (2H, d, J = 8.3 Hz), 7.40-7.19 (12H, m), 3.61 (4H, s), 21 0.87 (2H, m), 0.71 (2H, m).
22 Benzyl-[1-(4-trimeth~silanyleth~nyl-phenyl-cycloprop~]-amine 23 (Intermediate I26) 24 Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 110.0 mg, 0.36 mmol) in triethylamine (8 mL) was 26 treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with 27 argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then 28 added followed by dichlorobis(triphenylphosphine)palladium(II) (38.0 mg, 1 0.05 mmol). The resulting reaction mixture was heated to 70 °C for Sd. The 2 title compound 85 mg (74%) was isolated by chromatography (1 - 10% EtOAc 3 - hexanes).
4 'H NMR (CDC13) 8: 7.46 (2H, d, J = 8.3 Hz), 7.31-7.22 (7H, m), 3.67 (2H, s), 1.06 (2H, m), 0.94 (2H, m), 0.26 (9H, s).
6 Benzyl-f 1-(4-ethynylphenyl~-cycloprop~ll-amine (Intermediate 127) 7 Using General Pocedure E; benzyl-[1-(4-trimethylsilanylethynyl-8 phenyl)-cyclopropyl]-amine (Intermediate 126, 85.0 mg, 0.27 mmol) in 9 methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) I O and stirred overnight at ambient temperature. The crude alkyne (65 mg, 11 100%) was used directly in the next reaction.
12 'H NMR (CDCl3) 8: 7.49 (2H, d, J = 7.9 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.23 13 (5H, m), 3.68 (2H, s), 3.08 (1H, s), 1.07 (2H, m), 0.95 (2H, m).
14 Eth;~ 4-(4-(1-benzylamino-cXclopropyl)-phenyleth~yl]-benzoate (Compound 111, General Formula 2) 16 Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-17 amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate 18 (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with 19 copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes.
Dichlorobis (triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added 21 and the reaction mixture was stirred overnight at room temperature. Column 22 chromatography (2-5% EtOAc - hexanes) afforded 90 mg (90%) of the title 23 compound as an orange solid.
24 1H NMR (CDC13) b: 8.05 (2H, d, J = 8.3 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.43 (2H, d, J = 8.1 Hz), 7.32-7.22 (5H, m), 4.40 (2H, q, J
26 = 7.1 Hz), 3.72 (2H, s), 1.42 (2H, t, J = 7.1 Hz), 1.01 (2H, m), 0.99 (2H, m).
27 4-(~1-Benzylamino-c~clopro~yl~phenylethxn~]-benzoic acid (Compound 28 112, General Formula 2) 1 Using General Procedure I; a solution of ethyl 4-[4-(1-benzylamino-2 cyclopropyl)-phenylethynyl]-benzoate (Compound 111, 75.0 mg, 0.19 mmol) 3 in ethanol (4 mL) and tetrahydrofuran (4 mL) was treated with NaOH (80.0 4 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (50%) of the title compound as 6 a colorless solid.
7 1H NMR (CD30D) 8: 7.93 (2H, d, J = 8.3 Hz), 7.61-7.51 (6H, m), 7.32-7.23 8 (5H, m), 3.98 (2H, s), 1.33(2H, m), 1.19 (2H, m).
9 Dibenzyl-[1-(,4-trimeth;~silanylethynyl-phenyl-c~prop~]-amine (Intermediate 128) 11 Using General Procedure D; dibenzyl-[1-(4-bromophenyl)-12 cyclopropyl]-amine (Intermediate 125, 45.0 mg, 0.11 mmol) in triethylamine 13 (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then 14 sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.35 g, 3.6 mmols) was then added followed by 16 dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The 17 resulting reaction mixture was heated to 70 °C for Sd. The title compound 40 18 mg (88%) was isolated by chromatography (hexanes).
19 'H NMR (CDC13) 8: 7.52 (2H, d, J = 8.3 Hz), 7.36-7.24 (12H, m), 3.60 (4H, s), 0.87 (2H, m), 0.67 (2H, m), 0.29 (9H, s).
21 Dibenzyl-[1-(4-eth;~n~phenyl)-c~clopropyl]-amine (Intermediate 129) 22 Using General Procedure E; dibenzyl-[1-(4-trimethylsilanylethynyl-23 phenyl)-cyclopropyl]-amine (Intermediate 128, 100.0 mg, 0.26 mmol) in 24 methanol (5 mL) was treated with potassium carbonate (60.0 mg, 0.44 mmol) and stirred overnight at ambient temperature. The crude alkyne (80 mg, 99%) 26 was used directly in the next reaction.
27 'H NMR (CDC13) ~: 7.53 (2H, d, J = 7.9 Hz), 7.36 (2H, d, J = 7.9 Hz), 7.28-28 7.25 (10H, m), 3.62 (4H, s), 3.11 (1H, s), 0.88 (2H, m), 0.68 (2H, m).
1 Ethvl 4 f 4 ( 1 dibenzylamino cyclopronyll-phenylethynyll-benzoate 2 (Compound 113, General Formula 2) 3 Using General Procedure F; dibenzyl-[1-(4-ethynylphenyl)-4 cyclopropyl]-amine (Intermediate 129, 40.0 mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was 6 treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 7 minutes. Dichlorobis (triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) 8 was added and the reaction mixture was stirred overnight at room temperature.
9 Column chromatography (2-5% EtOAc - hexanes) afforded the title compound as an oil.
11 1H NMR (CDC13) ~: 8.04 (2H, d, J = 8.5 Hz), 7.79 (4H, m), 7.42 (2H, d, J =
12 7.9 Hz), 7.29-7.17 (10H, m), 4.40 (2H, q, J = 7.1 Hz), 3.63 (4H, s), 1.42 (3H, t, 13 J = 7.1 Hz), 0.88 (2H, m), 0.73 (2H, m).
14 4-f4-(1-Dibenzylamino-cvclopropyll-phenylethynyl]-benzoic acid (Compound 114, Formula 2) 16 Using General Procedure I; a solution of ethyl 4-[4-(1-dibenzylamino-17 cyclopropyl)-phenylethynyl]-benzoate (Compound I13, 48.0 mg, 0.10 mmol) 18 in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 19 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 42.0 mg (93%) of the title compound as 21 a colorless solid.
22 1H NMR (d6-DMSO) 8: 7.98 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 7.64 23 (2H, d, J = 7.9 Hz), 7.47 (2H, d, J = 7.9 Hz), 7.28-7.20 (10H, m), 3.57 (4H, s), 24 0.84 (2H, m), 0.69 (2H, m).
Benzvl-f 1-(4-bromo~henYll-c~clopropyl]-methylamine (Intermediate 130) 26 To a solution of benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine 27 (Intermediate 124, 100.0 mg, 0.33 mmol) in 5 mL of acetone was added 28 KZCO3 (91 mg, 0.66 mmol) and iodomethane (2.28 g, 16.1 mmols). The 1 resulting mixture was stirred at 25 °C for 20 hours, diluted with EtzO, and 2 washed with H20 and saturated aqueous NaCl. The solution was dried 3 (MgS04) and concentrated under reduced pressure to give 90 mg (86%) of the 4 title compound.
1H NMR (CDCl3) S: 7.47 (2H, d, J = 8.5 Hz), 7.29-7.18 (7H, m), 3.53 (2H, s), 6 2.07 (3H, s), 1.07 (2H, m), 0.86 (2H, m).
7 Benzyl f 1 (4 trimethXlsilanylethynyl-phenyl-cyclonronyll-methylamine 8 (Intermediate 131) 9 Using General Procedure D; benzyl-[I-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130, 90.0 mg, 0.28 mmol) in triethylamine (8 11 mL) was treated with copper(I)iodide (6.0 mg, 0.03 mmol) and then sparged 12 with argon for S minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was 13 then added followed by dichlorobis(triphenylphosphine)palladium(II) (20.0 14 mg, 0.03 mmol). The resulting reaction mixture was heated to 70 °C
for 5 days. The title compound 80 mg (84%) was isolated by chromatography (0-16 2% EtOAc-hexanes).
17 'H NMR (CDCl3) ~: 7.46 (2H, d, J = 8.2 Hz), 7.32-7.18 (7H, m), 3.52 (2H, s), 18 2.06 (3H, s), 1.06 (2H, m), 0.87(2H, m), 0.26 (9H, s).
19 Benzvl-(1-(4-ethyn~phen~l-c~prop~]-rnethylamine (Intermediate 132) Using General Procedure E; benzyl-[I-(4-trimethylsilanylethynyl-21 phenyl)-cyclopropyl]-methylamine (Intermediate 131, 80.0 mg, 0.24 mmol) 22 in methanol (5 mL) was treated with potassium carbonate (80.0 mg, 0.59 23 mmol) and stirred overnight at ambient temperature. The crude alkyne (60 24 mg, 99%) was used directly in the next reaction.
IH NMR (CDC13) 8: 7.49 (2H, d, J = 8.2 Hz), 7.33-7.21 (7H, m), 3.55 (2H, s), 26 3.08 (1H, s), 2.08 (3H, s), 1.07 (2H, m), 0.89 (2H, m).
27 Eth,~l 4-~4-f 1-(bent 1-~ylamino~-cycloaroyyl]~phenylethyn~~-benzoate 2~ (Compound 115, General Formula 2) 1 Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-2 methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo 3 benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (S mL) was 4 treated with copper(I)iodide ( 18.0 mg, 0.10 mmol) and sparged with argon for S S minutes. Dichlorobis (triphenylphosphine)palladium(II) (6S mg, 0.10 mmol) 6 was added and the reaction mixture was stirred overnight at room temperature.
7 Column chromatography (2-S% EtOAc - hexanes) afforded 86 mg (7S%) of 8 the title compound as an oil.
9 1H NMR (CDCl3) 8: 8.03 (2H, d, J = 8.S Hz), 7.59 (2H, d, J = 8.S Hz), 7.53 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.25 (SH, m), 4.39 (2H, q, J =
7.1 11 Hz), 3.57 (2H, s), 2.10 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 1.10 (2H, m), 0.92 12 (2H, m).
13 4-f4~1-Benz l~xlamino-cycloprop~ll-phenyleth~~]-benzoic acid 14 (Compound 1I6, General Formula 2) 1 S Using General Procedure I; a solution of ethyl 4- f 4-[1-(benzyl-16 methylamino)-cyclopropyl]-phenylethynyl~-benzoate (Compound 115, 65.0 17 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 18 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and 19 stirred overnight at room temperature. Work-up afforded 45.0 mg (7S%) of the title compound as a solid.
21 'H NMR (d6-DMSO) 8: 7.96 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 7.58 22 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.29-7.18 (SH, m), 3.52 (2H, s), 23 2.00 (3H, s),1.02 (2H, m), 0.87 (2H, m).
24 ~4-Bromo-2-meth 1-y phen,~~l)-methanol (Intermediate 133) 2S A solution of methyl 4-bromo-2-methyl-benzoate (1.0S g, 4.58 mmols) 26 in 10 mL of Et20 was cooled to 0 °C and treated with LiAIH4 (177.0 mg, 4.58 27 mmols), stirred for 3 hours, and then carefully quenched with HZO. The 28 mixture was extracted with Et20 and the combined organic layers were 1 washed with HZO and saturated aqueous NaCl, dried (MgS04), and 2 concentrated under reduced pressure. The title compound, 830.0 mg (90%), 3 was isolated by column chromatography (10-30% EtOAc-hexanes) as a 4 colorless oil.
1H NMR (CDC13) 8: 7.30 (2H, m), 7.18 (1H, d, J = 8.8 Hz), 4.57 (2H, d, J =
6 5.5 Hz), 2.27 (3H, s), 2.13 (1H, t, J = 5.5 Hz).
7 (4-Bromo-2-methyl-benz~oxyl-trimethylsilane (Intermediate 134) 8 To a solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 9 133, 500.0 mg, 2.48 mmols), in 10 mL THF was added triethylamine (374.0 mg, 3.70 mmols) and chlorotrimethylsilane (297.0 mg, 2.70 mmols). The 11 resulting solution was stirred for 17 hours at 25 °C and then treated with H20 12 and extracted with Et20. The combined organic layers were washed with HZO, 13 10% aqueous HCI, saturated NaHC03, and saturated NaCI before being dried 14 (MgS04) and concentrated under reduced pressure. The title compound, 550.0 I S mg (81 %), was isolated by column chromatography (5% EtOAc-hexanes) as a 16 colorless oil.
17 1H NMR (CDC13) b: 7.35-7.28 (3H, m), 4.64 (2H, s), 2.29 (3H, s), 0.20 (9H, 18 s).
19 2-Methyl-4-trimethylsilanylethxnyl-1-trimeth~lsilanyloxymethxl-benzene (Intermediate 135) 21 Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-22 trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 23 mL) was treated with copper(I)iodide (3 8.0 mg, 0.20 mmol) and then sparged 24 with argon for 5 minutes. Trimethylsilyl acetylene ( 1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 26 mg, 0.20 mmol). The resulting reaction mixture was heated to 70 °C
for 5 27 days. The title compound (380.0 mg, 65%) was isolated by chromatography 28 (0 - 2% EtOAc - hexanes) as an orange oil.
1 'H NMR (CDC13) 8: 7.31 (3H, m), 4.64 (2H, s), 2.24 (3H, s), 0.24 (9H, s), 0.15 2 (9H, s).
3 (4-Ethvn~-2-meth T~l-phenyll-methanol (Intermediate 136) 4 Using General Procedure E; 2-methyl-4-trimethylsilanylethynyl-1-trimethylsilananyloxymethyl-benzene (Intermediate 135, 380.0 mg, 1.30 6 mmols) in methanol (10 mL) was treated with potassium carbonate (180.0 mg, 7 1.3 mmol) and stirred overnight at ambient temperature. The crude alkyne 8 was purified by column chromatography (5-20% EtOAc-hexanes) to give 9 100.0 mg (34%) of the title compound.
'H NMR (CDCI3) 8: 7.06 (3H, m), 4.42 (2H, d, J = 5.2 Hz), 2.81 (1H, s), 2.05 11 (3H, s), 1.59 ( 1 H, t, J = 5.2 Hz).
12 Eth,~(4-hydxox~meth,~-3-meth 1-y phen~eth~n~ -benzoate (Compound 13 117, General Formula 6) _ 14 Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate 16 (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with 17 copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes.
18 Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added 19 and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc - hexanes) afforded 130.0 mg (99%) of the 21 title compound as an orange solid.
22 'H NMR (CDCI3) 8: 7.98 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.36 23 (3H, m), 4.65 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 2.40 (1H, s), 2.30 (3H, s), 1.39 24 (3H, t, J = 7.1 Hz).
Ethyl 4-(4-bromomethyl-3-meth ~~l-phen~leth~n~l-benzoate (Intermediate 26 137) 27 A solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-28 benzoate (Compound 117, 130.0 mg, 0.44 mmol) and triphenylphosphine 1 (150.0 mg, 0.57 mmol) in 5 mL CH2C12 was cooled to 0 °C and N
2 bromosuccinimide (101.0 mg, 0.57 mmol) was added in 5 portions over 20 3 minutes. The solution was warmed to 25 °C and stirred for 17 hours.
The 4 reaction was quenched by the addition of dilute aqueous NaHC03. The resulting mixture was extracted with EtzO and the combined organic layers 6 were washed with HZO and saturated aqueous NaCl before being dried 7 (NaZS04) and concentrated under reduced pressure. The title compound, 120.0 8 mg (76%), was isolated by column chromatography (2-5% EtOAc-hexanes) as 9 a colorless solid.
'H NMR (CDC13) 8: 8.01 (2H, d, J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz), 7.32 11 (3H, m), 4.48 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 2.40 (3H, s), 1.39 (3H, t, J =
12 7.1 Hz).
13 Ethyl4-(4-imidazol-1-yl-meths-3-methvl-phenyleth~~l-benzoate 14 (Compound 118, General Formula 6) A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF was 16 treated with NaH (11.0 mg, 0.44 mmol) and heated to 90 °C. After 1h a 17 solution of ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate 18 (Intermediate 137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added and 19 stirnng at 90 °C continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 21 90.0 mg (71 %) was isolated by column chromatography (20-100% EtOAc-22 hexanes) as a colorless solid.
23 1H NMR (CDC13) ~: 8.02 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.51 24 (lH,s),7.40(lH,s),7.36(lH,dd,J=1.2,7.9Hz),7.10(lH,s),6.93(lH,d,J
= 7.9 Hz), 6.88 (1H, t, J = 1.7 Hz), 5.12 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 2.27 26 (3H, s), 1.40 (3H, t, J = 7.1 Hz).
27 ~4-Imidazol-1- 1-methXl-3-methyl-phenyleth~nyl)-benzoic acid 28 (Compound 119, General Formula 6) 1 Using General Procedure I; a solution of ethyl 4-(4-imidazol-1-2 ylmethyl-3-methyl-phenylethynyl)-benzoate (Compound 1I8, 82.0 mg, 0.24 3 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH
4 (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight S at room temperature. Work-up afforded S 1.0 mg (68%) of the title compound 6 as a solid.
7 'H NMR (d6-DMSO) S: 9.20 (1H, s), 7.97 (2H, d, J = 8.2 Hz), 7.73 (2H, m), 8 7.65 (2H, d, J = 8.2 Hz), 7.52 (1H, s), 7.46 (1H, d, J = 7.9 Hz), 7.13 (1H, d, J =
9 7.9 Hz), S.SO (2H, s), 2.32 (3H, s).
4-Bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138) 11 A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 12 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in S mL
13 CH2Clz was cooled to 0 °C and N bromosuccinimide (309.0 mg, 1.74 mmol) 14 was added in S portions over 20 minutes. The solution was warmed to 2S
°C
and stirred for 17 hours. The reaction was quenched by the addition of dilute 16 aqueous NaHC03. The resulting mixture was extracted with Et20 and the 17 combined organic layers were washed with H20 and saturated aqueous NaCI
18 before being dried (NazS04) and concentrated under reduced pressure. The 19 title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil.
21 1 H NMR (CDC13) 8: 7.32 ( 1 H, d, J = 2.0 Hz), 7.29 ( 1 H, dd, J = 2.0, 7.9 Hz), 22 7.15 (1H, d, J = 7.9 Hz), 4.43 (2H, s), 2.37 (3H, s).
23 1-(4-Bromo-2-meth 1-~yl)-1H imidazole (Intermediate 139) 24 A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was 2S treated with NaH (20.0 mg, 0.86 mmol) and heated to 90 °C. After 1h a 26 solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 27 190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90 °C
28 continued for lhour. The solution was cooled to room temperature and 1 concentrated under reduced pressure. The title compound, 160.0 mg (88%) 2 was isolated by column chromatography (5% MeOH-EtOAc) as a colorless 3 solid.
4 'H NMR (CDC13) ~: 7.46 (1H, s), 7.34 (1H, dd, J = 1.8 Hz), 7.30 (1H, dd, J =
1.8,8.2Hz),7.08(lH,t,J=1.2Hz),6.83(lH,t,J=l.2Hz),6.80(lH,d,J=
6 8.2 Hz), 5.03 (2H, s), 2.23 (3H, s).
7 1-~2-MethXl-4-trimethvlsilanyleth~nyl-benzyl)-1H imidazole (Intermediate 8 I40) 9 Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H
imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) 11 was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with 12 argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then 13 added followed by dichlorobis(triphenylphosphine)palladium(II) (45.0 mg, 14 0.07 mmol). The resulting reaction mixture was heated to 70 °C for 5 days.
The title compound (140.0 mg, 82%) was isolated by chromatography (5%
16 MeOH-EtOAc ) as an orange oil.
17 1H NMR (CDCl3) 8: 7.53 (1H, s), 7.38 (1H, s), 7.34 (1H, d, J = 8.0 Hz), 7.15 18 ( 1 H, s), 6.94 ( 1 H, s), 6.91 ( 1 H, d, J = 8.0 Hz), 5.14 (2H, s), 2.29 (3H, s), 0.31 19 (9H, s).
1-(4-Ethynyl-2-meth,1-~yl)-1H imidazole (Intermediate 141) 21 Using General Procedure E; I-(2-methyl-4-trimethylsilanylethynyl-22 benzyl)-11I imidazole (Intermediate 140, 140.0 mg, 0.53 mmols) in methanol 23 (5 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and 24 stirred overnight at ambient temperature. The crude alkyne (105 mg, 100%) was used directly in the next reaction.
.26 1H NMR (CDC13) 8: 7.49 (1H, s), 7.35 (1H, s), 7.31 (1H, dd, J = 1.7, 7.9 Hz), 27 7.10 ( 1 H, s), 6.69 ( 1 H, d, J = 7.9 Hz), 6. 85 ( 1 H, t, J =1.2 Hz), 5.14 (2H, s), 28 3.08 (1H, s), 2.26 (3H, s).
1 Methyl [4 ~4 imidazol 1 y1 methyl 3 methyl-uhenylethY_nyll-phenyll-acetate 2 (Compound 120, General Formula 6) 3 Using General Procedure F; 1-(4-ethynyl-2-methyl-benzyl)-1H
4 imidazole (Intermediate 141, 101.0 mg, 0.53 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 145.0 mg, 0.53 mmol) in triethylamine (5 6 mL) was treated with copper(I)iodide (34.0 mg, 0.18 mmol) and sparged with 7 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (124 mg, 8 0.18 mmol) was added and the reaction mixture was stirred overnight at room 9 temperature. Column chromatography (5% MeOH-EtOAc) afforded 45.0 mg (25%) of the title compound as an orange oil.
11 1H NMR (CDCl3) b: 7.47 (3H, m), 7.35 (3H, m), 7.27 (3H, m), 6.91 (1H, d, J
=
12 7.3 Hz), 5.11 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 2.26 (3H, s).
13 f4~(4-Imidazol-1-yl-meth,~-3-methyl-phenylethynyl)-phenyl]-acetic acid 14 (Compound 121, General Formula 6) Using General Procedure I; a solution of methyl [4-(4-imidazol-1-16 ylmethyl-3-methyl-phenylethynyl)-phenyl]-acetate (Compound 120, 45.0 mg, 17 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with 18 NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred 19 overnight at room temperature. Work-up afforded 30.0 mg (70%) of the title compound as a pale-orange solid.
21 1H NMR (d4-MeOH) 8: 8.97 (1H, s), 7.60 (2H, d J = 8.8 Hz), 7.47 (3H, m), 22 7.41 ( 1 H, d, J = 7.9 Hz), 7.3 0 (2H, d, J = 7.9 Hz), 7.23 ( 1 H, d, J =
7.9 Hz), 23 5.51 (2H, s), 3.64 (2H, s), 2.33 (3H, s).
24 1-Isopropyl-3-methox~-benzene (Intermediate 142) To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL of 26 acetone was added K.ZC03 (7.50 g, 54.3 mmols) and iodomethane (10.3 g, 72.5 27 mmols). The resulting solution was heated to 50 °C and stirred for 18 hours, 28 cooled to room temperature, and concentrated under reduced pressure. The 1 residual oil was dissolved in Et20 and washed with HZO, saturated aqueous 2 NaHC03, and saturated aqueous NaCI before being dried (MgS04) and 3 concentrated under reduced pressure. The crude methyl ether was used 4 without further purification.
S 'H NMR (CDC13) 8: 7.22 (1H, t, J = 8.1 Hz), 6.84-6.72 (3H, m), 3.81 (3H, s), 6 2.88 (1H, septet, J = 7.0 Hz), 1.25 (6H, d, J = 7.0 Hz).
7 1-Bromo-2-iso~rop~l-4-methoxy-benzene (Intermediate 143) 8 A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 9 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CC14 was treated with N bromosuccinimide (4.98 g, 28.0 mmols) at 35 °C for 18 hours. An 11 additional portion of N bromosuccinimide (830.0 mg, 4.46 mmols) was added 12 and stirring continued for 6 hours. The mixture was cooled to room 13 temperature, H20 was added, and the mixture was filtered to remove the 14 solids. The mixture was extracted with Ea0 and the combined organic layers were washed with 10% aqueous HCl, HZO, saturated aqueous NaHC03, and 16 saturated NaCl before being dried (MgS04) and concentrated under reduced 17 pressure. Column chromatography (2.5% EtOAc-hexanes) afforded 4.34 g 18 (81 %) of the title compound as a pale-yellow oil.
19 'H NMR (CDC13) S: 7.4I ( I H, d, J = 8.8 Hz), 6.82 ( 1 H, d, J = 2.6 Hz), 6.61 (1H, dd, J = 2.6, 8.8 Hz), 3.79 (3H, s), 3.31 (1H, septet, J = 6.7 Hz), 1.23 (6H, 21 d,J=6.7Hz).
22 4-Bromo-3-isoprop.~~l-phenol (Intermediate 144) 23 To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene 24 (Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CHZC12 at -78 °C was added BBr3 (4.81 g, 19.2 mmols; 19.2 mL of a 1M solution in CH2Clz). After stirring 26 for 3 hours at -78 °C the solution was warmed to 0 °C for 3 hours and then at 27 25 °C for 1 hour before being quenched with H20. The mixture was diluted 28 with Et20 and washed with H20 and saturated aqueous NaCl, dried (NaZSO~) 1 and concentrated under reduced pressure. Column chromatography (2.5-10%
2 EtOAc-hexanes) afforded the title compound as a colorless oil.
3 'H NMR (CDC13) b: 7.38 (1H, d, J = 8.5 Hz), 6.79 (1H, d, J = 2.9 Hz), 6.57 4 ( 1 H, dd, J = 2.9, 8.5 Hz), 3 .31 ( 1 H, septet, J = 7.0 Hz), 1.22 (6H, d, J = 7.0 Hz).
6 (4-Bromo-3-iso~ropyl-phenoxxl-tent-butyl-dimeth~-silane (Intermediate 7 145) 8 A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 9 5.25 mmols), chloro-tent-butyl-dimethylsilane (0.95 g, 6.30 mmols), and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25 °C for 3 11 hours. The solution was diluted with H20 and extracted with Et20 and the 12 combined organic layers were washed with HzO, saturated aqueous NaCI, and 13 dried (MgS04) before being concentrated under reduced pressure. Column 14 chromatography (1-2% EtOAc-hexanes) afforded 1.50 g (87%) of the title compound as a colorless oil.
16 1H NMR (CDC13) ~: 7.32 (1H, d, J = 8.8 Hz), 6.73 (1H, d, J = 3.0 Hz), 6.52 17 ( 1 H, dd, J = 3 .0, 8 . 8 Hz), 3 .26 ( 1 H, septet, J = 6.7 Hz), 1.19 (6H, d, J = 6.7 18 Hz), 0.96 (9H, s), 0.17 (6H, s).
19 4-(Tent-butyl-dimeth 1-y silan~loxyl-2-isopropyl-benzaldehyde (Intermediate 146) 21 A solution of (4-bromo-3-isopropyl-phenoxy)-tent-butyl-dimethyl-22 silane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E20 was cooled to -23 78 °C and treated with tent-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a 24 1.7M solution in pentane). After 30 minutes the reaction was quenched with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. The solution 26 was diluted with HzO, extracted with Et20 and the combined organic layers 27 washed with H20 and saturated aqueous NaCl before being dried (MgS04) and 28 concentrated under reduced pressure. Column chromatography (2% EtOAc-1 hexanes) afforded 480.0 mg (SS%) of the title compound as a colorless oil.
2 1H NMR (CDC13) 8: 10.19 (1H, s), 7.72 (1H, d, J = 8.5 Hz), 6.85 (1H, d, J =
3 2.3 Hz), 6.77 (1H, dd, J = 2.3, 8.5 Hz), 3.97 (1H, septet, J = 6.7 Hz), 1.27 (6H, 4 d, J = 6.7 Hz), 1.00 (9H, s), 0.25 (6H, s).
4-Hydrox -~isopronyl-benzaldehyde (Intermediate 147) 6 To a solution of 4-(test-butyl-dimethyl-silanyloxy)-2-isopropyl-7 benzaldehyde (Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0 8 °C was added tetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL
of a 9 1M solution in THF). The pale-yellow solution was stirred for 30 minutes and quenched by the addition of ice cold H20. The mixture was extracted with 11 EtaO and the combined organic layers were washed with H20 and saturated 12 aqueous NaCl before being dried (NaZS04) and concentrated under reduced 13 pressure. Column chromatography (20% EtOAc-hexanes) afforded 500.0 mg 14 (96%) of the title compound as a colorless solid.
IS 1H NMR (CDCl3) 8: 10.15 (1H, s), 7.79 (1H, d, J = 8.S Hz), 6.95 (1H, d, J =
16 2.3 Hz), 6.86 ( 1 H, dd, J = 2.3, 8.5 Hz), 3.96 ( 1 H, septet, J = 6.7 Hz), 1.29 (6H, 17 d,J=6.7Hz).
18 4-Form,1-~pro~~phenyl 1,1 1-trifluoro-methansulfonate (Intermediate 19 148) A solution of 4-hydroxy-2-isopropyl-benzaldehyde (Intermediate 147, 21 300.0 mg, 1.83 mmol) in 10 mL of CH2C12 was cooled to 0 °C and to it was 22 added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-S-chloropyridine (754.0 mg, 23 1.92 mmol) and triethylamine (592.0 mg, 5.85 mmols). The resulting solution 24 was warmed to room temperature and stirred for 4.5 hours. The reaction was quenched by the addition of HBO and the mixture extracted with EtOAc and 26 the combined organic layers were washed with 10% aqueous HCI, saturated 27 aqueous NaHC03, H20, and saturated aqueous NaCI. The solution was dried 28 (MgS04) and concentrated under reduced pressure. The title compound was 1 isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless 2 oil, 470.0 mg (87%).
3 'H NMR (CDCl3) 8: 10.37 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J =
4 2.3 Hz), 7.26 ( 1 H, dd, J = 2.3, 8 . 5 Hz), 4.00 ( 1 H, septet, J = 6.7 Hz), 1.3 3 (6H, d, J = 6.7 Hz), 6 4 Hydroxymeth~l-3-isonro~yl-phenyl 1,,1,1-trifluoro-methansulfonate 7 (Intermediate 149) 8 To a solution of 4-formyl-3-isopropyl-phenyl 1,1,1-trifluoro-9 methansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL MeOH
at 0 °C was added NaBH4 (72.0 mg, 1.91 mmols). After stirring 2 hours at 0 11 °C the reaction was carefully quenched with HZO and extracted with Et20.
12 The combined organic layers were washed with Ha0 and saturated aqueous 13 NaCl, dried (MgS04), and concetrated under reduced pressure. The title 14 compound was isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless oil, 355.0 mg (90%).
16 iH NMR (CDC13) 8: 7.45 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 2.7 Hz), 7.08 17 ( 1 H, dd, J = 2.7, 8.5 Hz), 4.74 (2H, d, J = 5.3 Hz), 3 .21 ( 1 H, septet, J = 7.0 18 Hz), 2.12 ( 1 H, t, J = 5.3 Hz), 1.24 (6H, d, J = 7.0 Hz).
19 4-(Tent-but 1-~dim_eth 1-y silan~loxxmethyll-3-isopropyl-phenyl 1 1 1-trifluoro-methansulfonate (Intermediate 150) 21 A solution of 4-hydroxymethyl-3-isopropyl-phenyl 1,1,1-trifluoro-22 methansulfonate (Intermediate 149, 760.0 mg, 2.55 mmols), chloro-tert-23 butyl-dimethylsilane (470.0 mg, 3.18 mmols), and imidazole (225.0 mg, 3.25 24 mmols) in 6 mL DMF was stirred at 25 °C for 17 hours. The solution was 2S diluted with H20 and extracted with Et20 and the combined organic layers 26 were washed with 10% aqueous HCI, saturated aqueous NaHC03, HZO, and 27 saturated aqueous NaCl, and dried (MgS04) before being concentrated under 28 reduced pressure. Column chromatography (2-5% EtOAc-hexanes) afforded 1 970.0 mg (92%) of the title compound as a colorless oil.
2 1H NMR (CDC13) 8: 7.49 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 2.3 Hz), 7.06 3 (1H, dd, J = 2.3, 8.5 Hz), 4.75 (2H, s), 3.10 (1H, septet, J = 6.7 Hz), 1.21 (6H, 4 d, J = 6.7 Hz), 0.93 (9H, s), 0.10 (6H, s).
1-~Ter~t-butyl-dimethxl-silanXlox~lnethyll-2-isoaropyl-4-6 trimeth. l~~ethynyl-benzene (Intermediate 151) 7 To a solution of 4-(te~~t-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-8 phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 150, 970.0 mg, 2.35 9 mmols) in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15 minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then added 11 followed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09 12 mmol). The resulting reaction mixture vvas heated to 95 °C for 20 hours. The 13 solution was cooled to room temperature and concentrated under reduced 14 pressure. The title compound (200.0 mg, 78%) was isolated by chromatography (0-25% EtOAc-hexanes) as an orange oil.
16 1H NMR (CDC13) 8: 7.37-7.25 (3H, m), 4.75 (2H, s), 3.08 (1H, septet, J =
7.0 17 Hz), 1.21 (6H, d, J = 7.0 Hz), 0.92 (9H, s), 0.25 (9H, s), 0.09 (6H, s).
18 Test-but ~~1-(4-ethynyl-2-isoprop 1-b~enz_~~l-dimethyl-silane (Intermediate 19 152) Using General Procedure E; 1-(test-butyl-dimethyl-silanyloxymethyl)-21 2-isopropyl-4-trimethylsilanylethynyl-benzene (Intermediate 151, 850.0 mg, 22 2.36 mmols) in methanol (25 mL) was treated with potassium carbonate 23 (250.0 mg, 1.81 mmols) and stirred overnight at ambient temperature. The 24 crude alkyne (650 mg, 95%) was used directly in the next reaction.
1H NMR (CDCl3) 8: 7.41-7.25 (3H, m), 4.77 (2H, s), 3.07 (1H, septet, J = 7.0 26 Hz), 3.05 (1H, s), 1.22 (6H, d, J = 7.0 Hz), 0.94 (9H, s), 0.11 (6H, s).
27 Ethyl 4-[4 ~tert-butyl-dimethyl-silanxlox~methyl~-3-isopropyl-28 phen~lethynyl]-benzoate (Intermediate 153) 1 Using General procedure F; test-butyl-(4-ethynyl-2-isopropyl-2 benzyloxy)-dimethyl-silane (Intermediate 152, 300.0 mg, 1.04 mmols) and 3 ethyl-4-iodo benzoate (Reagent A, 287.0 mg, 1.04 mmols) in triethylamine 4 (8mL) was treated with copper(I)iodide (50.0 mg, 0.26 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (182 6 mg, 0.26 mmol) was added and the reaction mixture was stirred overnight at 7 room temperature. Column chromatography (2-4% EtOAc - hexanes) 8 afforded 310.0 mg (68%) of the title compound as an orange solid. .
9 'H NMR (CDC13) b: 8.03 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.48-7.37 (3H, m), 4.80 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 3.14 (1H, septet, J =
6.8 11 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.27 (6H, d, J = 6.8 Hz), 0.96 (9H, s), 0.12 (6H, 12 s).
13 Meth.~~4-f4- test-butyl-dimethxl-silanyloxymethyl)-3-isopropy-1-14 phen, l~yn~ll-phenyl-acetate (Intermediate 154) Using General Procedure F; test-butyl-(4-ethynyl-2-isopropyl-16 benzyloxy)-dimethyl-silane (Intermediate 152, 355.0 mg, 1.26 mmols) and 17 methyl-(4-iodophenyl)-acetate (Reagent B, 349.0 mg, 1.26 mmols) in 18 triethylamine (8 mL) was treated with copper(I)iodide (60.0 mg, 0.32 mmol) 19 and sparged with argon for 5 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (222 mg, 0.32 mmol) was added 21 and the reaction mixture was stirred overnight at room temperature. Column 22 chromatography (2-5% EtOAc-hexanes) afforded 288.0 mg (66%) of the title 23 compound as an orange oil.
24 1H NMR (CDC13) b: 7.49 (2H, d, J = 8.5 Hz), 7.43-7.35 (3H, m), 7.25 (2H, d, J
= 8.5 Hz), 4.77 (2H, s), 3.69 (3H, s), 3.63 (2H, s), 3.11 (1H, septet, J = 6.7 26 Hz), 1.25 (6H, d, J = 6.7 Hz), 0.94 (9H, s), 0.10 (6H, s).
27 Ethyl f4-(4-hydroxymethyl-3-isopropyl-phen~lethyn~l-benzoate 28 (Compound 122, General Formula 6) 1 To a solution of ethyl 4-[4-(test butyl-dimethyl-silanyloxymethyl)-3-2 isopropyl-phenylethynyl]-benzoate (Intermediate 153, 310.0 mg, 0.71 mmol) 3 in 4 mL THF at 0 °C was added tetrabutylammonium fluoride (371.0 mg, 1.42 4 mmols; 1.4 mL of a 1M solution in THF). The pale-yellow solution was stirred for 10 minutes and quenched by the addition of ice cold H20. The 6 mixture was extracted with Et20 and the combined organic layers were 7 washed with Ha0 and saturated aqueous NaCl before being dried (Na2S04) 8 and concentrated under reduced pressure. Column chromatography (20-30%
9 EtOAc-hexanes) afforded 200.0 mg (87%) of the title compound as a colorless solid.
11 'H NMR (CDC13) 8: 7.98 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.48 12 ( 1 H, s), 7.3 5 (2H, m), 4.71 (2H, s), 4.3 5 (2H, q, J = 7.1 Hz), 3 .19 ( 1 H, septet, J
13 = 7.0 Hz), 2.51 (1H, s), 1.39 (3H, t, J = 7.1 Hz), 1.25 (6H, d, J = 7.0 Hz).
14 Methyl f4- 4-h~droxymethyl-3-isopropyl-phen 1y ethyn~l-phenyll-acetate I S (Compound 123, General Formula 6) 16 To a solution of methyl f 4-[4-(test-butyl-dimethyl-silanyloxymethyl)-17 3-isopropyl-phenylethynyl]-phenyl-acetate (Intermediate 154, 288.0 mg, 18 0.66 mmol) in 5 mL THF at 0 °C was added tetrabutylammonium fluoride 19 (471.0 mg, 1.80 mmols; 1.8 mL of a 1M solution in THF). The pale-yellow solution was stirred for 15 minutes and quenched by the addition of ice cold 21 H20. The mixture was extracted with EtzO and the combined organic layers 22 were washed with HZO and saturated aqueous NaCI before being dried 23 (Na2S04) and concentrated under reduced pressure. Column chromatography 24 (5-10% EtOAc-hexanes) afforded 180.0 mg (85%) of the title compound as a colorless solid.
26 'H NMR (CDCl3) 8: 7.48 (3H, m), 7.32 (2H, m), 7.24 (2H, d, J = 8.5 Hz), 4.69 27 (2H, s), 3.68 (3H, s), 3.62 (2H, s), 3.18 (1H, septet, J = 7.0 Hz), 2.21 (1H, s), 28 1.25 (6H, d, J = 7.0 Hz).
1 Ethvl ~4 (4 bromomethyl 3 isopropyl-phenylethynyll-benzoate 2 (Intermediate 155) 3 A solution of ethyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-4 benzoate (Compound 122, 200.0 mg, 0.62 mmol) and triphenylphosphine S (211.0 mg, 0.81 mmol) in 5 mL CH2C12 was cooled to 0 °C and N
6 bromosuccinimide (144.0 mg, 0.81 mmol) was added in 5 portions over 20 7 minutes. The solution was warmed to 25 °C and stirred for 17 hours.
The 8 reaction was quenched by the addition of dilute aqueous NaHC03. The 9 resulting mixture was extracted with Et20 and the combined organic layers were washed with H20 and saturated aqueous NaCI before being dried 11 (NaZS04) and concentrated under reduced pressure. The title compound, 220.0 12 mg (93%), was isolated by column chromatography (5% EtOAc-hexanes) as a 13 pale-yellow solid.
14 1H NMR (CDC13) ~: 8.03 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.48 ( 1 H, s), 7.31 (2H, m) 4.5 5 (2H, s), 4.3 9 (2H, q, J = 7.1 Hz), 3 .29 ( 1 H, septet, J
16 = 7.0 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.30 (6H, d, J = 7.0 Hz).
17 Meth j~4-bromomethXl-3-iso~ropyl-phen~ethynYl)-phen~]-acetate 18 (Intermediate 156) 19 A solution of methyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and 21 triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CHZC12 was cooled to 0 22 °C and N bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions 23 over 20 minutes. The solution was warmed to 25 °C and stirred for 17 hours.
24 The reaction was quenched by the addition of dilute aqueous NaHC03. The resulting mixture was extracted with Et20 and the combined organic layers 26 were washed with H20 and saturated aqueous NaCl before being dried 27 (NaZS04) and concentrated under reduced pressure. The title compound, 212.0 28 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) 1 as a pale-yellow oil.
2 1H NMR (CDC13) b: 7.48 (3H, m), 7.28 (4H, m), 4.55 (2H, s), 3.69 (3H, s), 3 3.63 (2H, s), 3.28 (1H, septet, J = 7.0 Hz), 1.30 (6H, d, J = 7.0 Hz).
4 Ethyl [4-(4-imidazol-1- 1-meth 1-~propyl-phenyleth~yll-phen~]-S benzoate (Compound 124, General Formula 6) 6 A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-7 benzoate (Intermediate 155, 120.0 mg, 0.31 mmol) and 1-acetylimidazole 8 (36.0 mg, 0.33 mmol) in S mL CH3CN was heated at 6S °C for 4 hours and 9 then at SS °C for 16 hours. The solution was cooled to room temperature, diluted with H20 and made basic by addition of NaZC03, and extracted with 11 EtOAc. The combined organic layers were washed with H20 and saturated 12 aqueous NaCI, dried (MgS04), and concentrated under reduced pressure.
13 Column chromatography (1% Et3N in S% MeOH-EtOAc) afforded 75.0 mg 14 (65%) of the title compound as a colorless solid.
1H NMR (CDC13) 8: 8.03 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.S Hz), 7.53 16 (1H, d, J = 1.S Hz), 7.49 (1H, s), 7.35 (1H, dd, J = 1.5, 7.9 Hz), 7.09 (1H, bs), 17 6.98 (1H, d, J = 7.9 Hz), 6.85 (1H, bs), 5.19 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 18 3.08 (1H, septet, J = 6.8 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.20 (6H, d, J =
6.8 Hz).
19 Meths[4-(4-imidazol-1- 1-~~isopropyl-phen~leth~nyl)~henyl]=
acetate (Compound 125, General Formula 6) 21 A solution of methyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-22 phenyl]-acetate (Intermediate 156, 72.0 mg, 0.19 mmol) and 1-23 acetylimidazole (22.0 mg, 0.20 mmol) in S mL CH3CN was heated at 6S
°C
24 for 8h and then at SS °C for 16 hours. The solution was cooled to room 2S temperature, diluted with H20 and made basic by addition of Na2C03, and 26 extracted with EtOAc. The combined organic layers, were washed with H20 27 and saturated aqueous NaCI, dried (MgS04), and concentrated under reduced 28 pressure. Column chromatography (0.5% Et3N in S% MeOH-EtOAc) afforded " 1 40.0 mg (58%) of the title compound as a colorless solid.
2 'H NMR (CDCl3) 8: 7.49 (4H, m), 7.33 (1H, dd, J = 1.5, 7.9 Hz), 7.28 (2H, d, 3 J=8.SHz),7.08(lH,t,J=1.2Hz),6.95(lH,d,J=7.9Hz),6.84(lH,t,J=
4 1.2 Hz), 5.17 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 3.06 (1H, septet, J = 6.8 Hz), 1.20 (6H, d, J = 6.8 Hz).
6 [4-(4-Imidazol-1-yl-methyl-3-isoaropyl-phenylethynyll-phenyl]-benzoic acid 7 (Compound 126, General Formula 6) 8 ~Tsing General Procedure I; a solution of ethyl [4-(4-imidazol-1-9 ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate (Compound 124, 75.0 mg, 0.20 mmol) in ethanol (4 mL) and tetrahydrofuran ( 1 mL) was treated 11 with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and 12 stirred overnight at room temperature. Work-up afforded 68.0 mg (88%) of 13 the title compound as a colorless solid.
14 1H NMR (d4-MeOH) ~: 9.01 (1H, s), 8.01 (2H, d, J = 8.2 Hz), 7.63-7.57 (5H, 1S m), 7.44 (IH, d, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), S.S9 (2H, s), 3.I7 (1H, 16 septet, J = 6.8 Hz), 1.20 (6H, d, J = 6.8 Hz).
17 [~4-Imidazol-1-yl-meth,~isopropyl-phenXlethynyll~phenyl]-acetic acid 18 (Compound 127, General Formula 6) 19 lJsing General Procedure I; a solution of methyl [4-(4-imidazol-I-ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 125, 40.0 21 mg, 0.11 mmol) in ethanol (4 mL) and tetrahydrofuran ( 1 mL) was treated 22 with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and 23 stirred overnight at room temperature. Work-up afforded 22.0 mg (S2%) of 24 the title compound as a colorless solid.
'H NMR (d4-MeOH) S: 9.02 (1H, bs), 7.62 (1H, t, J = 1.4 Hz), 7.58 (2H, m), 26 7.49 (2H, d, J = 8.2 Hz), 7.43 (1H, dd, J = 1.5, 7.9 Hz), 7.31 (3H, m), 5.58 27 (2H, s), 3.68 (2H, s), 3.16 (1H, septet, J = 6.7 Hz), 1.18 (6H, d, J = 6.7 Hz).
28 4-Bromo-N c~propyl-2-methyl-benzamide (Intermediate 157) 1 A solution of 4-bromo-2-methylbenzoic acid and SOC12 was refluxed 2 for 3 hours, cooled to room temperature and concentrated under reduced 3 pressure. The residue was dissolved in 30 mL CH2C12 and combined with 4 cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0 mmols).
The solution was stirred for 18 hours and then diluted with EtOAc before 6 being washed with 5% aqueous HCI, saturated NaHC03, and saturated 7 aqueous NaCl. The solution was dried (MgS04) and concentrated under 8 reduced pressure leaving the title compound as a colorless solid.
9 1H NMR (CDCl3) ~: 7.34 ( 1 H, d, J = 2.3 Hz), 7.28 ( 1 H, dd, J = 2.3, 8.2 Hz), 7.13 (1H, d, J = 8.2 Hz), 6.10 (1H, bs), 2.85 (1H, m), 2.37 (3H, s), 0.85 (2H, 11 m), 0.59 (2H, m).
12 (4-Bromo-2-meth 1-~yl)-cycloprop~l-amine (Intermediate 158) 13 To a solution of 4-bromo-N cyclopropyl-2-methyl-benzamide 14 (Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH3~SMe2 (1.08 g, 14.24 mmols). The solution was heated to 60 °C
for 6 16 hours, cooled to room temperature and carefully treated with saturated 17 aqueous Na2C03 (30 mL) and stirred for 17 hours. This mixture was extracted 18 with EtOAc and the combined organic layers were washed with HZO, saturated 19 aqueous NaCI before being dried (MgS04) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-21 15% EtOAc-hexanes).
22 1H NMR (CDC13) 8: 7.26 (2H, m), 7.12 (1H, d, J = 7.9 Hz), 3.76 (2H, s), 2.31 23 (3H, s), 2.14 (1H, m), 0.44 (2H, m), 0.36 (2H, m).
24 (4-Bromo-2-meth 1-benz~~c~pro~yl-ether-amine (Intermediate 159) A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine 26 (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), 27 and KZC03 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60 °C fox 28 18 hours. The mixture was cooled to room temperature, diluted with H20, and 1 extracted with EtOAc. The combined organic layers were washed with Hz0 2 and saturated aqueous NaCl before being dried (MgS04) and concentrated 3 under reduced pressure. The title compound was isolated by column 4 chromatography (2.5% EtOAc-hexanes).
'H NMR (CDC13) 8: 7.23 (2H, m), 7.12 (1H, d, J = 7.6 Hz), 3.62 (2H, s), 2.56 6 (2H, q, J = 7.3 Hz), 2.29 (3H, s), 1.75 (1H, m), 1.04 (3H, t, J = 7.3 Hz), 0.39 7 (2H, m), 0.30 (2H, m).
8 Cyclopropyl-ethyl-(2-methyl-4-trimeth, ls~. 1~,~.~benz,~~l~amine 9 (Intermediate 160) Using General Procedure D; (4-bromo-2-methyl-benzyl)-cyclopropyl-11 ethyl-amine (Intermediate 159, 620.0 mg, 2.31 mmols) in triethylamine (8 12 mL) was treated with copper(I)iodide (44.0 mg, 0.23 mmol) and then sparged 13 with argon for 15 minutes. Trimethylsilylacetylene ( 1.04 g, 10.6 mmols) was 14 then added followed by dichlorobis-(triphenylphosphine)palladium(II) (162.0 mg, 0.23 mmol). The resulting reaction mixture was heated to 70 °C for 16 days. The title compound (650.0 mg, 98%) was isolated by chromatography 17 (1-4% EtOAc - hexanes).
18 'H NMR (CDCl3) S: 7.32 (1H, s), 7.20 (2H, m), 3.65 (2H, s), 2.5S (2H, q, J
=
19 7.3 Hz), 2.28 (3H, s), 1.74 (1H, m), 1.03 (3H, t, J = 7.3 Hz), 0.36 (2H, m), 0.27 (2H, m), 0.24 (9H, s).
21 C~clopropyl-ether(4-ethynyl-2-methyl-benzvll-amine (Intermediate 161) 22 Using General Procedure E; cyclopropyl-ethyl-(2-methyl-4-23 trimethylsilanylethynyl-benzyl)-amine (Intermediate 160, 650.0 mg, 2.30 24 mmols) in methanol (lOmL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne 26 (495 mg, 99%) was used directly in the next reaction.
27 'H NMR (CDCl3) 8: 7.32 (1H, s), 7.21 (2H, m), 3.66 (2H, s), 3.01 (1H, s), 2.56 28 (2H, q, J = 7.3 Hz), 2.29 (3H, s), 1.76 (1H, m), 1.04 (3H, t, J = 7.3 Hz), 0.40 I (2H, m), 0.29 (2H, m).
2 Ethyl~4- ~4-((c~cloprop~yl-amino)-meths]-3-methyl-phen~~nyl~-3 benzoate (Compound 128, General Formula 6) 4 Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo 6 benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was 7 treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 8 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 9 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc - hexanes) afforded the 11 title compound.
12 1H NMR (CDC13) 8: 8.01 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.31-13 7.24 (3H, m), 4.38 (2H, q, J = 7.1 Hz), 3.68 (2H, s), 2.58 (2H, q, J = 7.3 Hz), 14 2.32 (3H, s), 1.77 (1H, m), 1.39 (3H, t, J = 7.1 Hz), 1.05 (3H, t, J = 7.3 Hz), 0.39 (2H, m), 0.31 (2H, m).
16 Methyl (4-14-[(c~~cloprop~~l-amino)-methyll-3-methyl-phenyleth~n~)-17 phenyl)-acetate) (Compound 129, General Formula 6) I8 Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-19 benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 mmols) in triethylamine (8 21 mL) was treated with copper(I)iodide (67.0 mg, 0.35 mmol) and sparged with 22 argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 23 0.35 mmol) was added and the reaction mixture was stirred overnight at room 24 temperature. Column chromatography (5-7% EtOAc - hexanes) afforded 270.0 mg (53%) of the title compound as a pale-yellow oil.
26 'H NMR (CDC13) 8: 7.47 (2H, d, J = 7.9 Hz), 7.30-7.22 (5H, m), 3.70 (3H, s), 27 3.68 (2H, s), 3.63 (2H, s), 2.58 (2H, q, J = 7.3 Hz), 2.32 (3H, s), 1.77 (1H, m), 28 1.05 (3H, t, J = 7.3 Hz), 0.39 (2H, m), 0.30 (2H, m).
1 4-~4-[(CYcloprop~yl-aminol-methXl]-3-methyl-phen l~~yl -benzoic 2 acid: (Compound 130, General Formula 6) 3 Using General Procedure I; a solution of ethyl 4-~4-[(cyclopropyl-4 ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoate (Compound 128, 130.0 mg, 0.36 mmol) in ethanol (5 mL) and tetrahydrofuran {5 mL) was 6 treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) 7 and stirred overnight at room temperature. Work-up afforded 115.0 mg (96%) 8 of the title compound as a colorless solid.
9 'H NMR (d6-acetone) 8: 8.05 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.2 Hz), 7.32 (3H, m), 3.73 (2H, s), 2.59 (2H, q, J = 7.3 Hz), 2.35 (3H, s), 1.83 (1H, m), 11 1.05 (3H, t, J = 7.3 Hz), 0.38 (2H, m), 0.27 (2H, m).
12 (4- i4-[(C~loprop~yl-amino)-meths]-3-methyl-phenyleth~yl~phen~)-13 acetic acid (Compound 131, General Formula 6) 14 Using General Procedure I; a solution of methyl (4- f 4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl~-phenyl)-acetate (Compound 16 129, 140.0 mg, 0.39 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was 17 treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) 18 and stirred overnight at room temperature. Work-up followed by HPLC
19 (Partisil-10 pac 10% Ha0-CH3CN) afforded the title compound.
1H NMR (CDC13) 8: 7.45 (2H, d, J = 8.2 Hz), 7.25 (5H, m), 4.16 (2H, m), 3.82 21 (2H, s), 3.56 (2H, s), 2.75 (2H, q, J = 7.3 Hz), 2.30 (3H, s), 1.86 (1H, m), 1.14 22 (3H, t, J = 7.3 Hz), 0.54 (2H, m), 0.46 (2H, m).
23 Ethyl~~4-cyclopropylaminometh 1-3~-iso_propyl-then l~~n~ -benzoate 24 (Compound 132, General Formula 6) A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-26 benzoate (Intermediate 155, 110.0 mg, 0.29 mmol) and cyclopropylamine 27 (420.0 mg, 7.4 mmols) in EtOH (5 mL) was stirred at 25 °C for 6 hours and 28 then concentrated under reduced pressure. The residue was dissolved in 1 EtOAc and washed with saturated aqueous NaHC03, H20 and saturated 2 aqueous NaCI. The solution was dried (MgS04) and concentrated under 3 reduced pressure to give 103 mg (99%) of the title compound as an orange oil.
4 1H NMR (CDCl3) 8: 8.01 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.5 Hz), 7.47 ( 1 H, s), 7.3 0 (2H, m), 4.3 8 (2H, q, J = 7.1 Hz), 3.89 (2H, s), 3.26 ( 1 H, septet, J
6 = 7.0 Hz), 2.17 ( 1 H, m), 1.40 (3H, t, J = 7.1 Hz), 1.26 (6H, d, J = 7.0 Hz), 0.45 7 (2H, m), 0.39 (2H, m).
8 Eth~f4-[(c ~cloprop~yl-amino)-meths]-3-isoprop~phen~lethyn~~-9 benzoate (Compound 133, General Formula 6) To a solution of ethyl {4-(4-cyclopropylaminomethyl-3-isopropyl-11 phenylethynyl~-benzoate (Compound 132, 103.0 mg, 0.29 mmol) in 6 mL of 12 acetone was added ethyl iodide (67.0 mg, 0.43 mmol) and K2C03 (79.0 mg, 13 0.57 mmol). The mixture was stirred at 60 °C for 6 hours, cooled to room 14 temperature and quenched by the addition of H20. The mixture was extracted with EtOAc and the combined organic layers were washed with H20 and 16 saturated aqueous NaCI before being dried (MgS04) and concentrated under 17 reduced pressure. Column chromatography (4-5% EtOAc - hexanes) afforded 18 . 68.0 mg (59%) of the title compound.
19 IH NMR (CDC13) S: 8.01 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.44 (1H, s), 7.28 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 3.73 (2H, s), 3.55 (1H, septet, J
21 = 6.6 Hz), 2.57 (2H, q, J = 7.3 Hz), 1.75 (1H, m), 1.40 (3H, t, J = 7.1 hz), 1.22 22 (6H, d, J = 6.6 Hz), 1.05 (3H, t, J = 7.3 Hz), 0.37 (2H, m), 0.28 (2H, m).
23 4-~4-[~CyclopropYl-ethyl-amino)-methyl]-3-isoprop 1-~phen~eth~~~-24 benzoic acid (Compound 134, General Formula 6) Using General Procedure I; a solution of ethyl 4-~4-[(cyclopropyl-26 ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 27 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 28 treated with NaOH (600.0 mg,15.0 mmols, 3.0 mL of a SN aqueous solution) 1 and stirred overnight at room temperature and then at 55 °C for 9 hours.
2 Work-up followed by crystallization of the solid residue from hot CH3CN
3 afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
4 'H NMR (d6-acetone) $: 8.05 (2H, d, J = 8.1 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.49 (1H, s), 7.32 (2H, m), 3.78 (2H, s), 3.44 (1H, septet, J = 6.7 Hz), 2.59 6 (2H, q, J = 7.3 Hz), 1.80 (1H, m), 1.21 (6H, d, J = 6.7 Hz), 1.05 (3H, t, J
= 7.3 7 Hz), 0.40 (2H, m), 0.26 (2H, m).
8 Meth[4-(8,8-dimethXl-5-oxo-SY6,7,8-tetrahydro-naphthalen-2- ~~l-eth~yl),~
9 phenyl-acetate (Compound 4, General Formula 8) Using General Procedure F; 6-ethynyl-4,4-dimethyl-3,4-dihydro-2H
11 naphthalen-1-one (Intermediate 13, 190.0 mg, 0.96 mmol) and methyl-(4-12 iodophenyl)-acetate (Reagent B, 245.0 mg, 0.96 mmol) in triethyl amine (8 I3 mL) was treated with copper(I)iodide (46 mg, 0.24 mmol) and sparged with 14 argon for 1S minutes. Dichlorobis(triphenylphosphine)palladium(II) (168 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight at room 16 temperature. Column chromatography (10-20% EtOAc - hexanes) afforded 17 250.0 mg (75%) of the title compound as a pale-yellow solid.
18 'H NMR (CDC13) 8: 7.99 (1H, d, J = 7.9 Hz), 7.57 (1H, d, J = 1.5 Hz), 7.51 19 (2H, d, J = 8.5 Hz), 7.43 ( 1 H, dd, J = 1.5, 7.9 Hz), 7.29 (2H, d, J = 8.5 Hz), 3.70 (3H, s), 3.65 (2H, s), 2.73 (2H, t, J = 7.0 Hz), 2.04 (2H, t, J = 7.0 Hz), 21 1.41 (6H, s).
22 Meth[~5-h~~,8-dimeth~l-5,6,7,8-tetrahydro-naphthalen-2-23 ethyn~~phenyl]t-acetate (Compound 135, General Formula 4) 24 To a solution of methyl [4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 4) in 5 mL MeOH at 0 26 °C was added NaBH4 (18.0 mg, 0.48 mmol). The reaction was stirred at 0 °C
27 for 2 hours and then quenched by the addition of H20. The solution was 28 diluted with Et20 and washed with H20 and saturated aqueous NaCI before 1 being dried (MgS04) and the solvents were removed under reduced pressure.
2 Column chromatography (20-40% EtOAc-hexanes) afforded 140.0 mg (87%) 3 of the title compound as a colorless oil.
4 1H NMR (CDC13) b: 7.49 (3H, m), 7.39 (1H, d, J = 7.9 Hz), 7.31 (1H, dd, J =
1.5, 7.9 Hz), 7.25 (2H, d, J = 8.2 Hz), 4.58 (1H, bs), 3.68 (3H, s), 3.62 (2H, s), 6 2.05 (1H, m), 1.79 (2H, m), 1.60 (1H, m), 1.33 (3H, s), 1.26 (3H, s).
7 Meth[4-(5-imidazol-1-~,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-8 Xlethyn~~phen,~T1]-acetate (Compound 136, General Formula 4) 9 A solution of methyl [4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 11 mmol) and carbonyldiimidazole (136.0 mg, 0.84 mmol) in 5 mL THF was 12 heated to 65 °C for 48 hours. The solution was cooled to room temperature 13 and concentrated under reduced pressure. The residue was dissolved in EtzO
14 and washed with 5% aqueous NaOH, HZO, and saturated aqueous NaCI before being dried (NaaS04) and concentrated under reduced pressure. Column 16. chromatography (5% MeOH-CHZCla) afforded 50.0 mg (31%) of the title 17 compound as a colorless solid.
18 1H NMR (CDC13) 8: 7.57 (1H, d, J = 1.5 Hz), 7.52-7.45 (3H, m), 7.27 (3H, m), 19 7.08 (1H, s), 6.81 (2H, m), 5.30 (1H, t, J = 5.8 Hz), 3.71 (3H, s), 3.65 (2H, s), 2.20 (2H, m), 1.75 (2H, m), 1.40 (3H, s), 1.36 (3H, s).
21 [~5-Imidazol-1-~l-,8-dimeth~ 6 7.8-tetrahydro-naphthalen-2-~~yl)-22 phenyl]-acetic acid (Compound 137, General Formula 4) 23 Using General Procedure I; a solution of methyl [4-(5-imidazol-1-yl-24 8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated with 26 NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred 27 overnight at room temperature. Work-up afforded 40.0 mg (83%) of the title 28 compound as a pale-orange solid.
29 'H NMR (d4-MeOH) 8: 8.93 (1H, s), 7.68 (1H, s), 7.61 (1H, s), 7.54 (1H, s), 1 7.47 (2H, d, J = 8.2 Hz), 7.31 (3H, m), 6.95 ( 1 H, d, J = 8.2 Hz), 5.83 ( 1 H, t, J
2 = 5.8 Hz), 3.68 (1H, s), 3.63 (1H, s), 2.38 (1H, m), 2.26 (1H, m), 1.76 (2H, m), 3 1.45 (3H, s), 1.36 (3H, s).
4 Ethyl [4-(5-imidazol-1-yl-8,8-dimeth~l-5 6,7,8-tetrah d~ronaphthalen-2- ~~1-ethyn~l)-benzoate (Compound 138, General Formula 4) 6 A solution of ethyl [4-(S-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-7 naphthalen-2-yl-ethynyl)-benzoate (180.0 mg, 0.52 mmol) and 8 carbonyldiimidazole (176.0 mg, 1.08 mmol) in 5 mL THF was heated to 65 °C
9 for 21 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in Et20 and washed with 11 55 aqueous NaOH, H20, and saturated aqueous NaCI before being dried 12 (NaZSO~) and concentrated under reuced pressure. Column chromatography 13 (5% MeOH-CHZC12) afforded 50.0 mg (24%) of the title compound as a I4 colorless solid.
1H NMR (CDC13) 8: 8.03 (2H, d, J = 7.9 Hz), 7.59 (3H, m), 7.46 (1H, s), 7.29 16 ( 1 H, dd, J = 1. 5, 8.3 Hz), 7.09 ( 1 H, s), 6. 82 ( I H, d, J = 8 .2 Hz), 6. 81 ( 1 H, s), 17 5.31 (1H, t, J = 5.8 Hz), 4.39 (2H, q, J = 7.1 Hz), 2.20 (2H, m), 1.75 (2H, m), 18 1.40 (9H, m).
19 [4-(S-Imidazol-I ;yl-88,~-dimethyl-55,6,7,8-tetrahydro-naphthalen-2-Xl-ethynyll-benzoic acid (Compound 139, General Formula 4) 21 Using General Procedure I; a solution of ethyl [4-(5-imidazol-1-yl-8,8-22 dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 23 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was 24 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) 26 of the title compound as a colorless solid.
27 1H NMR (d4-MeOH) 8: 8.92 ( 1 H, s), 8.04 (2H, d, J = 8.2 Hz), 7.74 ( 1 H, d, J =
28 1.5 Hz), 7.62 (3H, m), 7.57 ( 1 H, t, J = 1.5 Hz), 7.3 8 ( 1 H, dd, J =1.5, 7.9 Hz), 29 6.97 (1H, d, J = 7.9 Hz), 5.83 (IH, t, J = 5.8 Hz), 2.33 (2H, m), 1.78 (2H, m), 1 1.47 (3H, s), 1.39 (3H, s).
2 2-Isopr~yl-4-trifluoromethanesulfonXloxy-benzyl acetate (Intermediate 3 162) 4 To a solution of 4-hydroxymethyl-3-isopropylphenyl 1,1,1-trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol) in 5 mL
6 CH2C12 was added acetyl chloride (75.0 mg, 0.9b mmol) and pyridine(101.0 7 mg, 1.38 mmols). After stirnng for 3 hours at 25 °C the reaction was 8 quenched by the addition of HZO and the resulting mixture extracted with 9 EtOAc. The combined organic layers were washed with Hz0 and saturated aqueous NaCl, dried (lVIgSO4) and concentrated under reduced pressure. The 11 title compound, 182 mg (84%), was isolated from the residual oil by column 12 chromatography (5 - 10% EtOAc-hexanes) as a colorless oil.
13 ' H NMR (CDCl3) 8: 7.43 ( 1 H, d, J = 8. 7 Hz), 7.19 ( 1 H, d, J = 2. 7 Hz), 7.09 14 ( 1 H, dd, J = 2.7, 8.5 Hz), 5.17 (2H, s), 3.18 ( 1 H, septet, J = 6.7 Hz), 2.10 (3H, s), 1.26 (6H, d, J = 6.7 Hz).
16 4-Isopropen~lox meth 1-prop 1-phenyl 1-trifluoromethanesulfonate 17 (Intermediate 163) 18 Using General Procedure 1; 2-isopropyl-4-19 trifluoromethanesulfonyloxy-benzyl acetate (Intermediate 162, 182.0 mg, 0.54 mmols), and 1.1 mL of Tebbe's Reagent ( 159.0 mg, 0.56 mmols) afforded 21 130.0 mg (72%) of the title compound as a colorless oil after column 22 chromatography (2-5% EtOAc-hexanes).
23 1H NMR (CDC13) 8: 7.43 (1H, d, J = 8.S Hz), 7.18 (1H, d, J = 2.6 Hz), 7.09 24 ( 1 H, dd, J = 2.6, 8.5 Hz), 4.75 (2H, s), 3 .98 (2H, s), 3 .12 ( 1 H, septet, J = 6.7 Hz), 1.88 (3H, s), 1.25 (6H, d, J = Hz).
26 3-Isopropyl-4-(1-methyl-cyclopropox~meth~l-phen~ 1 27 trifluoromethanesulfonate (Intermediate 164) 28 Using General Procedure 2; 4-isopropenyloxymethyl-3-isopropylphenyl 1 1,1,1-trifluoromethanesulfonate (Intermediate 163, 130. 0 mg, 0.39 mmol), 2 Et2Zn (272.0 mg, 2.2 mmols), and CH2I2 (702.0 mg, 2.6 mmols) in 3.0 mL
3 Et~O afforded 120.0 mg (89%) of the title compound as a colorless oil after 4 column chromatography (4-5% EtOAc - hexanes).
'H NMR (CDC13) 8: 7.39 (1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 2.7 Hz), 7.05 6 (1H, dd, J = 2.7, 8.5 Hz), 4.54 (2H, s), 3.16 (1H, septet, J = 6.7 Hz), 1.47 (3H, 7 s), 1.24 (6H, d, J = 6.7 Hz), 0.86 (2H, m), 0.48 (2H, m).
8 (3-Isoprop~-4-(1-methyl-c~propoxymeth~l-phenyleth~yl]-9 trimeth. ls~ (Tntermediate 165) Using General Procedure D; 3-isopropyl-4-( 1-methyl-11 cyclopropoxymethyl)-phenyl l,l,l-trifluoromethanesulfonate (Intermediate 12 164, 120.0 mg, 0.34mmo1) in triethylamine (2 mL) and anhydrous DMF (5 13 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 14 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (24.0 mg, 0.03 mmol). The 16 resulting reaction mixture was heated to 95 °C for 60 hours. The title 17 compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc -18 hexanes).
19 IH NMR (CDC13) ~: 7.36 (1H, s), 7.24 (2H, bs), 4.53 (2H, s), 3.11 (1H, septet, J = 6.7 Hz), 1.45 (3H, s), 1.22 (6H, d, J = 6.7 Hz), 0.85 (2H, m), 0.44 (2H, m), 21 0.25 (9H, s).
22 4-Ethyn 1-2-isopropyl-1-(1-methyl-cyclopropoxymeth~)-benzene 23 (Intermediate 166) 24 Using General Procedure E; [3-isopropyl-4-( 1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane (Intermediate 165, 26 110.0 mg, 0.37 mmol) in methanol (6 mL) was treated with potassium 27 carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature.
28 The crude alkyne (84 mg, 100%) was used directly in the next reaction.
1 1H NMR (CDC13) 8: 7.55 (1H, s), 7.41 (2H, m), 4.68 (2H, s), 3.26 (1H, septet, 2 J = 6.8 Hz), 3.18 (1H, s), 1.60 (3H, s), 1.37 (6H, d, J = 6.8 Hz), 0.99 (2H, m), 3 0.59 (2H, m).
4 Methyl f4-~3-isopropyl-4~1-methyl-c~clopropox~~l-phen l~~nyll' phenyll-acetate (Compound 140, General Formula 6) 6 Using General Procedure F; 4-ethynyl-2-isopropyl-1-(1-methyl-7 cyclopropoxymethyl)-benzene (Intermediate 166, 78.0 mg, 0.34 mmol) and 8 methyl-(4-iodophenyl)-acetate (Reagent B, 94.0 mg, 0.34 mmol) in 9 triethylamine (8 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.
11 Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol) was added 12 and the reaction mixture was stirred at room temperature for 3.5 hours.
13 Column chromatography (2-5% EtOAc - hexanes) afforded 77.0 mg (60%) of 14 the title compound as a yellow oil.
1H NMR (CDC13) 8: 7.49 (2H, d, J = 8.2 Hz), 7.43 (1H, d, J = 1.5 Hz), 7.33-16 7.24 (4H, m), 4.55 (2H, s), 3.70 (3H, s), 3.63 (2H, s), 3.14 (1H, septet, J
= 6.8 17 Hz), 1.47 (3H, s), 1.25 (6H, d, J = 6.8 Hz), 0.86 (2H, m), 0.46 (2H, m).
18 ~4-[3-Isopropyl-methyl-c~clopropox~meth~~-phen l~ethyn~]-phenyl}-19 acetic acid (Compound 141, Formula 6) Using General Procedure I; a solution methyl f 4-[3-isopropyl-4-(1-21 methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate (Compound 22 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 23 treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3N aqueous solution) 24 and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H20/CH3CN) afforded of the title compound as a 26 colorless solid.
27 'H NMR (CDC13) 8: 7.50 (2H, d, J = 8.2 Hz), 7.43 (1H, s), 7.33-7.24 (4H, m), 28 4.55 (2H, s), 3.65 (2H, s), 3.14 (1H, septet, J = 6.7 Hz), 1.47 (3H, s), 1.25 (6H, 1 d, J = 6.7 Hz), 0.87 (2H, m), 0.46 (2H, m).
2 2,6-Di-tert-butyl-4-trimeth, lsy ilan,~ethynyl-phenol: (Intermediate 167) 3 Following General Procedure D and using 4-bromo-2,6-di-t-butyl-4 phenol (1.438, Smmol), triethyl amine (lSmL), anhydrous tetrahydrofuran (lSmL), copper(I)iodide (0.06g., 0.31mmol), trimethylsilyl acetylene (4.9g, 6 SOmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.18g, 0.26mmol) 7 followed by flash column chromatography over silica gel (230-400 mesh) 8 using hexane as eluent, the title compound was obtained (1.35g, 90%).
9 1H NMR (300 MHz, CDCl3): 8 7.29 (s, 2H), 5.35 (s, 1H), 1.42 (s, 18H), 0.24 (s, 9H).
11 X3,5-Di-tent-but~methoxy-phen l~~n~)-trimeth~ilane: (Intermediate 12 168) 13 A solution 2,6-di-tert-butyl-4-trimethylsilanylethynyl-phenol 14 (Intermediate 167, 0.302g, lmmol) in acetone (SmL) was treated with potassium carbonate (0.138g, lmmol) and methyl iodide (0.142g, lmmol) and 16 stirred overnight at room temperature. The volatiles were distilled off in 17 vacuo and the residue was purified by flash column chromatography on silica 18 gel (230-400 mesh) using ethyl acetate as the eluent to afford the title 19 compound as a white solid (0.28g, 90%).
1H NMR (300 MHz, CDCl3): 8 7.41 (s, 2H), 3.70 (s, 3H), 1.49 (s, 18H), 0.30 21 (s, 9H).
22 1.3-Di-tert-bu 1-tY 5eth~nyl-2-methoxX-benzene: (Intermediate 169) 23 Following General Procedure E and (3,5-di-tert-butyl-4-methoxy-24 phenylethynyl)-trimethyl-silane (Intermediate 168, 0.28g, 0.9mmol), potassium carbonate (0.988, 7.lmmol) and methanol (lOmL) followed by flash 26 column chromatography over silica gel (230-400 mesh) using hexane as the 27 eluent, the title compound was obtained (0.238, 100%).
28 'H NMR (300 MHz, CDC13): b 7.46 (s, 2H), 3.75 (s, 3H), 3.05 (s, 1H), 1.49 (s, 1 18H).
2 [4-(3,5-Di-tert-butyl-4-methox -y_phen,~,~m, 11-~T phen~ll-acetic acid meth 3 ester: (Compound 142, General Formula 5) 4 Following General Procedure F and using 1,3-di-test-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.0948, 0.36mmo1), methyl-4-iodo 6 phenyl acetate (Reagent B, 0.098, 0.32mmo1), triethyl amine (SmL), 7 anhydrous tetrahydrofuran (SmL), copper(I)iodide (0.028, O.lmmol) and 8 dichlorobis(triphenylphosphine)palladium(II) (0.068, 0.085mmo1) followed by 9 flash column chromatography over silica gel (230-400 mesh) using 10 % ethyl acetate in hexane as the eluent, the title compound (0.1148, 81 %) was obtained 11 as an oil.
12 'H NMR (300 MHz, CDC13): 8 7.52 (d, 2H, J= 8.OHz), 7.46 (s, 2H), 7.28 (d, 13 2H, J= 8.2Hz), 3.72 (s, 3H), 3.71(s, 3H), 3.66 (s, 2H), 1.47 (s, 18H).
14 ~f4-(3,5-Di-tert-butyl-4-methoxy-phenyleth~yl)-phmyl]-acetic acid:
(Compound 143, General Formula 5) 16 Following General Procedure I and using [4-(3,5-di-test-butyl-4-17 methoxy-phenylethynyl)-phenyl]-acetic acid methyl ester (Compound 142, 18 0.1148, 0.29mmo1), SM aqueous sodium hydroxide solution (2mL) and 19 ethanol (4mL), followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white 21 solid (0.0978, 88%).
22 IH NMR (300 MHz, CDCl3): b 7.55(d, 2H, J= 8.OHz), 7.48 (s, 2H), 7.30 (d, 23 2H, J= 8.2Hz), 3.74 (s, 3H), 3.69 (s, 2H), 1.49 (s, 18H).
24 [4-(3,5-Di-test-butyl-4-methoxy-phenyleth~nyl)-2-fluoro-phen~]-acetic acid meth,1~: (Compound 144, General Formula 5) 26 Following General Procedure F and using 1,3-di-test-butyl-5-ethynyl-2-27 methoxy-benzene (Intermediate 169, 0.0878, 0.33mmo1), methyl-2-fluoro-4-28 iodo phenyl acetate (Reagent H, 0.0888, 0.30mmo1), triethyl amine (SmL), 29 anhydrous tetrahydrofuran (lOmL), copper(I)iodide (0.028, O.lmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.068, 0.085mmol) followed by 1 flash column chromatography over silica gel (230-400 mesh) using 10 % ethyl 2 acetate in hexane as the eluent, the title compound (0.1228, 89%) was 3 obtained.
4 1H NMR (300 MHz, CDC13): 8 7.46 (s, 2H), 7.33-7.24 (m, 3H), 3.75 (s, 3H), 3.73(s, 3H), 3.72 (s, 2H), 1.48 (s, 18H).
6 [~3,5-Di-test-butyl-4-methox~phen l~yn~l-2-fluoro-pheny~-acetic acid:
7 (Compound 145, General Formula 5) 8 Following General Procedure I and using [4-(3,5-di-test-butyl-4-9 methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester.
(Compound 144, 0.1228, 0.29mmol), SM aqueous sodium hydroxide solution 11 ( 1mL) and ethanol (4mL), followed preparative reverse phase HPLC using 12 10% water in acetonitrile as the mobile phase, the title compound was 13 obtained as a white solid (0.0778, 65%).
14 'H NMR (300 MHz, CDC13): S 7.42 (s, 2H), 7.29-7.19 (m, 3H), 3.71 (s, 2H), 3.69 (s, 3H), 1.43 (s, 18H).
S
Y
Formula 5 1 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 2 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 3 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 4 groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C1_6-trialkylsilyl 6 or benzyl;
7 Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 8 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 9 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C=C-, 11 -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 12 -CO-NRl-, 13 NRl-CO-, 14 -CO-O-, -O-CO-, 16 -CS-NRI-, 17 NRl-CS-, 18 -CO-S-, 19 -S-CO-, -N=N-;
21 Rl is independently H or alkyl of 1 to 6 carbons;
22 RZ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 23 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 24 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 26 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 27 of 1 to 6 carbons or benzyl;
28 m is an integer having the values 0 to 3;
1 R7 is H, alkyl of I to 6 carbons, cycloalkyl of 3 to 6 carbons or lower 2 alkyl substituted cycloalkyl of 1 to 6 carbons;
3 n is an integer having the values of 1 to 4, and 4 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
6 The novel compounds used in the method of treatment of the present 7 invention are also shown in Formula 6 n~Z A(R2)-(CH2)n COOR$
14 Formula 6 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 16 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 17 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl I8 groups being optionally substituted with one or two RZ groups;
19 X2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR7, SR7 or NRR7 where R is H, alkyl of I to 6 carbons or benzyl;
21 Y is H, alkyl of 1 to I O carbons, benzyl, lower alkyl or halogen 22 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 23 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
24 Z 1S -C---C-, -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 26 -CO-NRl-, 27 NRl-CO-, 28 -CO-O-, 1 -O-CO-, 2 -CS-NRI-, 3 NRl-CS-, 4 -CO-S-, -S-CO-, 6 -N=N-;
7 Rl is independently H or alkyl of 1 to 6 carbons;
8 R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 9 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
11 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro 12 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 13 of 1 to 6 carbons or benzyl;
14 m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower 16 alkyl substituted cycloalkyl of 3 to 6 carbons or C1_6-trialkylsilyl.
17 n is an integer having the values of 0 to 4, and I8 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a 19 pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present 21 invention are also shown in Formula 7 24 (~)° A(RZ)-(CHZ)~ COORS
27 l~~lulula 7 28 (R') 1 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 2 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 3 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 4 groups being optionally substituted with one or two RZ groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen 6 substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 7 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or 8 I;
9 Z is -C---C-, -(CRl=CRl)n~ where n' is an integer having the value 1 - 5, 11 -CO-NRl-, 12 NRl-CO-, 13 -CO-O-, 14 -O-CO-, -CS-NRl-, 16 NRl-CS-, 17 -CO-S-, 18 -S-CO-, .
19 -N=N-;
Rl is independently H or alkyl of 1 to 6 carbons;
21 p is an integer having the values of 0 to 5;
22 Ra is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro 23 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 24 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CFA, fluoro 26 substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 27 of 1 to 6 carbons or benzyl;
28 m is an integer having the values 0 to 2;
1 R~ is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 2 alkyl of 1 to 6 carbons, or halogen;
3 o is an integer having the values of 0 to 4;
4 n is an integer having the values of 0 to 4, and 5 Rg is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a canon of a 6 pharmaceutically acceptable base.
7 The novel compounds used in the method of treatment of the present 8 invention are also shown in Formula 8 9 o d.
11 (R4)o Z A(R2)-(CH 2)n COOK $
13 y 14 Formula 8 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a 16 group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 17 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl 18 groups being optionally substituted with one or two R2 groups;
19 X3 is S, or O, C(Rl)2, or CO;
Yl is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, 21 benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
22 Z is -C---C-, 23 -(CRl=CRl)"~ where n' is an integer having the value 1 - 5, 24 -CO-NRl-, NRl-CO-, 26 -CO-O-, 27 -O-CO-, 28 -CS-NRl-, 1 NR1-CS-a 2 -CO-S-, 3 -S-CO-, 4 -N=N-Rl is independently H or alkyl of 1 to 6 carbons;
6 RZ is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro 7 substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 8 to 6 carbons;
9 R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro ZO substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio 11 of 1 to 6 carbons or benzyl;
12 m is an integer having the values 0 to 2;
13 R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted 14 alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
16 n is an integer having the values of 0 to 4, and 17 R8 is H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a 18 pharmaceutically acceptable base, the compound meeting at least one of the 19 provisos selected from the group consisting of:
Yl is cycloalkyl, 21 when Yl is not cycloalkyl then X3 is O or S and n is 1, 22 when Yl is not cycloalkyl then X3 is CO, and n is 1, 23 when Yl is not cycloalkyl then X3 is CO and the moiety A is 24 substituted with at least one F group.
In accordance with the invention the novel compounds of Formula 1 26 through Formula 8 as well as the previously known compounds disclosed 27 below in the specification axe used for the prevention or treatment of diseases 28 and conditions in mammals, including humans, those diseases or conditions 1 that are prevented, treated, ameliorated, or the onset of which is delayed by 2 administration of retinoid compounds or by the mammalian organism's 3 naturally occurring retinoic acid. Because the compounds act as inhibitors of 4 the breakdown of retinoic acid, the invention also relates to the use of the compounds of Formula 1 through Formula 8 in conjunction with retinoic 6 acid or other retinoids. In this regard it is noted that retionoids are useful for 7 the treatment of skin-related diseases, including, without limitation, actinic 8 keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, 9 psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, barriers disease, lichen planus, 11 prevention and reversal of glucocorticoid damage (steroid atrophy), as a 12 topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse 13 the effects of age and photo damage to the skin. The retinoids are also useful 14 for the prevention and treatment of metabolic diseases such as type II non-insulin dependent diabetes mellitus (NIDDM) and for prevention and 16 treatment of cancerous and precancerous conditions, including, premalignant 17 and malignant hyperproliferative diseases such as cancers of the breast, skin, 18 prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral 19 cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of 21 Kaposi's sarcoma. Retinoids can also be used as agents to treat diseases of the 22 eye, including, without limitation, proliferative vitreoretinopathy (PVR), 23 retinal detachment, dry eye and other corneopathies, as well as in the treatment 24 and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, 26 prevention of post-angioplasty restenosis and as an agent to increase the level 27 of circulating tissue plasminogen activator (TPA). Other uses for retinoids 28 include the prevention and treatment of conditions and diseases associated 1 with human papilloma virus (HPV), including warts and genital warts, various 2 inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's 3 disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's 4 disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the 6 induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration 7 of hair growth, including combination therapies with the present compounds 8 and other agents such as MinoxidilR, diseases associated with the immune 9 system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of 11 wound healing, including modulation of chelosis.
12 This invention also relates to a pharmaceutical formulation comprising 13 one or more compounds of Formula 1 through Formula 8 or one or more of 14 the previously known compounds disclosed below in the specification, in admixture with a pharmaceutically acceptable excipient, said formulation 16 being adapted for administration to a mammal , including a human being, to 17 treat or alleviate the conditions which were described above as treatable by 18 retinoids, or which are controlled by or responsive to the organism's native 19 retinoic acid. These formulations can also be co-administered with retinoids to enhance or prolong the effects of medications containing retinoids or of the 21 organism's native retinoic acid.
22 The present invention also relates to a method of providing a compound 23 which is an inhibitor of the enzyme cytochrome P450R.AI, wherein the method 24 of providing the cytochrome P450RAI inhibitory compound comprises:
identifying a compound that has activity as a retinoid in any of the art 26 recognized assays which demonstrate retinoid-like activity, the retinoid 27 compound having a formula such that it includes a benzoic acid, benzoic acid 28 ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or 1 ester moiety, with a partial structure of -A(R2)-(CH2)"-COOR8 where the 2 symbols are defined as in Formulas I through 8, and where n is 0, and 3 selecting a compound that is a homolog of the previously identified 4 retinoid compound where in the formula of the homolog n is I or 2, preferably 1. Said homolog, if it is not a previously known compound can be prepared 6 by homologation procedures well known to the synthetic organic chemist, 7 such as for example the well known A~~cdt-Eiste~t synthesis. Alternatively, 8 said homologs can be prepared by any of the applicable synthetic processes 9 illustrated below for the preparation of the novel compounds of Formulas 1 through 8 wherein the symbol n represents the integral 1 (one).
12 Figure 1 is a schematic representation of the P450RAI cell based assay 13 utilized to evaluate the ability of the compounds of the invention to inhibit the 14 Cytochrome P450RAI enzyme.
BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION
16 P450RAI-1 Cell-Based Inhibitor Assay:
17 Figure 1 shows a schematic diagram of the P450RAI-1 cell based 18 assay. P450RAI-1 stably transfected HeLa cells are maintained in 100 19 millimolar tissue culture dishes in Modified Eagle's Medium (MEM) containing 10 % Fetal Bovine Serum (FBS) and 100 p,g/ml hygromycin.
21 Exponentially growing cells are harvested by incubating in trypsin. Cells are 22 then washed with 1X Phosphate Buffered Saline (PBS) and plated in a 48-well 23 plate at 5 X105 cells in 0.2 ml MEM medium containing 10 % FBS and 0.05 24 ~.Ci [3H]-RA in the presence or absence of increasing concentrations of the test compounds. The compounds are diluted in 100% DMSO and then added in 26 triplicate wells at either 10, 1 or 0.1 ~.M final concentration. As a positive 27 control for RA metabolism inhibition, cells are also incubated with 28 ketoconazole at 100, 10 and 1 p,M. Cell are incubated for 3 hours at 37°C.
1 The retinoids are then extracted using the procedure of Bligh et al. (1959) 2 Canadian Journal of Biochemistry 37, 911-917, modified by using 3 methylenechloride instead of chloroform. The publication Bligh et al. (1959) 4 Canadian Journal of Biochemistry 37, 911-917 is specifically incorporated 5 herein by reference. The water soluble radioactivity is quantified using a ~3-6 scintillation counter. ICSO values represent the concentration of inhibitor 7 required to inhibit all-t~ahs-RA metabolism by 50 percent and are derived 8 manually from log-transformed data. The ICso values obtained in this assay 9 for several novel compounds used in accordance with the invention are 10 disclosed in Table 1 below. The ICSO values obtained in this assay for 11 several previously known compounds the cythochrome P450RAI inhibitory 12 activity of which has been discovered in accordance with the present 13 invention, are disclosed in Table 1A below.
14 Assa~rs of Retinoid-like or Retinoid Antagonist and Inverse Aaonist-like 15 Biological Activity 16 Assays described below measure the ability of a compound to bind to, 17 andlor activate various retinoid receptor subtypes. When in these assays a 18 compound binds to a given receptor subtype and activates the transcription of 19 a reporter gene through that subtype, then the compound is considered an 20 agonist of that receptor subtype. Conversely, a compound is considered an 21 antagonist of a given receptor subtype if in the below described co-tranfection 22 assays the compound does not cause significant transcriptional activation of 23 the receptor regulated reporter gene, but nevertheless binds to the receptor 24 with a Kd value of less than approximately 1 micromolar. In the below 25 described assays the ability of the compounds to bind to RARa, RARE, RAR.~, 26 RXRa, RXR~ and RXRr receptors, and the ability or inability of the 27 compounds to activate transcription of a reporter gene through these receptor 28 subtypes can be tested.
1 As far as specific assays are concerned, a chimeric receptor 2 transactivation assay which tests for agonist-like activity in the RARa, RARE, 3 and RAR.~, receptor subtypes, and which is based on work published by 4 Feigne~ P. L, and Holm M. (1989) Focus, 112 is described in detail in United States Patent No. 5,455,265. The specification of United States Patent No.
6 5,455,265 is hereby expressly incorporated by reference. The numeric results 7 obtained with several preferred novel compounds used in accordance with the 8 invention in this assay are shown below in Table 1. These data demonstrate 9 that generally speaking the compounds of Formulas 1 through 8, are not agonists (or only weak agonists) of RAR retinoic receptors, and also that they 11 do not bind, or in some cases bind only weakly to RAR retinoid receptors.
12 A holoreceptor transactivation assay and a Iigand binding assay 13 which measure the antagonist/agonist like activity of the compounds used in 14 accordance with the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published PCT Application 16 No. WO W093/11755 (particularly on pages 30 - 33 and 37 - 41) published on 17 June 24, 1993, the specification of which is also incorporated herein by 18 reference. A detailed experimental procedure for holoreceptor 19 transactivations has been described by Heyman et al. Cell 68, 397 - 406, (1992); Allegretto et al. J. Biol. Chem. 268, 26625 - 26633, and Ma~zgelsdoif 21 et al. The Retinoids: Biology, Chemistry and Medicine, pp 319 - 349, Raven 22 Press Ltd., New York, which are expressly incorporated herein by reference.
23 The results obtained in this assay are expressed in ECso numbers, as they are 24 also in the chimeric receptor transactivation assay. The results of ligand binding assay are expressed in Kd numbers. (See Cheng et al. Biochemical 26 Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by 27 reference.) 28 The results if the ligand binding assay for several preferred novel 1 compounds used in accordance with the invention are included in Table 1. In 2 the holoreceptor transactivation assay, tested for RXRa, R~,~, and RXR.~
3 receptors, the novel compounds are, generally speaking, entirely devoid of 4 activity, demonstrating that the novel compounds do not act as RXR agonists.
6 TABLE ~.
7 Compound GeneralTable RAR. P450RAI
8 # Formula#1 ECso/(EFFICACY)/KdnM INHIBITION
DATA
y INTACT HELA
ICSO~M
(44) (42) > I 0 2058 409 >10K
(3 7) > 10 11 3 4 5 280 4.8 9.8 (28) (54) (52) 3 145 0.8 158 >10K >10 >10K >10K
13 108 2 3 6.6 283 141 (15) (36) (10) >10 >10 >10 >I0 >10K >10K >10K
1 2 33 1.2 6.8 (207) (126) (140) 1.7 69 1.3 363 0.19 15K 3636 >10K
0.34 21K 4272 >10K
>10 >10K >10K >10K
69 2 3 313 12 52.6 (10) (50) (31) >10 6 73 2 3 WA 22.5 91 (39) (24) >10 3.5 11K 14K >10K
0.28 14 2.2 84 9 44 1 2 49 1.7 7.5 (138) (100) (116) 0.27 37 1.9 392 >10 >10K >10K >10K
(80) (67) >10 (20) (50) (46) >10 0.95 >10K >10K >10K
2 g4 2 3 NA NA NA
>10 >10K >10K >10K
(114) (39) (SS) >10 (36) O.SS
9148 2815 >10K
S g 4 S NA 363 NA
(96) 0.4 lOK 3781 ZSK
1.4 >10K >10K >10K
7 8S 2 3 976 3.S 2.5 (60) (77) (6S) >10 0.8 9 13 4 S NA 3.2 116 (6.6) (9) 3.1 10 8 9 S7 0.3 6 (146) (86) (94) 0.7 0.033 0.025 lOK 5317 2884 0.13 61.5 15 2.5 0.4 >10K >I OK >1 OK
0.18 >10K >100K >100K
2.2 >10K >10K >10K
>10 1.1 0.18 0.05 1.6 0.1 0.4 0.09 0.03 50 0.014 0.05 0.022 >10 0.13 0.18 1.6 9 I43 Ov 145 0.2 lThe "Table #"
refers to Table through provided below where the compound is identified with reference to a corresponding specific formula of Formulas through 16.
16 Table 1A below provides data similar to those provided in Table 1, for 17 certain previously known compounds which have been discovered in 18 accordance with the present invention to be useful as inhibitors of cytochrome 19 P450RAI. These compounds are shown by Formula A through O and have compounds numbers 201 through 247.
2 Compound GeneralRAR P450RAI
3 #~ FormulaECSO/(EFFICACY)/KdnM INHIBITION
DATA
a (3 y INTACT HELA
ICSOI~M
4 201 A >10K >10K 180 0.52 300 (12) L
90 1105 (24) 202 A 0.6 6 203 C 0.62 7 204 C 0.7 9 206 C 1.8 207 D 1.2 12 209 E 1.7 (25) (122) (61) 14 211 E I.5 16 214 E 1.9 17 215 A 6.2 18 216 D 3.3 19 217 G 6.3 218 D 3.4 21 219 G 3.2 23 221 C >10 24 222 F >10 1 F >10 2 224 C 5.5 3 225 C >10 4 226 C >10 227 C 1.3 , 7 229 G 1.6 8 230 D 5.1 9 231 K 4.1 232 D 4.2 11 233 M 1.3 12 234 M 4.7 14 236 E 5.5 237 J 6.8 16 238 A 7.2 18 241 N 5.5 19 242 I 5.8 243 L 7.4 21 244 G 5.1 22 245 H 3.3 23 246 J 3.1 2 As is known the topical retinoid all-trans-retinoic acid (ATRA) and oral 3 retinoids such as 13-cis RA and etretinate are known to induce substantial skin 4 irritation in humans. This irritation is a direct result of activation of the RAR
nuclear receptors. Analysis of retinoid topical irritation is also a highly 6 reproducible method of determining iu vivo retinoid potency. The SKH1-7 h~-BR or hairless mouse provides a convenient animal model of topical 8 irritation, since retinoid-induced skin flaking and abrasion can be readily 9 scored by eye (Staudeven et al., "Specific antagonist of retinoid toxicity in mice." Toxicol. Appl. Pharmacol.,138:169-175, (1996); Tlaache~, et al., 11 "Receptor specificity of retinoid-induced hyperplasia. Effect of RXR-selective 12 agonists and correlation with topical irritation". J. Pharm. Exp. Ther., 282:528-13 534, (1997)). As is demonstrated below the topical application of P450RAI
14 inhibitors in accordance with the present invention also causes an increase in the endogenous levels of ATRA that results in ATRA-induced irritation in 16 skin of hairless mice. The attached data table discloses the retinoid-mimetic 17 effects of some P450RAI inhibitor compounds in accordance with the present 18 invention on the skin of hairless mice.
19 Methods Female hairless mice (CrI:SKH1-h~BR), S-7 weeks old, were obtained 21 from Charles River Breeding Labs (Wilmington, MA). Animals were about 6 22 weeks old at the start of the experiments. Food (Purina Rodent Chow 5001) 23 and reverse osmosis water were provided ad libitum. Mice were housed 24 individually throughout the dosing period. In some experiments, mice that fit within a defined weight range, e.g., 21-25g, were selected from the available 26 stock and then randomly assigned to the various treatment groups, using body 27 weight as the randomization variable.
28 The compounds to be tested were dissolved in acetone for application 1 to the backs of the mice.
2 Mice were treated topically on the back in a volume of 4.0 ml/kg (0.07-3 0.12m1) adjusted daily so as to deliver a fixed dose of test compound per g 4 body weight. Doses are disclosed as nmol/25g.
5 Unless indicated otherwise, mice were treated with retinoids once daily 6 on days 1 through 5 and observed on days 2, 3, 4, 5, 6, 7 and 8.
7 The mice were weighed daily and the dorsal skin was graded daily 8 using separate semi-quantitative scales to determine flaking and abrasion.
9 These flaking and abrasion scores were combined with weight change (if any) 10 to create a cutaneous toxicity score (Blackjack score).
11 Cutaneous Toxicity Score 12 A visual grading scale was used for characterizing topical irritation on a 13 daily basis. The grading scale used is as follows:
15 Flakin Abrasions 16 0 = none 0 = none 17 1 = slight (small flakes, 1 = slight (one or two abrasions <50% with 18 coverage) a light pink color) 19 2 = mild (small flakes, 50% 2 = mild (several abrasions with a 20 coverage) pink color) 21 3 = moderate (small flakes, 3 = moderate (one or two deep >50%
22 coverage & large flakes, abrasions with red color, <25% <25%
23 coverage) coverage) 24 4 = severe (small flakes, 4 = severe (multiple deep >50% abrasions 25 coverage & large flakes, with red color, >25% coverage) 25-SO%
26 coverage) 27 5 = very severe (large flakes, >50%
28 coverage) 1 Topical Toxicity Score .
2 The flaking and abrasion observations were combined with body 3 weight observations to calculate a single, semiquantitative topical or cutaneous 4 "toxicity score" as detailed below. The toxicity score (also known as "blackjack score" since the theoretical maximum is 21) takes into account the 6 maximal severity, and the time of onset of skin flaking and abrasions and the 7 extent of weight between the first and last days of the experiment. Below are 8 listed the seven numerical components of the toxicity score and an explanation 9 of how those values are combined to calculate the toxicity score. .
1. Flaking-Maximal Severity:
11 Highest flaking score attained during observation period.
12 2. Flaking-Day of Onset of grade 2 or worse:
13 0 - > 8 days 14 1-day8 2-day6or7 16 3-day4or5 17 4-day2or3 18 3. Flaking-Average Severity:
19 Flaking severity scores are summed and divided by the number of observation days.
21 4. Abrasion-Maximal Severity:
22 Highest abrasion score attained during observation period.
23 5. Abrasion-Day of Onset of grade 2 or worse:
24 Same scale as (2) above.
6. Abrasion-Average Severity:
26 Abrasion severity scores axe summed and divided by the number 27 of observation days.
28 7. Systemic Toxicity (weight loss):
1 0_<lg 2 1-lto2g 3 2-2to4g 3-4to6g 4 - >6g or dead 6 Calculation of Composite Flaking Score 7 Flaking onset score (2) and average severity score (3) are summed and 8 divided by two. The quotient is added to the maximal severity score (1).
9 Composite flaking scores are calculated for each individual animal in a group, averaged, and rounded to the nearest integer. Values can range from 0-9.
11 Calculation of Composite Abrasion Score 12 Abrasion onset score (5) and average severity score (6) are summed and 13 divided by two. The quotient is added to the maximal severity score (4).
14 Composite abrasion scores are calculated for each individual animal in a group, averaged and rounded to the nearest integer. Values can range from 0-16 8.
17 Calculation of Toxicity Score 18 Composite flaking score, composite abrasion score, and systemic 19 toxicity score are summed to give the "toxicity score." Toxicity scores are calculated for each individual animal in a group, averaged, and rounded to the 21 nearest integer. Values can range from 0-21 and are expressed in Table 1B
22 below as the mean ~ SD of the values for a group.
23 Calculation of Percentage Change in Body Weight 24 The body weight at the time of the last weighing (day 8, 1 l, or 12) was subtracted from the initial body weight. The difference was divided by the 26 initial body weight, multiplied by 100%, and rounded to the nearest integer.
27 Values were calculated for each individual animal and the mean and standard 28 deviation for each group are shown.
2 Cutaneous Toxicity Score (Blackjack Score) 3 Compound No. 100 300 1000 nmole nmole nmole 4 5 0 (~3 .
IS 1~1 5~2 6 36 1~1 110 7 38 1~1 101 g 8 5~2 8~3 121 9 22 0~0 0~0 1 ~ 1 I37 1~1 1~1 ' S~2 11 48 1~1 3~1 7~2 12 50 1~0 3~2 8~2 13 58 0~0 0~0 0~0 14 131 1~1 0~1 1~1 127 0~0 0~0 0~0 16 18 0~0 5~2 102 17 247 1~0 2~1 6~1 Modes of Administration The compounds used in the methods of treatment of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
Thus, in the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used.
Any common topical formulation such 1 as a solution, suspension, gel, ointment, or salve and the like may be used.
2 Preparation of such topical formulations are well described in the art of 3 pharmaceutical formulations as exemplified, for example, by Remington's 4 Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, the compounds could also be 6 administered as a powder or spray, particularly in aerosol form. If the drug is 7 to be administered systemically, it may be confected as a powder, pill, tablet or 8 the like or as a syrup or elixir suitable for oral administration. For intravenous 9 or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it 11 may be useful to formulate these compounds by injection. In certain cases, it 12 may be useful to formulate these compounds in suppository form or as 13 extended release formulation for deposit under the skin or intramuscular 14 inj ection.
Other medicaments can be added to such topical formulation for such 16 secondary purposes as treating skin dryness; providing protection against light;
17 other medications for treating dermatoses; medicaments for preventing 18 infection, reducing irntation, inflammation and the like.
19 Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds, or to control by 21 naturally occurring retinoic acid will be effected by administration of the 22 therapeutically effective dose of one or more compounds used in accordance 23 with the instant invention. A therapeutic concentration will be that 24 concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the compound potentially may be used in 26 prophylactic manner to prevent onset of a particular condition.
27 A useful therapeutic or prophylactic concentration will vary from 28 condition to condition and in certain instances may vary with the severity of 1 the condition being treated and the patient's susceptibility to treatment.
2 Accordingly, no single concentration will be uniformly useful, but will require 3 modification depending on the particularities of the disease being treated.
4 Such concentrations can be arnved at through routine experimentation.
5 However, it is anticipated that in the treatment of, for example, acne, or similar 6 dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per 7 milliliter of formulation will constitute a therapeutically effective 8 concentration for total application. If administered systemically, an amount 9 between 0.01 and 5 mg per kg of body weight per day would be expected to 10 effect a therapeutic result in the treatment of many diseases for which these 11 compounds are useful.
12 In some applications pharmaceutical formulations containing the CP-13 450RAI inhibitory compounds may be co-administered with formulations 14 containing retinoids. In such cases the dose of the cytochrome P450RAI
15 inhibitors compounds is in the range of 0.01 and 5 mg per kg body weight per 16 day.
18 Definitions 19 The term alkyl refers to and covers any and all groups which are known 20 as normal alkyl and branched-chain alkyl. Unless specified otherwise, Iower 21 alkyl means the above-defined broad definition of alkyl groups having 1 to 22 carbons in case of normal Iower alkyl, and 3 to 6 carbons for lower branch 23 chained alkyl groups. A pharmaceutically acceptable salt may be prepared for 24 any compound used in accordance with the invention having a functionality 25 capable of forming a salt, for example an acid functionality. A
26 pharmaceutically acceptable salt is any salt which retains the activity of the 27 parent compound and does not impart any deleterious or untoward effect on 28 the subject to which it is administered and in the context in which it is 1 administered.
2 Pharmaceutically acceptable salts may be derived from organic or 3 inorganic bases. The salt may be a mono or polyvalent ion. Of particular 4 interest are the inorganic ions, sodium, potassium, calcium, and magnesium.
Organic salts may be made with amines, particularly ammonium salts such as 6 mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed 7 with caffeine, tromethamine and similar molecules. Where there is a nitrogen 8 sufficiently basic as to be capable of forming acid addition salts, such may be 9 formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as 11 hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of 12 simple organic acids such as mono-, di- or tri- acid may also be used.
13 Some compounds used in accordance with the present invention may 14 have traps and cis (E and Z) isomers. Unless specific orientation of substituents relative to a double bond or a ring is indicated in the name of the 16 respective compound, and/or by specifically showing in the structural formula 17 the orientation of the substituents relative to the double bond or ring the 18 invention covers traps as well as cis isomers.
19 Some of the compounds used in accordance with the present invention may contain one or more chiral centers and therefore may exist in 21 enantiomeric and diastereomeric forms. The scope of the present invention is 22 intended to cover all isomers pen se, as well as mixtures of cis and tans 23 isomers, mixtures of diastereomers and racemic mixtures of enantiomers 24 (optical isomers) as well. A bond drawn with a wavy line indicates that the carbon to which the bond is attached can be in any of the applicable possible 26 configurations.
27 General Synthetic Methodology 28 The novel compounds used in accordance with the invention are 1 encompassed by the general Formulas 1 through 8 provided above. The 2 previously known compounds the cytochrome P450RAI activity of which has 3 been discovered in accordance with the present invention are identified below, 4 and references are provided which enable their preparation by one of ordinary skill in the art of synthetic organic chemistry. In each of these 6 formulas a linker or tethering group designated Z covalently connects an 7 aromatic or heteroaromatic moiety designated A(R2)-(CH2)ri COOR8 and 8 another cyclic moiety which in accordance with these formulas is a substituted 9 phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety. Generally speaking a 11 compound such as X4-A(R2)-(CH2)"COORg is commercially available, or 12 can be made in accordance with the chemical literature, or with such 13 modification of known chemical processes which are within the skill of the 14 practicing organic chemist. The group X4 represents a reactive group, which is suitable for coupling the X4 A(R2)-(CH2)ri COORg compound to a 16 derivative of the substituted phenyl, substituted tetrahydronaphthalene, 17 substituted chroman, thiochroman, tetrahydroquinoline or 18 tetrahydroisoquinoline moiety so that as a result of the coupling the linker or 19 tether moiety Z is formed. In many instances the group X4 is a leaving group such as halogen, or trifluoromethanesulfonyloxy, or a group capable of 21 participating in a Wittig or Horher Emmons reaction. In some instances the 22 group X4 is an ethynyl group capable of undergoing a coupling reaction with a 23 leaving group (such as a halogen or a trifluoromethanesulfonyloxy group) 24 attached to the substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline or 26 tetrahydroisoquinoline moiety. The group X4 can also represent an OH or an 27 NH2 group that forms an ester (COO) or amide (CONH) linker, respectively, 28 when reacted with an activated carboxyl derivative of the substituted phenyl, 1 substituted tetrahydronaphthalene, substituted chroman, thiochroman, 2 tetrahydroquinoline or tetrahydroisoquinoline moiety. Examples for the 3 compounds of formula X4_A(R2)-(CH2)n COORg are provided in the specific 4 examples below. Further examples where the X4 group is halogen are ethyl S 4-iodobenzoate, ethyl 6-iodonicotinate, ethyl S-iodofuran-3-carboxylate, ethyl 6 S-iodothiophen-3-carboxylate, ethyl 5-iodofuran-2-carboxylate, ethyl 5-7 iodothiophen-2-carboxylate, and analogous halogenated derivatives of the 8 respective pyridazine, pyrazine and other heteroaryl carboxylic acid esters.
9 The analogous aryl and and heteroaryl hydroxyl compounds and amines, wherein the halogen of the above-listed compounds is replaced by OH or NH2 11 respectively, also serve as additional examples for the reagents of the formula 12 X4-A(R2)-(CH2)"-COOR8. In these examples X4 is OH or NH2, respectively.
13 Still further in accordance with the general synthetic methodology to 14 provide the compounds of Formulas 1 through 8 a derivative of the 1 S substituted phenyl, substituted tetrahydronaphthalene, substituted chroman, 16 thiochroman, tetrahydroquinoline or tetrahydroisoquinoline moiety is 17 synthesized first, having a covalently attached XS group. The X5 group reacts 18 with the X4 group of the reagent X4-A(R2)-(CH2)"COORg to form the linker 19 designated Z in Formulas 1 through 8. The XS group is one that is capable of participating in a catalyzed coupling reaction, (such as an ethynyl group when 21 X4 is a leaving group), or a leaving group (such as halogen or 22 trifluoromethanesulfonyloxy when X4 is an ethynyl group) , or an activated 23 carboxylic acid function (when X4 is OH or NH2). The XS group can also be 24 an OH, SH or NH2 group when the X4 group is an activated carboxylic acid 2S function. Specific examples for substituted phenyl, substituted 26 tetrahydronaphthalene, substituted chroman, thiochroman, tetrahydroquinoline 27 or tetrahydroisoquinoline intermediates having an XS functionality axe 28 provided below, and are also available in the chemical scientific and patent 1 literature. Generally speaking, for reagents and reactions covalently joining a 2 substituted tetrahydronaphthalene, substituted chroman, thiochroman, or 3 tetrahydroquinoline intermediate with a substituted aryl or heteroaryl group, 4 such as X4-A(R2)-(CH2)"COOR8, to form a compound including the linker designated Z, reference is made to United States Patent Nos. 5,648,503;
6 5,723,666 and 5,952,345 the specification of each of which are expressly 7 incorporated herein by reference.
8 The substituted phenyl, tetrahydronaphthalene, chroman, thiochroman, 9 tetrahydroquinoline or tetrahydroisoquinoline moiety of the novel compounds used in accordance with the invention are derivatized in a manner to include 11 the specific substituents (such as for example the cycloalkyl substituents) 12 encompassed within the scope of the invention, either before or after the -13 A(R2)-(CH2)ri COOR8 moiety has been attached and the linker Z has formed, 14 as illustrated by the below described specific examples.
The -(CH2)"COOR8 moiety of the compounds of Formulas 1 through $ can 16 be modified in order to obtain still further novel compounds. One such 17 modif cation is saponification of compounds where the R8 group is an alkyl or 18 -CHZO(C1_6-alkyl) group. Another modification is esterification of the 19 carboxylic acid function when the R8 group is H or a cation. Such saponification and esterification reactions are well known in the art and within 21 the skill of the practicing organic chemist. Still another modification of the 22 compounds used in accordance with the invention (or of the intermediates X4-23 A(R2)-(CH2)"COORg, or of precursors to these intermediates) is the 24 homologation of the (CH2)n group. The latter can be accomplished, for example, by the well known A~ndt-Eistert method of homologation, or other 26 known methods of homologation.
27 The previously known compounds which have been discovered to be 28 inhibitors of cythochrome P450RAI and which are used in accordance with 1 the present invention are made, generally speaking, pursuant to the teachings 2 of a patent or publication which is identified in connection with each of the 3 known compounds. These patents or publications are incorporated by 4 reference in the present specification.
5 The synthetic procedure of homologation that may be utilized for 6 providing a compound having the partial structure of -A(R2)-(CH2)ri COOR8 7 where n is 1, or 2 (one or two), preferably 1 (one), can be one of the several 8 known procedures of homologation of carboxylic acids or esters, such as the 9 A~hdt-Eistert procedure that is described ihte~ alia in March, Advanced 10 Organic Chemistry: Reactions, Mechanisms, and Structure, pages 809-810, 11 McGraw-Hill Publishers, 1968, incorporated herein by reference.
Alternatively 12 the homologs of the partial structure of -A(R2)-(CHz)"COOR8 are 13 synthesized in accordance with the synthetic schemes disclosed herein in 14 connection with the preparation of the novel compounds.
is SPECIFIC EMBODIMENTS
16 With reference to the symbol A in Formulas 1 through 8, the preferred 17 novel compounds used in accordance with the present invention are those 18. where A is phenyl, naphthyl, pyridyl, thienyl or furyl. Even more preferred 19 are compounds where A is phenyl. As far as substitutions on the A (phenyl) 20 and A (pyridyl) groups are concerned, compounds are preferred where the 21 phenyl group is 1,4 (pare) substituted and where the pyridine ring is 2,5 22 substituted. (Substitution in the 2,5 positions in the "pyridine"
nomenclature 23 corresponds to substitution in the 6-position in the "nicotinic acid"
24 nomenclature.) In the presently preferred novel compounds used in 25 accordance with the invention either there is no R2 substituent on the A
group, 26 or the R2 substituent is preferably a fluoro group that is preferably located on 27 the aromatic carbon adjacent (ortho) to the carbon bearing the -(CH2)ri 28 COORg group.
I As far as the -(CIi2)~ COORS is concerned the use of novel 2 compounds is preferred where n is 0, 1 or 2, and even more preferred where n 3 is 1. In Formulas 5 and 8 only compounds where n is 1 or 2 are preferred, 4 with n=1 being most preferred. For the Rg group H, lower alkyl of 1 to 3 carbons, and -CH20(C1_6-alkyl) groups are preferred, as well as the 6 pharmaceutically acceptable salts of the free acids when R8 is H. Among the 7 lower alkyl and -CH20(C1_6-alkyl) groups ethyl and OCH2CH3, respectively, 8 are presently most preferred.
9 The linker group Z in all of the novel compounds used in accordance IO with the invention is preferably ethynyl 11 (-C=C-), ester (CO-O), ethenyl, (-CRl =CRl-) or amide (CONRI). Among 12 these the ethynyl (-C=C-) and ester (CO-O) linkers are most preferred.
13 Moreover, preferably the linker Z is attached to the 6 position in Formula 1, 14 to the 4 position in Formula 2, to the 6 position in Formula 3, to the 6 position in Formula 4, to the 4 position in Formula 5, to the 4 position in 16 Formula 6, to the 6 position in Formula 7, and to the 6 position in Formula 17 8. These positions are indicated by arabic numerals in Formulas 1 through 8.
18 The Rl group substituting the non-aromatic rings in Formulas 1, 3, 4, 7 I9 and 8 is preferably alkyl, more preferably alkyl of 1 to 3 carbons, and most preferably methyl. The Rl group substituting the cyclopropane ring in 21 Formulas 1, 2, 3 and 7 is preferably non-existent (p is 0), or is alkyl of 1 to 3 22 carbons, even more preferably methyl.
23 The X group in Formulas 1 and 5 is preferably O, and in Formula 2 X
24 is preferably O or NR.
The Xl group in Formula 4 is preferably 1-imidazolyl, substituted I-26 imidazolyl, or NRR6, where R6 is preferably cyclopropyl or branched-chain 27 alkyl. The X2 group in Formula 6 is preferably I-imidazolyl or substituted 28 1-imidazolyl.
1 The X3 group in Formula 8 is preferably O or C=O.
2 The Y group is preferably H, lower alkyl of 1 to 3 carbons, cycloalkyl, 3 lower alkyl substituted cycloalkyl, or halogen. Among these, H, Cl, and 4 cyclopropyl are most preferred.
The Yl group of Formula 8 is preferably H, lower alkyl of 1 to 3 6 carbons, cycloalkyl, or lower alkyl substituted cycloalkyl. Among these H, 7 ethyl and cyclopropyl are presently most preferred.
8 The most preferred novel compounds used in accordance with the 9 invention are disclosed in Tables 2 through 9 with reference to Formulas 9 through 16. The compounds specifically shown in Tables 2 through 9 are 11 carboxylic acids, but it should be understood that the use of the corresponding 12 C1_3alkyl esters, methoxymethyl (OCH2CH3) esters and of pharmaceutically 13 acceptable salts of the acids shown in these tables is also highly preferred.
14 It should also be apparent that the preferred compounds shown in Table 2 with reference to the more specific Formula 9 are within the scope of 16 Formula 1.
17 Similarly, the preferred compounds shown in Table 3 with reference to 18 the more specific Formula 14 are within the scope of Formula 2;
19 the preferred compounds shown in Table 4 with reference to the more specific Formula 11 are within the scope of Formula 3;
21 the preferred compounds shown in Table 5 with reference to the more 22 specific Formula 12 are within the scope of Formula 4;
23 the preferred compounds shown in Table 6 with reference to the more 24 specific Formula 13 are within the scope of Formula 5;
the preferred compounds shown in Table 7 with reference to the more 26 specific Formula 14 are within the scope of Formula 6;
27 the preferred compounds shown in Table 8 with reference to the more 28 specific Formula 15 are within the scope of Formula 7, and 1 the preferred compounds shown in Table with reference to the more 2 ecific 16 Formula are s within the scope of Formula 8.
p 4 ~
1 ~,f,r(CH2)n COOH
Z
x Y
Formula 13 Compound X Y Z RZ n Position of 14 No. (CHZ)"COOH
16 40 O H -C=C- H 0 4 17 42 O H -C=C- H 1 4 18 44 O H -C=C- F 0 4 19 48 O cyclopropyl-C=C- H 1 4 50 O cyclopropyl-C=C- F 1 4 21 52 O cyclopropyl-C=C- H 0 4 22 54 O cyclopropyl-C=C- F 0 4 23 58 O cyclopropyl-CO-O- H 1 4 24 60 O cyclopropyl-CO-O- H 1 3 66 CH3N H -C=C- H 0 4 Ri roTilluia m g TABLE
Compound No. RS X Rs n 12 110 n-propyl (n-propyl)NH 0 13 112 benzyl NH H 0 14 114 benzyl (n-benzyl)NH 0 108 n-propyl NH H 0 16 116 benzyl methylN H 0 17 77 benzyl O H 0 18 78 benzyl O H 1 19 70 methyl O H 1 69 methyl O H 0 21 73 isopropyl O H 0 22 74 isopropyl O H 1 23 82 benzyl O methyl 1 24 81 benzyl O methyl 0 89 (CH3)3C-CHZ- O methyl 0 26 90 (CH3)3C-CH2- O methyl 1 27 94 benzyl O ethyl 1 28 93 benzyl O ethyl 0 1 g( isopropyl O methyl I
2 g5 isopropyl O methyl 0 3 105 ethyl O t-butyl 0 4 106 ethyl O t-butyl I
9g I isopropyl I O I ethyl ~ I
16 Formula 11 22 Compound No. Ra COOH
12 Formula 12 22 Compound No. Xz R2 n 24 3 methyl,cyclopropyl-NH 0 8 methyl,cyclopropyl-NH 1 26 13 methyl,cyclopropyl-NF 0 27 18 methyl,cyclopropyl-NF 1 28 139 1-imidazolyl H 0 29 13 7 1-imidazolyl H 1 26 methyl,isopropyl-N H 0 14 Formula 13 1 g TABLE
Compound No. R2 R~ Y R3 21 143 H methyl t-butyl t-butyl 22 145 F methyl t-butyl t-butyl R3 ~ ~ (CH2)"COOH
6 ~
12 Formula 18 Compound X2 R3 n No.
119 1-imidazolyl methyl 0 21 121 1-imidazolyl methyl 1 22 127 I-imidazolyl iso-propyl1 23 126 1-imidazolyl iso-propyl0 24 134 ethyl,cyclopropyl-N iso-propyl0 130 ethyl,cyclopropyl-N methyl 0 26 131 ethyl,cyclopropyl-N methyl 1 27 141 (1-methyl)cyclopropyl- iso- 1 oxy propyl i vaiai.,siw ~..
1 g TABLE
19 .
~ Compound R R2 n No.
22 63 Me H 1 -COOH
Z (CH2)n ' 13 Formula 21 Compound X3 YI R3 Z RZ n 22 No.
23 28 O H methyl -C=C- H 1 24 3 0 O H methyl -C = C- F 0 25 5 CO H H -C=C H 1 26 10 CO H H -C=C- F 0 27 36 O cyclopropyl methyl -C=C- H 1 28 38 O cyclopropyl methyl -C=C- F 1 29 46 O H methyl -CO-O- H 1 31 32 O H methyl -C=C- F 1 32 56 O ethyl methyl -C=C- H 1 33 34 O cyclopropyl methyl -C=C- H 0 34 15 CO H H -C=C- F 1 1 The compounds used in accordance with the invention can be 2 synthesized by applying the general synthetic methodology described above, 3 and by such modifications of the hereinafter described specific synthetic routes 4 which will become readily apparent to the practicing synthetic organic chemist in light of this disclosure and in view of general knowledge available in the 6 art. The hereinafter disclosed specific reaction schemes are directed to the 7 synthesis of exemplary and preferred compounds used in accordance with the 8 invention. Whereas each of the specific and exemplary synthetic routes shown 9 in these schemes may describe specific compounds only within the scope of one or two of the general Formulas 1 through 8, the synthetic processes and 11 methods used therein are adaptable within the skill of the practicing organic I2 chemist and can be used with such adaptation for the synthesis of compounds 13 used in accordance with the invention which are not specifically described 14 herein as examples.
Reaction Scheme 1 discloses a presently preferred synthetic route to 16 certain intermediates or reagents having the general formula X4-A(R2)-CH2)n 17 COORg, where the symbol A represents a di-, or tri-substituted phenyl 18 moiety. These intermediates are utilized in the synthesis of the novel 19 compounds used in accordance with the invention.
4 I W COOH M~O~ H2S04 I W COOCH3 I / y /
reagetu' B
~~3 NBS, A1BN, CC14 I ~ Br NaCN, EtOF4;H2_O ~ a'1 I
irate~medir~te 1 intermediate 2 EtOI~ p-TSA, PhH, Dec~t-Stcnx I ~ COpEt or 1. ROhT F~OH, refuac I reage~ C
2. EtOH, HZSOø be~ene, Dew-Stork CN KOH, EtOH;HzO ~ COOH E~H HZSOø PhH, Decor-Stank I ~ COOEf 12 ~ HO I / F HD '~ F
NO '~ F
13 iHtermediate 4 inrtermediate S
COOEt 1. Pd Ph CZ - TMS I ~ COOEt 14 T.fzO~ NEt3, CHaClZ ~ ~ .~z z~
I / F ~F
T~ Cul, NEt3, THF; 70°C
iHtermedide 6 ~. KzC03 MeOH reaget2t D
17 H9C OBut COON N~ w COOBr.~
I / H3Gi OBt~ I /
18 HO PhCH3, 80°C HO reageht E
f-/O H3C OBu~ HO
21 I ~ c°°H "3~~'--~°B~'' I ~ c°°a"~
22 PhcH,~, so°c reage,.~ F
24 REACTIDNSC~1 ~COOMe 6 ~ CHs gM~O~, H20, pyridiHe ~ COOH MeOH, HzS04 7 ~ / 1 I / F 1 / F
I~F
reagetrt' G
MeOH, p-T~S'A, PIt,F~ Dept-Strn~k I ~ C p 12 \ clu I II /~F I / F
intermedi~e 2 reageYtt H
COOH F~OH, HzS04 ~ COOEt H~F H / F
17 re ertt I
intermediate 4 REACTIDNSC13~IE1 CONTINUED
1 Reaction Scheme 2 discloses presently preferred synthetic routes to 2 obtain exemplary and preferred novel tetrahydronaphthalenone compounds 3 within the scope of Formula 8 where the the symbol X3 represents a C=O
4 group, Z represents an ethynyl moiety or a -COO- (ester) function, and A is a substituted phenyl moiety.
6 Reaction Scheme 3 discloses presently preferred synthetic routes to 7 obtain exemplary and preferred novel tetrahydronaphthalene compounds 8 within the scope of Formula 4 where Xl represents a dialkyl substituted 9 nitrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
Reaction Scheme 4 discloses presently preferred synthetic routes to 11 obtain exemplary and preferred novel isoquinoline compounds within the 12 scope of Formula 3 where the symbol Y represents hydrogen, Z is an 13 ethynyl moiety and A is a substituted phenyl moiety.
14 Reaction Scheme 5 discloses presently preferred synthetic routes to obtain exemplary and preferred novel chroman compounds within the scope of 16 Formula 8 where the symbol Yl represents hydrogen, Z is an ethynyl moiety 17 or an ester (COO) function, and A is a substituted phenyl moiety.
o poH3 TiCI~, MezZn, \ ~3 Crz03, AcOH, HZO \
\ I Ir I r cr-r ez ~c..H. r 2 2, 3 InteTntediate 8 intermediate 9 BBr3, CHzCZ2 \ OH ~3' CHZCZZ \ oTf p~Z~2~ - TMS
I r a I \ I r Crrl, NEt3, THF, 70°C
O 'N"NTfz O
intermediate 10 intermediate 11 TMS
I \ ~ gZC03~MeOH I ~ ~ 1'~l2az~ ~; NFt3 / r Cs~I, reagent A, B o~ C
intermediate 12 interntediate 13 r I 7cooR
\ j ~ 'X hOl~HaO, MeOHTHFH20 I r O
intermediate 14 n = D X =H R = CH3CHa Compound4 n=1 X =HR=CH3 Compourrd5 n=1 X=H
Compound 14 ~: =1 X = F R = CH3CH2 Compound IS n =1 X = F
/ COOEt I \ DTP P~2~z, ~ No's, ~ I \ ~ v 'F lMNaOH, EtOhl, 80°C
r COOEt /
o Ir o intermediate 11 ~ F
reagent D Compoiurd 9 \ I F
I
O Compoundl0 ~ OTf 1. Pd(OAc)Z, dppp, EDC, NEt3, CO
i w c O
DMSO o urtermedir~e 11 reagent E Compound 20 2. CF3COOH, CHZCl2 .REACTIDNSC.F~IE2 CONTINUED
~ I 7u~1. NaCNBH3, D-'NHZ
v ~X AcOH,AcCN
w I / 2. MeT, KZCO~, CH3COCH3 3 hO1ZH20, MeOI~l THFHZO
6 orIMNaDH, EtOH, THF, 80°C
intermediate 14 n = 0 X =H R = CH3CHz Compomtd 3 >? = 0 X = H
7 Compound4 n=1 X =HR=CH3 Compound8 n=1 X =H
Comporuul9 n = 0 X = FR = CH3CH2 Compound 13 n = 0 X = F
Compound 14 n =1 X = F R = CH3CH2 Comporurd 18 n =1 X = F
cooEr 9 rMS i 1. NaCNBH3, ~""NHZ ~ ~ I ~ reagent A
AcOH,AcCN
~ ' I i 2. Me,I, KZCO~, CH3COCH3 ,~N Pd~~s~z, ~ N~s,THF
11 ~ 3.ICzCO~, MeOH, EtOAc intermediate 12 intermediate 29 14 H, EtOH, THF, 80°C
Compound 25 Comporurd 26 1 g REACTIONSCI~IE3 zZ I ~ O~ Cr20~, AcOH, H
O OMe TiCI Me N, t , cHzCh, ~c~r3 /
antermediate IS
intermediate 16 NaN3, HzSO~, PkH ~ ~ LiAIfI~, THF w ~ HCOOH, EDCI, CHZCZZ
HN ~ / ~ HN
(reference 1) O
intermedide 17 ~~e~~e 18 7 ~ BBr~, CHZC22 Of-1~(ai-Ft)~, FJ.MgBr r\~OH
_ w ONC'N / OHC' I / T~ F~Iter .N /
8 . (ref~ce 2) intemtediate 19 ~~e~Jitte 20 imtennedi~de 21 N~~ ~Ti~z ~ OTf Pd(OAc)Z, ~1PPP~ CO ~ OOOEt w N I / EtOH EDC, NF~3, DMSO N
~ d- ~ ~' N~NTf2 11 intermedie~e 22 intennedicte 23 Br w Br ~O .P.Plc3, CBr~, CHZCl2 12 Z DIBAIr.T~ CH~GZ N
2. TPAP, NMO
13 cxZczZ, cx3cN
irrterneediate 25 iWermediote 26 TPAP=tetpropyl a.~nmonium penrtJsenate , NMO=N-methylmoipltolineN-oxide reference 1 Tomita et aG J. Gre»i. .S'va (c),1969,183188 16 ref~ce 2 Giap&nslai et d Angew. Cfienr. l~ Edm EigL,1996, 35, 413-414 d~EACTIDNSC~LEME~
2 . i I ~coori x / reage~:t B or C
3 n Bull, l~lF' N I ~ ~~~ 2' ~N ~ X=r~ F
iritermedi~te 27 Compound ZI X = F R = C1Y3CH2 Compound23X=H R=CH3 ~ I ' 7 ~ ~ x ~oxH2o, Nreox~H2o w' g ~N~ X=H,F
Compound 22 X = F
Compound 24 X =H
11 REACTIONSCI~IE4 CONTINUED
/ I T,~ooR
x Pd(PPk~aCGz, THF, NEt3 w ~ IMNaOH, F~OH, 80°C
Cul, reagent C or G
U. S. Patent Nos. S, 045,551 and 5, 616,597 Compomrd 29 X = F n = 0 R = CH3 Comporurd 31 X = F n =1 R = CH3CHZ
Tr~00H
/ ~ X
Compound 30 X = F n = 0 Compound 32 X = F n =1 Br I ~ ~H 1. SOCZZ, benzene ~Bnli, ether; COZ
/ / 2. pyridine, intermediate 39 reagent E
O / ~~ O / COOH
CF3COOH, CHZCl2 ~ w O~ O
Compound 45 Conrporurd 46 REACTIONSCFIFNES
1 Reaction Scheme 6 discloses presently preferred synthetic routes to 2 obtain other exemplary and preferred novel chroman compounds within the 3 scope of Formula 8 where the symbol Yl represents a cyclopropyl group, Z
4 is an ethynyl moiety and A is a substituted phenyl moiety.
Reaction Scheme 7 discloses presently preferred synthetic routes to 6 obtain exemplary and preferred novel chroman compounds within the scope of 7 Formula 1 where the symbol X represents oxygen (O), Y represents 8 hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
9 Reaction Scheme 8 discloses presently preferred synthetic routes to obtain other exemplary and preferred novel chroman compounds within the 11 scope of Formula 1 where the symbol X represents oxygen (O), Y represents 12 a cyclopropyl group, Z is an ethynyl moiety and A is a substituted phenyl 13 moiety.
4 \ &"~Clq, CIZCH(OCH~ ~ ~' CH2 F~'1t3, THF ~ Br / ~/ ~/
CHZCl2,1'hCH3 GHD
intermediate 30 intermediate 31 SiMe~
CHN OAc Ether I w ~~.~za2~ = TMS
z 2, ~ ~z, /
7 / CsI, NEt3, THF, 70°C
intermediate 32 intermediate 33 i 1 Q EZC03~ MeOH I ~ / ~~31 z~z, ~ NF~3 CuI, reagent A, B or C
13 i'ø~edir~e 34 Compound 33 X =H n = 0 R = CH3CH~
Compound 35 X =H n =1 R = CH3 14 Compound 37 X = F n =1 R = CH3CH~
IMNaOl~ EtOH, 80°C
19 Compound 34 X =H n = 0 Compound36 X=H n=1 Compound 38 X = F n =1 2~
21 REACTIONSCF~IE 6 3 ~, ~.
F~ 2 CHzCIz w 4 I ~ ~ Tebbe Reagent I % CHzIa~ z ~
-, U.S.Pr~etttNo.5,399,561~aA1~~3 it~~e~~e35 irtte~medi~te 36 Si7Vfe3 7 Pd(Pl~t~zClz, -= TMS ~ ~ RZC03, MeOH I w Cul, NEt~, THF; 70°C o intermediate 37 intermediate 38 i~00R
1 O / ~ I X IMNaDH, EtOH, 80°C
Pd(PPIt~zClz, THF, NF~'3 11 ~ re~~ A, B or G
13 Comporutd 39 X =H n = 0 R = CH3CHz Compouttd4l X=Hn=1 R=CH3 14 Conrpound43 X=F n=0 R=CH3 i ( r~ooH
x 18 Compound 40 X =H n = 0 Compowrd42 X=H n=1 19 Compound 44 X = F n = 0 21 RF,ACTIONSCIi~ISE 7 T~cc~, azcH~ocH~ ~ ~' cH2 ~t3, ~' ~ / I / o l ~-cxZa2, ~cH3 6 ~o \
7 intermedide 36 intermedi~e 40 ~erynedi~e 41 SiMe3 CHzNz, Pd(DAc)z, F~Iser ~ ~' Pd(PPk~zaz, = TMS \
I/ I/
aur, NF.t3, T~; 7o°c o 11 i,~~e~~e 42 ~~e~~e 43 14 gzCp3~ MeOH ' ~ / Pd(PPliglzaz~ THF,1VF~3 ~ ~ Cul, reagent A, B, G or intermediate 44 17 Compoui:d47 X=H n=1 R=CH3 Comporued49 X=F ~:=1 R=CH3 1 g Componrui SI X =H n = 0 R = CH3CHz Compound53 X=F n=0 R=CH3 21 IMNaOH, F~OH, 80°C
23 ~mporn~d 48 X =H n =1 24 C°~°~dSO X=F n=1 Compound S2 X =H n = 0 Compound S4 X = F n = 0 REACTIDNSCI~IEB
1 Reaction Scheme 9 discloses presently preferred synthetic routes to 2 obtain exemplary and preferred novel tetrahydroquinoline compounds within 3 the scope of Formula 1 where the symbol X represents an alkyl substituted 4 nitrogen (alkyl-N), Y represents hydrogen, Z is an ethynyl moiety and A is a 5 substituted phenyl moiety.
Reaction Schemes 10 and 11 disclose presently preferred synthetic 7 routes to obtain exemplary and preferred novel phenyl compounds within the 8 scope of Formula 2 where the symbol X represents oxygen (O), RS is alkyl or 9 benzyl, Z is an ethynyl moiety and A is a substituted phenyl moiety.
10 Reaction Scheme 12 discloses presently preferred synthetic routes to 11 obtain exemplary and preferred novel phenyl compounds within the scope of 12 Formula 2 where the symbol RS-X represents an alkyl, dialkyl, benzyl or 13 dibenzyl substituted nitrogen, Z is an ethynyl moiety and A is a substituted 14 phenyl moiety.
15 Reaction Schemes 13 and 14 disclose presently preferred synthetic 16 routes to obtain exemplary and preferred novel phenyl compounds within the 17 scope of Formula 6 where the symbol X2 represents a (1-imidazolyl) moiety, 18 Z is an ethynyl moiety and A is a substituted phenyl moiety.
w Br 3 ~ er- ~~ ~ y'' atct3, x4o°c I
Nlt CH Q
4 HN a~ 2 2 I
intermediate 54 intermediate 55 sin~3 6 ~~o~)~ ~ga, I ~ ~' PdlPn~~zct2, ._-_ Tnns I w 7 THF; F~her N C~l, NEt3, THI; 70°C
intermediate 56 intermedirte 57 g / CODEt 1) KZC03, MeOH j \ IMNaOH, EtOH, THF; 80°C
1 O Z) 4 I C6H4-COOEt, Pd(PPk~~, N I /
NEt3, Carl, THF I
Cvmpourrd 65 13 ~ I
~I i 14 ~ nr~
I
Compormd 66 REACTIDNSCF~IE9 2 ~G'~,v~aa3 3 ~I~SO~, R'OH R ~ ~' ~~ ~~s or R ~ ~KzCOz, acetone, Rx' R.~O ~ ~
(.( I ~ or~ a TebbeReage~
SOCIZ; R'Ohl, pysidiase intermedirteG2 R=H R'=i~ropyl intermediate 67 R=H R'=benzyl R=I~ Me, F~ uedirte 72 R=Me R'=benzyl intermedir~e 77 R=Me R'=i propyl 6 ir~teimedir~e 82 R=Me R'=neopentyl u~terneedir~e SG R=El' R'=benzyl 7 urtermedi~e 91 R=Ft R'=i~ropyl R ~, 1. Pcl(Pl~t~ZCl2, - TMs R Br CHzIZ, F~22n, CH2Clz I W
R~~~ ~ R,~~ ~ Cul, NEt3, THF, 70°C
ir~teimediate SS R=H R'=Me 2. KZC03, MeOH
iatertnedirte 63 R=H R'=i~ropyl i~ermediate59 R=H R'=Me i~termedicte 68 R=H R'=benzyl irrtermedide Gø R=H R'=ipropyl intermedir~e 73 R=Me R'=beyyl intermedir~e G9 R=H R'=ber~zyl 11 intermediate 78 R=Me R'=ipropyl ioterneedirte 74 R=Me R'=benZyl intermediate 83 R=Me R'=neopeHtyl intermediate 79 R=Me R'=ipropyl 12 intermediate 87 R=Ft R'=beryl ihte~medir~e 84 R=Me R'=neopentyl irrtermediafe 92 R = Fl R'= i-propyl intermediate 88 R =F~ R'= benzyl intermedi~e 93 R=F~ R'=i propyl REACTIONSCI~ME10 2 ~ % 1. .Pd(PPh~zCdz~ THF, NF~~, Gal, I . ~..,..,..
R
R,~ ~ I ~ reagent A or reagent B R
3 2. NaDH R~~~
intermediate 61 R=H R'=Me intermediate 66 R =H R'=i propyl intermediate 71 R =H R'=beaazyl Compound 69 n = 0 R =H R'=methyl iaatermediate 76 R=Me R'=benZyl Compound 70 s:=1 R=H R'=metlryl inteamediate 81 R =Me R'= i pabpyl Compound 73 n = 0 R =H R'= i propyl intermediate 85 R =Me R'= neopeaatyl Compoauad 74 n =1 R = H R'= i propyl iartermediate 90 R = Et R'= beaazyl Compoauad 77 n = 0 R =H R'= benzyl 7 irateamedis>xe95 R=Et R'=i~ropyl Compound 78 aa=1 R=H R'=benzyl Compoauad 81 as = 0 R = Me R'= benzyl Compound 82 n =1 R =Me R'= benzyl Compoauad 85 n = 0 R = Me R'= i~a»pyl Compound 86 n=1 R=Me R'=i~ropyl Comporuad 89 n = 0 R = Me R'=neopeadyl Compoaurd 90 n=1 R=Me R'=aaeopeartyl Compound 93 n = 0 R = F~ R'= benzyl Compoauad 94 n =1 R = Et R'= beaazyl Compoauad 97 n = 0 R = EC R'=i propyl Compound 98 as =1 R = F~ R'= i panpyl 12 g~C~ONSCII~I~ElO CONTINtTFD
2 pMe 1, NBS, CCI~, reflrr~c OH
2. B81'g, ~Z~Z
3. separate isomers by column 4 intermediate 104 ~~ALCHs R ~ OTIPS .~.Cf ~ CH3 R ~ OH 1. TII'SCI, DMF, imidazo~
~-0.
2. ~Buh, Et20; ClCOOEt y Tebbe Reagerrt R = i~ropyl intermediate 97 R = i propyl 7 irrtermediate104 R=t-butyl intermedirde106 R=tbutyl R OTIPS R ~ OTIPS
g ~ ~ CHiI2, F~2Zn, CHZCIz TBAF, THF
i ~o ~ i intermediate 98 R = i propyl intermediate 99 R = i propyl intermediate 107 R =t butyl irrtermedirte 108 R =t butyl 11 1. 5 C~C3HS1V 2 NT f2, NEt3, G'IIZCl2 12 ~ R ~ ~ ~ 2.1'd~=~1 z~z, - TMS R w ~O
13 ate; Ness, Tip; 7o°c 3. KZC03, MeOH i~.~e~~e 103 R = i propyl 14 intermediate 100 R = i~ropyl intermediate 112 R = t butyl intermediate 109 R =t butyl 1. Pd(PPJt~2Cl2, THF, NEt3, Cut, R
1 ( reagent A or reagent B
2. NaOH
Compound 101 n = 0 R =i propyl 17 Compound 102 n =1 R = i propyl TIPS tri-iso propylsilyl Compound 105 n = 0 R =t butyl Compound 106 n =1 R =t butyl 18 TBAF=teGrarr~ brdyl ammonium fluoride 19 d ~ w o i 5 C~C3HS1V 2 lVT~f'z = ~ 'O
o=s=o x~c~oNSC~m I
2 ~ 1. KOH, OH(CH~~OH, w ~Br(CH~~Br, NaOH NC ~ / re~
3 N~ I / 2. NF.~3, t BuOH, P(O)(OPh)ZN3 3. 3MHCl intermediate 113 5 ~ gnBr~ R ~ Br HpN / °r ' R'~N
1. CH3CHZCOCI, pyridine intermediate 116 2. BH3:MexS iy~~erliate 118 R =1'~ R'= n propyl 7 or intermediate 121 R = n propyl, R'= n propyl CH3CH2CHO, NaCNBH3 iy~~edi~e 124 R=H, R'=beryl irderrnediate IZS R=beryl, R'=beryl w ~ Mel, R'ZC03, acetone ~,,~fi~ / ~N /
intermediate 130 11 .-w ~ 1.1'd~~z~z~ - TMS
R~.-N I / RN
Gsl, Nl~g, TIH;
2. IC2C03, MeOH
~~e~~e R=H, R'= n-propyl intermediate R=l~ R'= n propyl ~~e~~e R=nZnnropy~ R'=n 118 123 propyl 14 intermediate R =n propyl, R'=n intermediate R=H, R'=beryl 121 propyl 127 intermediate R=H, R'=beryl intermediate R = beryl R'=
124 129 beryl intermediate R = beryly R'= u~ern:ediate R=methyl R'=beryl 125 beryl 132 IS intermediate R=ntethy~ R'=beryl I7 / cooH
Z Pd(PPIa~2Cl2, THF, NF~3, GrI, w 1 g ø r CbH4COOF~
R ~ ~ Comporurd 108 R=H, R'=n~ropyl 2. NaOH R..N / Compound I10 R =n propy, R'=r:~ropyl 19 Compound 112 R=- H, R'= beryl Compound 114 R=beryl; R'=berz~yl Compourrd 116 R = met&y~ R'= beryl ~C~ONSC~12 &'~turø ~ w B''TMSC~ NF~3, T~ ~ % er 1. Pa~,~2c~Z,._-_ rnns F~x~,~ Grl, NFt~, THF, 70°C
2. If2C0~, MeOH
isrter~ediate 133 intermediate 134 S
/ COOEt 7 % / w I NBS, PPls3, CHZCZ2 P~1 z~Z~ ~; NF13 i ~
Gel, reagerst A
Comporuul117 irrtermedirte 136 cooEt ~ i 11 ~ ~ / v ~ % v 1. Imidsrzole, NsrFl, DMF
2. NaOH
13 Br irrtermedirste 137 ~ ~ ComPoiussl119 1 S ~ ~ ~W ~~ ~ZGZ I ~ ~ Isxid~nle, Nahl DMF
16 OH Br u~~~~e 138 ~N intennedirtte 139 17 irrtermedirte 133 1. P~,~actZ, = runs ~ i 1. Pd(PPIs~ZCIz, THF, NF~3 Gsl, NBt~, THF, 70°C
Grl, reagerst B
2 ~ 2. KaCO~, MeOH ~ ) ~ NCH
M
istterrtsedirte 141 H
23 REACTIONSC1~1~E13 ZS
~ 1. MeT, IC2C03, acetone ~ ~ 1. BBr~, CHZCl2 ~ OTSS
4 I '~ 2. NBS, CCZ4 I '~ 2. T~SCl, Imidrr~ole OH
3. t Bali; DMF
irdemtediate 143 intermediate 146 7 1. TBAF, THF ~ OTf 1 ~C~t~2~a~ = TMS
I
2. 5 CL-C~IS1V 2 iVT~f'a, R'F~~, CHZCZZ ('~ CuI, NF~3, Tf~; 70°C
8 3. NaBH~ O
4. TBSCZ, Irrrida~ole, DMF 2~ ~2C~3~ MeOH
intermediate 150 ~R
11 ~ \ d~~a~a' ~ NF~3 1. TB 4F, THF _ 2. NB~S, PPh3, CHZCZ2 Cu.~ reagerrtA orreagent~
OTBS
intermediate 152 intermediate 153 n = 0 R = ethyl 13 intermediate 154 n =1 R = ~netlryl 14 . , i Tri ooH
~R
1 S ~ I , 1,1_~~yl imidagole, CH3CN
r r 16 I , 2. NaOH ~ Co orurd 12b n = 0 N
Con:porard 127 r: =1 intermediate ISS n ~ 0 R = ethyl 1 g irrterneediate 156 n =1 R = methyl TBS=t brrtylrJimethylsilyl 19 a w °~s.cF3 5 C~C~ISN 2 NTfz =
o=s=o cF~ RFACTIDNSCIi~1E14 1 Reaction Scheme 15 disclose presently preferred synthetic routes to 2 obtain exemplary and preferred novel phenyl compounds within the scope of 3 Formula 6 where X2 represents an alkyl and cyclopropyl substituted n ztrogen 4 (X2 = (alkyl,cycloalkyl)N) , Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
6 Reaction Scheme 16 discloses presently preferred synthetic routes to 7 obtain exemplary and preferred novel tetrahydronaphthalene compounds 8 within the scope of Formula 4 where the symbol Xl represents a ( 1-9 imidazolyl) moiety, Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
11 Reaction Scheme 17 discloses presently preferred synthetic routes to 12 obtain exemplary and preferred novel phenyl compounds within the scope of 13 Formula 6 where the symbol X2 represents a 1-methyl-cyclopropoxy moiety, 14 Y represents hydrogen, Z is an ethynyl moiety and A is a substituted phenyl moiety.
16 Reaction Scheme 18 discloses presently preferred synthetic routes to 17 obtain exemplary and preferred novel phenyl compounds within the scope of 18 Formula 5 where the symbol X represents oxygen (O), Y represents a 19 tertiary-butyl group, Z is an ethynyl moiety and A is a substituted phenyl moiety.
~v-2 I ~ ~Z SOClz; PYndine, cyclopropyl amine ~ I ~ Fl'T, KZCO3, acetone 2. BH3:MezS
u~te~mediote 158 4 _ ~~~~~~~
8f' 1. Pd~l~2a2~"_ TICS ~ ~ ~ ~2~r ~NEtS
N I / N I /
G~l; reagent A or reagent B
a~; NFt3, ~; ~o°C ~' Z. .K2C03, MeOH
irrtermedi~e 159 intermedirte 161 I ~CppR
9 ~N I / NaOH
~mpo~d 128 n = 0 R = F.1 Compound 130 s: = 0 / ~t Compound 129 n =1 R =Me Compound 131 n =1 11 cooEt i cyclopropyl marine, EtOH I / ~ xzCOs v 12 ~ ./ HN acetone I/
it~tetmedide ISS
14 _____ Compound132 _____ \ r ~' \ i 16 ~ ComPo~d 133 .~ I / Compound 134 17 ' v v RF4CTIDNSCI~IE15 $0 1'~~zaz~ ~ 1VF1'3 3'~, MeOHlEtOH
$ ~ r CSuI, reagentff or B
O
intermediate 13 n=0 R=Et 1 O Comporu~d 4 s: =1 R =Me 11 ~ ~ ~cooR
12 ~ ~ Y 1. N,N'-car~5nr~yl,~liimid~nle, THF
2. NaOH
13 ot~
14 n=o R=.~
Comporuid 135 n --__ 1 R =Me Compound 137 n =1 Compom:1139 n = 0 RF~1 CTION,SCI~l~El6 3 \ OH ~ OTf ~'ebbe reagent HOHz~ I r 4 CHsCOC~ pyridine OAc irdermedid'e 149 it~ermediate 162 6 O l % OT~zizr ~'zZn I \ OTf I. Pd(PI~'c~aClzr = TMS
C5~1, NF~~, THF, 70°C
intermediate 163 2. IfZC03, MeOH
intermediate 164 intermediate 166 cOOH
I. Pd~t3~2~2r ~ ~3 \
1~ \
CuY, reagent B ~ ~~, I I 2. NaOH
12 Comporuid Id1 13 r~cTroNSCx~x~
IS
1. ~'C~~z~a~ = TMS I ~ ~ Pd(P.~c~aCla, THF, NF~3 3 _ HO ~ ~ N~ ~, ~~ H3 ~ Cul, reagent B or reagent H
2. MeI, KZC03, acetone 3. R'ZC03, MeOH intermediate 169 xOH
12 Compound 142 R =H Compound 143 R =H
Compound 144 R = F Compound I4S R = F
REACTIDNSC~IE18 1 Certain known compounds which have been discovered in accordance 2 with the present invention to be useful as inhibitors of cytochrome P450RAI
3 are shown by Formula A where R8 generally represents H, alkyl of I to 6 4 carbons, -CH20(C~_6-alkyl), or a canon of a pharmaceutically acceptable base, and where the other variables have the following specific values:
I8 In Compound 201 X5 = O, X6 = CH, n = 0, Rg = H or a canon of a 19 pharmaceutically acceptable base and R1Q = CH3.
In Compound 202 XS = S, X6 = CH, n = l, R8 = H or a canon of a 21 pharmaceutically acceptable base and Rlo = H.
22 In Compound 210 XS = S, X6 = CH, n = 2, R$ = H or a canon of a 23 pharmaceutically acceptable base and R~o = H.
24 InCompound215X5=S, X6=CH,n=O, R8=Horacationofa pharmaceutically acceptable base and Rlo = H.
26 In Compound 238 XS = S, X6 = N, n = 0, R8 = H or a cation of a 27 pharmaceutically acceptable base, Rlo = H.
28 Compound 201 is described as compound 4 in United States Patent 1 No. 4,980,369 incorporated herein by reference. Compounds 202, 21D, and 2 215 are described in United States Patent No. 4,810,804 incorporated herein 3 by reference. Compound 215 is example 12 of Patent No. ,4810,804.
4 Compound 238 is described in United States Patent No. 5,089,509 incorporated herein by reference (see Claim S of Patent No. 5,089,509).
6 Other known compounds which have been discovered in accordance 7 with the present invention to be useful as inhibitors of cytochrome P450RAI
8 are shown by Formula B where R8 generally represents H, alkyl of 1 to 6 9 carbons, -CHzO(C1_6-alkyl), or a canon of a pharmaceutically acceptable base.
21 Specifically in Compound 240 Rg is H ox a cation of a pharmaceutically 22 acceptable base. Compound 240 is described and can be made in accordance 23 with the teachings of United States Patent Nos. 5,089,509, ,5,602,130 or 24 5,348,972 all of which are incorporated herein by reference.
1 Still other known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula C where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(Ci_6-alkyl), or a ration of a pharmaceutically 5 acceptable base, and whexe the other variables have the following specific 6 values:
10 N ~ ~ COORS
H
11 Roc Xs 12 ula C Rs2 16 In Compound 203 Rg is H or a ration of a pharmaceutically acceptable base, 17 Rlo = CH3, Rll = Cl, Rl~ = F and X6 = CH.
18 In Compound 204 R8 is H or a ration of a pharmaceutically acceptable base, 19 Rlo = CH3, Rll = cyclopropyl, R12 = F and X6 = CH.
In Compound 205 R8 is H or a ration of a pharmaceutically acceptable base, 21 Rlo = CH3, Rll - CF3, R12 = F and X6 = CH.
22 In Compound 206 Rg is H or a ration of a pharmaceutically acceptable base, 23 Rlo = CH3CH2, Rll = Br, R12 = F and X6 = CH.
24 In Compound 220 Rg is H or a ration of a pharmaceutically acceptable base, 2S Rlo = CH3, Rll = CH3, R12 = F and X6 = CH.
26 In Compound 221 Rg is H or a ration of a pharmaceutically acceptable base, 27 Rlo = CH3, Rll = CI, R12 = F and X6 = N.
28 In Compound 224 Rg is H or a ration of a pharmaceutically acceptable base, 1 Rlo = CH3, Rll = phenyl, R12 = F and X6 = CH.
2 In Compound 225 R8 is H or a ration of a pharmaceutically acceptable base, 3 RIO = H, Rll = Br, R12 = F and X6 = CH.
4 Tn Compound 226 R8 is H or a ration of a pharmaceutically acceptable base, Rlo = CH3, RI1 = OCH3, R12 = F and X6 = CH.
6 In Compound 227 R8 is H or a ration of a pharmaceutically acceptable base, 7 Rlo = CH3, Rll = CH3, R12 = H and X6 = CH.
8 Tn Compound 228 R8 is H or a ration of a pharmaceutically acceptable base, 9 Rla = CH3, Rll = H, R12 = F and X6 = CH.
Tn Compound 247 Rg is H or a ration of a pharmaceutically acceptable base, I I Rlo = CH3, Rll = Br, Rl2 = F and Xb = CH.
12 In Compound 248 R8 is H or a canon of a pharmaceutically acceptable base, 13 Rlo = CH3, Rll =- CF3CF2, R12 = F and X6 = CH.
14 In Compound 249 R8 is H or a ration of a pharmaceutically acceptable base, Rio = CH3, Rll = CH3,CH2, R12 = F and X6 = CH.
16 In Compound 250 Rg is H or a ration of a pharmaceutically acceptable base, 17 Rlo = CH3, Rll ' iso-propyl, R12 = F and X6 = CH.
18 In Compound 25~ Rg is H or a ration of a pharmaceutically acceptable base, 19 Rlo = CH3, Rll = (1-methyl)cyclopropyl, R12 = F and X6 = CH.
Tn Compound 252 R8 is H ox a ration of a pharmaceutically acceptable base, 21 Rla = CH3, Rll = tertiary-butyl, R12 = F and X6 = CH.
22 In Compound 253 R8 is H ox a ration of a pharmaceutically acceptable base, 23 Rio = CH3, Rll = (2,2-difluoro)cyclopropyl R12 = F and X6 = CH.
24 In Compound 254 Rg is H or a ration of a pharmaceutically acceptable base, Rlo = CH3, Rll = (cyclopropyl)methyl, R12 = F and X6 = CH.
26 Compounds 203 - 206, 220, 221, 224 - 228 and 247 - 254 are 27 described and can be made in accordance with the teachings of United States 28 Patent No. 5,675,024 which is incorporated herein by reference. (Compound 1 205 is compound or example 14, Compound 225 is compound or example 10, 2 and Compound 228 is compound or example 32 in Patent No. 5,675,024.
3 Compound 220 is also described in United States Patent No. 5,965,606, 4 incorporated herein by reference.
Still other known compounds which have been discovered in 6 accordance with the present invention to be useful as inhibitors of cytochrome 7 P450RA.I are shown by Formula D where R8 generally represents H, alkyl of 8 1 to 6 carbons, -CH20(C1_6-alkyl), or a canon of a pharmaceutically 9 acceptable base, and where the other variables have the following specific values:
R1a R14 13 ~ ~ ~----COORB
1 s ~ ,/ R12 Fo~rnulaD
16 ~
"13 R13 21 In Compound 207 R8 is H or a ration of a pharmaceutically acceptable base, 22 R12 = H, the two R13 groups jointly represent an oxo (=O) function and R14 =
23 CH3.
24 In Compound 208 R8 is H or a ration of a pharmaceutically acceptable base, R12 = H, R13 = H and R14 = CH3.
2b In Compound 216 R8 is H or a canon of a pharmaceutically acceptable base, 27 R12 = H, R13 = CH3 and R14 = CH3.
28 In Compound 21$ ,R8 is H or a ration of a pharmaceutically acceptable base, 1 R12 = H, R13 = CH3 and R14 = H.
2 In Compound 230 R8 is H or a canon of a pharmaceutically acceptable base, 3 R12 = F, R13 = CH3 and R14 = CH3.
4 In Compound 232 Rs is H or a cation of a pharmaceutically acceptable base, R12 = H, one of the R13 groups is H, the other is OH and R14 = CH3.
6 Compound 207 is described (as compound 7) in United States Patent 7 No. 5,489,584 incorporated herein by reference. Compound 232 is described 8 (as compound 42) in United States Patent No. 5,654,469 incorporated herein 9 by reference. Compounds 208, 216 and 218 are described in the publication by Cha~d~a~atna el al. J. Eur. J. Med. Chem., Suppl. to Vol. 30, 1995, 506s-11 517s. Compound 230 can also be made in accordance with the teachings of 12 the publication by Cha~cd~a~atna el al. J. Eur. J. Med. Chem., Suppl to VoI.
13 30, 1995, 506s-517s, incorporated herein by reference, or by such modification 14 of the synthetic procedures of this reference which will be readily apparent to those skilled in the art.
16 StiII further known compounds which have been discovered in 17 accordance with the present invention to be useful as inhibitors of cytochrome 18 P450RAI are shown by Formula E where R8 generally represents H, alkyl of 19 1 to 6 carbons, -CH2O(C1_6-alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific 21 values:
R~5 ~ n ~ ~-- COORS
27 R~s 1 In Compound 209 Rg is H or a cation of a pharmaceutically acceptable base, 2 R12 = H, Rls = tertiary-butyl, R16 = OH and R17 = Cl.
3 In Compound 211 Rs is H or a canon of a pharmaceutically acceptable base, 4 R12 = H, R15 = tertiary-butyl, R16 = OCH3 and R17 = tertiary-butyl.
In Compound 214 R8 is H or a canon of a pharmaceutically acceptable base, 6 R12 = H, Rls = 1-adamantyl, R16 = OCH3 and R17 = H.
7 In Compound 235 Rg is H or a cation of a pharmaceutically acceptable base, $ R12 = H, Rls = tertiary-butyl, R16 = OH and R17 = tertiary-butyl.
9 In Compound 236 R8 is H or a cation of a pharmaceutically acceptable base, R12 = F, R15 = tertiary-butyl, R16 = OH and R17 = H.
11 Compound 211 is described and can be made in accordance with the 12 teachings of United States Patent No. 5,202,471, and Compound 235 is 13 described and can be made in accordance with the teachings of United States 14 Patent No. 5,498,795. The specification of Patent Nos. 5,202,471 and 5,498,795 are incorporated herein by reference. Compounds 209, 214 and 16 236 can also be made in accordance with the teachings of United States Patent 17 Nos. 5,202,471 and 5,498,795 with such modifications of the synthetic 18 procedures which will be readily apparent to those skilled in the art.
19 Still more known compounds which have been discovered in accordance with the present invention to be useful as inhibitors of cytochrome 21 P450RAI are shown by Foxmula F where Rg generally represents H, alkyl of 22 1 to 6 carbons, -CH20(Cl_~-alkyl), or a cation of a pharmaceutically 23 acceptable base, and where the other variables have the following specific 24 values:
O
,' NH ~ ~ CODRg 7 R~2 nula F
11 Tn Compound 222 Rg is H or a cation of a pharmaceutically acceptable base, 12 R12 = F, R15 = tertiary-butyl, R16 = CH3CH20 and R17 = I.
13 In Compound 223 R8 is H or a cation of a pharmaceutically acceptable base, 14 R12 = F, Rls = tertiary-butyl, R16 = CH3CH20 and R17 = Br.
Compounds 222 and 223 are described and can be made in accordance 16 with the teachings of United States Patent Nos. 5,663,357 and 5,917,048, the .
17 specifications of which are incorporated herein by reference.
18 Yet more known compounds which have been discovered in 19 accordance with the present invention to be useful as inhibitors of cytochrome P450RAI are shown by Formula G where R8 generally represents H, alkyl of 21 1 to 6 carbons, -CHzO(C~_6-alkyl), or a cation of a pharmaceutically 22 acceptable base, and where the other variables have the following specific 23 values:
' CODRB
6 ~s 7 R~z r Fo~nula G
s 11 In Compound 212 R8 is H or a cation of a pharmaceutically acceptable base, 12 R12 = H, X6 = CH and X7 = (CH3)~C.
13 In Compound 217 Rg is H or a cation of a pharmaceutically acceptable base, 14 R12 = H, X6 = CH and X7 = CH2.
1 S In Compound 219 R8 is H or a cation of a pharmaceutically acceptable base, I6 R12=H, X6=CH and X7=S.
17 In Compound 229 R8 is H or a cation of a pharmaceutically acceptable base, 18 R12 = F, X6 = CH and X7 = CHI.
19 In Compound 244 R8 is H or a cation of a pharmaceutically acceptable base, R12 = H, X6 = N and X7 = CH2.
21 Compounds 217 is described (as example or compound 4) and can be 22 made in accordance with the teachings of United States Patent Nos.
4,739,098 23 the specification of which is incorporated herein by reference. Compounds 24 219 is described (as compound 2) and can be made in accordance with the 2S teachings of United States Patent Nos. 5,688,957, the specification of which is 26 incorporated herein by reference. Compound 212 and Compound 229 can be 27 made in accordance with the teachings of United States Patent Nos.
4,739,098 28 and in case of Compound 212 also in accordance with United States Patent 1 No. 5,426,118, with such modifications of the synthetic procedures which will 2 be readily apparent to those skilled in the art. The specification of United 3 States Patent No. 5,426,118 is incorporated herein by reference. Compound 4 244 is described (as compound or example 7) and can be made in accordance with the teachings of United States Patent Nos. 4,923,884, the specification of 6 which is incorporated herein by reference.
7 Still more known compounds which have been discovered in 8 accordance with the present invention to be useful as inhibitors of cytochrome 9 P450R.AI are shown by Formula H where R8 generally represents H, alkyl of 1 to 6 carbons, -CH20(C1_6-alkyl), or a canon of a pharmaceutically 11 acceptable base.
16 _ ~ ~ ~~--OOORB
Formula H
23 Specifically in Compound 245 R8 is H or a canon of a pharmaceutically 24 acceptable base.
Compounds 245 is described and can be made in accordance with the 26 teachings of United States Patent Nos. 4,923,884.
1 Further known compounds which have been discovered in accordance 2 with the present invention to be useful as inhibitors of cytochrome P450R.AI
3 are shown by Formula T where Rg generally represents H, alkyl of 1 to 6 4 carbons, -CH20(C1_6-alkyl), or a ration of a pharmaceutically acceptable base.
COOf~8 14 ~'o~raulal 17 Specifically in Compound 242 R8 is H or a ration of a pharmaceutically 18 acceptable base.
19 Compound 242 is described in the publication by Befn2a~d et al.
Biochem. Biophys. Res. Commun., 1992, Vol. 186, 977-9~3, incorporated 21 herein by reference.
1 Still more known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula J where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base, and where the other variables have the following specific 6 values:
NH ~ ~ COORS
12 ~'~2 14 Form~rla J
18 In Compound 237 Rg is H or a cation of a pharmaceutically acceptable base, 19 Rlz = F, Rl$ = H and R19 = H.
In Compound 246 R8 is H or a canon of a pharmaceutically acceptable base, 21 R12=H,RIg=OH andRl9=F.
22 Compounds 237 and 246 are described and can be made in accordance 23 with the teachings of United States Patent Nos. 5,675,024 and 5,856,490.
24 Compound 237 is compound or example 2 of Patent No. 5,675,024. The specification of United States Patent No. 5,856,490 is incorporated herein by 26 reference.
1 Additional known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula K where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(C~_6-alkyl), or a cation of a pharmaceutically 5 acceptable base.
11 ~ ~ ~ COORS
13 s.....~ulal~
17 Specifically in Compound 231 R8 is H or a cation of a pharmaceutically 18 acceptable base.
19 Compound 231 is described (as compound 2) in United States Patent No, 5,006,550, the specification of which is incorporated herein by reference.
1 Still more known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P450RAI are shown by Formula L where R8 generally represents H, alkyl of 4 1 to 6 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically S acceptable base.
l0 0 ~ ~ COORS
12 ;ula L
16 Specifically in Compound 243 R8 is H or a cation of a pharmaceutically 17 acceptable base.
~ 8 Compound 243 is described (as example or compound 7) in United 19 States Patent No. 5,130,335, the specification of which is incorporated herein 20 by reference.
1 Still more known compounds which have been discovered in 2 accordance with the present invention to be useful as inhibitors of cytochrome 3 P4SORAI axe shown by Formula M where Rg generally represents H, alkyl of 4 1 to 6 carbons, -CH20(Cl_6-alkyl), or a cation of a pharmaceutically S acceptable base, and where the other variables have the following specific 6 values:
16 In Compound 233 R$ is H or a cation of a pharmaceutically acceptable base, 17 Rls = I-adamantyl and R16 = OH.
I8 In Compound 234 R8 is H or a cation of a pharmaceutically acceptable base, 19 R15 = 1-adamantyl and R16 = OCH3.
Compounds 233 and 234 are described in the publication by Shoot et 21 al. J. M. EP 199636 (1986) incorporated herein by reference.
1 Further known compounds which have been discovered in accordance 2 with the present invention to be useful as inhibitors of cytochrome P450RAI
3 are shown by Formula N where R8 generally represents H, alkyl of 1 to 6 4 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
COOR$
17 Specif cally in Compound 241 R$ is H or a cation of a pharmaceutically 18 acceptable base. .
19 Compound 241 is described in the publieation by Dawsoh et al. J.
Med. Chem., 1983, Vol. 26, 1653-1656. incorporated herein by reference.
1 Still further compounds which have been discovered in accordance with 2 the present invention to be useful as inhibitors of cytochrome P450RAI are 3 shown by Formula 4 where R8 generally represents H, alkyl of 1 to 6 4 carbons, -CH20(C1_6-alkyl), or a cation of a pharmaceutically acceptable base.
\ \ \ \
v ~' ~' V 'COOK 8 8 \
lFormula O
12 Specifically in Compound 247 Rg is H or a cation of a 13 pharmaceutically acceptable base. Compound 247 is described in the 14 publication by Wiuum et al. I1 Farmaco, 1997, Vol. 52, l, p39-42, incorporated herein by reference.
16 The P450RAI inhibition data of this compound are provided in Table 17 1A, and the cutaneous toxicity score (blackjack score) of the compound in the 18 topical skin irritation tests provided above, are disclosed in Table 1B.
2 4-Hydroxy phenyl acetic acid-t-bu 1 ester (Reagent E) 3 A stirred suspension of 4-hydroxy-phenyl acetic acid (0. Z S2g, l mmol) 4 in anhydrous toluene (SmL) was heated at 80°C and N,N-dimethyl formamide-S di-t-butyl acetal (lmL, 4.17mmol) was added when the solution became 6 homogenous. After O.Sh, the reaction mixture was cooled to ambient 7 temperature and the volatiles were distilled off in vacuo. The residue was 8 diluted with water and extracted with diethyl ether (x2). The combined 9 organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil which was subjected to flash column 11 chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in 12 hexane as the eluent to afford the title compound as a solid (0.1 1g, S6%).
13 1H-NMR (300 MHz, CDCl3):8 1.44(s, 9H), 3.45(s, 2H), 6.SS(s, 1H), 6.69(d, J
14 = 8.8Hz, 2H), 7.06(d, J = B.SHz, 2H).
3-H drox~phenKl acetic acid-t-butyl ester (Reagent F) 16 A stirred suspension of 3-hydroxy-phenyl acetic acid (1.52g, l Ommol) 17 in anhydrous toluene (20mL) was heated at 80°C and N,N-dimethyl 18 formamide-di-t-butyl acetal (9.6mL, 40mmol) was added when the solution 19 became homogenous. After O.Sh, the reaction mixture was cooled to ambient temperature and the volatiles were distilled off in vacuo. Th residue was 21 diluted with water and extracted with diethyl ether (x2). The combined 22 organic extract was dried over anhydrous sodium sulfate, filtered and 23 evaporated in vacuo to afford an oil which was subjected to flash column 24 chromatography over silica gel (230-400 mesh) using 16% ethyl acetate in 2S hexane as the eluent to afford the title compound as a solid (1.17g, S6%).
26 'H-NMR (300 MHz, CDCl3):8 1.47(s, 9H), 3.49(s, 2H), 6.30(s, 1H), 6.70-6.79 27 (m, 2H), 6.81(d, J = 7.6Hz, 1H), 7.16(t, J = 7.7Hz, 1H).
28 Methyl-2-fluoxo-4-iodo benzoate (Reagent G) 1 A solution of 2-fluoro-4-iodo toluene (5g, 26.6mmo1) in pyridine (2mL) 2 and water (20mL) was treated with potassium permanganate ( I 6.6g, 3 lOSmmol) and heated at 150°C overnight. The reaction mixture was then 4 cooled to room temperature and filtered and the filtrate was extracted with hexane. The aqueous phase was acidified with 10% hydrochloric acid and 6 extracted with ethyl acetate. The organic phase was dried over anhydrous 7 sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved 8 in 20mL of methanol, treated with concentrated sulfuric acid (1mL) and 9 refluxed overnight. The volatiles were distilled off in vacuo and the residue was dissolved in diethyl ether, washed with brine, dried over anhydrous 11 sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column 12 chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in 13 hexane as the eluent afforded the title compound as an oil (0.26g, 5%).
14 'H NMR (300 MHz, CDCl3): ~ 7.60 (m, 4H), 3.93 (s, 3H).
Eth.1-Toro-4-hydroxy benzoate (Reagent I) 16 A solution of 2-fluoro-4-hydroxy benzoic acid (Intermediate 4, 3g, 17 19.2mmol) in ethanol (65mL) and benzene (90mL) was treated with 18 concentrated sulfuric acid (l.SmL) and heated at reflux overnight using a 19 Dean-Stark water trap. The volatiles were distilled off in vacuo and the residue was diluted with water and diethyl ether. The phases were separated 21 and the organic phase was washed with saturated aqueous sodium bicarbonate 22 (x1), water (x1) and brine (x1), dried over anhydrous magnesium sulfate, 23 filtered and evaporated in vacuo to afford the title compound as a solid (3.07g, 24 86%).
'H-NMR (300 MHz, CD3COCD3): 8 1.34 (t, J= 7.lHz, 3H), 4.32 (q, J=
26 7.lHz, 2H), 6.66(dd, J = 2.6, 10.9Hz, 1H), 6.76 (dd, J= 2.3, 8.SHz, 1H), 27 7.83(d, J= 8.4Hz, 1H), 9.91 (s, 1H).
28 Ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6) 29 A stirred, cooled (ice bath) solution of ethyl-2-fluoro-4-hydroxy-1 benzoate (Intermediate 5, 0.368g, 2mmol) and 2,6-di-tert-butyl-4-methyl-2 pyridine (0.81 g, 8mmo1) in 8mL of dichloromethane was treated with 3 trifluoromethanesulfonic anhydride (0.1g, 4mmo1). The reaction mixture was 4 allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-6 400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title 7 compound (0.53g, 85%).
8 1H-NMR (300 MHz, CDCl3): ~ 1.41 (t, J= 7.3Hz, 3H), 4.42 (q, J= 7.lHz, 9 2H), 7.12-7.20(m, 2H), 8.08(t, J= 8.3Hz, 1H).
Eth~l-2-fluoro-4-trimeth,~lsilanylethynyl-benzoate (Intermediate 7) 11 A solution of ethyl-2-fluoro-4- trifluoromethylsulfonyloxy-benzoate 12 (Intermediate 6, 1.82g, 6mmol) in triethyl amine ( l2mL) and anhydrous 13 tetrahydrofuran (30mL) was treated with copper(I)iodide (0.12g, 0.6mmol) 14 and sparged with argon. Dichlorobis(triphenylphosphine)palladium(II) (0.43g, 0.6mmo1) was added followed by (trimethylsilyl)acetylene (3.6mL, 24mmol) 16 and the resulting reaction mixture was heated at 70°C overnight. It was then 17 cooled to ambient temperature, diluted with diethyl ether and filtered over a 18 bed of celite. The filtrate was evaporated in vacuo to an oil which was 19 subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as 21 an orange oil (1.5g, quantitative).
22 rH-NMR (300 MHz, CDC13):8 0.011 (s, 9H), 1.13(t, J= 7.lHz, 3H), 4.13 (q, J
23 = 7.lHz, 2H), 6.93-7.02(m, 2H), 7.07 (s, 1H), 7.61(t, J= 7.9Hz, 1H).
24 Ethyl-4-eth~nyl-2-fluoro benzoate (Reagent D) A solution of ethyl-2-fluoro-4-trimethylsilanylethynyl-benzoate 26 (Intermediate 7, 1.5g, 6mmo1) in ethanol (l6mL) was treated with potassium 27 carbonate (1.485g, 10.74mmo1) and stirred overnight at room temperature.
28 The reaction mixture was then diluted with water and extracted with diethyl 29 ether (x2). The combined organic phase was dried over anhydrous magnesium 1 sulfate, filtered and evaporated in vacuo to afford an orange oil. Flash column 2 chromatography over silica gel (230-400 mesh) using S% ethyl acetate in 3 hexane as the eluent afforded the title compound (1g, 86%).
4 1H-NMR (300 MHz, CDC13):8 1.39 (t, J= 7.lHz, 3H), 3.26 (s, 1H), 4.39 (q, J
= 7.lHz, 2H), 7.22-7.33 (m, 2H), 7.88(t, J= 7.7Hz, 1H).
6 Methyl-4-iodo-phenyl acetate (Reagent B) 7 A solution of 4-iodo phenyl acetic acid (Sg, l9mmol) in methanol was 8 treated with concentrated sulfuric acid (O.SmL) and refluxed overnight. The 9 volatiles were distilled off in vacuo and the residue was dissolved in ethyl 010 acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and 11 evaporated in vacuo to an oil which was subjected to flash column 12 chromatography over silica gel (230-400 mesh) using S% ethyl acetate in 13 hexane as the eluent to afford the title compound as a clear oil (Sg, 9S%).
14 'H NMR (300 MHz, CDC13): ~ 7.63 (d, 2H, J= 8.SHz), 7.01 (d, 2H, J=
1S B.OHz), 3.67 (s, 3H), 3.SS (s, 2H).
16 2-Fluoro-4-iodo-phenyl acetonitrile (Intermediate 2) 17 A solution of 2-fluoro-4-iodo-benzyl bromide (Intermediate 1, 2.S6g, 18 8.1 Smmol) in ethanol (SSmL and water (lOmL) was treated with sodium 19 cyanide (2.1 Sg, 43.86mmo1) and refluxed for O.Sh. The volatiles were distilled 20 off in vacuo and the residue was diluted with water and extracted with diethyl 21 ether (x2). The combined organic extract was washed with water (x1) and 22 brine (x1), dried over anhydrous magnesium sulfate, filtered and evaporated in 23 vacuo to afford the title compound as a pale yellow solid (2.OSg, 96%).
24 'H-NMR (300 MHz, CDC13): 8 3.71(s, 3H), 7.16(t, J= 8.2Hz, 1H), 7.45(dd, J
2S = 1.7, 9.lHz, 1H), 7.51(dd, J= 1.5, 8.2Hz, 1H).
26 2-Fluoro-4-iodo-phenyl acetic acid (Intermediate 3) 27 A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 28 2.OSg, 7.83mmo1) in ethanol (SOmL and water (lSmL) was treated with 29 potassium hydroxide (3.4g, 60.7mmol) and refluxed for 4h. The volatiles were 1 distilled off in vacuo and the residue was diluted with water and poured into 2 cold, dilute hydrochloric acid and the precipitated solid was filtered. The solid 3 was dissolved in diethyl ether, and the organic solution was dried over 4 anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound a pale yellow solid (I.75g, 79%).
6 'H-NMR (300 MHz, CDCl3):8 3.64 (s, 2H), 6.98(t, J= 7.9Hz, 1H), 7.25-7.46 7 (m, 2H), 9.60-10.40(br s, 1H).
8 Ethyl-2-fluoro-4-iodo-phenyl acetate (Reagent C) 9 A solution of 2-fluoro-iodo-phenyl acetic acid (Intermediate 3, 1.75g, 6.22mmol) in ethanol (SOmL) and benzene (100mL) was treated with 11 concentrated sulfuric acid ( 1.4mL) and heated at reflux overnight using a 12 Dean-Stark water trap. The volatiles were distilled off in vacuo and the 13 residue was diluted with water and diethyl ether. The phases were separated 14 and the organic phase was washed with saturated aqueous sodium bicarbonate (x1), water (xI) and brine (x1), dried over anhydrous magnesium sulfate, 16 filtered and evaporated in vacuo to afford an oil which was subjected to flash 17 column chromatography over silica gel (230-400 mesh) using 5%-10% ethyl 18 acetate in hexane as the eluent to afford the title compound as a pale yellow 19 solid (1.4g, 73%).
'H-NMR (300 MHz, CDC13): 8 1.25 (t, J= 7.lHz, 3H), 3.60 (s, 2H), 4.I6 (q, J
21 = 7.lHz, 2H), 6.99(t, J = B.OHz, IH), 7.39-7.44(m, 2H).
22 Methyl-2-fluoro-4-iodo-phenyl acetate (Reagent H) 23 A solution of 2-fluoro-4-iodo-phenyl acetonitrile (Intermediate 2, 3g, 24 1 I .4Smmo1) in methanol (SOmL) and benzene (SOmL) was treated with p-toluene sulfonic acid (2.5g, 13.1 Smmol) and heated at reflux overnight using a 26 Dean-Stark water trap. The volatiles were distilled off in vacuo and the 27 residue was diluted with water and diethyl ether. The phases were separated 28 and the organic phase was washed with saturated aqueous sodium bicarbonate 29 (x1), water (x1) and brine (xI), dried over anhydrous magnesium sulfate, 1 filtered and evaporated in vacuo to afford an oil which was subjected to flash 2 column chromatography over silica gel (230-400 mesh) using 6% ethyl acetate 3 in hexane as the eluent to afford the title compound as a colorless oil (2.7g, 4 80%).
1H-NMR (300 MHz, CDCl3): 8 3.62 (s, 2H), 3.70 (s, 3H), 6.99(t, J = 7.9Hz, 6 1H), 7.39-7.45(m, 2H).
7 GENERAL PROCEDURE A: 7-Methoxy-1 1-dimethyl-1,2,3,4-8 tetrah~dronaphthalene (Intermediate 8) 9 A stirred, cooled (-40°C) solution of titanium tetrachloride in anhydrous dichloromethane (1M, 20mL) under argon, was treated with a solution of 11 dimethyl zinc (2M, 40mL) in toluene. After 0.5h, a solution of 7-methoxy-1-12 tetralone (1.76g, lOmmol) in anhydrous dichloromethane (5mL) was 13 cannulated into the reaction mixture and the resulting solution was allowed to 14 warm to ambient temperature and stirred overnight. The reaction mixture was then cooled to -40°C and cautiously quenched with methanol (llmL). It was 16 diluted with dichloromethane and saturated aqueous ammonium chloride 17 solution. The phases were separated and the aqueous phase was extracted with 18 dichloromethane (x2mL). The combined organic phase was dried over 19 anhydrous sodium sulfate, filtered and evaporated in vacuo to the title compound (1.75g, 92%) as an oil.
21 1H-NMR (300 MHz, CDC13):8 1.33(s, 6H), 1.67-1.71(m, 2H), 1.79-1.90(m, 22 ZH), 2.75(t, J = 6.2Hz, 2H), 3.83(s, 3H), 6.72(dd, J = 2.6, 8.3Hz, 1H), 6.93(d, 23 J = 2.6Hz, 1 H), 7.02(d, J = 8.3Hz, 1 H).
24 GENERAL PROCEDURE B: 6-Methox~-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 9) 26 A solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene 27 (Intermediate 8, 1.658, 8.7 mmol) in 7.5mL of glacial acetic acid was cooled 28 to 0°C and treated with a solution of chromium trioxide (2ga 20mmo1) in 8mL
29 of acetic acid and 7mL of water. The reaction mixture was then allowed to 1 warm to ambient temperature and stirred overnight. It was diluted with water 2 and extracted with diethyl ether (x2). The combined organic phase was 3 washed with water (x1), saturated aqueous sodium bicarbonate (x1) and brine 4 (x1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (1.64g, 93%) as a yellow oil.
6 IH-NMR (300 MHz, CDCl3):8 1.34(s, 6H), 1.96(t, J = 7.lHz, 2H), 2.64(t, J =
7 7.1 Hz, 2H), 3 . 83 (s, 3 H), 6.77(dd, J = 2.6, 8.7Hz, 1 H), 6. 83 (d, J =
2. SHz, 1 H), 8 7.98(d, J = 8.7Hz, 1H).
9 6-H,~xy-4~4-dimethXl-1~2 3 4-tetrah~drOnaphthalene-1-one (Intermediate 10) 11 A stirred, cooled (-78°C) solution of 6-methoxy-4,4-dimethyl-1,2,3,4-12 tetrahydronaphthalene-1-one (Intermediate 9, 0.8, 3mmo1) under argon was 13 treated with a 1M solution of boron tribromide (lOmL). The reaction mixture 14 was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to -78°C, quenched and diluted with saturated 16 aqueous sodium bicarbonate solution and the aqueous phase was extracted 17 with dichloromethane (x2). The combined organic phase was dried over 18 anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash 19 column chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent afforded the title compound (0.3g, 52%) as a 21 yellow viscous oil.
22 iH-NMR (300 MHz, CDC13):8 1.33(s, bH), 1.97(t, J = 6.8Hz, 2H), 2.71 (t, J =
23 6.7Hz, 2H), 6.81(dd, J = 2.3, 8.SHz, 1H), 6.94(d, J = 2.3Hz, 1H), 7.98(d, J
=
24 8.7Hz, 1H), 9.35(s, 1H).
GENERAL PROCEDURE C: 4 4-Dimethyl-6-trifluorometh~lsulfonyloxy-26 1,2~3,4-tetrahvdronaphthalene-1-one (Intermediate 11) 27 A stirred, cooled (0°C) solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-28 terahydronaphthalene-1-one (Intermediate 10, 0.3g, l.6mmo1) in anhydrous 29 dichloromethane (lOmL) was treated with 4-(dimethylamino)pyridine (0.36g, 1 3.27mmo1) followed by 2-~N,N'-bis(trifluoromethylsulfonyl)amino]-5-2 chloropyridine (0.798, 2mmo1). After stirring at ambient temperature for 3 0.75h, the reaction mixture was diluted with dichloromethane and washed with 4 water (x1). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over 6 silica gel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluent 7 afforded the title compound (0.462g, 90%) as an off white solid.
8 1H-NMR (300 MHz, CDC13): 8 1.36(s, 6H), 2.01 (t, J = 6.8Hz, 2H), 2.70(t, J =
9 6.7Hz, 2H), 7.15(dd, J = 2.5, 8.7Hz, 1H), 7.28(d, J = 2.4Hz, 1H), 8.06(d, J
=
8.7Hz, 1H).
11 GENERAL PROCEDURE D: 4~4-Dimethyl-6-trimethylsilanyl-eth~yl-12 1 2 3 4-tetrah~dronaphthalene-1-one (Intermediate 12) 13 A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-14 tetrahydronaphthalene-1-one (Intermediate 11, 0.46g, 1.43mmo1) in triethyl amine (3mL) and anhydrous tetrahydrofuran (8mL) was treated with 16 copper(I)iodide (0.1g, 0.53mmo1) and sparged with argon for 5 minutes.
17 Trimethylsilyl acetylene (0.85mL, 6mmo1) was then added followed by 18 dichlorobis(triphenylphosphine)palladium(II) (0.25g, 0.36mmol). The 19 resulting reaction mixture was heated at 70°C for 17h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of 21 celite. The filtrate was evaporated vacuo to an oil which was subjected to 22 flash column chromatography over silica gel (230-400 mesh) using 5% ethyl 23 acetate in hexane as the eluent to afford the title compound (0.28g, 72%).
24 tH-NMR (300 MHz, CDC13): 8 0.26(s, 9H), 1.36(s, 6H), 1.99(t, J = 6.8Hz, 2H), 2.69(t, J = 6.7Hz, 2H), 7.35(dd, J = 1.7, 8.2Hz, 1H), 7.49 (unresolved d, 26 1H), 7.93(d, J = 8.lHz, 1H).
27 GENERAL PROCEDURE E: 6-Eth~Xl-4,4-dimeth~l-1,2,3,4-28 tetrah.~phthalene-1-one (Intermediate 13) 1 A solution of 4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-2 tetrahydronaphthalene-1-one (Intermediate 12, 0.28g, 1.03mmol) in methanol 3 (1 OmL) was treated with potassium carbonate (0.74g, 5.35mmo1) and stirred at 4 ambient temperature for 4h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with diethyl ether (x2). The 6 combined organic extract was dried over anhydrous magnesium sulfate, 7 filtered and evaporated in vacuo to afford the title compound (0.19g, 89%) as 8 an oil that solidified on standing.
9 1H-NMR (300 MHz, CDCl3):8 1.33(s, 6H), I .96(t, J = 6.8Hz, 2H), 2.67(t, J =
6.8Hz, 2H), 3.25(S, 1H), 7.33(dd, J = 1.5, 8.lHz, 1H), 7.49 (d, J = I .SHz, 11 1H), 7.13(d, J = 8.lHz, 1H).
12 GENERAL PROCEDURE F: 4~8 8-Dimeth~l-5-oxo-5 6 7 8-tetrahydro-13 naphthalene-2 ~1-ethyn~)-benzoic acid eth 1y ester (Intermediate 14) 14 A solution of 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.23g, l.lmmol) and ethyl-4-iodo benzoate (Reagent 16 A, 0.36g, I.3mmo1) in triethyl amine (7mL) and anhydrous tetrahydrofuran 17 (3mL) was treated with copper(I)iodide (0.114g, 0.6mmol) and sparged with 18 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 19 0.33mmo1) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite.
21 The filtrate was evaporated in vacuo to a brown oil that was subjected to flash 22 column chromatography over silica gel (230-400 mesh) using 6-7% ethyl 23 acetate in hexane as the eluent to afford the title compound (0.29g, 72%) as a 24 pale brown solid.
'H-NMR (300 MHz, CDC13): 8 I.3(t, J = 7. lHz, 3H), 1.37(s, 6H), 1.80 (t, J =
26 6.8Hz, 2H), 2.69(t, J = 6.8Hz, 2H), 4.35(q, J = 7.lHz, 2H), 7.40(dd, J =
1.5, 27 8.2Hz, 1H), 7.51 (d, J = 1.6Hz, 1H), 7.57 (d, J = 8.3Hz, 2H), 7.96(d, J =
28 8,2Hz, 1H), 7.99(d, J = 8.SHz, 2H).
1 GENERAL PROCEDURE G 4 (5 Cyclopropylamino-8 8-dimethyl-5,6,7,8-2 tetrahy~phthalene 2y1-ethyn~)-benzoic acid ethyl ester (Compound 1, 3 General Formula 4) 4 A solution of 4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Intermediate 14, 0.148, 0.4mmo1) in 3mL
6 of dichloromethane and 2mL of acetonitrile was treated with cyclopropyl 7 amine(lmL, 14.45mmo1). After 5 minutes, acetic acid (1mL) was added 8 followed by sodium cyanoborohydride (0.13g, 2mmo1). The reaction was 9 stirred overnight at ambient temperature. It was then diluted with water and saturated aqueous sodium carbonate solution and extracted with 11 dichloromethane (x2). The combined organic extract was dried over 12 anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash 13~ column chromatography over silica gel (230-400 mesh) using 20% ethyl 14 acetate in hexane as the eluent afforded the title compound (0.1 g, 62%) as a pale yellow solid.
16 1H-NMR (300 MHz, CDCl3): 8 0.30-0.60(m, 4H), 1.28(s, 3H), 1.35 (s, 3H), 17 1.30(t, J = 7.lHz, 3H), 1.55-1.61(m, 1H), 1.83-2.05(m, 3H), 2.25 (quintet, J=
18 3 .0 Hz, 1 H), 3 .80 (t, J = 4.9Hz, 1 H), 4.39(q, J =. 7.1 Hz, 2H), 7.27-7.3 6(m, 19 2H), 7.52 (s, 1H), 7.55(d, J= 8.3Hz, 2H), 8:03(d, J= 8.5Hz, 2H).
GENERAL PROCEDURE H 4-[(5-Cycloprop, 1-Y meth-amino-8 8-dimethyl=
21 5 6 7 8-tetrah~dro-naphthalene-2-~ynyll-benzoic acid ethyl ester 22 (Compound 2, General Formula 4) 23 A solution of 4-(5-cyclopropylamino-8,8-dimethyl-5,6,7,8-tetrahydro-24 naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Compound 1, 0.064g, 0.16mmo1) in acetone (2mL) was treated with potassium carbonate (0.6g, 26 4.34mmo1) and methyl iodide (lmL, l6mmol) and stirred overnight at ambient 27 temperature. The volatiles were distilled off in vacuo and the residue was 28 diluted with water and extracted with dichloromethane (x2). The combined 1 organic extract was dried over anhydrous sodium sulfate, filtexed and 2 evaporated in vacuo to afford the title compound (0.06S8, 99%).
3 1H-NMR (300 MHz, CDCl3): ~ 0.28-0.49 (m, 4H), 1.21(s, 3H), 1.26 (s, 3H), 4 1.33 (t, J = 7.lHz, 3H), 1.58-1.73 (m, 2H), 1.83-1.89 (m, 2H), 2.02-2.08 (m, 1H), 2.06 (s, 3H), 3.88 (t, J = 8.lHz, 1H), 4.32(q, J = 7.lHz, 2H), 7.20(d, J
=
6 7.8Hz, 1H), 7.41 (s, 1H), 7.46 (d, J = 7.8Hz, 1H), 7.52(d, J = 8.4Hz, 2H), 7 8.03(d, J = 8.3Hz, 2H).
8 GENERAL PROCEDURE I: 4-[( -S-Cyclonrouyl-methyl-aminol-8,8-dimethyl-9 S 6 7 8-tetrahydro-naphthalene-2y1-ethynyll-benzoic acid (Compound 3, General Formula 4) A solution of 4-[(S-cyclopropyl-methyl-amino)-8,8-11 dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-benzoic acid ethyl ester 12 (Compound 2, 0.06S8, O.lS8mmol) in ethanol (1mL) and tetrahydrofuran 13 (1mL) was treated with 1M aqueous sodium hydroxide solution (1mL) and 14 heated at 80°C for 1h. The volatiles were distilled off in vacuo and the residue 1 S was diluted with saturated aqueous ammonium chloride solution and extracted 16 with ethyl acetate (x2). The combined organic extract was dried over 17 anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid 18 that was washed with dichoromethane and dried to afford the title compound 19 (0.0298, 38%) as a white solid.
'H-NMR (300 MHz, CD3COCD3): 8 0.35-O.S1(m, 4H), 1.26(s, 3H), 1.29 (s, 21 3H), 1.60-1.82(m, 2H), 1.88-2.02(m, 2H), 2.02-2.15 (m, 1H), 2.10 (s, 3H), 22 3.93 (t, J = B.OHz, 1H), 7.26(dd, J = 1.5, 8.2Hz, 1H), 7.S 1 (d, J = l.SHz, 1H), 23 7.52(d, J = 8.2Hz, 1H), 7.62(d, J = 8.SHz, 2H), 8.02(d, J = 8.2Hz, 2H).
24 4-[(8 8-Dimeth~oxo-5,6,7,8-tetrah d~aphthalene-2-~l-eth~yl)-phenyl]-2S acetic acid methyl ester (Compound 4, General Formula 8) 26 Following general procedure F and using 6-ethynyl-4,4-dimethyl-27 1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.3128, l.Smmol), 4-28 iodo phenyl acetic acid methyl ester (Reagent B, O.SOg, l.8mmo1), triethyl 29 amine (7mL), anhydrous tetrahydrofuran (3mL), copper(I)iodide (0.048, 1 0.2mmo1) and dichlorobis(triphenylphosphine)palladium(II) (O.lSg, 2 0.213mmo1) followed by flash column chromatography over silica gel (230-3 400 mesh) using 16-20% ethyl acetate in hexane as the eluent, the title 4 compound was obtained as a pale yellow solid (0.42g, 76%).
'H-NMR (300 MHz, CDC13):8 1.42(s, 6H), 2.04(t, J = 6.7Hz, 2H), 2.74(t, J =
6 6.7Hz, 2H), 3.66(s, 2H), 3.71(x, 3H), 7.29 (d, J = 8.2Hz, 2H), 7.43(dd, J =
1.5, 7 7.9Hz, 1H), 7.52 (d, J = 8.2Hz, 2H), 7.57 (d, J = l.SHz, 1H), 8.00(d, J =
8 8.2Hz, 1H).
9 GENERAL PROCEDURE J: 4-[(8~8-Dimethyl-5-oxo-5 6,7,8-tetrahydro-naphthalene-2-~1-eth~nyll-phenyl]-acetic acid (Compound 5, General 11 Formula 8) 12 A solution of 4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-13 2-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 4, O.lg, 0.28mmo1) 14 in a mixture of methanol (2mL), tetrahydrofuran (3.SmL) and water (I.SmL) was treated with lithium hydroxide monohydrate (0.11 g, 2.62mmo1) and the 16 resulting reaction mixture was stirred at ambient temperature for 3h. The I7 volatiles were distilled off in vacuo and the residue was diluted with water and 18 dilute hydrochloric acid and extracted with ethyl acetate (x3). The combined 19 organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a pale yellow solid 21 (0.088g, 92%).
22 1H-NMR (300 MHz, CDC13): 8 1.41(s, 6H), 2.02(t, J = 6.7Hz, 2H), 2.74(t, J =
23 6.8Hz, 2H), 3.68(s, 2H), 7.28 (d, J = 8.2Hz, 2H), 7.42(dd, J = 1.5, 8.2Hz, 1H), 24 7.52 (d, J= 8.2Hz, 2H), 7.56 (d, J= l.SHz, 1H), 7.99(d, J= 8.2Hz, 1H).
4-f(5 ~CXclopropyl-amine-8 8-dimethxl- 5 6 7~8-tetrahydro-naphthalene-2-yl-26 eth~~)-phenyl]-acetic acid meth 1 e~ster_ (Compound 6, General Formula 27 4) 28 Following general procedure G and using 4-[(8,8-dimethyl-5-oxo-29 5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-acetic acid methyl ester 1 (Compound 4, 0.2g, 0.54mmo1), dichloromethane (4mL), acetonitrile(2mL), 2 cyclopropyl amine(lmL, 14.45mmol), acetic acid (1mL)and sodium 3 cyanoborohydride (0.168, 2.54mmol) followed by flash column 4 chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent the title compound was obtained as a pale yellow oil 6 (0.22g, 99%).
7 'H-NMR (300 MHz, CDC13): 8 0.38-0.60 (m, 4H), 1.26(s, 3H), 1.33(s, 3H), 8 1.50-1.59(m, 1H), 1.79-2.10 (m, 3H), 2.25(m, 1H), 3.63(s, 2H), 3.69(s, 3H), 9 3.79(t, J = 4.8Hz, 1H), 7.20-7.32 (m, 4H), 7.47(s, 1H), 7.58(d, J = 8.2Hz, 2H).
4 [~5 (Cyclopropyl-methyl-amino)-8 8-dimethyl- 5 6 7 8-tetrahydro-11 naphthalene-2-xl-eth~yll-phenxl]-acetic acid methyl ester (Compound 7, 12 General Formula 4) 13 Following general procedure H and using 4-[(5-(cyclopropyl-amino)-14 8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-phenyl]-acetic acid methyl ester (Compound 6, 0.15g, 0.37mmo1), acetone (5mL), potassium 16 carbonate ().)g, 7.95mmo1) and methyl iodide (lmL, l6mmol), the following 17 work-up was used. The volatiles were distilled off in vacuo and the residue 18 was diluted with water and extracted with dichloromethane (x2). The 19 combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound (0.148g, 97%).
21 1H-NMR (300 MHz, CDCl3): 8 0.38-0.58(m, 4H), 1.27(s, 3H), 1.31 (s, 3H), 22 1.68-1.81(m, 2H), 1.85-1.98(m, 2H), 2.08-2.15 (m, 1H), 2.12 (s, 3H), 3.62(s, 23 2H), 3.69(s, 3H), 3.94 (t, J = 7.9Hz, 1H), 7.24(d, J = 8.2Hz, 1H), 7.24 (d, J =
24 8.2Hz, 2H), 7.44-7.51(m, 4H).
4-[(5-(Cyclopropyl-methyl-amino)-8 8-dimethyl- 5 6 7 8-tetrah~dro-26 naphthalene-2-~~n~l-phenyl'-acetic acid (Compound 8, General 27 Formula 4) 28 Following general procedure J and using 4-[(5-(cyclopropyl-methyl-29 amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-phenyl]-1 acetic acid methyl ester (Compound 7, 0.148g, 0.357mmo1), methanol (2mL), 2 tetrahydrofuran (4mL), water (1mL) and lithium hydroxide monohydrate 3 (0.25g, 5.95mmol) followed by flash column chromatography over silica gel 4 (230-400 mesh) using 30-75% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.08g, 56%).
6 'H-NMR (300 MHz, CDCl3): 8 0.52-0.54(m, 2H), 0.68-0.70(m, 2H), 1.27(s, 7 3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H), 2.19-2.24(m, 1H), 8 2.24(s, 3H), 3.60(s, 2H), 4.18(t, J = 7.7Hz, 1H), 7.24(dd, J = 1.5, 8.2Hz, 1H), 9 7.26 (d, J = 8.2Hz, 2H), 7.43 (d, J = 8.2Hz, 1H), 7.47(s, 1H), 7.47(d, J _ 8.2Hz, 2H), 10.37(br s, 1H).
11 2-Fluoro-4-C($ 8-dimethX,l-5-oxo-5 6 7~8-tetrah d~phthalen-2-yl-12 eth~nyl]benzoic acid eth 1y ester (Compound 9, General Formula 8) 13 A solution of 4,4-dimethyl-6-trifluromethylsulfonyloxy-1,2,3,4-14 tetrahydronaphthalene-1-one (Intermediate 11, 0.3g, 0.9mmo1), copper(I)iodide (0.057g, 0.3mmo1) and ethyl-2-fluoro-4-ethynyl-benzoate 16 (Reagent D, 0.44g, 2.27mmol) in triethyl amine (2mL) and tetrahydrofuran 17 (3mL) was sparged with argon for 5 minutes and treated with 18 dichlorobis(triphenylphosphine)palladium(II) (0.135g, 0.192mmo1) and stirred 19 at room temperature overnight and then refluxed for 2h. It was then cooled to ambient temperature, diluted with diethyl ether and f ltered over a bed of 21 celite. The filtrate was evaporated in vacuo to an oil which was subjected to 22 flash column chromatography over silica gel (230-400 mesh) using 10-15%
23 ethyl acetate in hexane as the eluent to afford the title compound as a yellow 24 solid (0.228, 67%).
1H-NMR (300 MHz, CDC13): 8 1.38 (t, J = 7.OHz, 3H), 1.39(s, 6H), 2.01(t, J
26 = 6.7Hz, 2H), 2.71(t, J = 6.7Hz, 2H), 4.37(q, J= 7Hz, 2H), 7.28(dd, J= 0.9, 27 lOHz, IH), 7.34(dd, J= 0.9, 8.2Hz, 1H), 7.41 (dd, J = 1.5, 8.2Hz, 1H), 7.57(d, 28 J = 0.9Hz), 7.90(t, J= 7.9Hz, 1H), 7.93 (d, J= 7.9Hz, 1H).
1 2 Fluoro 4 (8 8 dimethyl 5 oxo 5 6 7 8 tetrahydro-naphthalen-2yl-ethynyl~-2 benzoic acid (Compound 10, General Formula 8) 3 A solution of 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-4 naphthalen-2-ylethynyl)benzoic acid ethyl ester (Compound 9, 0.1 g, 0.274mmol) in ethanol(4mL), methanol (2mL) and tetrahydrofuran (2mL) was 6 treated with 1M aqueous sodium hydroxide solution and heated at 70°C
for 7 1h. The volatiles were distilled off in vacuo and the residue was diluted with 8 water and dilute hydrochloric acid and extracted with ethyl acetate (x2).
The 9 combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid that was recrystallized from hot 11 aqueous acetonitrile to afford the title compound (0.025g, 27%).
12 1H-NMR (300 MHz, CDCl3): b 1.43(s, 6H), 2.05(t, J = 6.9Hz, 2H), 2.76(t, J =
13 6.9Hz, 2H), 7.26-7.47(m, 3H), 7.60(d, J = l.lHz, 1H), 7.99-8.05(m, 2H).
14 4-f 5- Cyclopropyl-aminol-8 8-dimethyl- 5,6 7,8-tetrah dy ro-naphthalene-2-yl-eth~Xl]-2-fluoro-benzoic acid ethyl ester (Compound 11, General Formula 16 4) 17 Following general procedure G and using 2-fluoro-4-(8,8-dimethyl-5-18 oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester 19 (Compound 9, 0.132g, 0.3mmol), dichloromethane (4mL), acetonitrile(2mL), cyclopropyl amine(lmL, 14.45mmol), acetic acid (1mL)and sodium 21 cyanoborohydride (0.18g, 2.86mmo1) followed by flash column 22 chromatography over silica gel (230-400 mesh) using 16-20% ethyl acetate in 23 hexane as the eluent, the title compound was obtained as a pale yellow oil 24 (0.1 g, 82%).
1H-NMR (300 MHz, CDC13):8 0.36-0.54 (m, 4H), 1.27(s, 3H), 1.33(s, 3H), 26 1.40(t, J= 7.OHz, 3H), 1.54-1.61(m, 2H), 1.82-2.05 (m, 2H), 2.26(m, 1H), 27 3.79 (t, J = 4.9Hz, 1H), 4.39(q, J= 7.lHz, 2H), 7.26-7.50(m, 4H), 7.87(s, 1H), 28 7.92 (t, J= 7.9Hz, 1H).
1 4 f 5 (Cyclopropyl methyl amino 8,8-dimethyl- 5 6 7 8-tetrahvdro-2 naphthalene 2 y1 -ethynyll-2-fluoro benzoic acid ethyl ester (Compound 12, 3 General Formula 4) 4 Following general procedure H and using 4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-6 benzoic acid ethyl ester (Compound 11, 0.18, 0.246mmo1), acetone (4mL), 7 potassium carbonate (0.9178, 6.63mmol) and methyl iodide (0.8mL, 1 lmmol), 8 the following work-up was used. The volatiles were distilled off in vacuo and 9 the residue was diluted with water and extracted with dichloromethane (x2).
The combined organic extract was dried over anhydrous sodium sulfate, 11 filtered and evaporated in vacuo to an oil. Flash column chromatography over 12 silica gel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluent 13 afforded the title compound as a pale yellow oil (0.1028, 98%).
14 'H-NMR (300 MHz, CDC13): 8 0.39-0.62 (m, 4H), 1.29(s, 3H), 1.34(s, 3H), 1.42(t, J= 6.9Hz, 3H), 1.65-1.82(m, 2H), 1.85-2.02 (m, 2H), 2.02-2.10(m, 16 1H), 2.15(s, 3H), 3.97(t, J = 7.7Hz, 1H), 4.42(q, J= 7.OHz, 2H), 7.28-7.36 (m, 17 3H), 7.59(s, 1H), 7.55(d, J = 7.9Hz, 2H), 7.92 (t, J= 7.SHz, 1H).
18 4-[5-(Cyclo~ropyl-meth,~l-amino)-8Y8-dimethyl- 5 6 7 8-tetrahydro-19 naphthalene-2-yl-ethynvl]-2-fluoro benzoic acid (Compound 13, General Formula 4) 21 Following general procedure I and using 4-[(5-cyclopropyl-methyl-22 amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl]-2-fluoro-23 benzoic acid ethyl ester (Compound 12, 0.1028, 0.23mmol), ethanol (4mL) 24 and 1 M aqueous sodium hydroxide solution (2mL) followed by flash column chromatography over silica gel (230-400 mesh) 30% ethyl acetate in hexane as 26 the eluent, the title compound was obtained as an off white solid(0.015g, 27 16%).
28 IH-NMR (300 MHz, CDC13): 8 0.54-0.65 (m, 4H), 1.29 (s, 3H), 1.32 (s, 3H), 29 1.68-1.83 (m, 2H), 1.97-2.05 (m, 2H), 2.18-2.25 (m, 1H), 2.25 (s, 3H), 4.13 (t, 1 J = 6.7Hz, 1H), 7.26-7.30 (m, 2H), 7.34 (dd, J = 1.5, 7.9Hz, 1H), 7.48 (d, J
=
2 1.8Hz, IH), 7.60 (d, J = 8.5Hz, 1H), 7.95 (t, J = 7.9Hz, 1H).
3 ~2 Fluoro 4 (8 8 dimethyl-5-oxo-5 6 7 8-tetrahydro-naphthalene-2-yl-4 ethvnyllsphen~]acetic acid ethyl ester (Compound 14, General Formula 8) Following general procedure F and using 6-ethynyl-4,4-dimethyl-6 1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.2988, 1.43mmo1), 7 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.448, 1.43mmo1), 8 triethyl amine (Intermediate 13, 3mL), anhydrous tetrahydrofuran (7mL), 9 copper(I)iodide (0.048, 0.2mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.158, 0.2I3mmo1) followed by 11 flash column chromatography over silica gel (230-400 mesh) using 14-16%
12 ethyl acetate in hexane as the eluent, the title compound was obtained as an oil 13 (0.438, 77%).
14 IH-NMR (300 MHz, CDC13): 8 1.26(t, J= 7.2Hz, 3H), 1.41(s, 6H), 2.04(t, J =
6.7Hz, 2H), 2.74(t, J = 6.7Hz, 2H), 3.68(s, 2H), 4.18(q, J= 7.lHz, 2H), 7.23-16 7.57(m, 4H), 7.59 (d, J = l.SHz, 1H), 7.99(d, J = 7.9Hz, 1H).
17 [2-Fluoro-4-~(8 8-dimethyl-5-oxo-5~6 7 8-tetrahydro-naphthalene-2- ~~1-18 ethynyl)nhen,1~1-acetic acid (Compound 15, General Formula 8) I9 Following general procedure J and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]acetic acid methyl 21 ester (Compound 14, 0.188, 0.48mmol), methanol (4mL), tetrahydrofuran 22 (8mL), water (2mL) and lithium hydroxide monohydrate (0.28, 4.76mmo1) 23 followed by flash column chromatography over silica gel (230-400 mesh) 24 using 50- 100% ethyl acetate in hexane as the eluent, the title compound was obtained as a dirty white solid (0.0688, 41%).
26 1H-NMR (300 MHz, CDCI3): 8 I.41(s, 6H), 2.03(t, J= 6.7Hz, 2H), 2.74(t, J=
27 6.8Hz, 2H), 3.73(s, 2H), 7.24-7.32(m, 3H), 7.42(dd, J= 1.5, 7.9Hz, 1H), 7.56 28 (s, 1H), 7.99(d, J = 7.9Hz, 1H), 9.40-10.00 (br s, 1H).
1 [4~~Cyc~lonrooyl aminol 8 8 dimethyl 5 6 7 8-tetrahydro-na-ahthalene-2-vl-2 eth~nyll-2-fluoro-phenyll acetic acid ethyl ester (Compound 16, General 3 Formula 4) 4 Following general procedure G and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl) phenyl]acetic acid ethyl ester 6 (Compound 14, 0.258g, 0.68mmol), dichloromethane (4mL), 7 acetonitrile(2mL), cyclopropyl amine(lmL, 14.45mmo1), acetic acid (1mL)and 8 sodium cyanoborohydride (0.266g, 4.23mmo1) followed by flash column 9 chromatography over silica gel (230-400 mesh) using 16-20-25% ethyl acetate in hexane as the eluent , the title compound was obtained as a pale yellow oil 11 (0.21g, 73%).
12 1H-NMR (300 MHz, CDC13):8 0.35-0.54 (m, 4H), 1.25(t, J= 7.lHz, 3H), 13 1.26(s, 3H), 1.32(s, 3H), 1.53-1.64(m, 1H), 1.82-2.05 (m, 3H), 2.21-2.28(m, 14 1H), 3.65(s, 2H), 3.78(t, J = S.OHz, 1H), 4.17(q, J= 7.lHz, 2H), 7.19-7.41 (m, 5H), 7.47(d, J = 1.SHz, 1H).
16 f4-(5-~Cyclopropyl-methyl-amino)-8 8-dimethyl~5 6 7 8-tetrah~dro-17 naphthalene-2-yl-eth~n~l-2-fluoro-phenyl]-acetic acid eth l~r 18 (Compound 17, General Formula 8) 19 Following general procedure H and using [4-((5-cyclopropyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2ylethynyl)-2-fluoro-21 phenyl]acetic acid ethyl ester (Compound 16, 0.21g, 0.5mmo1), acetone 22 (5mL), potassium carbonate (1.13g, 8.17mmo1) and methyl iodide (0.5mL, 23 8mmo1), the following work-up was used. The volatiles were distilled off in 24 vacuo and the residue was diluted with water and extracted with dichloromethane (x2). The combined organic extract was dried over 26 anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil.
27 Flash column chromatography over silica gel (230-400 mesh) using 8% ethyl 28 acetate in hexane as the eluent afforded the title compound (0.158, 69%).
1 'H-NMR (300 MHz, CDC13): 8 0.39-0.53(m, 4H), 1.27(s, 3H), 1.31 (s, 3H), 2 1.66-1.81(m, 2H), 1.89-2.05(m, 2H), 2.08-2.13 (m, 1H), 2.13 (s, 3H), 3.62(s, 3 2H), 3.94 (t, J = 8.OHz, 1H), 4.16(q, J= 7.lHz, 2H), 7.20-7.29(m, 4H), 7.44(d, 4 J = 1.SHz, 1H), 7.51 (d, J = 8.2Hz, 1H).
f4 (S~Cvclopropyl methyl aminol-~ 8-dimethyl- 5 6 7 8-tetrahydro-6 naphthalene-2-yl-ethynXl)-2-r fluoro-phenyll-acetic acid (Compound 18, 7 General Formula 4) 8 Following general procedure J and using [4-(5-(cyclopropyl-methyl-9 amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 17, 0.0258, 0.059mmol), methanol 11 (1mL), tetrahydrofuran (1mL), water (O.SmL) and lithium hydroxide 12 monohydrate (0.0608, 1.43mmol), the title compound was obtained as a white 13 solid (0.0238, 95%).
14 'H-NMR (300 MHz, CDC13):8 0.52-0.54(m, 2H), 0.68-0.70(m, 2H), 1.27(s, 3H), 1.29(s, 3H), 1.63-1.80(m, 2H), 1.95-2.17(m, 2H), 2.19-2.24(m, IH), 16 2.24(s, 3H), 3.60(s, 2H), 4.18(t, J = 7.7Hz, 1H), 7.19-7.28(m, 4H), 7.45 (d, J
17 = l.SHz, 1H), 7.49(d, J = 8.2Hz, 1H), 8.80-9.20(br s, 1H).
18 GENERAL PROCEDURE K: 8 8-Dimeth~l-5 6 7 8-tetrahydro-naphthalene-1-19 one-2-carboxxlic acid-4-(tent-butoxycarbon l~meth~lphenyl ester Compound 19, General Formula 8) 21 A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-I,2,3,4-22 tetrahydronaphthalene-I-one (Intermediate I1, 0.148, 0.434mmol), t-butyl-4-23 hydroxy-phenyl acetate (Reagent E, 0.148, 0.673mmol), palladium acetate 24 (0.0548, 0.24mmo1) and 1,3-bis(diphenylphosphino)propane (0.0828, 0.2mmol) in a mixture of dimethylsulfoxide (1mL), 1,2-dichloroethane 26 (l.SmL) and triethyl amine (1mL) was heated at 70°C under an atmosphere of 27 carbon monoxide overnight. The volatiles were distilled of in vacuo and the 28 residue was diluted with water and extracted with diethyl ether (x3). The 29 combined organic extract was dried over anhydrous magnesium sulfate, 1 filtered and evaporated in vacuo to an oil which was subjected to flash column 2 chromatography over silica gel (230-400 mesh) using 15% ethyl acetate in 3 hexane as the eluent to afford the title compound (0.1 1g, 53%).
4 1H-NMR (300 MHz, CDCI3): ~ 1.44(s, 3H), 1.44(s, 9H), 1.46 (s, 3H), 2.07(t, J
= 6.9Hz, 2H), 2.76(t, J = 6.8Hz, 2H), 3.55(s, 2H), 7.17 (d, J = 8.5Hz, 2H), 6 7.35(d, J = 8.5Hz, 2H), 8.05-8.13(m, 2H), 8.25 (d, J = l.SHz, 1H).
7 8 8 Dimeth~ 5-oxo-5~6 7 8-tetrahydro-naphthalene-2-carboxylic acid-4-8 (carbox~meth~)phen 1y ester (Compound 20, General Formula 8) 9 A solution of 8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4-(tent-butoxycarbonylmethyl)phenyl ester (Compound 19, 11 0.11 g, 0.229mmol) in dichloromethane (2mL) was treated with trifluoroacetic 12 acid (0.85mL and stirred at ambient temperature for 2.5h. The volatiles were 13 distilled off in vacuo and the residue was diluted with water and extracted with 14 ethyl acetate (x3). The combined organic phase was dried over anhydrous sodium sulfate, f Itered and evaporated in vacuo to afford a solid which was 16 subjected to flash column chromatography over silica gel (230-400 mesh) 17 using ethyl acetate as the eluent to afford the title compound (0.024g, 25%).
18 1H-NMR (300 MHz, CDCl3): S 1.46 (s, 6H), 2.08(t, J = 6.7Hz, 2H), 2.80(t, J
19 = 6.7Hz, 2H), 3.70(s, 2H), 7.20(d, J = 8.5Hz, 2H), 7.37(d, J = 8.SHz, 2H), 8.08(dd, J = 1.4, 8.2Hz, 1H), 8.14 (d, J = 8.2Hz, 1H), 8.24 (d, J = 1.2Hz, 1H).
21 5-Methox~3,3-dimethyl-indane (Intermediate 15) 22 Following general procedure A and using titanium tetrachloride 23 (5.5mL,50mmoL), anhydrous dichloromethane (80mL), 2M solution dimethyl 24 zinc (50mL) in toluene and a solution of 6-methoxy-indane-1-one (4.05g, 25mmo1) in dichloromethane (lOmL) the title compound was obtained as an 26 oil (3.13g, 71%).
27 'H-NMR (300 MHz, CDC13):8 1.37 (s, 6H), 2.04(t, J = 7.2Hz, 2H), 2.94(t, J =
28 7.2Hz, 2H), 3.89(s, 3H), 6.82(d, J= 2.lHz, 1H), 7.28(dd, J= 2.1, 7.OHz, 1H), 29 7.35 (d, J = 7.OHz, 1H).
1 5-Methoxy-3~3-dimethyl-indane-1-one (Intermediate 16) 2 Following general procedure B and using 5-methoxy-3,3-dimethyl 3 indane (Intermediate 15, 3.13g, 17.78mmol) in 20mL of glacial acetic acid 4 and a solution of chromium trioxide (3.91g, 39.1mmo1) in 20mL of acetic acid and 20mL of water the title compound was obtained as a viscous yellow oil 6 (3.3g, 97%).
7 iH-NMR (300 MHz, CDC13):8 1.37 (s, 6H), 2.54 (s, 2H), 3.87(s, 3H), 6.86-8 6.87 (m, 2H), 7.60 (d, J = 7.OHz, 1H).
9 6-Methoxy-4 4-dimethxl-1 2 3 4-tetrahXdro-isoquinoline-1-one (Intermediate 17) 11 A solution of 5-methoxy-3,3-dimethyl-indane-1-one (Intermediate 16, 12 3.3g, 17.4mmo1) in benzene (SOmL) was treated with concentrated sulfuric 13 acid (lOmL) and heated to 60°C. Sodium azide (1.95g, 30mmo1) was added in 14 small portions and after the addition was complete, the reaction mixture was heated further for 4h. It was then cooled, diluted with water and extracted with 16 chloroform (x3). The combined organic phase was dried over anhydrous 17 magnesium sulfate, filtered and evaporated in vacuo to afford the title 18 compound as a brown solid (3.5g, quantitative by weight).
19 1H-NMR (300 MHz, CDC13): b 1.31 (s, 6H), 3.28 (s, 2H), 3.83(s, 3H), 6.78 (d, J = 2.6Hz, 1H), 6.82(dd, J = 2.6Hz, 8.SHz, 1H), 7.59 (s, 1H), 8.02 (d, J=
21 8.2Hz, 1H).
22 6-Methoxy-4,4-dimethyl-1,2,3 4-tetrahydro-isoquinoline (Intermediate 18) 23 A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-24 1-one (Intermediate 17, 3.5g, l7mmol) in 100mL of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (1.3g, 26 34.ZSmmol) in small portions and the resulting suspension was refluxed for 27 hours under argon. The reaction mixture was then cooled in an ice bath and 28 cautiously quenched with saturated aqueous sodium sulfate solution and the 29 resulting slurry was filtered and the filter-cake washed well with ethyl acetate.
1 The filtrate and washings were evaporated in vacuo to a brown oil which was 2 dissolved in chloroform, the solution was dried over anhydrous magnesium 3 sulfate, filtered and evaporated in vacuo to afford the title compound (3.2g, 4 100%).
1H-NMR (300 MHz, CDCl3): 8 1.27 (s, 6H), 2.22 (s, 1H), 2.84 (s, 2H), 3.79 (s, 6 3H), 3.95 (s, 2H), 6.68(dd, J = 2.4Hz, 8.3Hz,1H), 6.86(d, J = 2.4Hz, 1H), 6.91 7 (d, J= 8.3Hz, 1H).
8 6 Methoxy-4 4-dimethyl-1 2 3 4-tetrahydro-isoc~uinoline-2-carbaldehyde 9 (Intermediate 19) A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline 11 (Intermediate 18, 3.2g, 16.7mmol) in anhydrous dichloromethane (40mL) 12 was treated with formic acid (lmL, 26.5mmo1) followed 1-(3-13 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9g, 20.34mmo1) 14 and the resulting solution was stirred at ambient temperature overnight. It was then diluted with chloroform and washed with water (x 1 ) and brine (x 1 ), dried 16 over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 17 the title compound as pale brown viscous oil (3.26g, 90%).
18 'H-NMR (300 MHz, CDC13): 8 1.28 (s, 6H), 3.32 (s, 0.7H), 3.54 (s, 0.3H), 19 3.79(s, 3H), 4.54 (s, 0.3H), 4.66(s, 0.7H), 6.71(dd, J= 2.6Hz, 8.2Hz, 1H), 6.85-6.97(m, 1H), 7.02-7.27(m, 1H), 8.15(s, 0.7H), 8.34(s, 0.3H), 8.40-8.80 21 (br s, 1H).
22 6-Hydrox~-4 4-dimethyl-11 2 3 4-tetrahydro-isoquinoline-2-carbaldehyde 23 (Intermediate 20) A stirred, cooled (-78°C) solution of 6-methoxy-4,4-24 dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 19, 3 .26g, 15mmol) in anhydrous dichloromethane ( 15mL) was treated with 1 M
26 solution of boron tribromide in dichloromethane (50mL) stirred at ambient 27 temperature for 3h. It was then cooled again to 78°C and quenched carefully 28 with saturated aqueous sodium carbonate solution, diluted with water and the 29 aqueous phase was extracted with ethyl acetate (x2). The combined organic 1 extract was dried over anhydrous sodium sulfate, filtered and evaporated in 2 vacuo to afford the title compound as a solid foam (3g, 99%).
3 IH-NMR (300 MHz, CDC13): 8 1.23 (s, 6H), 3.31 (s, 0.7H), 3.54 (s, 0.3H), 4 4.51 (s, 0.3H), 4.64 (s, 0.7H), 6.70-6.75(m, 1H), 6.84-6.90(m, 2H), 7.50 7.80(br s, 1H), 8.12(s, 0.7H), 8.32(s, 0.3H).
6 2 C, cly opropyl 6-h~drox~-4~4-dimethyl -1 2 3 4-tetrahydro-isoauinoline 7 (Intermediate 21) 8 A stirred, cooled (0°C)solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-9 tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3g, 11.21mmo1) in anhydrous tetrahydrofuran (40mL) under argon was treated with titanium 11 tetra-iso-propoxide (8.28mL, 28mmo1) followed by 3M solution of ethyl 12 magnesium bromide in diethyl ether ( 18.7mL) and the reaction mixture was 13 then heated at 55°C overnight. It was then cooled in an ice-bath, quenched 14 with saturated aqueous ammonium chloride solution and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous sodium 16 sulfate, filtered and evaporated in vacuo to afford a yellow oily solid.
Flash 17 column chromatography over silica gel (230-400 mesh) using 10-20% ethyl 18 acetate in hexane as the eluent afforded the title compound as a pale yellow 19 solid (l.SSg, 63%).
1H-NMR (300 MHz, CD3COCD3): 8 0.016-O.I6(m, 4H), 0.847 (s, 6H), 1.37 21 (m, 1H), 2.20(s, 2H), 3.25 (s, 2H), 6.22(dd, J= 2.4, 8.2Hz, 1H), 6.41(d, J=
22 2.6Hz, 1H), 6.47(d, J= 8.2Hz, 1H), 7.62(s, 1H).
23 2-Cycloprop~-4 4-dimethyl-6-trifluorometh~sulfon~~1,2,3,4-tetrahydro-24 isoc~uinoline (Intermediate 22) Following general procedure C and using 2-cyclopropyl-6-hydroxy-4,4-26 dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 21, 1.5g, 6.9mmo1) in 27 anhydrous dichloromethane (30mL), triethyl amine (l.SmL, 10.39mmo1) and 28 [N,N'-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (2.758, 7mmo1) 29 followed by flash column chromatography over silica gel (230-400 mesh) 1 using 8% ethyl acetate in hexane as the eluent the title compound was obtained 2 (2.23g, 92%) as oil. 'H-NMR (300 MHz, CDC13): 8 0.42-0.54(m, 4H), 1.25(s, 3 6H), 1.76(m, 1H), 2.62(s, 2H), 3.74(s, 2H), 6.98(dd, J= 2.3, 8.4Hz, 1H), 4 7.16(d, J = 8.2Hz, 1H), 7.I4(d, J = 2.3Hz, 1H).
EthXl 2 cvclopropyl 4 4-dimeth~ 2 3 4-tetrahydroisoauinoline-6-6 carbox~ate (Intermediate 23) 7 Following general procedure K and using 2-cyclopropyl-4,4-dimethyl-8 6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydro-isoquinoline (Intermediate 9 22, 1.6g, 4.6mmo1), palladium acetate (0.127g, 0.56mmo1), 1,3-bis(diphenylphosphino)propane (0.160g, 0.39mmo1), dimethylsulfoxide 11 (2mL), 1,2-dichloroethane (SmL), triethyl amine (2mL) , ethanol (SmL) and an 12 atmosphere of carbon monoxide followed by flash column chromatography 13 over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent 14 the title compound was obtained as an oil (1g, 79%).
'H-NMR (300 MHz, CDCl3):8 0.44-0.54(m, 4H), 1.27(s, 6H), 1.38 (t, J =
16 7Hz, 3H), 1.73(m, 1H), 2.62(s, 2H), 3.76(s, 2H), 4.35 (q, J = 7.lHz, 2H), 17 7.04(d, J = 7.9Hz, 1H), 7.74 (dd, J = 1.7, 7.9Hz, 1H), 7.97(d, J = l.BHz, 1H).
18 2-Cyclopro~yl-6-h~drox n~~-4 4-dimeth~-1 2 3 4-tetrahydroisoquinoline 19 (Intermediate 24) A stirred cooled (-78°C)solution of ethyl-2-cyclopropyl-4,4-dimethyl-21 1,2,3,4-tetrahydro isoquinoline-6-carboxylate (Intermediate 23, 1g, 22 3.66mmo1) in anhydrous dichloromethane (20mL) under argon was treated 23 with a 1M solution of di-iso-butyl aluminum hydride in dichloromethane 24 (lOmL) and the reaction mixture was warmed to -20°C over 1h. It was then quenched with saturated aqueous ammonium chloride solution and diluted 26 with dichloromethane and filtered over a bed of celite. The phases were 27 separated and the aqueous phase was extracted with dichloromethane (x1).
28 The combined organic extract was dried over anhydrous sodium sulfate, 1 filtered and evaporated in vacuo to afford the title compound as a viscous oil 2 (0.74g, 87%).
3 iH-NMR (300 MHz, CDCl3): 8 0.45-0.53(m, 4H), 1.25(s, 6H), 1.72-1.82(m, 4 2H), 2.61(s, 2H), 3.73(s, 2H), 4.61 (d, J = SHz, 2H), 6.98(d, J = 7.9Hz, 1H), 7.07 (dd, J = 1.5, 7.6Hz, 1H), 7.27(s, 1H).
6 2 Cyclopropyl 4 4 dimethvl-I 2 3 4-tetrahydroisoquinoline-6-carbaldehyde 7 (Intermediate 25) 8 A solution of 2-cyclopropyl-6-hydroxymethyl-4,4-dimethyl-1,2,3,4-9 tetrahydroisoquinoline (Intermediate 24, 0.74g, 3.2mmo1) in dichloromethane (lOmL) and acetonitrile (2.SmL) was treated sequentially with 4A°
molecular 11 sieves powder (1.06g), tetra-h-propyl ammonium perruthenate (O.OSOg, 12 0. l4mmol) and N-methyl morpholine N-oxide ( 1.1 g, 9.8mmo1). After stirring 13 at ambient temperature for O.Sh, it was diluted with SmL of hexane and 14 subjected to flash column chromatography over silica gel (230-400 mesh) using IO% ethyl acetate in hexane as the eluent to afford the title compound as 16 an oil (0.278, 37%).
17 1H-NMR (300 MHz, CDC13):8 0.44-0.56(m, 4H), 1.30(s, 6H), 1.79(m, 1H), 18 2.66(s, 2H), 3.82(s, 2H), 7.17(d, J = 7.9Hz, 1H), 7.60 (dd, J = 1.6, 7.9Hz, 1H), 19 7.82(d, J = I .BHz, 1H), 9.95 (s, 1H).
6-(2 2-Dibromo-vinxll-2-cycloprop~l-4,4-dimethyl-1,2,3,4-21 tetrahydroisoquinoline (Intermediate 26) 22 A stirred, cooled (ice-bath) solution of triphenyl phosphine (0.53g, 23 2mmo1) in anhydrous dichloromethane was treated with carbon tetrabromide 24 (0.35g, lmmol) under argon. After O.Sh, a solution of 2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 25, 26 0.13g, 0.57mmo1) in dichloromethane (2mL) was cannulated into the reaction 27 mixture. After 1.5h between 0°C and 10°C, the reaction mixture was subjected 28 to flash column chromatography over silica gel (230-400 mesh) using 3-5%
1 ethyl acetate in hexane as the eluent to afford the title compound as a viscous, 2 pale yellow oil (0.18g, 82%).
3 'H-NMR (300 MHz, CDC13):8 0.49-O.S7(m, 4H), 1.31(s, 6H), 1.80(m, 1H), 4 2.67(s, 2H), 3.77(s, 2H), 7.04(d, J = 7.9Hz, 1H), 7.29 (dd, J = 1.7, 7.9Hz, 1H), S 7.49 (s, 1H), 7.50(d, J = l.7Hz, 1H).
6 2 Cxcloprop~-6-eth~n~l-4~4-dimethyl-1 2 3 4-tetrahydroisoauinoline 7 (Intermediate 27) 8 A stirred, cooled (-78°C) solution of 6-(2,2-dibromo-vinyl)-2-9 cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 26, 0.18g, 0.47mmo1) in tetrahydrofuran (2mL) was treated 11 with 1.6M solution of h-butyl lithium (0.6mL, 0.96mmo1) under argon. The 12 reaction mixture was allowed to warm to -20°C over l.Sh, quenched with 13 saturated aqueous ammonium chloride solution and extracted with diethyl 14 ether (x2). The combined organic phase was dried over anhydrous magnesium 1 S sulfate, filtered and evaporated in vacuo to afford the title compound as an oil 16 (0.1 g, 94%).
17 'H-NMR (300 MHz, CDC13):~ 0.47-O.SS(m, 4H), 1.28(s, 6H), 1.77(m, 1H), 18 2.63(s, 2H), 3.OS(s, 1H), 3.67(s, 2H), 6.98(d, J = 7.6Hz, 1H), 7.26 (dd, J
=
19 1.5, 7.9Hz, 1H), 7.46(d, J = l.SHz, 1H).
[4-(2-Cyclopropyl-4s4-dimethyl-1 2~3 4-tetrahydro-isoquinolin-6-yl-ethynyl)-21 2-fluoro-phenyll-acetic acid eth 1y ester (Compound 21, General Formula 3) 22 Following general procedure F and using 2-cyclopropyl-6-ethynyl-4,4-23 dimethyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13g, 24 O.S71mmo1), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.16g, 2S O.S2mmol), triethyl amine (0.8mL), anhydrous tetrahydrofuran (2mL), 26 copper(I)iodide (0.0S 1 g, 0.27mmo1) and 27 dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0. l4mmol) followed by 28 flash column chromatography over silica gel (230-400 mesh) using 10% ethyl 29 acetate in hexane as the eluent, O.lg of the title compound was obtained as an 1 oil. It was further purified by preparative normal phase HPLC on a partisil-2 silica column using 10% ethyl acetate in hexane as the mobile phase (0.055g, 3 24%).
4 1H-NMR (300 MHz, CDCl3):8 0.42-0.51(m, 4H), 1.26(t, J= 7.3Hz, 3H), 1.27(s, 6H), 1.75(m, 1H), 2.6I(s, 2H), 3.66(x, 2H), 3.74(s, 2H), 4.18 (q, J=
6 7.3Hz, 2H), 6.97 (d, J = 7.9Hz, 1H), 7.20-7.29(m, 4H), 7.45(d, J = 1.SHz, 7 1H).
8 f4 (2 Cyclopro~rl-4 4-dimethyl-1 2 3,4-tetrah~dro-isoquinolin-6-yl-ethynyll-9 2-fluoro-phenvl]-acetic acid (Compound 22, General Formula 3) Following general procedure J and using [4-(2-cyclopropyl-4,4-I1 dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-acetic 12 acid ethyl ester (Compound 21, 0.055g, 0.135mmol), methanol (2mL), 13 tetrahydrofuran (4mL), water (1mL) and lithium hydroxide monohydrate 14 (0.117g, 2.97mmo1) the title compound was obtained as a pale yellow solid foam (0.040g, 78%).
16 1H-NMR (300 MHz, CDCl3): 8 0.52-0.65(m, 4H), 1.27(s, 6H), 1.84(m, 1H), 17 2.71(s, 2H), 3.61(s, 2H), 3.85(s, 2H), 6.98(d, J = 7.9Hz, 1H), 7.06 (t, J =
18 7.6Hz, 1H), 7.17-7.25(m, 3H), 7.43(d, J= l.2Hz, 1H), 8.60-9.00(br s, 1H).
19 [~2-C cly opropyl-4 4-dimethyl-1 2,3 4-tetrah_ydro-isoquinolin-6-yl-ethynyll-phenyll-acetic acid meth.1~ (Compound 23, General Formula 3) 21 Following general procedure F and using 2-cyclopropyl-4,4-dimethyl-22 6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13g, 23 0.571mmol), 4-iodo phenyl acetic acid methyl ester (Reagent B, 0.168, 24 0.58mmol), triethyl amine (0.5mL), anhydrous tetrahydrofuran (2mL), copper(I)iodide (0.04g, 0.21mmo1) and 26 dichlorobis(triphenylphosphine)palladium(II) (0.12g, 0.17mmo1) followed by 27 flash column chromatography over silica gel (230-400 mesh) using 10% ethyl 28 acetate in hexane as the eluent, 0.05g of the title compound was obtained as an 29 oil. It was further purified by preparative normal phase HPLC on a partisil-1 silica column using 10% ethyl acetate in hexane as the mobile phase (0.01 g, 2 6%).
3 'H-NMR (300 MHz, CDC13): ~ 0.42-0.58(m, 4H), 1.29(m, 6H), 1.79(m, 1H), 4 2.64(s, 2H), 3.67(s, 3H), 3.72(s, 2H), 3.77(s, 2H), 7.09 (d, J = 7.9Hz, 1H), 7.28(dd, J = 1.5, 7.9Hz, 1H), 7.36 (d, J = 7.9Hz, 2H), 7.50 (d, J = 1.6Hz, 1H), 6 7.51 (d, J = 7.9Hz, 2H).
7 ~4 (2 C~clo~ropyl 4 4-dimethyl-1 2 3 4-tetrahydro-isoquinolin-6-yl-ethynyl)-8 phenvll-acetic acid (Compound 24, General Formula 3) 9 Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-acetic acid 11 methyl ester (Compound 23, O.OIg, 0.027mmo1), methanol (1mL), 12 tetrahydrofuran (1mL), water (O.SmL) and lithium hydroxide monohydrate 13 (0.042g, lmmol) the title compound was obtained as a pale yellow solid foam 14 (0.0065g, 68%).
1H-NMR (300 MHz, CDC13): S 0.35-0.52(m, 4H), 1.24(s, 6H), 1.74(m, 1H), 16 2.59(s, 2H), 3.64(s, 2H), 3.71(s, 2H), 7.03 (d, J = 8.2Hz, 1H), 7.22(dd, J
=
17 1.4, 7.9Hz, 1H), 7.33 (d, J = 8.2Hz, 2H), 7.46 (d, J = 8.2Hz, 2H), 7.47(s, 1H).
18 1-(Iso-prowl-meth-aminol-6-trimethylsilan 1y eth~nyl-4 4-dimethyl-1,2,3,4-19 tetrahydro-naphthalene (Intermediate 28) Following general procedure G and using a solution of 4,4-dimethyl-6-21 trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene 2-one (Intermediate 22 12, 0.2g, 0.78mmo1), dichloromethane (4mL), acetonitrile (2mL), acetic acid 23 (1mL), isopropyl amine (lmL, 11.74mmo1) and sodium cyanoborohydride 24 (0.19g, 3.02mmo1), after l5days of reaction time and work up afforded an intermediate (0.148, 60%, 0.47mmo1) which was used following general 26 procedure H along with acetone (2mL), potassium carbonate (0.6g, 4.34mmol) 27 and methyl iodide (O.SmL, 8mmol). The crude product after work up was 28 subjected to flash column chromatography over silica gel (230-400 mesh) 1 using 15% ethyl acetate in hexane as the eluent to afford the title compound as 2 a pale yellow oil (0.14g, 95%).
3 1H-NMR (300 MHz, CDC13): 8 0.001(s, 9H), 0.85 (d, J= 6.4Hz, 6H), 0.98 (s, 4 3H), 1.03 (s, 3H), 1.32-1.60 (m, 4H), 1.81(s, 3H), 2.64(heptet, J= 6.4Hz, 1H), 3.65 (dd, J = 6.1, 9.4Hz, 1H), 6.97 (dd, J = 1.7, 7.9Hz, 1H), 7.13 (d, J=
6 1.7Hz, 1 H), 7.82 (d, J = 7.9Hz, 1 H).
7 6 Ethynxl 1 (iso pro 1-y methyl-amino 4 4-dimeth~-1 2 3 4-tetrahydro-8 naphthalene (Intermediate 29) 9 Following general procedure E and using 1-(methyl-iso-propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene 11 (Intermediate 28, 0.14g, 0.45mmo1), methanol (SmL), potassium carbonate 12 (0.61g, 4.41mmol) and ethyl acetate the title compound (0.092g, 80%) was 13 obtained as an oil.
14 'H-NMR (300 MHz, CDCl3):8 1.11(d, J= 6.4Hz, 6H), 1.23(s, 3H), 1.28(s, 3H), 1.51-1.87 (m, 4H), 2.09(s, 3H), 2.90 (heptet, J = 6.4Hz, 1H), 3.00(s, 1H), 16 3.91 (dd, J= 5.8, lO.OHz, 1H), 7.25(dd, J = 1.7, 8.2Hz, 1H), 7.41 (d, J =
17 1.7Hz, 1 H), 7.70(d, J = 8.2Hz, 1 H).
18 4-jS~Iso-propyl-methyl-aminol-8 8-dimeth~l-5,6 7~8-tetrahydro-naphthalene-19 2-.yl-ethyn~ll-benzoic acid ethyl ester (Compound 25, General Formula 4) Following general procedure F and 6-ethynyl-1-(iso-propyl-methyl-21 amino)-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 29, 22 0.092g, 0.36mmol), ethyl-4-iodo benzoate (Reagent A, 0.12g, 0.48mmo1), 23 triethyl amine (1mL), tetrahydrofuran (2mL), copper(I)iodide (0.028g, 24 0.14mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.075g, 0.1 lmmol) followed by flash column chromatography over silica gel (230-400 26 mesh) using 10-15% ethyl acetate in hexane as the eluent the title compound 27 was obtained (0.04g, 27%).
28 iH-NMR (300 MHz, CDCl3): 8 1.12 (d, J= 6.SHz, 6H), 1.27 (s, 3H), I.31 (s, 29 3H), 1.40 (t, J = 7.OHz, 3H), 1.62-1.89 (m, 4H), 2.10(s, 3H), 2.92 (heptet, J =
1 6.4Hz, 1H), 3.94(dd, J = 6.1, 9.7Hz, 1H), 4.38(q, J = 7.lHz, 2H), 7.31(dd, J
=
2 1.4, 8.2Hz, 1H), 7.46 (d, J = 1.7Hz, 1H), 7.58 (d, J = 8.2Hz, 2H), 7.75(d, J
=
3 8.2Hz, 1 H), 8.01 (d, J = 8.2Hz, 2H).
4 4 [S~Iso propyl methyl-amino)-8 8-dimethyl-55 6 7 8-tetrahydro-naphthalene-2-vl-eth~nyl)]-benzoic acid (Compound 26, General Formula 4) 6 Following general procedure I and using 4-[5-(iso-propyl-methyl-7 amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)]-benzoic 8 acid ethyl ester (Compound 25, 0.048, O.Olmmol), ethanol (2mL), 9 tetrahydrofuran (ImL) and 1M aqueous sodium hydroxide solution (lxnL) followed by recrystallization from diethylether-hexane, the title compound 11 was obtained as an off white solid (0.0)08, 27%).
12 'H-NMR (300 MHz, CDC13): b 1.30(d, J= 6.OHz, 6H), 1.31(s, 9H), 1.67-13 1.98(m, 4H), 2.35 (s, 3H), 3.19 (heptet, J= 6.4Hz, 1H), 4.36 (t, J = 7.6Hz, 14 1H), 7.28(dd, J= 1.4, 8.2Hz, 1H), 7.48 (d, J = l.4Hz, 1H), 7.55 (d, J =
8.2Hz, 2H), 7.81 (d, J = 8.2Hz, 1H), 8.05 (d, J = 8.2Hz, 2H).
16 f 4 ~2 2 4 4-Tetrameth~l-chroman-6-xI-eth~n~l phen~] acetic acid methyl 17 ester (Compound 27, General Formula 8) 18 Following general procedure F and using 6-ethynyl-2,2,4,4-19 tetramethylchroman (synthesis described in U.S. Patent Nos. 5,045,551 and 5,616,597 incorporated herein by reference) (0.0608, 0.28mmo1), methyl-4-21 iodo phenyl acetate (Reagent B, 0.0788, 0.28mmo1), triethyl amine (4mL), 22 tetrahydrofuran (4mL), copper(I)iodide (0.0308, 0.16mmol) and 23 dichlorobis(triphenylphosphine)palladium(II) (0.11 g, 0.16mmol) followed by 24 flash column chromatography over silica gel (230-400 mesh) using 5-10 ethyl acetate in hexane as the eluent the title compound was obtained (0.0478, 26 46%).
27 1H NMR (300 MHz, CDC13): S 7.48-7.45 (m, 3H), 7.25-7.23 (m, 3H), 6.75 (d, 28 1H, J= 8.2Hz), 3.70 (s, 3H), 3.62 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35 (s, 29 6H).
1 GENERAL PROCEDURE L: f 4-(2 2 4 4-Tetramethyl-chroman-6-yl-ethynyll 2 phenyll acetic acid (Compound 28, General Formula 8) 3 A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl]
4 acetic acid methyl ester (Compound 27, 0.0478, 0.13mmol) in 5mL of methanol was treated with 1M sodium hydroxide solution (2mL) and heated at 6 55°C for 2h. The volatiles were distilled off in vacuo and the residue was 7 acidified with 10% hydrochloric acid and extracted with ethyl acetate (x2).
8 The combined organic phase was washed with brine (x1), dried over 9 anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in 11 acetonitrile as the mobile phase to afford the title compound (0.0348, 82%). 'H
12 NMR (300 MHz, CDC13): ~ 7.49-7.45 (m, 3H), 7.26-7.22 (m, 3H), 6.75 (d, 13 1H, J= 8.2Hz), 3.65 (s, 2H), 1.84 (s, 2H), 1.36 (s, 6H), 1.35 (s, 6H).
14 2-Fluoro-4-(2 2 4 4-tetramethyl-chroman-6-~yn~l~ benzoic acid meth ester (Compound 29, General Formula 8) 16 Following general procedure F and using 6-ethynyl-2,2,4,4-17 tetramethylchroman (0.118, O.Slmmol), methyl-2-fluoro-4-iodo-benzoate 18 (Reagent G, 0.148, 0.51mmo1), triethyl amine (5mL), tetrahydrofuran(lOmL), 19 copper(I)iodide(0.030g, 0.16mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 10g, 0.16mmo1) followed by 21 flash column chromatography over silica gel (230-400 mesh) using 5-10 22 ethyl acetate in hexane as the eluent, the title compound was obtained (0.148, 23 79%).
24 'H NMR (300 MHz, CDC13): 8 7.82 (t, 1H, J= 7.9Hz), 7.39 (d, 1H, J=
l.BHz), 7.25-7.16 (m, 3H), 6.69 (d, 1H, J= 8.2Hz), 3.85 (s, 3H), 1.77 (s, 2H), 26 1.29 (s, 6H), 1.28 (s, 6H).
27 2-Fluoro-4-(2,2 4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid 28 (Compound 30, General Formula 8) 1 Following general procedure L and using 2-fluoro-4-(2,2,4,4-2 tetramethyl-chroman-6-yl-ethynyl)-benzoic acid methyl ester (Compound 29, 3 0.14g, 0.4mmo1), 5mL of methanol and 1M sodium hydroxide solution (2mL) 4 followed by recrystallization from ethyl acetate, the title compound was obtained (0.083g, 58%).
6 'H NMR (300 MHz, CD3COCD3): 8 8.00 (t, 1H, J= 7.8Hz), 7.63 (d, 1H, J=
7 2.lHz), 7.45 (dd, 1H, J= 1.5, 7.9Hz), 7.38 (dd, 1H, J= 1.5, 11.4Hz), 7.32 (dd, 8 1H, J= 2.1, 8.2Hz), 6.81 (d, 1H, J= 8.SHz), 1.92 (s, 2H), 1.41 (s, 6H), 1.38 (s, 9 6H).
[2-Fluoro-4-f2 2 4 4-tetramethyl-chroman-6-yl-eth~nyl~phenyll acetic acid I 1 ethyl ester (Compound 31, General Formula 8) 12 . Following general procedure F and using 6-ethynyl-2,2,4,4-13 tetramethylchroman (0.204g, 0.95mmo1), ethyl-2-fluoro-4-iodo phenyl acetate 14 (Reagent C, 0.263g, 0.86mmo1), triethyl amine, tetrahydrofuran, 1 S copper(I)iodide (0.025g, 0. l3mmol) and 16 dichlorobis(triphenylphosphine)palladium(II) (0.075g, 0.1 lmmol) followed by 17 flash column chromatography over silica gel (230-400 mesh) using 5-10 18 ethyl acetate in hexane as the eluent, the title compound was obtained (0.2I g, 19 ~ 62%).
IH NMR (300 MHz, CDC13): 8 7.46 (d, 1H, J= 2.IHz), 7.25-7.21 (m, 4H), 21 6.69 (d, 1 H, J = 8. SHz), 4.16 (q, 2H, J = 7.1 Hz), 3.65 (s, 2H), 1. 82 (s, 2H), 22 1.35 (s, 6H), 1.35 (s, 6H), 1.24 (t, 3H, J= 7.2Hz).
23 2-Fluoro-4- 2 2 4 4-tetramethyl-chxoman-6-yl-ethyn~ phenyl] acetic acid 24 (Compound 32, General Formula 8) Following general procedure L and using [2-fluoro-4-(2,2,4,4-26 tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid ethyl ester (Compound 27 31, 0.21g, 0.58mmo1), 5mL of methanol and 1M sodium hydroxide solution 28 (2mL) followed by flash column chromatography over silica gel (230-400 1 mesh) using SO% ethyl acetate in hexane, the title compound was obtained as a 2 solid (0.184g, 93%).
3 'H NMR (300 MHz, CDC13): 8 11.40 (br s, 1H), 7.48 (d, 1H, J= l.BHz), 7.46-4 7.16 (m, 4H), 6.76 (d, 1H, J= 8.2Hz), 3.69 (s, 2H), 1.82 (s, 2H), 1.34 (s, 12H).
S 3-MethXl-but-2-enoic acid 4-bromo-phen 1y ester:
6 To a stirred, cooled (ice bath) suspension of sodium hydride (2.4g, 7 100mmo1) in anhydrous tetrahydrofuran (200mL), 4-bromo phenol (17.3g, 8 100mmo1) was added followed by 3,3,-dimethyl acryloyl chloride (11.14mL, 9 100mmol). After 4hours at ambient temperature, the reaction mixture was poured into brine and extracted with diethyl ether (x2). The combined organic I 1 phase was dried over anhydrous sodium sulfate, filtered and evaporated in 12 vacuo to afford an oil which was subjected to flash column chromatography 13 over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent 14 to afford the title compound (1 Sg, S9%).
1S. 'H-NMR (300 MHz, CDCl3):S 2.00(s, 3H), 2.23(s, 3H), 5.89(s, 1H), 7.00(d, J
16 = 8.8Hz, 2H), 7.49(d, J = 8.8Hz, 2H).
17 6-Bromo-4.4-dimethyl-chroman-2-one:
18 A solution of 3-methyl-but-2-enoic acid 4-bromo-phenyl ester (7g, 19 27.6mmo1) in anhydrous dichloromethane (200mL) was cooled (ice bath) and treated with aluminum chloride (6.6g, 49.6mmol) and the reaction mixture was 21 stirred overnight at ambient temperature. The reaction mixture was quenched 22 with saturated aqueous sodium bicarbonate solution and extracted with diethyl 23 ether (x2). The combined organic extract was washed woth brine (x1), dried 24 over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an 2S oil which was purified by flash column chromatography over silica gel (230-26 400 mesh) using Z.S% ethyl acetate in hexane as the eluent to afford the title 27 compound (4.2g, 57%).
28 'H-NMR (300 MHz, CDC13):8 1.36(s, 6H), 2.62(s, 2H), 6.95(d, J = 8.SHz, 29 1H), 7.37(dd, J = 2.4, B.SHz, 1H), 7.43(d, J = 2.3Hz, 1H).
1 4-Bromo-2-f 3-h d~ roxX-1 1 3-trimethyl-butyll-phenol:
2 A solution of 6-bromo-4,4-dimethyl-chroman-2-one (1g, 3.92mmol) in 3 anhydrous tetrahydrofuran (20mL) was treated with 3M solution of ethyl 4 magnesium bromide (2.6mL) and stirred at ambient temperature for 2hours.
The reaction mixture was poured into cold dilute hydrochloric acid and 6 extracted with ethyl acetate (x2). The combined organic extract was dried 7 over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a 8 residue which was subjected to flash column chromatography over silica gel 9 (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as a pale yellow solid (1.1g, 100%).
11 1H-NMR (300 MHz, CDC13):b 1.14(s, 6H), 1.44(s, 6H), 2.20(s, 2H), 6.49(d, J
12 = 8.4Hz,lH), 7.15(dd, J = 2.4, 8.SHz, 1H), 7.37(d, J = 2.4Hz, 1H).
13 6-Bromo-2,2,414-tetrameth~-chroman:
14 A solution of 4-bromo-2-(3-hydroxy-1,1,3-trimethyl-butyl)-phenol (1.1g, 3.92mmo1) andp-toluene sulfonic acid (0.744g, 3.92mmol) in benzene 16 (20mL) was refluxed overnight. The reaction mixture cooled to ambient 17 temperature, filtered on silica gel and washed with 10% ethyl acetate in 18 hexane. The filtrate and washings were evaporated in vacuo to an oil which 19 was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a 2I pale yellow oil (0.848, 80%).
22 'H-NMR (300 MHz, CDCl3):8 1.34(s, 6H), 1.35(s, 6H), 1.82(s, 2H), 6.68(d, J
23 = 8.4Hz, 1 H), 7.16(dd, J = 2.7, 8.7Hz, 1 H), 7.3 7(d, J = 2.6Hz, 1 H).
24 The synthesis of this compound, as described here, is in close analogy to the synthesis of 6-bromo-2,2,4,4-tetramethylthiochroman, as described in 26 United States Patent No. 5,045,551 27 2 2 4 4-tetramethyl-6-f2-trimeth~ l~)eth~nyl chroman:
28 Following general procedure D and using 6-bromo-2,2,4,4-tetramethyl 29 chroman (0.5g, 1.87mmo1), triethyl amine (5mL), anhydrous tetrahydrofuran 1 (lSmL),copper(I)iodide (0.1078, 0.156mmo1), trimethylsilyl acetylene (1.848, 2 18.7mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.398, 3 0.56mmol) the title compound was obtained as a brown oil (0.618, 100%).
4 1H NMR (300 MHz, CDCl3): 8 7.43 (d, 1H, J= 2.lHz), 7.23 (dd, 1H, J= 7.9, 2.lHz), 6.73 (d, 1H, J= 8.2Hz), 1.83 (s, 2H), 1.36 (s, 12H), 0.28 (s, 9H).
6 6-Eth,~nyl-2,2,4,4-tetramethyl chroman:
7 Following general procedure E and using 2,2,4,4-tetramethyl-6-(2-8 trimethylsilyl)ethynyl chroman (0.618, 1.87mmo1), potassium carbonate ( 1.98, 9 13.74mmo1) and methanol the title compound was obtained (0.48, 90%).
I0 'H NMR (300 MHz, CDCI3): 8 7.47 (d, 1H, J= 2.lHz), 7.24 (dd, 1H, J= 7.9, 11 2.lHz), 6.76 (d, 1H, J= 8.2Hz), 3.01 (s, 1H), 1.85 (s, 2H), 1.37 (s, 6H), 1.36 12 (s, 6H).
13 An alternative synthesis for this compound is described in United States 14 Patent Nos. 5,045,551 and 5,616,597 GENERAL PROCEDURE M: 6-Bromo-2,2,4 4-tetramethyl-chroman-8-16 carbaldehyde (Intermediate 30) 17 A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl 18 chroman, (0.5g, 1.865mmol) in anhydrous dichloromethane (SmL) was treated 19 with a 1M solution (1.86mL, 1.86mmo1) of titanium tetrachloride in dichloromethane followed by a,a,-dichloro methyl ether (0.2148, 1.865mmol).
21 The reaction mixture was allowed to warm to ambient temperature for 4h. The 22 reaction mixture was diluted with diethyl ether, washed with brine (x1) and 23 dried over anhydrous sodium sulfate, filtered and evaporated in vczcuo to a 24 residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane to afford the title compound 26 as a yellow solid (0.528, 94%).
27 1H NMR (300 MHz, CDCl3): 810.38 (s, 1H), 7.72 (d, 1H, J= 2.6Hz), 7.57 (d, 28 1 H, J = 2. 6Hz), 1. 8 8 (s, 2H), 1.41 (s, 6H), 1.3 6 (s, 6H).
1 GENERAL PROCEDURE N: 6-Bromo-8-vinyl -2 2 4 4-tetramethyl- chroman 2 (Intermediate 31) 3 A solution of methylidene triphenyl phosphorane [generated from 4 methyl triphenylphosphonium bromide (7g, 20mmo1) and ( 11.BmL, 19mmo1) S of a 1.6M solution of h-butyl lithium in hexanes ] was added 6-bromo-2,2,4,4-6 tetramethyl chroman-8-carbaldehyde (Intermediate 30, O.S2g, 1.75mmo1).
7 After 1 h the reaction mixture was diluted with hexane, washed with brine (x 1 ), 8 dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a 9 clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the 11 title compound as a clear oil (0.378, 72%).
12 1H NMR (300 MHz, CDC13): 8 7.46 (d, 1H, J= 2.SHz), 7.33 (d, 1H, J=
13 2.SHz), 7.03 (dd, 1H, J= 11.3, 17.9Hz), 5.75 (dd, 1H, J= 1.4, 17.9Hz), 5.30 14 (dd, 1H, J= 1.4, 11.3Hz), 1.8S (s, 2H), 1.39 (s, 6H), 1.37 (s, 6H).
1 S GENERAL PROCEDURE O: 6-Bromo-8-c~propxl-2,2,4,4-tetramethyl 16 chroman (Intermediate 32) 17 A stirred, cooled (-30°C) solution of 6-bromo-8-vinyl-2,2,4,4-18 tetramethyl chroman (Intermediate 31, 0.37g, 1.26mmo1) in diethyl ether was 19 treated with a solution of diazomethane in diethyl ether and catalytic amount of palladium (II)acetate (~30mg). The reaction mixture was allowed to warm 21 to ambient temperature and subjected to flash column chromatography over 22 silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to 23 afford the title compound as a clear, pale yellow oil (0.376g, 97%).
24 1H NMR (300 MHz, CDC13): 8 7.17 (d, 1H, J= 2.3Hz), 6.73 (d, 1H, J=
2S 2.6Hz), 2.19-2.16 (m, 1H), 1.83 (s, 2H), 1.37 (s, 6H), 1.33 (s, 6H), 0.94-0.88 26 (m, 2H), 0.64-0.59 (m, 2H).
27 8-C cly opro~yl-6-trimeth 1y silan 1y eth,~~l-2 2 4 4-tetramethyl chroman 28 (Intermediate 33) 1 Following general procedure D and using 6-bxomo-8-cyclopropyl-2 2,2,4,4-tetramethyl chroman (Intermediate 32, 0.3768, 1.22mmo1), 3 (trimethylsilyl)acetylene (4mL, 2$mmol), triethyl amine (3mL), anhydrous 4 tetrahydrofuran (SmL), copper(I)iodide (0.0258, 0.13mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.11mmo1), the title 6 compound was obtained as an oil (0.1738, 43%).
7 1H NMR (300 MHz, CDC13): 8 7.36 (d, 1H, J= 2.2Hz), 6.90 (d, 1H, J=
8 l.9Hz), 2.31-2.22 (m, 1H), 1.96 (s, 2H), 1.49 (s, 6H), I.46 (s, 6H), 1.05-0.88 9 (m, 2H), 0.78-0.72 (m, 2H), 0.37 (s, 9H).
8-Cxclopro~yl-6-eth~nyl-2 2 4~4-tetrameth~l chroman (Intermediate 34) 11 Following general procedure E and using 8-cyclopropyl-6-12 trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 33, 0.178, 13 0.68mmol), methanol and potassium carbonate (0.28, 1.47mmol) the title 14 compound was obtained as an oil (0.0648, 47%).
1H NMR (300 MHz, CDCl3): ~ 7.38 (d, 1H, J= l.9Hz), 6.92 (d, 1H, J=
16 l.9Hz), 3.08 (s, 1H), 2.32-2.23 (m, 1H), 1.96 (s, 2H), 1.50 (s, 6H), 1.46 (s, 17 6H), 1.05-0.99 (m, 2H), 0.77-0.72 (m, 2H).
18 4~8-CXcloprop~-2~2 4 4 tetrameth~hroman-6-yl-eth~~ll-benzoic acid 19 ethyl ester (Compound 33, General Formula 8) Following general procedure F and using 8-cyclopropyl-6-ethynyl-21 2,2,4,4-tetramethylchroman (Intermediate 34, O.lg, 0.38mmol), ethyl-4-iodo-22 benzoate (Reagent A, O.lg, 0.34mmol), triethyl amine (SmL), 23 tetrahydrofuran(lOmL), copper(I)iodide(0.025g, 0.13mmo1) and 24 dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.1 lmmol) followed by flash column chromatography over silica gel (230-400 mesh) using S-10 26 ethyl acetate in hexane as the eluent, the title compound was obtained (0.1358, 27 89%).
28 1H NMR (300 MHz, CDCl3): ~ 8.00 (d, 2H, J= 8.2Hz), 7.55 (d, 2H, J=
29 8.2Hz), 7.30 (d, 1H, J= l.BHz), 6.84 (d, IH, J= 2.OHz), 4.38 (q, 2H, J=
1 6.9Hz), 2.22-2.12 (m, 1H), 1.85 (s, 2H), 1.40 (t, 3H, J= 6.9Hz), 1.38 (s, 6H), 2 1.36 (s, 6H), 0.92-0.88 (m, 2H), 0.67-0.62 (m, 2H).
3 4 ~~clopropyl-2 2 4 4-tetramethyl-chroman-6-yl-ethynyll-benzoic acid 4 (Compound 34, General Formula 8) S Following general procedure L and using 4-(8-cyclopropyl-2,2,4,4-6 tetramethyl-chroman-6-yl-ethynyl)-benzoic acid ethyl ester (Compound 33, 7 0.13Sg, 0.34mmol), SmL of methanol and IM sodium hydroxide solution 8 (2mL) followed by preparative reverse phase HPLC using 10% water in 9 acetonitrile as the mobile phase, the title compound was obtained as a solid IO (0.093g, 73%).
11 1H NMR (300 MHz, CDC13): 8 1 I.26 (br s, 1H), 8.08 (d, 2H, J= 8.2Hz), 7.59 12 (d, 2H, J = 8.2Hz), 7.31 (d, 1 H, J = 1.BHz), 6.8 S (d, 1 H, J = 2.1 Hz), 2.22-2.13 13 (m, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.36 (s, 6H), 0.95-0.87 (m, 2H), 0.68-0.63 14 (m, 2H).
1 S f 4-(8-Cyclopropyl-s2 4 4-tetramethyl-chroman-6-~yn~2phen~] acetic 16 acid methyl ester (Compound 35, General Formula 8) 17 Following general procedure F and using 8-cyclopropyl-6-ethynyl-18 2,2,4,4-tetramethylchroman (Intermediate 34, 0.096g, 0.38mmo1), methyl-4-19 iodo phenyl acetate (Reagent B, 0.094g, 0.34mmo1), triethyl amine (3mL), 20 tetrahydrofuran (3mL), copper(I)iodide (0.025g; 0.13mmo1) and 21 dichlorobis(triphenylphosphine)palladium(II) (0.07Sg, 0.11mmol) the title 22 compound was obtained (0.137g, 90%). 1H NMR (300 MHz, CDCl3): b 7.47 23 (d, 2H, J= 7.9Hz), 7.29 (d, 1H, J= l.BHz), 7.24 (d, 2H, J= 7.9 Hz), 6.82 (d, 24 1H, J= 2.lHz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22-2.I3 (m, 1H), I.BS (s, 2H), 2S 1.38 (s, 6H), 1.36 (s, 6H), 0.94-0.86 (m, 2H), 0.68-0.63 (m, 2H).
26 [4-(8-C.yclopropyl-2 2 4 4-tetrameth~-chroman-6-yl-ethynyl~phen~] acetic 27 acid (Compound 36, General Formula 8) 28 Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-29 tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid methyl ester I (Compound 35, 0.137g, 0.30mmo1), SmL of methanol and 1M sodium 2 hydroxide solution (2mL) followed by preparative reverse phase HPLC using 3 10% water in acetonitrile as the mobile phase, the title compound was 4 obtained as a solid (0.11g, 80%).
1H NMR (300 MHz, CDCl3): 8 I 1.56 (br s, 1H), 7.47 (d, 2H, J= 8.9Hz), 7.28 6 (d, 1H, J= l.9Hz), 7.23 (d, 2H, J= 8.SHz), 6.82 (d, 1H, J= l.9Hz), 3.62 (s, 7 2H), 2.21-2.12 (m, 1H), 1.83 (s, 2H), 1.36 (s, 6H), 1.34 (s, 6H), 0.93-0.82 (m, 8 2H), 0.72-0.62 (m, 2H).
9 f4-(8-Cyclopropyl-2 2 4 4-tetramethyl-chroman-6-~-eth~nyl)-2-fluorophenyll acetic acid ether ester (Compound 37, General Formula 8) 1 I Following general procedure F and using 8-cyclopropyl-6-ethynyl-12 2,2,4,4-tetramethylchroman (Intermediate 34, 0.096g, 0.38mmol), ethyl-2-13 fluoro-4-iodo phenyl acetate (Reagent C, 0.104g, 0.34mmo1), triethyl amine 14 (3mL), tetrahydrofuran (3mL), copper(I)iodide (0.020g, O.lmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.085mmo1) the title 16 compound was obtained (0.14g, 8S%).
17 'H NMR (300 MHz, CDC13): 8 7.31 (d, 1.H, J= l.9Hz), 7.29-7.21 (m, 3H), 18 6.85 (d, 1H, J= l.9Hz), 4.20 (q, 2H, J= 7.lHz), 3.68 (s, 2H), 2.24-2.14 (m, 19 1H), 1.87 (s, 2H), 1.40 (s, 6H), 1.38 (s, 6H), 1.28 (t, 3H, J= 7.lHz), 0.96-0.85 (m, 2H), 0.70-0.64 (m, 2H).
21 f4-(8-C~propyl-2 2 4 4-tetramethXl-chroman-6-yl-eth~n~)-2-fluorophenyll 22 acetic acid (Compound 38, General Formula 8) 23 Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-24 tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl] acetic acid ethyl ester (Compound 37, 0.14g, 0.323mmo1), SmL of methanol and 1M sodium 26 hydroxide solution (2mL) followed by reverse phase HPLC using 10% water 27 in acetonitrile as the mobile phase, the title compound was obtained as a solid 28 (0.110g, 80%).
1 1H NMR (300 MHz, CDC13): ~ 7.28 (d, 1H, J= 2.lHz), 7.27-7.17 (m, 3H), 2 6.82 (d, 1H, J= l.BHz), 3.70 (s, 2H), 2.21-2.11 (m, 1H), 1.84 (s, 2H), 1.37 (s, 3 6H), 1.35 (s, 6H), 0.94-0.87 (m, 2H), 0.67-0.62 (m, ZH).
4 GENERAL PROCEDURE P: 6-Bromo-4 4-dimeth~methylene chroman (Intermediate 3S) 6 A stirred, cooled (ice bath) solution of 6-bromo-4,4-dimethyl-chroman-7 2-one available in accordance with U.S. Patent No. 5,399,561 incorporated 8 herein by reference ( 1 g, 3.92mmo1) in SmL of anhydrous tetrahydrofuran was 9 treated with a 0.5 M solution of p.-chloro-~.-methylene-[bis(cyclopentadienyl)titanium]dimethylaluminum (Tebbe reagent) in toluene 11 (8.23mL, 4.12mmo1). After 10 minutes, the reaction mixture was poured into 12 ice-water mixture containing SOmL of 1M sodium hydroxide and extracted I 3 with hexane. The hexane extract was washed with brine (x 1 ), filtered over a 14 bed of celite and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the 16 eluent to afford the title compound (0.74g, 74%) as a clear oil.
17 1H NMR (300 MHz, CDC13): b 7.34 (d, 1H, J= 2.3Hz), 7.23 (dd, 1H, J=
18 2.3,8.SHz), 6.77 (d, 1H, J= 8.OHz), 4.61 (d, 1H, J= 0.73Hz), 4.17 (d, 1H, J=
19 0.73Hz), 2.33 (s, 2H), 1.27 (s, 6H).
GENERAL PROCEDURE Q: 6-Bromo-3 4-dihydro-4,4-dimeth ls~ piro'[2H 1-21 benzop r~,1'-c~propanel (Intermediate 36) 22 A solution of diethyl zinc in hexane (1M, 7.lmL) was treated with 23 diiodomethane (1.89g, 7.lmmol). After 5 minutes, a solution of 6-bromo-4,4-24 dimethyl-2-methylene chroman (Intermediate 35, 0.448, 1.77mmol) in 3mL
of hexane was added and the solution was refluxed for 1h. The reaction 26 mixture was then cooled to ambient temperature, diluted with hexane, washed 27 with brine (x1), dried over anhydrous sodium sulfate, filtered and evaporated 28 in vacuo to a residue which was subjected to flash column chromatography 1 over silica gel (230-400 mesh) using hexane as the eluent to obtain the title 2 compound (0.44g, 93%).
3 1H NMR (300 MHz, CDC13): 8 7.47 (d, 1H, J= 2.3Hz), 7.23 (dd, 1H, J=
4 2.3, 8.SHz), 6.70 (d, 1H, J= 8.OHz), 1.96 (s, 2H), 1.47 (s, 6H), 1.09-1.05 (m, 2H), 0.74-0.70 (m, 2H).
6 3 4-Dih d~ 4-dimethyl-6-~trimethylsilanyl eth~~piro[2H 1-benzopyran-7 2,1'-c~propanel (Intermediate 37) 8 Following general procedure D and using 6-bromo-3,4-dihydro-4,4-9 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 36, 0.44g, I.65mmo1), triethyl amine (4mL), anhydrous tetrahydrofuran (SmL), 11 copper(I)iodide (0.95g, O.Smmol), trimethylsilyl acetylene (1.62g, l6.Smmol) 12 and dichlorobis(triphenylphosphine)palladium(II) (0.4g, 0.56mmol), the title 13 compound was obtained as a brown oil (0.4g, 86%).
14 1H NMR (300 MHz, CDCl3): 8 7.44 (d, 1 H, J = 2. I Hz), 7.18 (dd, 1 H, J =
2.1,8.SHz), 6.65 (d, 1H, J= B.SHz), 1.87 (s, 2H), 1.37 (s, 6H), 1.01-0.97 (m, 16 2H), 0.65-0.61 (m, 2H), 0.26 (s, 9H).
17 6-Eth m~,4-dih~dro-4,4-dimeth~piro[2H 1-benzopyran-2,1'-18 cvclopropanel (Intermediate 38) 19 Following general procedure E and using 3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H 1-benzopyran-2,1'-cyclopropane]
21 (Intermediate 37, 0.4g, 1.42mmo1), potassium carbonate (0.98g, 7.lmmol) 22 and methanol, the title compound was obtained as a yellow oil (0.3g, 100%).
23 'H NMR (300 MHz, CDCl3): 8 7.44 (d, 1H, J= 2.lHz), 7.18 (dd, 1H, J= 2.1, 24 8.SHz), 6.65 (d, 1H, J= 8.SHz), 2.97 (s, 1H), 1.86 (s, 2H), 1.37 (s, 6H), 1.00-0.95 (m, 2H), 0.64-0.59 (m, 2H).
26 Benzoic acid, 4-[(3~4-dih~dro-4 4-dimethy-ls~iro[2H 1-benzopyran-2,1'-27 c.~clopro~pane~ 6=yl~eth~,~]-ethyl ester (Compound 39, General Formula 1) 28 Following general procedure F and using 6-ethynyl-3,4-dihydro-4,4-29 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 38, 0.06g, 1 0.28mmo1), ethyl-4-iodo-benzoate (Reagent A, 0.0868, 0.31mmo1), triethyl 2 amine (4mL), tetrahydrofuran(4mL), copper(I)iodide(0.032g, 0.17mmo1) and 3 dichlorobis(triphenylphosphine)palladium(II) (0.1188, 0.17mmol) followed by 4 flash column chromatography over silica gel (230-400 mesh) using 5-10 ethyl acetate in hexane as the eluent, the title compound was obtained (0.078, 6 70%).
7 1H NMR (300 MHz, CDC13): 8 8.01 (d, 2H, J= 8.2Hz), 7.56 (d, 2H, J=
8 B.SHz), 7.49 (d, 1H, J= 2.lHz), 7.24 (dd, 1H, J= 2.1,8.SHz), 6.70 (d, 1H, J=
9 8.SHz), 4.38 (q, 2H, J= 7.lHz), 1.89 (s, 2H), 1.40 (s, 6H), 1.40 (t, 3H, J=
7.OHz), 1.02-0.98 (m, 2H), 0.67-0.62 (m, 2H).
11 Benzoic acid~4-~(3 4-dih~dro-4 4-dimethXlsniro[2H 1-benzopyran-2,1'-12 cyclopropane]-6-,1~)eth~~]~ (Compound 40, General Formula 1) 13 Following general procedure L and using benzoic acid, 4-[(3,4-dihydro-4,4-14 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-ethyl ester (Compound 39, 0.078, 0.196mmol), SmL of ethanol and 1M sodium 16 hydroxide solution (2mL) followed by preparative reverse phase HPLC using 17 10% water in acetonitrile as the mobile phase, the title compound was 18 obtained as a solid (0.0348, 52%).
19 'H NMR (300 MHz, CD3COCD3): 8 8.05 (d, 2H, J= 8.2Hz), 7.64 (d, 2H, J=
8.2Hz), 7.60 (d, 1H, J= 2.lHz), 7.28 (dd, 1H, J= 2.1, 8.SHz), 6.73 (d, 1H, J=
21 8.SHz), 1.95 (s, ZH), 1.43 (s, 6H), 0.96-0.92 (m, 2H), 0.74-0.71 (m, 2H).
22 Benzeneacetic acid, 4-x(3,4-dih,~,4-dimethvlspiro[2H 1-benzopyran-2,1'-23 cyclopropane]-6;Ylleth~rn 1y 1-meth.~I ester (Compound 41, General Formula 24 1) Following general procedure F and using 6-ethynyl-3,4-dihydro-4,4-26 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 3$, , 27 0.0608, 0.28mmo1), methyl-4-iodo phenyl acetate (Reagent B, 0.0788, 28 0.28mmol), triethyl amine (4mL), tetrahydrofuran (4mL), copper(I)iodide 29 (0.0328, 0.17mmo1) and dichlorobis(triphenylphosphine)palladium(II) 1 (0.118g, 0.17mmo1) followed by flash column chromatography over silica gel 2 (230-400 mesh) using 5 % ethyl acetate in hexane as the eluent, the title 3 compound was obtained (0.084g, 84%).
4 1H NMR (300 MHz, CDCl3): 8 7.48-7.45 (m, 3H), 7.26-7.20 (m, 3H), 6.67 (d, 1H, J= B.SHz), 3.70 (s, 3H), 3.63 (s, 2H), 1.89 (s, 2H), 1.40 (s, 3H), 1.40 (s, 6 3H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).
7 Benzeneacetic acid~4-[C3 4-dihydro-4~4-dimethylspiro[2H 1-benzopyran-2,1'-8 c~clopropane]-6-~)ethyn~l]- (Compound 42, Formula 1) 9 A solution of benzeneacetic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-methyl 11 ester (Compound 41, 0.084g, 0.24mmo1) in SmL of methanol was treated 12 with 1M sodium hydroxide solution (2mL) and heated at 55°C for 2h.
The 13 volatiles were distilled off in vacuo and the residue was acidified with 10%
14 hydrochloric acid and extracted with ethyl acetate (x2). The combined organic phase was washed with brine (x1), dried over anhydrous sodium sulfate, 16 filtered and evaporated in vacuo to a residue which was purified by preparative 17 reverse phase HPLC using 10% water in acetonitrile as the mobile phase to 18 afford the title compound (0.080g, 100%).
19 1H NMR (300 MHz, CD3COCD3): b 7.49-7.46 (m, 3H), 7.25 (d, 2H, J=
8.2Hz), 7.22 (dd, 1H J= 2.1,8.SHz), 6.68 (d, 1H, J= 8.SHz), 3.66 (s, 2H), 1.88 21 (s, 2H), 1.44 (s, 6H), 1.01-0.97 (m, 2H), 0.67-0.61 (m, 2H).
22 2-Fluoro-benzoic acid, 4-[(3 4-dih d~~4-dimeth~pirof2H 1-benzopyran-23 2,1'-c,~clopr~ane]-6-, l~lethyny~-methyl ester (Compound 43, General 24 Formula 1) Following general procedure F and 6-ethynyl-3,4-dihydro-4,4 26 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 38, 27 O.OSOg, 0.23mmo1), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.069g, 28 0.24mmol), triethyl amine (SmL), tetrahydrofuran(SmL), 29 copper(I)iodide(0.013g, 0.07mmo1) and 1 dichlorobis(triphenylphosphine)palladium(II) (0.0498, 0.07mmol) followed by 2 flash column chromatography over silica gel (230-400 mesh) using S-10 3 ethyl acetate in hexane as the eluent, the title compound was obtained (0.0808, 4 100%).
S 1H NMR (300 MHz, CDC13): 8 7.90 (t, 1H, J= 7.9Hz), 7.63 (d, 1H, J=
6 l.BHz), 7.32 (dd, 1H, J=1.5, 8.2Hz), 7.26 (dd, 1H, J= 1.5,11.4Hz), 7.24 (dd, 7 1H, J= 2.1, B.SHz), 6.7I (d, 1H, J= B.SHz), 1.97 (s, ZH), 1.44 (s, 6H), 0.98-8 0.94 (m, 2H), 0.76-0.71 (m, 2H).
9 2-Fluoro-benzoic acid 4-j(3 4-dih~dro-4 4-dimethylspiro[2H 1-benzopyran-2,1'-c~lopropane]-6-yl ethynyll' (Compound 44, General~Formula 1) 11 Following general procedure L and using 2-fluoro-benzoic acid, 4-12 [(3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-13 yI)ethynyl]-methyl ester (Compound 43, 0.088, 0.23mmol), SmL of methanol 14 and 2M sodium hydroxide solution (1mL) followed by flash column 1 S chromatography over silica gel (230-400 mesh) using ethyl acetate as the 16 eluent, the title compound was obtained (0.0208, 2S%).
17 1H NMR (300 MHz, CD3COCD3): 8 7.99 (t, 1H, J= 7.9Hz), 7.63 (d, 1H, J=
18 2.lHz), 7.44 (dd, 1H, J= 1..5, 7.9Hz), 7.37 (dd, 1H, J= 1.5, 11.4Hz), 7.31 (dd, 19 1H, J= 2.1, 8.SHz), 6.75 (d, 1H, J= 8.2Hz), 1.97 (s, 2H), 1.44 (s, 6H), 0.98-0.94 (m, 2H), 0.76-0.71 (m, 2H).
21 GENERAL PROCEDURE R: 2,2 4,4-Tetramethyl-chroman-6-carboxylic acid 22 (Intermediate 39) 23 A stirred, cooled (-78°C) solution of 6-bromo-2,2,4,4-tetramethyl 24 chroman ( 1.28, 4.47mmo1) in 1 SmL of anhydrous tetrahydrofuran was treated 2S with a 1.7M solution of tent-butyl lithium solution in pentane ( S.27mL, 26 8.9mmo1). After 10 minutes at -78°C, carbon dioxide (generated from dry ice) 27 was bubbled into the reaction mixture. The reaction mixture was allowed to 28 warm to ambient temperature. The reaction mixture was diluted with ethyl 29 acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and 1 evaporated in vacuo to a residue which was subjected to flash column 2 chromatography over silica gel (230-400 mesh) using ethyl acetate as the 3 eluent to afford the title compound as a white solid (1.1g, 92%).
4 'H NMR (300 MHz, CDCl3): 8 12.17 (br s, 1H), 8.09 (d, 1H, J= 2.lHz), 7.85 (dd, 1H, J= 2.1, 8.5Hz), 6.83 (d, 1H, J= 8.2Hz), 1.87 (s, 2H), 1.39 (s, 6H), 6 1.37 (s, 6H).
7 2 2 4 4-Tetramethyl-chxoman-6-carboxylic acid 4-(te~t-8 butoxycarbonylmethyl_lphen l~ (Compound 45, General Formula 8) 9 A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43mmo1) in thionyl chloride (lOmL) was refluxed for 2h. The thionyl 11 chloride was evaporated under reduced pressure and the residue was dissolved 12 in 5mL of dichloromethane and treated with triethyl amine (5mL) followed by 13 test-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088g, 0.427mmol). After I4 0.5h, the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to 16 afford the title compound (0.1g, 55%).
17 'H NMR (300 MHz, CDC13): b 8.15 (d, 1H, J= 2.lHz), 7.93 (dd, 1H, J= 2.1, I8 8.5Hz), 7.33 (d, 2H, J= 8.8Hz), 7.16 (d, 2H, J= 8.8Hz), 6.88 (d, 1H, J=
19 8.5Hz), 3.54 (s, 2H), 1.89 (s, 2H), 1.45 (s, 9H), 1.41 (s, 6H), 1.40 (s, 6H).
2,2,4,4-Tetramethyl-chroman-6-carbox~c acid 4-(carbox~methyl)phenyl 21 ester (Compound 46, General Formula 8) 22 A solution of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(tert-23 butoxycarbonylmethyl)phenyl ester (Compound 45, 0.1 g, 0.23mmo1) was 24 treated with 5mL of trifluoroacetic acid and stirred at ambient temperature for 1 h. The trifluoroacetic acid was distilled off under reduced pressure and the 26 residue was subjected to preparative reverse phase HPLC using 10% water in 27 acetonitrile as the mobile phase to afford the title compound as a white solid 28 (0.045g, 50%).
1 1H NMR (300 MHz, CDC13): 8 8.13 (d, 1H, J= 2.lHz), 7.92 (dd, 1H, J= 2.3, 2 8.SHz), 7.35 (d, 2H, J= 8.8Hz), 7.17 (d, 2H, J= B.SHz), 6.87 (d, IH, J=
3 8.SHz), 3.68 (s, 2H), 1.89 (s, 2H), 1.41 (s, 6H), 1.39 (s, 6H).
4 6-Bromo-8-carbaldehyde-3 4-dih~dro-4 4-dimethvls~iro[2H 1-benzop ry an-y 2,1'-cyclopropanel (Intermediate 40) 6 Following general procedure M and using 6-bromo-3,4-dihydro-4,4-7 dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane](Intermediate 36, 2.3g, 8 8.65mmo1), anhydrous dichloromethane (25mL), 1M solution (8.65mL, 9 8.65mmo1) of titanium tetrachloride in dichloromethane and a,a-dichloro methyl ether (1.09g, 9.52mmol) followed by flash column chromatography 11 using 10% ethyl acetate in hexane as the eluent, the title compound was 12 obtained as a yellow solid (2.06g, 81 %).
13 IH NMR (300 MHz, CDC13): 8 10.20 (s, 1H), 7.69 (d, 1H, J= 2.6Hz), 7.58 (d, 14 1 H, J= 2.6Hz), I .92 (s, 2H), 1.40 (s, 6H), 1.09-1.04 (m, 2H), 0.73-0.69 (m, 2H).
16 6-Bromo-3 4-dihydro-4,4-dimethyl-8-vinXlspiro[2H 1-benzopyran-2,1'-17 cvclopropanel (Intermediate 41) 18 Following general procedure N and using A solution of methylidene 19 triphenyl phosphorane [generated from methyl triphenylphosphonium 'bromide (7g, 20mmo1) and 1.6M solution of h-butyl lithium in hexanes (11.8mL, 21 l9mmol) ], 6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H 1-22 benzopyran-2,1'-cyclopropane](Intermediate 40, 2.06g, 7mmol) followed by 23 flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl 24 acetate in hexane as the eluent, the title compound was obtained as a clear oil (1.36g, 66%).
26 'H NMR (300 MHz, CDC13): 8 7.36 (d, 1H, J= 2.3Hz), 7.28 (d, 1H, J=
27 2.6Hz), 6. 80 (dd, 1 H, J = 11.1, 17.9Hz), 5.63 (dd, 1 H, J = 1.2, 17.9Hz), 5.19 28 (dd, 1H, J=1.2, 11.1Hz), 1.84 (s, 2H), 1.35 (s, 6H), 0.97 (t, 2H, J=
6.3Hz), 29 0.62 (d, 1H, J= 5.3Hz), 0.60 (d, 1H, J= 6.2Hz).
1 6-Bromo-8-c,~lopropyl-3~4-dihydro-4 4-dimeth ~~lspiro[2H 1-benzot?Vran-2 2.1'-c~propanel (Intermediate 42) 3 Following general procedure O and using A 6-bromo-3,4-dihydro-4,4 4 dimethyl-8-vinylspiro[2H 1-benzopyran-2,1'-cyclopropane] (Intermediate 41, 1.36g, 4.6mmol), a solution of diazomethane in diethyl ether and 6 palladium (II)acetate (~30mg) followed by flash column chromatography over 7 silica gel (230-400 mesh) using hexane as the eluent, the title compound was 8 obtained as a clear oil (1.388, 100%).
9 1H NMR (300 MHz, CDC13): 8 7.19 (d, 1H, J= 2.2Hz), 6.71 (d, 1H, J=
2.2Hz), 1.99-1.92 (m, 1H), 1.87 (s, 2H), 1.35 (s, 6H), 1.00-0.95 (m, 2H), 0.90-11 0.82 (m, 2H), 0.65-0.54 (m, 4H).
12 8-C,~prop,~-3,4-dihydro-4 4-dimethyl-6-(trimethXlsilanylleth~nylspiro[2H
13 1-benzop~ran-2~1'-c~lopropanel (Intermediate 43) 14 Following general procedure D and 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
16 (Intermediate 42, 0.74g, 2.4mmol), (trimethylsilyl)acetylene (4mL, 28mmo1), 17 triethyl amine (8mL), anhydrous tetrahydrofuran , copper(I)iodide (O.OSOg, 18 0.26mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.15g, 19 0.22mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound 21 was obtained as an oil (0.62g, 80%).
22 'H NMR (300 MHz, CDCl3): b 7.28 (d, 1H, J= l.9Hz), 6.77 (d, 1H, J=
23 l.9Hz), 2.03-1.94 (m, 1H), 1.91 (s, 2H), 1.40 (s, 6H), 1.05-0.98 (m, 2H), 0.95-24 0.83 (m, 2H), 0.69-0.59 (m, 4H), 0.27 (s, 9H).
8-C~lopropXl-6-ethyn~ 4-dihydro-4.4-dimethylspiro[2H 1-benzop~ran-26 2,1'-c~propanel (Intermediate 44) 27 Following general procedure E, and 8-cyclopropyl-3,4-dihydro-4,4-28 dimethyl-6-(trimethylsilanyl)ethynylspiro[2H 1-benzopyran-2,1'-29 cyclopropane] (Intermediate 43, 0.628, 1.9mmol), methanol and potassium 1 carbonate (0.58, 3.6mmol) followed by flash column chromatography over 2 silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the 3 title compound was obtained as an oil (0.58, 100%).
4 'H NMR (300 MHz, CDCl3): 8 7.30 (d, 1H, J= l.BHz), 6.80 (d, 1H, J=
2.OHz), 2.97 (s, 1H), 2.04-1.95 (m, 1H), 1.9I (s, 2H), 1.39 (s, 6H), 1.20-0.90 6 (m, 2H), 0.90-0.84 (m, 2H), 0.75-0.58 (m, 4H).
7 Benzeneacetic acid 4-~(8-cyclopropyl-3 4-dih~dro-4 4-dimethy-piro[2H 1-8 benzo~~-2 1'-c~clopropane]-6-~leth~~]-methfester (Compound 47, 9 General Formula I) Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-11 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
12 (Intermediate 44, 0.118, 0.43mmo1), methyl-4-iodo phenyl acetate (Reagent 13 B, 0.1148, 0.41mmo1), triethyl amine (5mL), tetrahydrofuran (3mL), I4 copper(I)iodide (0.0258, 0.13mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.1 lmmol), the title 16 compound was obtained as a clear oil (0.0968, 56%).
17 'H NMR (300 MHz, CDC13): 8 7.46 (d, 2H, J= 8.OHz), 7.31 (d, 1H, J=
18 l.9Hz), 7.24 (d, 2H, J= ~.2Hz), 6.81 (d, 1H, J= I.9Hz), 3.69 (s, 3H), 3.62 (s, 19 2H), 2.04-1.95 (m, 1H), 1.90 (s, 2H), 1.39 (s, 6H), 1.03-0.99 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).
21 Benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethy-piro'[2H 1-22 benzopyran-2,1'-cyclopropane]-6-ylleth~~]- (Compound 48, General 23 Formula 1) 24 Following general procedure L and using benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-26 cyclopropane]-6-yl)ethynyl]-methyl ester (Compound 47, 0.968, 0.24mmo1), 27 5mL of methanol and 1M sodium hydroxide solution (2mL) followed by flash 28 column chromatography over silica gel (230-400 mesh) using 15% methanol 1 in dichloromethane as the eluent, the title compound was obtained as a solid 2 (0.0848, 91%).
3 iH NMR (300 MHz, CDC13): 8 10.27 (br s, 1H), 7.46 (d, 2H, J= 8.2Hz), 7.30 4 (d, 1H, J= l.BHz), 7.23 (d, 2H, J= 8.2Hz), 6.80 (d, 1H, J= l.SHz), 3.63 (s, 2H), 2.07-1.94 (m, 1H), 1.89 (s, 2H), 1.39 (s, 6H), 1.03-0.98 (m, 2H), 0.89-6 0.82 (m, 2H), 0.73-0.59 (m, 4H).
7 4-[(8-C~cloprop~-3 4-dihydro-4 4-dimethylspiro[2H 1-benzopyran-2,1'-8 c c~~ane]-6-~)eth~ l~l-2-fluoro-benzeneacetic acid meth 1y ester 9 (Compound 49, General Formula 1) Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-11 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
12 (Intermediate 44, 0.1258, O.Smmol), methyl-2-fluoro-4-iodo phenyl acetate 13 (Reagent H, 0.148, O.Smmol), triethyl amine (3mL), tetrahydrofuran (3mL), 14 copper(I)iodide (0.0208, O.lmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.0608, 0.085mmo1) followed 16 by preparative normal phase HPLC using 10% ethyl acetate in hexane as the 17 mobile phase, the title compound was obtained (0.0968, 46%).
18 1H NMR (300 MHz, CDC13): 8 7.30 (d, 1H, J= 2.lHz), 7.26-7.18 (m, 3H), 19 6.80 (d, 1H, J= l.BHz), 3.71 (s, 3H), 3.67 (s, 2H), 2.04-1.94 (m, 1H), 1.90 (s, 2H), 1.40 (s, 6H), 1.18-0.99 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).
21 4-[(8-Cyclopropyl-3 4-dihydro-4,4-dimethylspiro[2H 1-benzop~ran-2,1'-22 cyclopropane]-6-, l~leth,~yl]-2-fluoro-benzeneacetic acid (Compound 50, 23 General Formula 1) 24 Following general procedure L and using 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-26 yl)ethynyl]-2-fluoro-benzeneacetic acid methyl ester (Compound 49, 0.0968, 27 0.23mmol), SmL of methanol and 1M sodium hydroxide solution (2mL) 28 followed by flash column chromatography over silica gel (230-400 mesh) 1 ~ using 15% methanol in dichloromethane as the eluent, the title compound was 2 obtained as a solid (0.093g, 100%).
3 1H NMR (300 MHz, CDC13): b 9.50 (br s, 1H), 7.27 (d, 1H, J= 2.lHz), 7.24-4 7.15 (m, 3H), 6.77 (d, 1H, J= l.SHz), 3.67 (s, 2H), 2.01-1.91 (m, 1H), 1.87 (s, 2H), 1.36 (s, 6H), 1.01-0.96 (m, 2H), 0.87-0.80 (m, 2H), 0.65-0.56 (m, 4H).
6 Benzoic acid 4-[(8-c~loprop~l-3~4-dihydro-4 4-dimethy-piro[2H 1-7 benzoR ry an-2 1'-c cy lonropane]-6-~lethynyll-ethyl ester (Compound 51, 8 General Formula 1) 9 Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
I I (Intermediate 44, O.OSg, 0.2mmo1), ethyl-4-iodo-benzoate (Reagent A, 12 O.OSSg, 0.2mmo1), triethyl amine (3mL), tetrahydrofuran(3mL), 13 copper(I)iodide(0.020g, 0.1 mmol) and 14 dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.085mmol), the title compound was obtained (0.06g, 75%).
16 'H NMR (300 MHz, CDC13): 8 8.00 (d, 2H, J= 8.2Hz), 7.55 (d, 2H, J=
17 8.2Hz), 7.33 (d, 1H, J= l.BHz), 6.83 (d, 1H, J= 2.lHz), 4.38 (q, 2H, J=
18 7.1 Hz), 2.04-1.95 (m, 1 H), 1.91 (s, 2H), 1.40 (s, 6H), 1.40 (t, 3 H, J =
7. OHz), 19 1.05-0.95 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.61 (m, 4H).
Benzoic acid, 4-[(8-c cly opropyl-3,4-dih dy ro-4,4-dimethylspiro[2H 1-21 benzop roan-2,1'-c~lopropane]-6-~leth~n~]- (Compound 52, General 22 Formula 1) 23 Following general procedure L and using benzoic acid, 4-[(8-24 cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-ethyl ester (Compound 51, 0.06g, O.lSmmol), 26 SmL of methanol and 1M sodium hydroxide solution (2mL) followed by 27 preparative reverse phase HPLC using 10% water in acetonitrile as the mobile 28 phase, the title compound was obtained as a solid (0.040g, 72%).
1 'H NMR (300 MHz, CDC13): ~ 8.08 (d, 2H, J= 8.8Hz), 7.60 (d, 2H, J=
2 8.8Hz), 7.34 (d, 1H, J= l.9Hz), 6.84 (d, 1H, J= l.9Hz), 2.05-1.96 (m, 1H), 3 1.92 (s, 2H), 1.41 (s, 6H), 1.05-0.95 (m, 2H), 0.92-0.83 (m, 2H), 0.75-0.60 (m, 4 4H).
4-[(8-C~loproi~yl-3 4-dihydro-4~4-dimethylsuiro[2H 1-benzop~ran-2,1'-6 cyclopropane]-6-,~~ethyny_1]-2-fluoro-benzoic acid meth 1y ester (Compound 7 53, General Formula 1) 8 Following general procedure F and using 8-cyclopropyl-6-ethynyl-3,4-9 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]
(Intermediate 44, 0.038, 0.1 lmmol), methyl-2-fluoro-4-iodo-benzoate 11 (Reagent G, 0.025g, 0.09mmol), triethyl amine (3mL), tetrahydrofuran(3mL), 12 copper(I)iodide(0.020g, O.lmmol) and 13 dichlorobis(triphenylphosphine)palladium(II) (0.068, 0.085mmo1) followed by 14 preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained as a white solid (0.019g, 40%).
16 1H NMR (300 MHz, CDC13): 8 7.97 (t, 1H, J= 7.8Hz), 7.34 (d, 1H, J=
17 1.9Hz), 7.32-7.25 (m, 2H), 6.83 (d, 1H, J= l.9Hz), 3.95 (s, 3H), 2.06-1.96 (m, 18 1H), 1.93 (s, 2H), 1.42 (s, 6H), 1.06-1.02 (m, 2H), 0.91-0.86 (m, 2H), 0.71-19 0.61 (m, 4H).
4-[(8-C cloprop~,4-dihydro-4,4-dimeth ls~[2H 1-benzop r~,l'-21 cyclopropane]-6-~leth~nyl]-2-fluoro-benzoic acid (Compound 54, General 22 Formula 1) 23 Following general procedure L and using 4-[(8-cyclopropyl-3,4-24 dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoic acid methyl ester (Compound 53, 0.019g, 26 0.047mmo1), SmL of methanol and 1M sodium hydroxide solution (2mL) 27 followed by preparative reverse phase HPLC using 10% water in acetonitrile 28 as the mobile phase, the title compound was obtained as a solid (0.01 g, 56%).
1 'H NMR (300 MHz, CDC13): 8 7.99 (t, IH, J= 8.OHz), 7.36 -7.28 (m, 3H), 2 6.83 (d, 1H, J= l.9Hz), 2.18-1.95 (m, 1H), 1.92 (s, 2H), 1.41 (s, 6H), 1.06-3 1.01 (m, 2H), 0.96-0.83 (m, 2H), 0.76-0.60 (m, 4H).
4 8-Acetyl-6-bromo-2 2 4 4-tetramethyl chroman (Intermediate 45) A stirred, cooled (ice bath) suspension of aluminum chloride (0.998, 6 7.46mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl 7 chloride (0.58g, 7.46mmo1). After 5 minutes, a solution of 6-bromo-2,2,4,4-8 tetramethyl chroman ( I g, 3.73mmol)in dichloromethane was added. The 9 reaction was allowed to warm to ambient temperature and stirred for 2h. The reaction mixture was then poured into ice containing 10% hydrochloric acid 11 and extracted with diethyl ether (x2). The combined organic phase was 12 washed with saturated aqueous sodium bicarbonate solution, dried over 13 anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which 14 was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as a 16 pale yellow oiI (0.95g, 83%). It was used as such for the next step without any 17 characterization.
18 6-promo-8-eth.~2,2,4 4 tetramethyl chroman (Intermediate 46) 19 A stirred, cooled (ice bath) solution of 8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 45, 0.958, 3.lmmol) in trifluoroacetic 21 acid (lOmL) was treated with triethylsilane (l4mL) and the resulting reaction 22 mixture was allowed to warm to ambient temperature and stirred overnight.
23 The volatiles were distilled off in vacuo and the residue was diluted with water 24 and extracted with hexane (x2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil which 26 was subjected to flash column chromatography over silica gel (230-400 mesh) 27 using hexane as the eluent to afford the title compound as a clear oil, 28 contaminated with a small amount to triethylsilane (O.Slg, 56%).
1 'H NMR (300 MHz, CDC13): 8 7.23 (d, 1H, J= 2.3Hz), 7.08 (d, 1H, J=
2 2.3Hz), 2.58 (q, 2H, J= 7.6Hz), 1.81 (s, 2H), 1.34 (s, 6H), 1.33 (s, 6H), 1.17 3 (t, 3H, J= 7.6Hz).
4 8-Ethyl-6-trimethylsilanXlethynyl-2~2 4 4-tetramethyl chroman (Intermediate S 47) 6 Following general procedure D and using 6-bromo-8-ethyl-2,2,4,4-7 tetramethyl chroman (Intermediate 46, O.Sg, 1.61mmo1), 8 (trimethylsilyl)acetylene (l.S7g, l6.lmmol), triethyl amine (8mL), anhydrous 9 tetrahydrofuran (lOmL), copper(I)iodide (0.02Sg, 0.13mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07Sg, 0.llmmol), followed 11 by flash column chromatography over silica gel (230-400 mesh) using S%
12 ethyl acetate in hexane as the eluent, the title compound was obtained as an oil 13 (0.137g, 27%).
14 ~H NMR (300 MHz, CDC13): 8 7.27 (d, 1H, J= 2.lHz), 7.10 (d, 1H, J=
2.lHz), 2.SS (q, 2H, J= 7.6Hz), 1.81 (s, 2H), 1.33 (s, 6H), 1.32 (s, 6H), 1.15 16 (t, 3H, J= 7.6Hz), 0.24 (s, 9H).
17 8-Ethyl-6-ethyn~,2,4.4-tetramethyl chroman (Intermediate 48) 18 Following general procedure E and using 8-ethyl-6-19 trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 47, 0.137g, 0.44mmol), methanol and potassium carbonate (0.1g, 0.72mmo1) 21 followed by flash column chromatography over silica gel (230-400 mesh) 22 using S% ethyl acetate in hexane as the eluent, the title compound was 23 obtained as an oil (0.066g, 62%).
24 'H NMR (300 MHz, CDC13): 8 7.33 (d, 1H, J= 2.2Hz), 7.15 (d, 1H, J=
2S l.6Hz), 2.99 (s, 1H), 2.59 (q, 2H, J= 7.6Hz), 1.84 (s, 2H), 1.37 (s, 6H), 1.35 26 (s, 6H), 1.19 (t, 3H, J= 7.6Hz).
27 ~4-~8-Ether 2 4 4-tetramethvl-chroman-6-yl-ethynyl) phen~] acetic acid 28 meth,1~ (Compound S5, General Formula 8) 1 Following general procedure F and using 8-ethyl-6-ethynyl-2,2,4,4-2 tetramethylchroman (Intermediate 48, 0.0338, 0.136mmol), methyl-4-iodo 3 phenyl acetate (Reagent B, 0.0348, 0.12mmol), triethyl amine (2mL), 4 tetrahydrofuran (2mL), copper(I)iodide (0.0258, 0.13mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.0758, 0.1 lmmol) the title 6 compound was obtained (0.0358, 73%).
7 1H NMR (300 MHz, CDC13): 8 7.49 (d, 2H, J= 7.9Hz), 7.35 (d, 1H, J=
8 l.BHz), 7.26 (d, 2H, J= 7.9Hz), 7.18 (d, 1H, J= l.9Hz), 3.72 (s, 3H), 3.65 (s, 9 2H), 2.61 (q, 2H, J= 7.SHz), 1.85 (s, 2H), 1.38 (s, 12H), 1.21 (t, 3H, J=
7.SHz).
11 [4-(8-Ethyl-2~2 4 4-tetrameth~-chroman-6-xl-ethyn~) phenyl] acetic acid 12 (Compound 56, General Formula 8) 13 Following general procedure L and using [4-(8-ethyl-2,2,4,4-14 tetramethyl-chroman-6-ylethynyl) phenyl] acetic acid methyl ester (Compound 55, 0.0358, O.lmmol), SmL of methanol and 1M sodium 16 hydroxide solution (1mL) followed by preparative reverse phase HPLC using 17 10% water in acetonitrile as the mobile phase, the title compound was 18 obtained as a solid (0.118, 25%).
19 1H NMR (300 MHz, CDC13): 8 7.48 (d, 2H, J= 8.OHz), 7.33 (d, 1H, J=
l.9Hz), 7.25 (d, 2H, J= B.OHz), 7.15 (d, 1H, J= l.9Hz), 3.65 (s, 2H), 2.59 (q, 21 2H, J= 7.SHz), 1.83 (s, 2H), 1.35 (s, 12H), 1.18 (t, 3H, J= 7.4Hz).
22 Sairo[2H 1-benzop~-2 1'-cyclopropane]-6-carboxylic acid, 8-c~prop~
23 3,4-dihydro-4,4-dimethyl- (Intermediate 49) 24 Following general procedure R and using 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H I-benzopyran-2,1'-cyclopropane]
26 (Intermediate 42, 0.458, 1.48mmol), anhydrous tetrahydrofuran (SmL), 1.7M
27 solution of tent-butyl lithium solution in pentane ( 1.74mL, 2.96mmo1) and 28 carbon dioxide generated from dry ice, followed by flash column 29 chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in 1 hexane as the eluent, the title compound was obtained as a white solid (0.34g, 2 85%).
3 1H NMR (300 MHz, CDCl3): 8 12.43 (br s, 1H), 7.94 (d, 1H, J= 2.lHz), 7.42 4 (d, 1H, J= l.BHz), 2.06-1.96 (m, 1H), 1.92 (s, 2H), 1.42 (s, 6H), 1.12-0.97 (m, 2H), 0.95-0.81 (m, 2H), 0.77-0.60 (m, 4H).
6 Spiro[2H 1-benzopyran-2~1'-cyclopronane~-6-carboxylic acid, 8-cyclopropyl-7 3 4-dihXdro-4~4-dimeth ~~1- 4-(tart-butoxxcarbon 1Y meth~lphenyl ester 8 (Compound 57, General Formula 1) 9 A solution of spiro[2H 1-benzopyran-2,1'-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, 0.06g, 11 0.22mmol) in anhydrous dichloromethane (SmL) was treated with test-butyl-4-12 hydroxy phenyl acetate (Reagent E, O.OSg, 0.22mmo1) followed by 1-(3-13 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.22mmo1) 14 and 4-dimethylaminopyridine (0.028g, 0.22mmo1). The resulting solution was stirred at ambient temperature overnight. The reaction mixture was subj acted 16 to flash column chromatography over silica gel (230-400 mesh) using 7%
17 ethyl acetate in hexane as the eluent to afford the title compound as a clear oil 18 that solidified on standing (0.048g, 48%).
19 1H NMR (300 MHz, CDC13): 8 7.91 (d, 1H, J= 2.lHz), 7.41 (d, 1H, J=
l.BHz), 7.24 (d, 2H, J= 8.8Hz), 7.05 (d, 2H, J= 8.SHz), 3.46 (s, 2H), 1.97-21 1.90 (m, 1H), 1.87 (s, 2H), 1.37 (s, 9H), 1.36 (s, 6H), 1.04-0.90 (m, 2H), 0.87-22 0.75 (m, 2H), 0.65-0.56 (m, 4H).
23 Spiro[2H 1-benzop rr~2 1'-c~propane]-6-carbox~ic acid, 8-c~loprop ~~l-24 3,4-dihydro-4,4-dimeth~l~ 4-(carboxymeth~lphenyl ester (Compound 58, General Formula 1) 26 A solution of spiro[2H 1-benzopyran-2,1'-cyclopropane]-6-carboxylic 27 acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 4-(te~t-28 butoxycarbonylmethyl)phenyl ester (Compound 57, 0.048g, O.lO5mmo1) was 29 treated with 2mL of trifluoroacetic acid and stirred at ambient temperature for 1 2h. The trifluoroacetic acid was distilled off under reduced pressure and the 2 residue was subjected to preparative reverse phase HPLC using 10% water in 3 acetonitrile as the mobile phase to afford the title compound as a white solid 4 (0.029g, 55%).
1H NMR (300 MHz, CDC13): 8 7.99 (d, 1H, J= 2.2Hz), 7.48 (d, 1H, J=
6 1.9Hz), 7.34 (d, 2H, J= 8.5Hz), 7.16 (d, 2H, J= 8.5Hz), 3.67 (s, 2H), 2.07-7 1.97 (m, 1H), 1.95 (s, 2H), 1.44 (s, 6H), 1.09-1.04 (m, 2H), 0.93-0.85 (m, 2H), 8 0.79-0.64 (m, 4H).
9 S i~ro[2H 1-benzopyran-2 1'-c~propane]-6-carboxylic acid, 8-c~clopropyl-3 4-dihydro-4 4-dimeth ~~l-, 3-(tent-butox~carbonylmeth~llphen 1~~ ester 11 (Compound 59, General Formula 1) 12 A solution of spiro[2H 1-benzopyran-2, I'-cyclopropane]-6-carboxylic 13 acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl- (Intermediate 49, O.OSg, 14 0.18mmo1) in anhydrous dichloromethane (SmL) was treated with tent-butyl-3-hydroxy phenyl acetate (Reagent F, 0.04g, 0.18mmo1) followed by 1-(3-16 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.029g, O.lmmol) 17 and 4-dimethylaminopyridine (0.022g, 0. l8mmol). The resulting solution was 18 stirred at ambient temperature overnight. The reaction mixture was subj ected 19 to flash column chromatography over silica gel (230-400 mesh) using 7%
ethyl acetate in hexane as the eluent to afford the title compound as a clear oil 21 that solidified on standing (0.020g, 23%).
22 1H NMR (300 MHz, CDC13): 8 7.98 (d, 1H, J= l.9Hz), 7.48 (d, 1H, J=
23 2.2Hz), 7.38 (t, 1H, J= 7.7Hz), 7.19-7.11 (m, 3H), 3.68 (s, 2H), 2.05-1.94 (m, 24 1H), 1.95 (s, 2H), 1.44 (s, 15H), 1.09-1.04 (m, 2H), 0.96-0.82 (m, 2H), 0.73-0.64 (m, 4H).
26 Spirof2H 1-benzop rah_n-2,1'-c~propane]-6-carboxylic acid, 8-c~cloprop ~~1-27 3,4-dih dro-4,4-dimethyl-, 3-(carboxymethyl)phen 1',~ ester (Compound 60, 28 General Formula 1) 1 A solution of spiro[2H 1-benzopyran-2,1'-cyclopropane]-6-carboxylic 2 acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 3-(te~t-3 butoxycarbonylmethyl)phenyl ester (Compound 59, 0.0208, 0.04mmol) was 4 treated with 2mL of trifluoroacetic acid and stirred at ambient temperature for - 2h. The trifluoroacetic acid was distilled off under reduced pressure and the 6 residue was subjected to preparative reverse phase HPLC using 10% water in 7 acetonitrile as the mobile phase to afford the title compound as a white solid 8 (0.01258, 62%).
9 1H NMR (300 MHz, CDC13): ~ 7.99 (d, 1H, J= 2.lHz), 7.49 (d, 1H, J=
2.lHz), 7.36 (t, 1H, J= 7.8Hz), 7.18-7.08 (m, 3H), 3.56 (s, ZH), 2.06-1.95 (m, 11 1H), 1.95 (s, 2H), 1.45 (s, 6H), 1.09-1.05 (m, 2H), 0.96-0.84 (m, 2H), 0.74-12 0.65 (m, 4H).
13 6-Bromo-4 4-dimeth~ 2 3 4-tetrah d~quinoline-1-carbaldeh~
14 (Intermediate 50) A solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydroquinoline, 16 available in accordance with United States Patent No. 5,089,509, the 17 specification of which is incorporated herein by reference (1.88, 7.5mmol) in 18 lOmL of formic acid was refluxed for 3h. The reaction mixture was then 19 cooled to ambient temperature and poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with diethyl ether (x2). The 21 combined organic phase was dried over anhydrous sodium sulfate, filtered and 22 evaporated in vacuo to a residue which was subjected to flash column 23 chromatography over silica gel (230-400 mesh) using 15-25% ethyl acetate in 24 hexane as the eluent to afford the title compound as a pale yellow solid (1.88, 90%).
26 iH NMR (300 MHz, CDC13): b 8.71 (s, 1H), 7.45 (d, 1H, J= 2.2Hz), 7.28 (dd, 27 1H, J= 2.2, 8.5Hz), 6.98 (d, 1H, J= 8.5Hz), 3.78 (t, 2H, J= 6.3Hz), 1.74 (t, 28 2H, J= 6.3Hz), 1.28 (s, 6H).
1 6-Bromo-1-c~clopropyl-4 4-dimethXl-1 2 3 4-tetrahydroauinoline 2 (Intermediate 51) 3 A stirred, cooled (0°C) solution of 6-bromo-4,4-dimethyl-1,2,3,4-4 tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7mmol) in anhydrous tetrahydrofuran (20mL) under argon was treated with titanium 6 tetra-iso-propoxide (2.15mL, 7.39mmo1) followed by 3M solution of ethyl 7 magnesium bromide in diethyl ether (5.6mL, 16.8mmol) and the reaction 8 mixture was then heated at 50°C overnight. It was then cooled in an ice-bath, 9 quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous 11 sodium sulfate, filtered over celite and evaporated in vacuo to residue which 12 was subjected to flash column chromatography over silica gel (230-400 mesh) 13 using 5% ethyl acetate in hexane as the eluent to afford the title compound as 14 an oil (1.2g, 64%).
1H NMR (300 MHz, CDC13): 8 7.24 (d, 1H, J= 2.SHz), 7.12 (dd, 1H, J= 2.2, 16 8.8Hz), 7.01 (d, 1H, J= 8.8Hz), 3.20 (t, 2H, J= 6.OHz), 2.27-2.20 (m, 1H), 17 1.68 (t, 2H, J= 5.9Hz), 1.24 (s, 3H), 1.23 (s, 3H), 0.83-0.77 (m, 2H), 0.60-18 0.55 (m, 2H).
19 1-C.~lopro~~l-6-trimethylsilanyleth~.~,4-dimeth~,2.3,4-tetrah~dro-eluinoline (Intermediate 52) 21 Following general procedure D and using 6-bromo-1-cyclopropyl-4,4-22 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8g, 2.86mmo1), 23 (trimethylsilyl)acetylene (SmL, 35mmo1), triethyl amine (lOmL), anhydrous 24 tetrahydrofuran, copper(I)iodide (0.080g, 0.42mmo1) and dichlorobis(triphenylphosphine)palladium(II) (0.240g, 0.34mmo1), the title 26 compound was obtained as an oil (0.678, 79%).
27 'H NMR (300 MHz, CDC13): 8 7.33 (d, 1H, J= l.BHz), 7.22 (dd, 1H, J= 2.1, 28 8.SHz), 7.06 (d, 1H, J= B.SHz), 3.27 (t, 2H, J= 5.9Hz), 2.37-2.31 (m, 1H), 1 1.70 (t, 2H, J= 6.OHz), 1.28 (s, 6H), 0.89-0.82 (m, 2H), 0.66-0.60 (m, 2H), 2 0.28 (s, 9H).
3 1-C~pro~yl-6-ethynyl-4 4-dimeth~-1 2 3L4-tetrahydroauinoline:
4 (Intermediate 53) Following general procedure E and using 1-cyclopropyl-6-6 trimethylsilanylethynyl-4,4-dimethyl-1,2,3,4-tetrahydroquinoline 7 (Intermediate 52, 0.40g, 1.34mmol), methanol and potassium carbonate 8 (0.2g, 1.47mmol) followed by flash column chromatography over silica gel 9 (230-400 mesh) using 2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.17g, 56%).
11 1H NMR (300 MHz, CDC13): 8 7.38 (d, 1H, J= 2.lHz), 7.27 (dd, 1H, J= 2.1, 12 8.5Hz), 7.11 (d, 1H, J= 8.5Hz), 3.30 (t, 2H, J= 6.OHz), 3.02 (s, 1H), 2.40-13 2.34 (m, 1H), 1.74 (t, 2H, J= 6.OHz), 1.30 (s, 6H), 0.93-0.85 (m, 2H), 0.70-14 0.63 (m, 2H).
4-(1-C cly opro~yl~4,4-dimeth~~2 3 4-tetrah d~quinolin-6-yl-ethynyl)-16 benzoic acid eth. l ester (Compound 61, General Formula 7) 17 Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-18 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.118, 0.43mmo1), 19 ethyl-4-iodo-benzoate (Reagent A, 0.11g, 0.9mmo1), triethyl amine (3mL), tetrahydrofuran(3mL), copper(I)iodide(0.02g, O.lmmol) and 21 dichlorobis(triphenylphosphine)palladium(II) (0.060g, 0.085mmol) followed 22 by flash column chromatography over silica gel (230-400 mesh) using 5-10%
23 ethyl acetate in hexane as the eluent, the title compound was obtained (0.05g, 24 31%).
'H NMR (300 MHz, CDC13): 8 7.99 (d, 2H, J= 8.2Hz), 7.54 (d, 2H, J=
26 8.2Hz), 7.37 (d, 1H, J= 2.lHz), 7.26 (dd, 1H, J= 2.1, 8.5Hz), 7.10 (d, 1H, J=
27 8.8Hz), 4.37 (q, 2H, J= 7.lHz), 3.28 (t, 2H, J= 6.OHz), 2.40-2.33 (m, 1H), 28 1.71 (t, 2H, J= 5.8Hz), 1.40 (t, 3H, J= 7.OHz), 1.27 (s, 6H), 0.94-0.82 (m, 29 2H), 0.65-0.60 (m, 2H).
1 4 (1 C cl~prop~,4-dimethyl-1 2 3 4-tetrah~droquinolin-6-yl-ethynyll-2 benzoic acid (Compound 62, General Formula 7) 3 Following general procedure L and using 4-(1-cyclopropyl-4,4-4 dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester (Compound 61, O.OSg, 0.13mmo1), SmL of ethanol and SM sodium hydroxide 6 solution (2mL) followed by recrystallization fiom hot ethyl acetate, the title 7 compound was obtained as a solid (0.0308, 64%).
8 'H NMR (300 MHz, DMSO-d6): b 7.92 (d, 2H, J= 8.2Hz), 7.57 (d, 2H, J=
9 8.2Hz), 7.33 (d, 1H, J= l.9Hz), 7.23 (dd, 1H, J= 1.9, B.SHz), 7.06 (d, 1H, J=
8.8Hz), 3.25 (t, 2H, J= 5.8Hz), 2.41-2.34 (m, 1H), 1.64 (t, 2H, J= 5.6Hz), 11 1.21 (s, 6H), 0.87-0.81 (m, 2H), 0.59-0.54 (m, 2H).
12 j4-(1-Cyclopropyl-4 4-dimethyl-1 2 3 4-tetrah d~quinolin-6-13 eth ~nvl)phenyl] acetic acid meth l~ ester (Compound 63, General Formula 14 7) Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-16 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, O.OSg, 0.22mmol), 17 methyl-4-iodo-phenyl acetate (Reagent B, O.OSSg, 0.2mmo1), triethyl amine 18 (SmL), tetrahydrofuran, copper(I)iodide(0.025g, 0.13mmo1) and 19 dichlorobis(triphenylphosphine)palladium(II) (0.758, 0.llmmol) followed preparative normal phase HPLC using 10 % ethyl acetate in hexane as the 21 mobile phase, the title compound was obtained (0.0898, 100%).
22 'H NMR (300 MHz, CDCl3): b 7.47 (d, 2H, J= 8.8Hz), 7.45 (d, 1H, J=
23 l.BHz), 7.35-7.22 (m, 2H), 7.10 (d, 2H, J= 8.8Hz), 3.70 (s, 3H), 3.63 (s, 2H), 24 3 .27 (t, 2H, J = 6.OHz), 2.3 7-2.31 (m, 1 H), 1.71 (t, 2H, J = 6.OHz), 1.27 (s, 6H), 0.89-0.81 (m, 2H), 0.65-0.60 (m, 2H).
26 [4=(1-C~clopropyl-4 4-dimeth~ 2 3 4-tetrahydro-quinolin-6-~yn~l-2-27 fluoro ~hen,~~l] acetic acid eth,~ster (Compound 64, General Formula 7) 28 Following general procedure F and using 1-cyclopropyl-6-ethynyl-4,4-29 dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 53, 0.118, 0.49mmo1), 1 ethyl-2-fluoro-4-iodo-phenyl acetate (Reagent C, 0.11 g, 0.9mmo1), triethyl 2 amine (3mL), tetrahydrofuran(3mL), copper(I)iodide(0.06g, 0.32mmol) and 3 dichlorobis(triphenylphosphine)palladium(II) (0.258, 0.36mmo1) followed by 4 flash column chromatography over silica gel (230-400 mesh) using 10 % ethyl acetate in hexane as the eluent, the title compound was obtained (0.1 g, 51 %).
6 IH NMR (300 MHz, CDCl3): 8 7.34 (d, 1H, J= 2.lHz), 7.25-7.17 (m, 3H), 7 7.09 (d, 2H, J= 8.8Hz), 4.17 (q, 2H, J= 7.lHz), 3.65 (s, 2H), 3.27 (t, 2H, J=
8 6.OHz), 2.38-2.31 (m, 1H), 1.69 (t, 2H, J= 6.OHz), 1.27 (s, 6H), 1.25 (t, 3H, J
9 = 7.lHz), 0.88-0.81 (m, 2H), 0.65-0.59 (m, 2H).
N-(4-Bromophen~l-N-methyl-3-methyl-2-butenamide (Intermediate 54) 11 3,3-Dimethylacryloyl chloride (3mL, 27mmo1) was added to a solution 12 of 4-bromo-N-methyl-aniline (4.55g, 25mmo1) in 150mL of dichloromethane 13 followed after 5 minutes by triethyl amine (SmL, 33mmol). After 2.5h at 14 ambient temperature, the reaction mixture was washed with water and the organic phase was dried over anhydrous sodium sulfate and evaporated in 16 vacuo to afford the title product as a brown oil in quantitative yield.
17 'H-NMR (300 MHz, CDC13): d 1.71 (s, 3H), 2.11(s, 3H), 3.28(s, 3H), 5.47(s, 1 ~ 1H), 7.05(d, J = 8.5Hz, 2H), 7.50(d; J = 8.2Hz, 2H).
19 6-Bromo-1,4,4-trimethyl-2-oxo-1,2,3,4-tetrah~quinoline (Intermediate 55) N-(4-bromophenyl)-N-methyl-3-methyl-2-butenamide 21 (Intermediate 54, 6.428, 24mmo1) was heated to 130°C and aluminum 22 chloride (5g, 37.4mmol) was added in portions over 0.5h. The reaction 23 mixture was stirred for 1 hour at the same temperature and then cooled to 24 room temperature. Ice was added cautiously to the solid, followed by ~200mL
of iced water. The reaction mixture was then extracted with ether (x2) and 26 dichloromethane (x1) and the combined organic phase was dried over 27 anhydrous magnesium sulfate and evaporated in vacuo to yield a brown solid.
28 The solid was treated with hexane-dichloromethane and filtered to afford 1.7g 29 of product. The mother liquor was evaporated and purified by flash column 1 chromatography on silica gel (230-400 mesh) to afford 2.9g of the title 2 compound as a solid (total 72%).
3 1H-NMR (300 MHz, CDC13): 81.29(s, 6H), 2.49(s, 2H), 3.36(s, 3H), 6.87(d, J
4 = 8.2Hz, 1H), 7.36(dd, J = 2.0, 8.SHz, 1H), 7.39(d, J = 2.OHz, 1H).
6-Bromo-1 4 4-trimethylspiro[2H I-I 2 3 4-tetrahydroquinoline-2,1'-6 c~propanel (Intermediate 56) 7 A stirred, cooled (-78°C) 3M solution of ethyl magnesium bromide in 8 ether (8.lmL, 24.25mmol) under argon was treated with anhydrous 9 tetrahydrofuran (20mL) followed by a solution of titanium tetra-iso-propoxide (3.15mL, 10.2mmo1) in tetrahydrofuran (lOmL). A solution of 6-bromo-I,4,4-11 trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (Intermediate 55, 2.6g, 12 9.7mmo1) was cannulated into the reaction mixture and the solution was 13 allowed to warm to room temperature overnight. It was then cooled in an ice-14 bath, quenched with saturated aqueous ammonium chloride solution, filtered over celite and the aqueous phase was extracted with diethyl ether (x2). The 16 combined organic phase was dried over anhydrous magnesium sulfate, filtered 17 and evaporated in vacuo to afford an orange oil. Flash column 18 chromatography over silica gel (230-400 mesh) using 2-4% ethyl acetate in 19 hexane as the eluent afforded the title compound as an oil which was ~70%
pure (1.7g, 63%) and O.Sg of recovered starting material.
21 1H-NMR (300 MHz, CDCl3): 8 0.58(t, J= 6.OHz, 2H), 0.91(t, J= 6.OHz, 2H), 22 1.35 (s, 6H), 1.70(s, 2H), 2.68 (s, 3H), 6.59 (d, J= 8.8Hz, 1H), 7.16(dd, J=
23 2.3, 8.8Hz, 1H), 7.33(d, J= 2.3Hz, 1H).
24 1,4,4-TrimethXl-6-(trimeth, ls~~ eth~~piro[2H 1-1,2,3,4-tetrahydxoquinoline-2x1'-cyclopropanel (Intermediate 57) 26 Following general procedure D and using 6-bromo-1,4,4-27 trimethylspiro[2H 1-1,2,3,4-tetrahydroquinoline-2,1'-cyclopropane]
28 (Intermediate 56, 0.56g, 2mmol), (trimethylsilyl)acetylene (1.13mL, 8mmol), 29 triethyl amine (4mL), anhydrous tetrahydrofuran (SmL), copper(I)iodide 1 (0.088, 0.4mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.288, 2 0.4mmo1), followed by flash column chromatography over silica gel (230-400 3 mesh) using hexane-2% ethyl acetate in hexane as the eluent, the title 4 compound was obtained as an oil (0.428, 70%).
'H NMR (300 MHz, CDCl3): 8 0.023(s, 9H), 0.33(t, J= 6.lHz, 2H), 0.71(t, J
6 = 6.lHz, 2H), 1.10(s, 6H), 1.45(s, 2H), 2.41 (s, 3H), 6.31(d, J= B.SHz, 1H), 7 6.96 (dd, J= 2.1, 8.SHz, 1H), 7.10(d, J= 2.lHz, 1H).
8 Benzoic acid 4-[~1 4 4-trimeth lspiro[2H 1-1 2 3 4-tetrah~~uinoline-2 1'-9 c~lopropane]-6-ylleth ~n~]-eth 1 ester (Compound 65, General Formula 1) Following general procedure E and using a solution of 1,4,4-trimethyl-11 6-(trimethylsilanyl)ethynylspiro[2H 1-1,2,3,4-tetrahydroquinoline-2,1'-12 cyclopropane] (Intermediate 57, 0.4168, l.4mmol), methanol (lOmL), ethyl 13 acetate (2mL) and potassium carbonate (1.088, mmol) a silyl deprotected 14 acetylenic intermediate was obtained which was used directly for the next step (0.258, 79%). Following general procedure F and using part of the acetylenic 16 intermediate obtained as above (0.118, O.Smmol), ethyl-4-iodo benzoate 17 (Reagent A, 0.1128, 0.4mmo1), triethyl amine (1mL), tetrahydrofuran 18 (2.SmL), copper(I)iodide (0.0508, 0.26mmo1) and 19 tetrakis(triphenylphosphine)palladium(0)(0.096g, 0.17mmo1) followed by flash column chromatography over silica gel (230-400 mesh) using 8% ethyl 2I acetate in hexane as the eluent and preparative HPLC on Partisil 10 silica 22 column using 10% ethyl acetate in hexane as the mobile phase, the title 23 compound was obtained as a yellow oil (0.0488, 26%).
24 1H-NMR (300 MHz, CDC13): 8 0.60 (t, J= 6.lHz, 2H), 0.99(t, J= 6.lHz, 2H), 1.37(s, 6H), I.42(t, J= 7.OHz, 3H), 1.73(s, 2H), 2.68(s, 3H), 4.40 (q, J =
26 7.OHz, ZH), 6.61(d, J = 8.8Hz, 1H), 7.28 (dd, J = 2.1, B.SHz, 1H), 7.42 (d, J =
27 2.1 Hz, 1 H), 7.57(d, J = 8.2Hz, 2H), 8.0I (d, J = 8.2Hz, 2H).
28 Benzoic acid, 4-[(1,4,4-trimeth lspiro[2H 1-1,2,3,4-tetrah~quinoline-2,I'-29 c.~pronane~ 6-, l~leth nv vllT (Compound 66, General Formula 1) 1 Following general procedure I and using benzoic acid, 4-[(1,4,4-2 trimethylspiro[2H 1-1,2,3,4-tetrahydroqunoline-2,1'-cyclopropane]-6-3 yl)ethynyl]-ethyl ester (Compound 65, 0.03g, 0.08mmo1), ethanol (2mL), 4 tetrahydrofuran (2mL) and 1M aqueous sodium hydroxide solution (1mL), the title compound was obtained as a yellow solid (0.020g, 67%).
6 1H-NMR (300 MHz, CD3COCD3): 8 0.60 (t, J= 5.8Hz, 2H), 1.03(t, J= 5.8Hz, 7 2H), 1.34(s, 6H), 1.74(s, 2H), 2.69(s, 3H), 6.60(d, J = 8.SHz, 1H), 7.23 (dd, J
8 = 2.0, 8.4Hz, 1H), 7.39 (d, J = 2.OHz, 1H), 7.58(d, J = 8.2Hz, 2H), 8.01(d, J
9 = 8.2Hz, 2H).
Esterification Methods:
11 Method A:
12 The carboxylic acid was combined with a solution of the desired 13 alcohol and concentrated sulfuric acid (20 to 1 v/v) and the resulting mixture 14 or solution (0.75 to 1.0 M) heated to reflux overnight. The solution was cooled to room temperature, diluted with Et~O, and washed with H20, 16 saturated aqueous NaHC03, and saturated aqueous NaCl before being dried 17 over MgS04. Concentration of the dry solution under reduced pressure 18 afforded the desired carboxylic ester of sufficient purity to be used directly in 19 the next reaction.
Method i3:
21 To a solution (0.67 to l .OM) of the carboxylic acid in acetone was 22 added 1.1 equivalents of the desired alkyl halide and 1.0 equivalents of solid 23 potassium carbonate. The resulting mixture was heated to reflux for 2h and 24 then allowed to stir at room temperature overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The product was isolated 26 from the residue by column chromatography using silica gel as the solid phase.
27 Method C:
28 A solution (1M) of the carboxylic acid in thionyl chloride was heated at 1 reflux until analysis of a reaction aliquot by IR spectroscopy showed the 2 absence of the aryl carboxylic acid carbonyl band ( 1705 - 1680 cm 1). The 3 solution was cooled to room temperature and concentrated under reduced 4 pressure to give the crude acyl chloride.
The acyl chloride was dissolved in CHZC12 and the resulting solution 6 (0.5 to 0.75M) treated with 1.1 equivalents the desired alcohol and 2.0 7 equivalents of pyridine. After stirring overnight at room temperature the 8 solution was diluted with Et~O and washed with H20, 10% aqueous HCl, 9 saturated aqueous NaHC03, and saturated aqueous NaCl before being dried over NaZS04. Concentration of the dry solution under reduced pressure 11 followed by column chromatography afforded the desired ester.
12 GENERAL PROCEDURE l .(preparation of Enol ethers):
13 A solution (0.35 M) of the aryl ester in anhydrous THF was cooled to 0 14 °C and treated with 1.0 equivalents of Tebbe's Reagent ([~,-chloro-~-methylene[bis(cyclopentadieny))titanium]-dimethylaluminum] 0.5 M in 16 toluene). After 30 minutes the solution was warmed to room temperature and 17 stirred for 30 minutes before being carefully added to a 0.1 N NaOH
solution 18 at 0 °C. This mixture was treated with hexanes and the solids removed by 19 filtration through a pad of Celite. The solids were washed with hexanes and the filtrate passed through a second pad of Celite to remove any newly formed 21 solids. The organic layer was dried (Na2S04) and concentrated under reduced 22 pressure. The desired enol ether was isolated from the residue by column 23 chromatography using 1-2% of Et3N added to the eluant. (note: prolonged 24 exposure of the product to the column can result in hydrolysis and formation of the corresponding methyl ketone.) 26 GENERAL PROCEDURE 2 (cyclopropanation of the enol ethers):
27 To a solution (0.3 M) of the enol ether in anhydrous Et20 was added 28 2.0 equivalent of Et2Zn (as a solution in hexanes) and 2.0 equivalents of CHZTZ.
1 The resulting solution was heated to reflux until analysis of a reaction aliquot 2 (by TLC or 1H NMR) indicated that all of the starting enol ether had been 3 consumed. (note: Additional equal amounts of EtzZn and CH2I2 can be added 4 to drive the reaction to completion.) Upon cooling to room temperature the reaction was carefully quenched by the addition of saturated aqueous NH4Cl.
6 The resulting mixture is extracted with Et20 and the combined organic layers 7 washed with HBO and saturated aqueous NaCl before being dried over Na2S04 8 and concentrated under reduced pressure. The product is isolated from the 9 residue by column chromatography.
1-Bromo-4-(1-methoxyvin~)-benzene: (Intermediate 58) 11 Using General Procedure 1; methyl 4-bromo-benzoate (600.0 mg, 2.78 12 mmols), and 5.6 mL of Tebbe's Reagent (794.0 mg, 2.78 mmols) afforded 13 420.0 mg (70%) of the title compound as a colorless oil after column 14 chromatography (100% hexanes).
1H NMR (CDCl3) 8: 7.48 - 7.45 (4H, m), 4.64 (1H, d, J = 2.9 Hz), 4.23 (1H, d, 16 J = 2.9 Hz), 3.73 (3H, s).
17 1-Bromo-4-(1-methoxycycloprop, l~l~benzene (Intermediate 59) 18 Using General Procedure 2; 1-bromo-4-( 1-methoxyvinyl)-benzene 19 (Intermediate 58, 410. 0 mg, 1.92 mmols), EtzZn (711.3 mg, 5.76 mmols), and CHaI2 (1.54 g, 5.76 mmols) in 4.0 mL Et20 afforded 300.0 mg (69%) of 21 the title compound as a colorless oil after chromatography (0-3% EtOAc -22 hexanes).
23 1H NMR (CDC13) 8: 7,46 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 3.21 24 (3H, s), 1.19 (2H, m), 0.94 (2H, m).
f4-(1-Methoxyc~cloprou~)-phen~h~yl]-trimeth ls~ ilane (Intermediate 26 60) 27 Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-28 benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and 1 anhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide (93.0 mg, 2 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl 3 acetylene (1.39 g, 14.2 mmols) was then added followed by 4 dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The S resulting reaction mixture was heated to 70 °C for 60h. The title compound 6 (286.0 mg, 90%) was isolated by chromatography (0 - 3% EtOAc - hexanes).
7 'H NMR (CDC13) ~: 7.35 (2H, d, J = 7.2 Hz), 7.14 (2H, d, J = 7.2 Hz), 3.14 8 (3H, s), 1.14 (2H, m), 0.88 (2H, m), 0.17 (9H, s).
9 1-Ethynyl-4-( 1-methox~~clopropyl)-benzene (Intermediate 61) Using General Procedure E; [4-(1-methoxycyclopropyl)-11 phenylethynyl]-trimethylsilane (Intermediate 60, 285.0 mg, 1.18 mmols) in 12 methanol (lOmL) was treated with potassium carbonate (I00.0 mg, 0.72 13 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 14 mg, 100%) was used directly in the next reaction.
1H NMR (CDC13) 8: 7.46 (2H, d, J = 8.2 Hz), 7.24 (2H, d, J = 8.2 Hz), 3.23 16 (3H, s), 3.06 (1H, s), 1.22 (2H, m), 0.98 (2H, m).
17 Ether 4-[4-(1-methox~~prop~)-phenyleth~~]-benzoate (Compound 67, 18 General Formula 2) 19 Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate 21 (Reagent A, 141.0 mg, O.S 1 mmol) in triethyl amine (6 mL) was treated with 22 copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon fox S minutes.
23 Dichlorobis(triphenylphosphine)palladium(II) ( 109 mg, 0.16 mmol) was added 24 and the reaction mixture was stirred overnight at zoom temperature. Column 2S chromatography (2-S% EtOAc - hexanes) afforded 135.0 mg (90%) of the title 26 compound as an orange solid.
27 'H NMR (CDCl3) 8: 8.02 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.52 28 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.8 Hz), 4.39 (2H, q, J = 7.1 Hz), 3.25 1 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.23 (2H, m), 1.00 (2H, m).
~nyll-phenyll -acetate 2 Methyl 14 f 4 ( 1 methoxycyclopropyl)-phen 3 (Compound 68, General Formula 2) 4 Using General Procedure F; 1-ethynyl-4-( 1-methoxycyclopropyl)-benzene (Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodophenyl)-6 acetate (Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was 7 treated with copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 8 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19 9 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc - hexanes) afforded 11 140.0 mg (78%) of the title compound as an orange solid.
12 'H NMR (CDC13) b: 7.50 (4H, d, J = 8.1 Hz), 7.28 (4H, d, J = 8.1 Hz), 3.76 13 (3H, s), 3.64 (2H, s), 3.25 (3H, s), 1.22 (2H, m), 0.99 (2H, m).
14 4-[4-(1-Methox~yclopropyl~phenylethynyl]-benzoic acid (Compound 69, General Formula 2) 16 Using General Procedure I; a solution of ethyl 4-[4-(1-17 methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0 mg, 18 0.34 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 19 NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 85.0 mg (86%) of the title 21 compound as an orange solid.
22 'H NMR (CDC13) ~: 8.05 (2H), 7.66 (2H), 7.56 (2H, d, J = 8.5 Hz), 7.35 (2H, 23 d, J = 8.6 Hz), 3.22 (3H, s), 1.21 (2H, m), 1.01 (2H, m).
24 ~4-[4-(1-Methox~cycl~ro~yll-phen 1y eth~nyll-phen~~acetic acid (Compound 70, General Formula 2) 26 Using General Procedure I; a solution of methyl ~4-[4-(1-27 methoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 68, 100.0 28 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 1 with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and 2 stirred overnight at room temperature. Work-up afforded 80.0 mg (84%) of 3 the title compound as an orange solid.
4 1H NMR (CDCl3) 8: 7.49 (4H), 7.27 (4H), 3.66 (2H, s), 3.25 (3H, s), 1.22 (2H, m), 0.99 (2H, m).
6 Isoprop~I 4-bromobenzoate (Intermediate 62) 7 Using General Esterification Procedure A; 4-bromobenzoic acid (1.50 8 g, 7.46 mmols) was combined with isopropyl alcohol to give 1.76 g (97%) of 9 the title compound as a colorless oil.
1H NMR (CDC13) 8: 7.90 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 11 5.24 (1H, septet, J = 6.2 Hz), 1.37 (6H, d, J = 6.2 Hz).
12 1-Bromo-4-~1-isopropoxyvinyll-benzene (Intermediate 63) 13 Using General Procedure l; isopropyl 4-bromobenzoate (Intermediate 14 62, 780.0 mg, 3.20 mmols) and 6.4 mL of Tebbe's Reagent (910.7 mg, 3.20 mmols) afforded 328.0 mg (43%) of the title compound as a colorless oil after 16 column chromatography (100% hexanes).
17 1H NMR (CDC13) 8: 7.46 (4H, m), 4.66 (1H, d, J = 2.6 Hz), 4.40 (1H, septet, J
18 = 6.2 Hz), 4.21 (1H, d, J = 2.6 Hz), 1.34 (6H, d, J = 6.2 Hz).
19 1-Bromo-4 ~1-isopropox cy yclopro~yl~benzene (Intermediate 64) Using General Procedure 2; 1-bromo-4-(1-isopropoxyvinyl)-benzene 21 (Intermediate 63, 328. 0 mg, 1.36 mmols), Et2Zn (335.9 mg, 2.72 mmols), 22 and CHzI2 (728.0 mg, 2.72 mmols) in 4.0 mL Et20 afforded 240.0 mg (70%) 23 of the title compound as a colorless oil after chromatography (3% EtOAc 24 hexanes).
'H NMR (CDC13) 8: 7.43 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 3.70 26 (1H, septet, J = 6.2 Hz), 1.18 (2H, m), 1.06 (6H, d, J = 6.2 Hz), 0.91 (2H, m).
27 ~~1-Isopropox c~ycloprop~l~phenyleth~n~]-trimeth~lsilane (Intermediate 28 65) 1 Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-2 benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) was 3 treated with copper(I)iodide ( 18.0 mg, 0.094 mmol) and then sparged with 4 argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 6 0.094 mmol). The resulting reaction mixture was heated to 70 °C for 5 days.
7 The title compound (250.0 mg, 98%) was isolated by chromatography (0 - 3%
8 EtOAc - hexanes) as an orange oil.
9 'H NMR (CDCI~) 8: 7.41 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 7.9 Hz), 3.70 ( 1 H, septet, J = 6.2 Hz), 1.18 (2H, m), 1.05 (6H, d, J = 6.2 Hz), 0.93 (2H, m), 11 0.94 (9H, s).
12 1-Eth~~-4-~(1-iso~ropox~~prop~l-benzene (Intermediate 66) 13 Using General Procedure E; [4-(1-isopropoxycyclopropyl)-14 phenylethynyl]-trimethylsilane (Intermediate 65, 260.0 mg, 0.96 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 16 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 17 mg, 100%) was used directly in the next reaction.
18 1H NMR (CDCl3) 8: 7.45 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8 Hz), 3.72 19 ( 1 H, septet, J = 6.2 Hz), 3.06 ( 1 H, s), 1.20 (2H, m), 1.07 (6H, d, J =
6.2 Hz), 0.95 (2H, m).
21 Ethyl4-[4-(1-isopropoxycyclopropyll-~hen~ynyl]-benzoate (Compound 22 71, General Formula 2) 23 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-24 benzene (Intermediate 66, 114.0 mg, 0.57 mmol) and ethyl-4-iodo benzoate (Reagent A, 731.0 mg, 0.63 mmol) in triethylamine (8 mL) was treated with 26 copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with argon for 5 minutes.
27 Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 0.19 mmol) was added 28 and the reaction mixture was stirred overnight at room temperature. Column 1 chromatography (2-4% EtOAc - hexanes) afforded 1 S 1.0 mg (76%) of the title 2 compound as an orange solid.
3 'H NMR (CDC13) 8: 8.02 (2H, d, J = 7.6 Hz), 7.58 (2H, d, J = 7.6 Hz), 7.50 4 (2H, d, J = 7.8 Hz), 7.39 (2H, d, J = 7.8 Hz), 4:39 (2H, q, J = 7.1 Hz), 3.74 (1H, septet, J = 6.2 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.22 (2H, m), 1.08 (6H, d, J =
6 6.2 Hz), 0.97 (2H, m).
7 MethX114-[4-(1-isopropoxycyclo~ropyll-phen~yn~l-phenyll-acetate 8 (Compound 72, General Formula 2) 9 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)-11 acetate (Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated 12 with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon fox 5 13 minutes. Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16 mmol) 14 was added and the reaction mixture was stirred overnight at room temperature.
Column chromatography (2-8% EtOAc - hexanes) afforded 110.0 mg (70%) 16 of the title compound as an orange oil.
17 'H NMR (CDCl3) 8: 7.20 (4H), 7.08 (2H, d, J = 7.0 Hz), 6.97 (2H, d, J = 7.9 18 Hz), 3.45 (1H, septet, J = 6.2 Hz), 3.41 (3H, s), 3.35 (2H, s), 0.91 (2H, m), 19 0.79 (6H, d, J = 6.2 Hz), 0.68 (2H, m).
4-[4-(1-Isobropoxyc~cloprop~l-phenYleth~yl]-benzoic acid (Compound 21 73, General Formula 2) 22 Using General Procedure I; a solution of ethyl 4-[4-(1-23 isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71, 110.0 mg, 24 0.32 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred 26 overnight at room temperature. Work-up afforded 89.0 mg (88%) of the title 27 compound as a yellow solid.
28 1H NMR (CDCl3) ~: 8.06 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 7.55 1 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 3.73 (1H, septet, J = 6.2 Hz), 1.18 2 (2H, m), 1.04 (6H, d, J = 6.2 Hz), 0.99 (2H, m).
3 d4 ~j4 f 1 Iso~ropoxycyclonropyll-phenylethynyll-phenyl~-acetic acid 4 (Compound 74, General Formula 2) Using General Procedure I; a solution of methyl {4-[4-(1-6 isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetate (Compound 72, 80.0 7 mg, 0.23 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 8 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and 9 stirred overnight at room temperature. Work-up afforded 48.0 mg (56%) of the title compound as a solid.
11 'H NMR (CDC13) 8: 7.20 (2H, d, J = 8.2 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.09 12 (2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.2 Hz), 3.46 (1H, septet, J = 6.2 Hz), 3.37 13 (2H, s), 0.92 (2H, m), 0.79 (6H, d, J = 6.2 Hz), 0.67 (2H, m).
14 Benzxl 4-bromobenzoate (Intermediate 67) Using General Esterification Method B; 4-bromobenzoic acid (2.01 g, 16 10.0 mmols), benzyl bromide (1.89 g, 11.1 mmols), and KZCO3 (1.40 g, 10.0 17 mmols) afforded 2.33 g (80%) of the title compound as a colorless solid after 18 column chromatography (3-10% EtOAc - hexanes).
19 1H NMR (CDCl3) 8: 7.89 (2H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.5 Hz), 7.43 -7.31 (5H), 5.33 (2H, s).
21 1-Bromo-4-(1-benz.~xyvin~l-benzene (Intermediate 68) 22 Using General Procedure 1; benzyl 4-bromobenzoate (Intermediate 23 67, 920.0 mg, 3.16 mmols) and 6.3 mL of Tebbe's Reagent (897.0 mg, 3.16 24 mmols) afforded 640.0 mg (70%) of the title compound after column chromatography (100% hexanes).
26 1H NMR (CDCl3) 8: 7.55 - 7.35 (9H), 4.95 (2H, s), 4.73 (1H, d, J = 2.9 Hz), 27 4.34 (1H, d, J = 2.9 Hz).
28 1-Bromo-4-(1-~enz~yc~clopropyl -benzene (Intermediate 69) 1 Using General Procedure 2; 1-bromo-4-(1-benzyloxyvinyl)-benzene 2 (Intermediate 68, 280. 0 mg, 0.97 mmol), Et2Zn (247.0 mg, 2.0 mmols), and 3 CHZIZ (536.0 mg, 2.0 mmols) in 2.0 mL Et2O afforded 159.0 mg (53%) of the 4 title compound as a colorless solid after chromatography (2-5% EtOAc -hexanes).
6 1H NMR (CDC13) 8: 7.49 - 7.24 (9H), 4.41 (2H, s), 1.29 (2H, m), 1.00 (2H, 7 m).
8 [4-(1-Benzylox c~yclopro~yll-phen~~nyl]-trimethylsilane (Intermediate 9 70) Using General Procedure D; 1-bromo-4-(1-benzyloxycyclopropyl)-11 benzene (Intermediate 69, 160.0 mg, 0.53 mmol) in triethylamine (5 mL) was 12 treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with 13 argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then 14 added followed by dichlorobis-(triphenylphosphine)palladium(II) (37.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C for Sd.
The 16 title compound (150.0 mg, 83%) was isolated by chromatography (0 - 3%
17 EtOAc - hexanes) as a pale-yellow oil.
18 'H NMR (CDCl3) 8: 7.21 (3H, m), 7.09 - 7.01 (6H, m), 4.18 (2H, s), 1.07 (2H, 19 m), 0.79 (2H, m), 0.02 (9H, s).
1-Eth~.~l-4-(1-benzXlox, c~yclopropyll-benzene (Intermediate 71) 21 Using General Procedure E; [4-(1-benzyloxycyclopropyl)-22 phenylethynyl]-trimethylsilane (Intermediate 70, 150.0 mg, 0.47 mmols) in 23 methanol (6 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) 24 and stirred overnight at ambient temperature. The crude allcyne (115 mg, 100%) was used directly in the next reaction.
26 1H NMR (CDC13) 8: 7.67 - 7.50 (2H, d, J = 8.2 Hz), 7.34 - 7.26 (7H, m), 4.43 27 (2H, s), 3.07 (1H, s), 1.32 (2H, m), 1.04 (2H, m).
28 Ethyl4-~4-(1-benzXlox~cyclopro~yll-phenxlethynyl]-benzoate (Compound 1 75, General Formula 2) 2 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3 benzene (Intermediate 71, 60.0 mg, 0.24 mmol) and ethyl-4-iodo benzoate 4 (Reagent A, 72.0 mg, 0.26 mmol) in triethylamine (4 mL) was treated with copper(I)iodide (17.0 mg, 0.09 mmol) and sparged with argon for 5 minutes.
6 Dichlorobis(triphenylphosphine)palladium(II) (61 mg, 0.09 mmol) was added 7 and the reaction mixture was stirred overnight at room temperature. Column 8 chromatography (2-4% EtOAc - hexanes) afforded 85.0 mg (91 %) of the title 9 compound as an orange oil.
IH NMR (CDC13) 8: 8.03 (2H, d, J = 8.2 Hz), 7.62-7.54 (4H, m), 7.39-7.26 11 (7H, m), 4.47 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz), 1.36 12 (2H, m), 1.07 (2H, m).
13 Methyl f 4-[4-( 1-benzylox c~yclopro~~-_phen 1~~~]-phen~~ -acetate 14 (Compound 76, General Formula 2) Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-16 benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-17 acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated 18 with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 19 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature.
21 Column chromatography (2-7% EtOAc - hexanes) afforded 64.0 mg (81 %) of 22 the title compound as a yellow oil.
23 'H NMR (CDC13) ~: 7.52-7.47 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H, s), 3.70 24 (3H, s), 3.64 (2H, s), 1.32 (2H, m), 1.06 (2H, m).
4-[4-(1-Benzylox~c~prop~l-phen~yn~]-benzoic acid (Compound 77, 26 General Formula 2) 27 Using General Procedure I; a solution of ethyl 4-[4-(1-28 benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0 mg, 1 0.20 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with 2 NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred 3 overnight at room temperature. Work-up afforded 65.0 mg (89%) of the title 4 compound as a solid.
1H NMR (CDC13) 8: 7.97 (2H, d, J = 8.5 Hz), 7.67 (2H, d, J = 8.7 Hz), 7.58 6 (2H, d, J = 8.5 Hz), 7.41-7.28 (7H, m), 4.44 (2H, s), 1.33 (2H, m), 1.12 (2H, 7 m).
8 ~4-[4-(1-BenzyloxycYclo~ropyll-phenylethyn~l]-phenyl~-acetic acid 9 (Compound 78, General Formula 2) Using General Procedure I; a solution of methyl f 4-[4-(1-11 benzyloxycyclopropyl)-phenylethynyl]-phenyl-acetate (Compound 76, 45.0 12 mg, 0.11 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 13 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and 14 stirred overnight at room temperature. Work-up afforded 35.0 mg (81%) of the title compound as a pale-yellow solid.
16 1H NMR (CDC13) ~: 7.49 (4H, m), 7.37-7.25 (9H, m), 4.44 (2H, s), 3.66 (2H, 17 s), 1.32 (2H, m), 1.05 (2H, m).
18 Benzyl 4-bromo-2-methylbenzoate (Intermediate 72) 19 Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3h with 10 mL SOCl2. The 21 resulting solution concentrated under reduced pressure and the crude acyl 22 chloride was combined with benzyl alcohol (1.08 g, lO.Ommols) and pyridine 23 ( 1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up 24 and column chromatography (2-5% EtOAc - hexanes) as a colorless oil.
1H NMR (CDC13) ~: 7.81 (1H, d, J = 8.5 Hz), 7.41-7.33 (7H, m), 5.32 (2H, s), 26 2.57 (3H, s).
27 4-Bromo-1-(1-benzylox v~inyll-2-meth~benzene (Intermediate 73) 28 Using General Procedure 1; benzyl 4-bromo-2-methylbenzoate 1 (Intermediate 72, 840.0 mg, 2.77 mmols) and 5.4 mL of Tebbe's Reagent 2 (788.0 mg, 2.77 mmols) afforded 640.0 mg (76%) of the title compound after 3 column chromatography (100% hexanes).
4 1H NMR (CDC13) 8: 7.38-7.19 (8H, m), 4.88 (2H, s), 4.45 (1H, d, J = 2.6 Hz), 4.25 (2H, d, J = 2.6 Hz), 2.35 (3H, s).
6 4-Bromo-1-(1-benzXloxxcyclo~ro~yll-2-methyl-benzene (Intermediate 74) 7 Using General Procedure 2; 4-bromo-1-(1-benzyloxyvinyl)-2-methyl-8 benzene (Intermediate 73, 400. 0 mg, 1.32 mmols), Et2Zn (325.0 mg, 2.63 9 mmols), and CH2I2 (704.0 mg, 2.63 mmols) in 4 mL Et20 afforded 380.0 mg (90%) of the title compound as a colorless oil after chromatography (2-5%
I 1 EtOAc - hexanes).
12 1H NMR (CDC13) 8: 7.42-7.20 (8H, m), 4.31 (2H, s), 2.58 (3H, s), I .25 (2H, 13 m), 0.94 (2H, m).
14 [4-(1-Benzyloxycycloprop~l-3-meth ~~1-phenylethynyl]-trimeth lsy'lane (Intermediate 75) 16 Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-17 methyl-benzene (Intermediate 74, 320.0 mg, 1.00 mmol) in triethylamine (8 I 8 mL) was treated with copper(I)iodide ( 19.0 mg, 0.1 mmol) and then sparged 19 with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 21 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
22 The title compound (300.0 mg, 89%) was isolated by chromatography (0 - 2%
23 EtOAc - hexanes).
24 'H NMR (CDC13) 8: 7.34-7.13 (8H, m), 4.24 (2H, s), 2.52 (3H, s), 1.20 (2H, m), 0.88 (2H, m), 0.25 (9H, s).
26 4- Eth,~.~(1-benz~lox, c~yclopropyl)-2-methyl-benzene (Intermediate 76) 27 Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-methyl-28 phenylethynyl]-trimethylsilane (Intermediate 75, 300.0 mg, 0.95 mmols) in 1 methanol (6 mL) was treated with potassium carbonate (120.0 mg, 0.87 mmol) 2 and stirred overnight at ambient temperature. The crude alkyne (185 mg, 3 79%) was used directly in the next reaction.
4 1H NMR (CDC13) 8: 7.37-7.16 (8H, m), 4.27 (2H, s), 3.07 (1H, s), 2.55 (3H, s), 1.21 (2H, m), 0.92 (2H, m).
6 Ether[4 (1-benz~yc~propyll-T 3-meth~phenylethynyll-benzoate 7 (Compound 79, General Formula 2) 8 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-9 methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was 11 treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 12 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) 13 was added and the reaction mixture was stirred overnight at room temperature.
14 Column chromatography (2-4% EtOAc - hexanes) afforded 68.0 mg (54%) of the title compound.
16 1H NMR (CDCl3) 8: 8.03 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.33-17 7.16 (8H, m), 4.39 (2H, q, J = 7.1 Hz), 4.29 (2H, s), 2.57 (3H, s), 1.40 (3H, t, J
18 = 7.1 Hz), 1.22 (2H, m), 0.93 (2H, m).
19 Methyl ~4-f4-(1-benz~~yclopropyll-3-meth~phenvlethynyl]-phenyll-acetate (Compound 80, General Formula 2) 21 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-22 methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and methyl- (4-23 iodophenyl)-acetate (Reagent B, 95.0 mg, 0.34 mmol) in triethylamine (5 mL) 24 was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 26 mmol) was added and the reaction mixture was stirred overnight at room 27 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 90.0 28 mg (71%) of the title compound as a pale-yellow oil.
1 1H NMR (CDC13) ~: 7.49 (2H, d, J = 8.2 Hz), 7.32-7.16 (10H, m), 4.28 (2H, 2 s), 3.70 (3H, s), 3.64 (2H, s), 2.56 (3H, s), 1.22 (2H, m), 0.92 (2H, m).
3 4 f4 (1 Benzxlox cy yclopropyl~-3-methyl-phenylethynyll-benzoic acid 4 (Compound 81, General Formula 2) Using General Procedure I; a solution of ethyl 4-[4-(1-6 benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 79, 7 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 8 treated with NaOH (360.0 mg, 9.0 rnmols, 3.0 mL of a 3N aqueous solution) 9 and stirred overnight at room temperature. Work-up afforded 48.0 mg (76%) of the title compound as a solid.
11 1H NMR (CDC13) ~: 8.10 (2H, d, J = 8.1 Hz), 7.63 (2H, d, J = 8.1 Hz), 7.44-12 7.16 (8H, m), 4.29 (2H, m), 2.58 (3H, s), 1.24 (2H, m), 0.94 (2H, m).
13 ~4-[4-(1-Benzylox~yclo_propel)-3-methyl-phenylethynyl]-phen~~ acetic acid 14 (Compound 82, General Formula 2) Using General Procedure I; a solution of methyl {4-[4-(1-16 benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 17 80, 75.0 mg, O.I 8 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 18 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 19 and stirred overnight at room temperature. Work-up afforded 30.0 mg (40%) of the title compound.
21 'H NMR (CDC13) S: 7.51 (2H, d, J = 8.2 Hz), 7.42 (1H, s), 7.33-7.17 (9H, m), 22 4.36 (2H, s), 3.67 (2H, s), 2.57 (3H, s), 1.23 (2H, m), 0.94 (2H, m).
23 Isopropyl 3-methyl-4-bromobenzoate (Intermediate 77) 24 Using General Esterification Procedure A; 4-bromo-2-methylbenzoic acid ( 1.6 g, 7.4 mmols) was combined with isopropyl alcohol to give 1.5 g 26 (79%) of the title compound as a colorless oil.
27 1H NMR (CDCl3) 8: 7.76 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 7.4 Hz), 7.37 28 (1H, dd, J = 1.4, 8.2 Hz), 5.23 (1H, septet, J = 6.2 Hz), 2.57 (3H, s), 1.37 (6H, 1 d, J = 6.2 Hz).
2 4 Bromo-1-(1-isopropoxyvinxl~-2-methyl-benzene (Intermediate 78) 3 Using General Procedure 1; isopropyl 2-methyl-4-bromobenzoate 4 (Intermediate 77, 800.0 mg, 3.11 mmols) and 6.2 mL of Tebbe's Reagent (885.2 mg, 3.11 mmols) afforded 595.0 mg (75%) of the title compound as a 6 colorless oil after column chromatography (100% hexanes).
7 'H NMR (CDC13) 8: 7.31-7.25 (2H, m), 7.16 (1H, d, J = 8.2 Hz), 4.34 (1H, 8 septet, J = 6.0 Hz), 4.31 (1H, d, J = 2.1 Hz), 4.18 (1H, d, J = 2.1 Hz), 2.33 (3H, 9 s), 1.31 (6H, d, J = 6.0 Hz).
4-Bromo-1-(1-isopro~oxycycloprop~l-2-meth-benzene (Intermediate 79) 11 Using General Procedure 2; 4-bromo-1-(1-isopropoxyvinyl)-2-methyl-12 benzene (Intermediate 78, 389. 0 mg, 1.53 mmols), EtZZn (376.6 mg, 3.05 13 mmols), and CH2I2 (817.0 mg, 3.05 mmols) in 3.0 mL EtzO afforded 340.0 mg 14 (84%) of the title compound as a colorless oil after chromatography (3%
EtOAc - hexanes).
16 1H NMR (CDCl3) 8: 7.33 (1H, d, J = 2.3 Hz), 7.24 (1H, dd, J = 2.3, 8.2 Hz), 17 7.13 (1H, d, J = 8.2 Hz), 3.57 (1H, septet, J = 6.1 Hz), 2.49 (3H, s), 1.00 (2H, 18 m), 0.97 (6H, d, J = 6. I Hz), 0.82 (2H, m).
19 [4-(1-Isopropoxycyclopropxll-3-meth ~~1-phenyleth~yl]-trimethylsilane (Intermediate 80) 21 Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-22 methyl-benzene (Intermediate 79, 250.0 mg, 0.95 mmol) in triethylamine (8 23 mL) was treated with copper(I)iodide (19.0 mg, 0.10 mmol) and then sparged 24 with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (70.0 26 mg, 0.1 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
27 The title compound (250.0 mg, 91%) was isolated by chromatography (0 - 3%
28 EtOAc - hexanes).
1 1H NMR (CDC13) 8: 7.32-7.17 (3H, m), 3.56 (1H, septet, J = 6.2 Hz), 2.48 2 (3H, s), 1.00 (2H, m), 0.95 (6H, d, J = 6.2 Hz), 0.83 (2H, m), 0.24 (9H, s).
3 4 Eth nyl-1- 1-isopropoxycyclopropyl -2-methyl-benzene (Intermediate 81) 4 Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 80, 250.0 mg, 0.87 mmol) in 6 methanol ( 10 mL) was treated with potassium carbonate ( 100.0 mg, 0.72 7 mmol) and stirred overnight at ambient temperature. The crude alkyne (180 8 mg, 98%) was used directly in the next reaction.
9 1H NMR (CDCl3) ~: 7.32 (1H, s), 7.23 (2H, m), 3.57 (1H, septet, J = 6.2 Hz), 3.05 (1H, s), 2.50 (3H, s), 1.11 (2H, m), 0.96 (6H, d, J = 6.2 Hz), 0.83 (2H, m).
11 Ethyl 4-j4 ~1-iso,.pro~ox c~yclopropyl)-3-methyl-phen 1~~~]-benzoate 12 (Compound 83, General Formula 2) 13 Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-14 methyl-benzene (Intermediate 81, 80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was 16 treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 17 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (91 mg, 0.13 18 mmol) was added and the reaction mixture was stirred overnight at room 19 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 75.0 mg (56%) of the title compound as an orange solid.
21 1H NMR (CDC13) 8: 8.02 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.39 22 (1H, s), 7.29-7.20 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 3.60 (1H, septet, J =
6.2 23 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.13 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0.87 (2H, 24 m).
Methy~4-f4-(1-isopropoxycycloprop~)-3-meth ~~l-phen~~nyll-phenyl~-26 acetate (Compound 84, General Formula 2) 27 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-3-28 methyl-benzene (Intermediate 81, 100.0 mg, 0.47 mmol) and methyl-(4-1 iodophenyl)-acetate (Reagent B, 129.0 mg, 0.45 mmol) in triethylamine (6 2 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with 3 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) ( 110 mg, 4 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 6 120.0 mg (71 %) of the title compound.
7 1H NMR (CDC13) ~: 7.48 (2H, d, J = 8.5 Hz), 7.36 (1H, s), 7.29-7.22 (4H, m), 8 3.70 (3H, s), 3.63 (2H, s), 3.60 (1H, septet, J = 6.2 Hz), 2.52 (3H, s), 1.09 (2H, 9 m), 0.97 (6H, d, J = 6.2 Hz), 0.86 (2H, m).
I0 4-(4-(1-Isopropox cy yclopropyll-3-meth ~~1-phen l~ethyn_~l-benzoic acid 11 (Compound 85, General Formula 2) 12 Using General Procedure I; a solution of ethyl 4-[4-(1-13 isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 83, 14 60.0 mg, 0.17 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) 16 and stirred overnight at room temperature. Work-up afforded 38.0 mg (69%) 17 of the title compound as a colorless solid.
18 1H NMR (d6-acetone) 8: 8.06 (2H, d, J = 8.5 Hz), 7.66 (2H, d, J = 8.5 Hz), 19 7.42 ( 1 H, s), 7.3 5 (2H, m), 3 .59 ( 1 H, septet, J = 6.2 Hz), 2.52 (3H, s), 1.07 (2H, m), 0.93 (6H, d, J = 6.2 Hz), 0.88 (2H, m).
21 ~4-(4-(1-Isopropoxycycloprop~l-3-methyl-phenylethyn~]_phenyl -acetic 22 acid (Compound 86, General Formula 2) 23 Using General Procedure I; a solution of methyl ~4-[4-(1-24 isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 84, 100.0 mg, 0.28 mmol) in ethanol (3 mL) and tetrahydrofuran 26 (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N
27 aqueous solution) and stirred overnight at room temperature. Work-up 28 afforded 60.0 mg (62%) of the title compound as a colorless solid.
1 1H NMR (CDC13) 8: 7.48 (2H, d, J = 7.6 Hz), 7.36 (1H, s), 7.25 (4H, m), 3.65 2 (2H, s), 3.60 (1H, septet, J = 6.2 Hz), 2.51 (3H, s), 1.12 (2H, m), 0.97 (6H, d, J
3 = 6.2 Hz), 0.86 (2H, m).
4 2 2-Dimethylpronyl 2-methyl-4-bromobenzoate (Intermediate 82) Using General Esterification Method C; 2-methyl-4-bromo-benzoic 6 acid (1.82 g, 8.47 mmols) was refluxed for 3h with 10 mL SOC12. The 7 resulting solution was concentrated under reduced pressure and the crude acyl 8 chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols) and 9 pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g, 68%) after work-up and column chromatography (2-S% EtOAc - hexanes) as a colorless 11 oil.
12 'H NMR (CDC13) &: 7.81 (1H, d, J = 8.2 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.39 13 (1H, dd, J = 2.0, 8.2 Hz), 3.99 (2H, s), 2.60 (3H, s), 1.03 (9H, s).
14 4-Bromo-1-f 1 ~2 2-dimethXl~rop~loxy -vine]-2-methyl-benzene (Intermediate 83) 16 Using General Procedure 1; 2,2-dimethylpropyl 2-methyl-4-17 bromobenzoate (Intermediate 82, 820.0 mg, 2.87 mmols) and 5.8 rnL of 18 Tebbe's Reagent (817.0 mg, 2.87 mmols) afforded 800.0 mg (98%) of the title 19 compound as a colorless oil after column chromatography (100% hexanes).
'H NMR (CDCl3) 8: 7.32 ( 1 H, d, J = 2.0 Hz), 7.28 ( 1 H, dd, J = 2.0, 8.2 Hz), 21 7.18 (1H, d, J = 8.2 Hz), 4.27 (1H, d, J = 2.1 Hz), 4.10 (1H, d, J = 2.1 Hz), 22 3.43 (2H, s), 2.33 (3H, s), 0.98 (9H, s).
23 4-Bromo-1-[~2 2-dimeth~propyloxx~cyclopropyl]-2-methyl-benzene 24 (Intermediate 84) Using General Procedure 2; 4-bromo-1-[1-(2,2-dimethylpropyloxy)-26 cyclopropyl]-2-methyl-benzene (Intermediate 83, 400. 0 mg, 1.43 mmols), 27 Et2Zn (353.2 mg, 2.86 mmols), and CH2I2 (760.0 mg, 2.86 mmols) in 3.0 mL
28 Et20 afforded 370.0 mg (87%) of the title compound as a colorless oil after 1 chromatography (3% EtOAc - hexanes).
2 'H NMR (CDC13) 8: 7.36 (1H, s),7.27 (1H, d, J = 8.5 Hz), 7.09 (1H, d, J =
7.9 3 Hz), 2.86 (2H, s), 2.52 (3H, s), 1.08 (2H, m), 0.83 (2H, m), 0.80 (9H, s).
4 f4 f 1 f 1 (2 2 Dimethylpro~yloxyl-cyclopronyll-3-methyl-phenylethvnvlll-trimethylsilane (Intermediate 84a) 6 Using General Procedure D; 4-bromo-1-[1-(2,2-dimethylpropyloxy)-7 cyclopropyl]-2-methyl-benzene (Intermediate 84, 255.0 mg, 0.86 mmol) in 8 triethylamine (8 mL) was treated with copper(I)iodide (17.0 mg, 0.09 mmol) 9 and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-I 1 (triphenylphosphine)palladium(II) (63.0 mg, 0.09 mmol). The resulting 12 reaction mixture was heated to 70 °C for 5d. The title compound (220.0 mg, 13 81%) was isolated by chromatography (1-2% EtOAc - hexanes).
14 'H NMR (CDCl3) 8: 7.30 (1H, s), 7.21 (1H, d, J = 7.6 Hz), 7.12 (1H, d, J =
8.6 Hz), 2.80 (2H, s), 2.47 (3H, s), 1.05 (2H, m), 0.82 (2H, m), 0.75 (9H, s), 0.24 I6 (9H, s).
17 4-Eth3myl-1-~-(2 2-dimeth~lurop~oxyl-cycloprop~l]-2-meth-benzene 18 (Intermediate 85) 19 Using General Procedure E; [4-[1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]]-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 84a, 21 220.0 mg, 0.83 mmol) in methanol (10 mL) was treated with potassium 22 carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature.
23 The crude alkyne (155 mg, 76%) was used directly in the next reaction.
24 'H NMR (CDC13) 8: 7.32 (1H, s), 7.24 (1H, d, J = 7.1 Hz), 7.15 (1H, d, J =
7.1 Hz), 3.04 (1H, s), 2.83 (2H, s), 2.49 (3H, s), 1.06 (2H, m), 0.83 (2H, m), 0.76 26 (9H, s).
27 Ethyl 4-[4-[1-(2 2-dimethxlnropyloxK -cycloprop~]-3-methyl-phenylethynyll-28 benzoate (Compound 87, General Formula 2) 1 Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-2 cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and 3 ethyl-4-iodo benzoate (Reagent A, 86.0 mg, 0.31 mmol) in triethylamine (5 4 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (78 mg, 6 0.11 mmol) was added and the reaction mixture was stirred overnight at room 7 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 60.0 8 mg (50%) of the title compound as an orange solid.
9 1H NMR (CDCl3) 8: 8.02 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.38 (lH,s),7.30(lH,dd,J=1.1,8.OHz),7.20(lH,d,J=8.OHz),4.38(2H,q,J
11 = 7.1 Hz), 2.84 (2H, s), 2.52 (3H, s), 1.40 (3H, t, J = 7.1 Hz), 1.07 (2H, m), 12 0.84 (2H, m), 0.77 (9H, s).
13 Methxl ~4-j4-f 1-(2 2-dimethylpropyloxyl-cyclopropyl]-3-methyl-14 phenyleth~nvl]-phen~)-acetate (Compound 88, General Formula 2) Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-16 cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and I7 methyl-(4-iodophenyl)-acetate (Reagent B, 86.0 mg, 0.31 mmol) in 18 triethylamine (6 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) 19 and sparged with argon for 5 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (78 mg, 0.11 mmol) was added 21 and the reaction mixture was stirred overnight at room temperature. Column 22 chromatography (2-4% EtOAc - hexanes) afforded 100.0 mg (83%) of the title 23 compound.
24 'H NMR (CDC13) 8: 7.48 (2H, d, J = 7.9 Hz), 7.36-7.24 (4H, m), 7.18 (1H, d, J
= 7.9 Hz), 3.70 (3H, s), 3.63 (2H, s), 2.84 (2H, s), 2.5I (3H, s), 1.07 (2H, m), 26 0.83 (2H, m), 0.77 (9H, s).
27 4-f4-[1-~2 2-Dimeth l~pro~~oxy~-cyclopronyll-3-methyl-phen~lethYnyll-28 benzoic acid (Compound 89, -General Formula 2) 1 Using General Procedure I; a solution of ethyl 4-[4-[1-(2,2-2 dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate 3 (Compound 87, 60.0 mg, 0.1 S mmol) in ethanol (3 mL) and tetrahydrofuran 4 (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N
aqueous solution) and stirred overnight at room temperature. Work-up 6 afforded 24.0 mg (43%) of the title compound as a colorless solid.
7 IH NMR (CDC13) 8: 8.06 (2H, d, J = 7.9 Hz), 7.65 (2H, d, J = 7.9 Hz), 7.42 8 (1H, s), 7.33 (2H, m), 2.89 (2H, s), 2.53 (3H, s), 1.07 (2H, m), 0.90 (2H, m), 9 0.77 (9H, s).
~4-f4-f 1-(2 2-Dimethylpropyloxyl.Tcyclopropyl]''-3-methyl-phenylethynyll-11 phenxl~ acetic acid (Compound 90, General Formula 2) 12 Using General Procedure I; a solution of methyl {4-[4-[1-(2,2-13 dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetate 14 (Compound 88, 95.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N
16 aqueous solution) and stirred overnight at room temperature. Work-up 17 afforded 49.0 mg (53%) of the title compound as a colorless solid.
18 'H NMR (CDC13) 8: 7.49 (2H, d, J = 8.2 Hz), 7.36 (1H, s), 7.27 (3H, m), 7.18 19 (1H, d, J = 7.9 Hz), 3.66 (2H, s), 2.84 (2H, s), Z.SI (3H, s), 1.07 (2H, m), 0.83 (2H, m), 0.77 (9H, s).
21 Benzyl 4-bromo-2-ethyl-benzoate (Intermediate 86) 22 Using General Esterification Method B; 4-bromo-2-ethyl-benzoic acid 23 (0.98 g, 4.25 rnmols), benzyl bromide (0.80 g, 4.68 mmols), and KZC03 (0.64 24 g, 4.68 mmols) afforded 1.0 g (74%) of the title compound after column chromatography (0-3% EtOAc - hexanes).
26 1H NMR (CDC13) 8: 7.76 (1H, d, J = 8.5 Hz), 7.41-7.33 (7H, m), 5.32 (2H, s), 27 2.95 (2H, q,a J = 7.6 Hz), 1.20 (3H, t, J = 7.6 Hz).
28 4-Bromo-1-(1-benzyloxXvin~l-2-ethyl-benzene. (Intermediate 87) 1 Using General Procedure 1; benzyl 4-bromo-2-ethylbenzoate 2 (Intermediate 86, 1.20 g, 3.78 mmols) and 7.6 mL of Tebbe's Reagent (1.08 3 g, 3.78 mmols) afforded 800.0 mg (66%) of the title compound after column 4 chromatography (100% hexanes).
1H NMR (CDC13) 8: 7.37-7.17 (8H, m), 4.88 (2H, s), 4.43 (1H, d, J = 2.1 Hz), 6~ 4.25 (1H, d, J = 2.1 Hz), 2.71 (2H, q, J = 7.6 Hz), 1.18 (3H, t, J = 7.6 Hz).
7 4-Bromo-1-(1-benz~loxycyclopropXll-2-ethyl-benzene (Intermediate 88) 8 Using General Procedure 2; 4-bromo-1-(1-benzyloxyvinyl)-2-ethyl-9 benzene (Intermediate 87, 330. 0 mg, 1.04 mmols), EtzZn (257.0 mg, 2.08 mmols), and CHaIz (557.0 mg, 2.08 mmols) in 4 mL Et20 afforded 241.0 mg 11 (70%) of the title compound as a colorless oil after chromatography (2-5%
12 EtOAc - hexanes).
13 'H NMR (CDCl3) 8: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.00 (2H, q, J = 7.6 Hz), 14 1.29-1.21 (5H, m), 0.90 (2H, m).
[4-(1-Benzyloxycyclopropyll-3-ethyl-phen l~~nyl]-trimethylsilane 16 (Intermediate 89) 17 Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-18 ethyl-benzene (Intermediate 88, 220.0 mg, 0.66 mmol) in triethylamine (8 19 mL) was treated with copper(I)iodide ( 14.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was 21 then added followed by dichlorobis-(triphenylphosphine)palladium(II) (50.0 22 mg, 0.07 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
23 The title compound was isolated by chromatography (0 - 2% EtOAc -24 hexanes).
1H NMR (CDCl3) b: 7.41-7.13 (8H, m), 4.24 (2H, s), 2.98 (2H, q, J = 7.6 Hz), 26 1.25 (3H, t, J = 7.6 Hz), 1.20 (2H, m), 0.90 (2H, m), 0.26 (9H, s).
27 4-Ethynyl-1-(1-benzyloxycyclopropyll-2-ethyl-benzene (Intermediate 90) 28 Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-ethyl-1 phenylethynyl]-trimethylsilane (Intermediate 89, 240 mg, 0.69 mmol) in 2 methanol (6 mL) was treated with potassium carbonate (10.0 mg, 0.72 mmol) 3 and stirred overnight at ambient temperature. The crude alkyne (190 mg, 4 99%) was used directly in the next reaction. 1H NMR (CDC13) 8: 7.43-7.15 (8H, m), 4.27 (2H, s), 3.08 (IH, s), 3.0I (2H, q, J = 7.6 Hz), 1.26 (3H, t, J
=
6 7.6 Hz), 1.22 (2H, m), 0.92 (2H, m).
7 Ethxl4 [4 (1 benzyloxycyclopropyll-3-ethyl-phenylethynyll-benzoate 8 (Compound 91, General Formula 2) 9 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo 11 benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was 12 treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 13 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) 14 was added and the reaction mixture was stirred overnight at room temperature.
Column chromatography (2-4% EtOAc - hexanes) afforded 100.0 mg (72%) 16 of the title compound.
17 'H NMR (CDC13) 8: 8.03 (2H, d, J = 7.9 Hz), 7.59 (2H, d, J = 7.9 Hz), 7.49 18 (1H, s), 7.36-7.16 (7H, m), 4.38 (2H, q, J = 7.1 Hz), 4.28 (2H, s), 3.04 (2H, q, 19 J = 7.6 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.23 (2H, m), 0.94 (2H, m).
21 Methyl (4-[4-(1-benzXloxycyclopro~~l-3-ethyl-phenylethyn~l]-phenyl~-22 acetate (Compound 92, General Formula 2) 23 Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-24 ethyl-benzene (Intermediate 90, 107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0 mg, 0.39 mmol) in triethylamine (5 26 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with 27 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 28 0.13 mmol) was added and the reaction mixture was stirred overnight at room 1 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 2 130.0 mg (79%) of the title compound as a pale-yellow oil.
3 'H NMR (CDC13) 8: 7.49 (3H, m), 7.32-7.16 (9H, m), 4.28 (2H, s), 3.7I (3H, 4 s), 3.64 (2H, s), 3.03 (2H, q, J = 7.6 Hz), I.32-1.23 (5H, m), 0.94 (2H, m).
4 [4 (1 Benzyloxycyclopropyll-3-ethyl-phenylethynyll-benzoic acid 6 (Compound 93, General Formula 2) 7 Using General Procedure I; a solution of ethyl 4-[4-(1-8 benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 91, 9 100.0 mg, 0.24 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 11 and stirred overnight at room temperature. Work-up and purification by 12 HPLC (Partisil 10-pac, 10% HZO/CH3CN) afforded the title compound as a 13 colorless solid.
14 'H NMR (CDC13) 8: 8.10 (2H, d, J = 8.5 Hz), 7.64 (2H, d, J = 8.5 Hz), 7.50 (1H, s), 7.35-7.16 (7H, m), 4.29 (2H, s), 3.04 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J
16 = 7.6 Hz), 1.25 (2H, m), 0.95 (2H, m).
17 ~4-f4~1-Benzylox~yclopro»yl)-3-ethy-1-phenylethyn~]-phen~, -acetic acid 18 (Compound 94, General Formula 2) 19 Using General Procedure I; a solution of methyl ~4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl)-acetate (Compound 21 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 22 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 23 and stirred overnight at room temperature. Work-up and purification by 24 HPLC (Partisil IO-pac, 10% H20/CH3CN) afforded the title compound.
'H NMR (CDCl3) ~: 7.49 (3H, m), 7.31-7.16 (9H, m), 4.28 (2H, s), 3.66 (2H, 26 s), 3.02 (2H, q, J = 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.23 (2H, m), 0.94 (2H, 27 m).
28 Isopropvl 2-ethXl-4-bromobenzoate (Intermediate 91) 1 Using General Esterification Procedure A; 4-bromo-2-ethyl-benzoic 2 acid (2.25 g, 9.9 mmols) was combined with isopropyl alcohol to give the title 3 compound as a colorless oil after column chromatography (2% EtOAc-4 hexanes).
1H NMR (CDC13) 8: 7.69 (1H, d, J = 8.5 Hz), 7.41 (1H, s), 7.36 (1H, d, J = 8.5 6 Hz), 5.23 (1H, septet, J = 6.2 Hz), 2.95 (2H, q, J = 7.6 Hz), 1.37 (6H, d, J
= 6.2 7 Hz), 1.23 (3H, t, J = 7.6 Hz).
8 4-Bromo-1-(1-isopropoxwinxl~2-ether-benzene (Intermediate 92) 9 Using General Procedure 1; isopropyl 2-ethyl-4-bromobenzoate (Intermediate 91, 1.21 g, 4.46 mmols) and 8.9 mL of Tebbe's Reagent ( 1.27 11 g, 4.46 mmols) afforded 570.0 mg (75%) of the title compound after column 12 chromatography (100% hexanes).
13 1H NMR (CDC13) b: 7.36 (1H, d, J = 2.0 Hz), 7.28 (1H, dd, J = 2.0, 8.0 Hz), 14 7. I 7 ( I H, d, J = 8.0 Hz), 4.39 ( 1 H, septet, J = 6.2 Hz), 4.31 ( 1 H, d, J = 2.1 Hz), 4.26 (1H, d, J = 2.1 Hz), 2.73 (2H, q, J = 7.6 Hz), 1.35 (6H, d, J = 6.2 Hz), 16 1.24 (3H, t, J = 7.6 Hz).
17 4-Bromo-1-(1-isopro~oxYcycloprop~ -2-ethyl-benzene (Intermediate 93) 18 Using General Procedure 2; 4-bromo-1-(1-isopropoxyvinyl)-2-ethyl-19 benzene (Intermediate 92, 570. 0 mg, 2.11 mmols), EtZZn (521.0 mg, 4.22 mmols), and CH2Iz (1.13 g, 4.22 mmols) in 7.0 mL Et20 afforded 500.0 mg 21 (85%) of the title compound as a colorless oil after chromatography (3%
22 EtOAc - hexanes).
23 1H NMR (CDC13) 8: 7.39 (1H, d, J = 2.1 Hz), 7.25 (1H, dd, J = 2.1, 8.1 Hz), 24 7.1 S ( 1 H, d, J = 8.1 Hz), 3.59 ( 1 H, septet, J = 6.2 Hz), 2.97 (2H, q, J = 7.6 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.11 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0:83 (2H, m).
26 [4-(1-Tsopropox ~cXclopropyll-3-ethyl-phenyleth~nyl)-trimethylsilane 27 (Intermediate 94) 28 Using General Procedure D; 4-bromo-1-(1-isopropoxycyclopropyl)-2-1 ethyl-benzene (Intermediate 93, 300.0 mg, 1.07 mmol) in triethylamine (8 2 mL) was treated with copper(I)iodide (20.0 mg, 0.11 mmol) and then sparged 3 with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was 4 then added followed by dichlorobis-(triphenylphosphine)palladium(II) (75.0 S mg, 0.11 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
6 The title compound (320.0 mg, 99%) was isolated by chromatography (0 - 2%
7 EtOAc - hexanes) as an orange oil.
8 'H NMR (CDCl3) 8: 7.37-7.21 (3H, m), 3.56 (1H, septet, J = 6.2 Hz), 2.96 9 (2H, q, J = 7.6 Hz), 1.27 (3H, t, J = 7.6 Hz), 1.10 (2H, m), 0.94 (6H, d, J
= 6.2 Hz), 0.84 (2H, m), 0.25 (9H, s).
11 4-Eth~nyl-1-f 1-isopropox c~yclopropyll-2-ethyl-benzene (Intermediate 95) 12 Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-ethyl-13 phenylethynyl]-trimethylsilane (Intermediate 94, 330.0 mg, 1.10 mmols) in 14 methanol (10 mL) was treated with potassium carbonate (150.0 mg, 1.10 1 S mmol) and stirred overnight at ambient temperature. The crude alkyne (23 8 16 mg, 9S%) was used directly in the next reaction.
17 1H NMR (CDC13) 8: 7.40-7.22 (3H, m), 3.59 (1H, septet, J = 6.2 Hz), 3.07 18 (1H, s), 2.97 (2H, q, J = 7.6 Hz), 1.28 (3H, t, J = 7.6 Hz), 1.12 (2H, m), 0.96 19 (6H, d, J = 6.2 Hz), 0.85 (2H, m).
Ether[~1-isopropox~cyclopropyll-3-ethyl-phenylethynyl]-benzoate 21 (Compound 95, General Formula 2) 22 Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-23 ethyl-benzene (Intermediate 95, 108.0 mg, 0.47 mmol) and ethyl-4-iodo 24 benzoate (Reagent A, 130.0 mg, 047 mmol) in triethylamine (S mL) was 2S treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 26 S minutes. Dichlorobis(triphenylphosphine)-palladium(II) (110 mg, 0.16 27 mmol) was added and the reaction mixture was stirred overnight at room 28 temperature. Column chromatography (2-4% EtOAc - hexanes) afforded 1 125.0 mg (71%) of the title compound as an oil.
2 1H NMR (CDC13) 8: 8.02 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.46 3 (1H, s), 7.33-7.26 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 3.62 (1H, septet, J =
6.2 4 Hz), 3.01 (2H, q, J = 7.6 Hz), 1.41 (3H, t, J = 7.1 Hz), 1.31 (3H, t, J =
7.1 Hz), 1.14 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0.88 (2H, m).
6 Methyl 144 (1 iso~ropox~~clopropyll-3-ethyl-phen~ethynyll-phenyl~-7 acetate (Compound 96, General Formula 2) 8 Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-3-9 ethyl-benzene (intermediate 95, 130.0 mg, 0.57 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 157.0 mg, 0.57 mmol) in triethylamine (5 11 mL) was treated with copper(I)iodide (36.0 mg, 0.19 mmol) and sparged with 12 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (133 mg, 13 0.19 mmol) was added and the reaction mixture was stirred overnight at room 14 temperature. Column chromatography (2-5% EtOAc - hexanes) afforded 150.0 mg (70%) of the title compound as an orange oil.
16 'H NMR (CDCl3) 8: 7.50-7.44 (3H, m), 7.27 (4H, m), 3.70 (3H, s), 3.64 (2H, 17 s), 3.62 (1H, septet, J = 6.2 Hz), 3.00 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J
= 7.6 18 Hz), 1.13 (2H, m), 0.97 (6H, d, J = 6.2 Hz), 0.87 (2H, m).
19 4-~4-(1-Isopropoxycyclopro~yll-3-eth ~~-1-phenylethXnyll-benzoic acid (Compound 97, General Formula 2) 21 Using General Procedure I; a solution of ethyl 4-[4-( 1-22 isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-benzoate (Compound 95, 23 110.0 mg, 0.29 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 24 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC
26 (partisil 10-pac, 10% H20/CH3CN) afforded the title compound as a colorless 27 solid.
28 1H NMR (d6-acetone) S: 8.06 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 1 7.49 (1H, s), 7.40-7.34 (2H, m), 3.61 (1H, septet, J = 6.2 Hz), 3.01 (2H, q, J =
2 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz), 1.08 (2H, m), 0.93 (6H, d, J = 6.2 Hz), 0.88 3 (2H, m).
4 ~4 f4 (I Isonropoxycyclopropyll 3 ethyl-phenylethynyll-phenyl~-acetic acid (Compound 98, General Formula 2) 6 Using General Procedure I; a solution of methyl {4-[4-(1-7 isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 8 96, 156.0 mg, 0.41 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 9 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and isolation by HPLC
11 (partisil 10-pac, 10% HZO/CH3CN) afforded 85.0 mg (57%) of the title 12 compound.
13 'H NMR (CDC13) 8: 7.54-7.48 (3H, m), 7.34-7.27 (4H, m), 3.68 (2H, s), 3.66 14 (1H, septet, J = 6.2 Hz), 3.03 (2H, q, J = 7.6 Hz), 1.33 (2H, t, J = 7.6 Hz), 1.17 (2H, m), 1.01 (6H, d, J = 6.2 Hz), 0.90 (2H, m).
16 (4-Bromo-3-iso~rop.~~l-phenoxyl-triiso~ropyl-silane (Intermediate 96) 17 To a solution of 4-bromo-3-isopropylphenol (880.0 mg, 4.09 mmols) 18 and imidazole (417.0 mg, 6.13 mmols) in 10 mL DMF was added chloro-19 triisopropylsilane (946.0 mg, 4.90 mmols). After stirring overnight at room temperature the solution was diluted with H20 and extracted with EtOAc. The 21 combined organic layers were washed with H2O and saturated aqueous NaCl 22 before being dried (MgS04) and concentrated under reduced pressure. The 23 title compound, 1.30 g (92%), was isolated by column chromatography (1-2%
24 EtOAc-hexanes) as a colorless oil.
'H NMR (CDCI3) ~: 7.34 (1H, d, J = 8.5 Hz), 6.8I (1H, d, J = 2.9 Hz), 6.59 26 (1H, dd, J = 2.9, 8.5 Hz), 3.31 (1H, septet, J = 7.0 Hz), 1.33-1.21 (3H, m), 1.24 27 (6H, d, J = 7.0 Hz), 1.13 (18H, d, J = 7.0 Hz).
28 Ethxl 2-isouropy_I_4-triiso~prop lsy ilanyloxy-benzoate (Intermediate 97) 1 To a solution of (4-bromo-3-isopropyl-phenoxy)-triisopropyl-silane 2 (Intermediate 96, 1.3 g, 3.8 mmols) in 15 mL Et20 cooled to -78 °C
was 3 added 4.9 mL of tent-butyllithium in pentane (532.0 mg, 8.3 mmols; 1.7 M).
4 After stirring for 30 minutes ethyl chloroformate (832.0 mg, 7.8 mmols) was added. The resulting solution was warmed to room temperature and quenched 6 by the addition of saturated aqueous NH4C1. The mixture was extracted with 7 EtOAc and the combined organic layers dried (MgS04) concentrated under 8 reduced pressure and the residue chromatographed (4% EtOAc-hexanes) to 9 give 1.09 g (85%) of the title compound as a colorless oil.
1H NMR (CDC13) ~: 7.72 (1H, d, J = 8.5 Hz), 6.87 (1H, d, J = 2.3 Hz), 6.69 11 (1H, dd, J = 2.3, 8.5 Hz), 3.88 (1H, septet; J = 7.1 Hz), 4.30 (2H, q, J =
7.1 12 Hz), 1.36 (3H, t, J = 7.1 Hz), 1.31-1.17 (9H, m), 1.09 (18H).
13 f4-(1-Ethoxwin~l-3-isopropyl-phenoxy]-triisopropyl-silane (Intermediate 14 98) Using General Procedure 1; ethyl 2-isopropyl-4-triisopropylsilanyloxy-16 benzoate (Intermediate 97, 450.0 mg, 1.34 mmols) and 2.0 mL of Tebbe's 17 Reagent (398.0 mg, 1.40 mmols) afforded the title compound after column 18 chromatography (100% hexanes).
19 'H NMR (CDC13) b: 7.11 (1H, d, J = 8.2 Hz), 6.78 (1H, d, J = 2.3 Hz), 6.63 (1H, dd, J = 2.3, 8.2 Hz), 4.23 (1H, d, J = 1.7 Hz), 4.10 (1H, d, J = 1.7 Hz), 21 3.86 (2H, q, J = 7.0 Hz), 3.16 (1H, septet, J = 7.0 Hz), 1.35 (3H, t, J =
7.1 Hz), 22 1.28-1.19 (3H, m), 1.19 (6H, d, J = 7.0 Hz), 1.11 (18H).
23 [4-(1-Ethox~cyclopropyll-3-isopropyl-phenox'~]-triisopropyl-silane 24 (Intermediate 99) Using General Procedure 2; [4-(1-ethoxyvinyl)-3-isopropyl-phenoxy]-26 triisopropyl-silane (Intermediate 98, 300. 0 mg, 0.83 mmols), Et2Zn (325.0 27 mg, 2.63 mmols), and CH2I2 (704.0 mg, 2.63 mmols) in 5.0 mL EtzO afforded 28 270.0 mg (86%) of the title compound as a colorless oil after chromatography 1 (O.S-2.S% EtOAc - hexanes).
2 'H NMR (CDC13) b: 7.06 (1H, d, J = 8.2 Hz), 6.81 (1H, d, J = 2.6 Hz), 6.59 3 ~ (1H, dd, J = 2.6, 8.2 Hz), 3.76 (1H, septet, J = 7.0 Hz), 3.25 (2H, q, J =
7.0 4 Hz), 1.30-1.20 (3H, m), 1.19 (6H, d, J = 7.0 Hz), 1.15 (2H, m), 1.10 (18H), S 1.02 (2H, t, J = 7.0 Hz), 0.82 (2H, m).
6 4-(1-Ethoxyc~propyll-3-isopropyl-phenol (Intermediate 100) 7 To a solution of [4-(1-ethoxycyclopropyl)-3-isopropyl-phenoxy]-8 triisopropyl-silane (Intermediate 99, 360.0 mg, 0.96mmo1) in 3 mL THF at 0 9 °C was added tetrabutylammonium fluoride (625.0 mg, 2.39 mmols, 2.4 mL of a 1 M solution in THF). The solution was stirred at 0 °C for 30 minutes and 11 then quenched by the addition of HZO. The mixture was extracted with EtOAc 12 and the combined organic layers were washed with HZO and saturated aqueous 13 NaCI before being dried (MgS04) and concentrated under reduced pressure.
14 The title compound ( 180 mg, 86%) was isolated from the residue by column 1S chromatography (4-10% EtOAc-hexanes) as a colorless solid.
16 'H NMR (CDC13) 8: 7.13 (1H, d, J = 8.2 Hz), 6.79 (1H, d, J = 2.6 H), 6.57 17 (1H, dd, J = 2.6, 8.2 Hz), 5.48 (1H, s), 3.79 (1H, septet, J = 7.0 Hz), 3.32 (2H, 18 q, J= 7.0 Hz), 1.21 (6H, d, J = 7.0 Hz), 1.12 (2H, m), 1.0S (3H, t, J = 7.0 Hz), 19 0.84 (2H, m).
~1-Ethox~~propyll-3-isopropyl-phenv1111-trifluoromethansulfonate 21 (Intermediate 101) 22 A solution of 4-(1-ethoxycyclopropyl)-3-isopropyl-phenol 23 (Intermediate 100, 172.0 mg, 0.78 mmol) in S mL of CHzCl2 was cooled to 0 24 °C and to it was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-S-2S chloropyridine (321.0 mg, 0.82 mmol) and triethylamine (240.0 mg, 2.4 26 mmols). The resulting solution was warmed to room temperature and stirred 27 overnight. The reaction was quenched by the addition of HZO and the mixture 28 extracted with EtOAc and the combined organic layers were washed with 10%
1 aqueous HCI, saturated aqueous NaHCO3, H20, and saturated aqueous NaCl.
2 The solution was dried (MgS04) and concentrated under reduced pressure.
3 The title compound was isolated by column chromatography (2-4% EtOAc-4 hexanes) as a colorless oil, 240.0 mg, 87%.
1 H NMR (CDCl3) b: 7.31 ( 1 H, d, J = 8.6 Hz), 7.18 ( 1 H, d, J = 2. 6 Hz), 7.00 6 (1H, dd, J = 2.6, 8.6 Hz), 3.87 (1H, septet, J = 7.0 Hz), 2.38 (2H, q, J =
7.0 7 Hz), 1.24 (6H, d, J = 7.0 Hz), 1.15 (2H, m), 1.04 (3H, t, J = 7.0 Hz), 0.86 (2H, 8 m).
9 f4 (1-Ethox~cyclopropyl)-3-iso~ro~y-1-phen~ethyn_~l-trimethylsilane (Intermediate 102) 11 Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropyl-12 phenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 13 mmol) in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5 14 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 16 mmol). The resulting reaction mixture was heated to 95 °C for Sd.
The title 17 compound, 200.0 mg (99%), was isolated by chromatography (0 - 2% EtOAc -18 hexanes) as an orange oil.
19 'H NMR (CDC13) 8: 7.43 (1H, d, J = 1.7 Hz), 7.25 (1H, dd, J = 1.7, 7.9 Hz), 7.16 ( 1 H, d, J = 7.9 Hz), 3.80 ( 1 H, septet, J =' 6. 8 Hz), 3.26 (2H, q, J
= 7.0 Hz), 21 1.24 (6H, d, J = 6.8 Hz), 1.24-1.10 (2H, m), 1.03 (3H, t, J = 7.0 Hz), 0.87 (2H, 22 s), 0.26 (9H, s).
23 ~1-Ethoxyc~prop~l)-4-ethvnyl-2-isopropylbenzene (Intermediate 103) 24 Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-trimethylsilane (Intermediate 102, 210.0 mg, 0.70 mmol) in 26 methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 27 mmol) and stirred overnight at ambient temperature. The crude alkyne was 28 used directly in the next reaction.
1 ' H NMR (CDC13) 8: 7.47 ( 1 H, d, J = 1.7 Hz), 7.23 ( 1 H, dd, J = 1.7, 7.6 Hz), 2 7. I 9 ( 1 H, d, J = 7.6 Hz), 3 .80 ( 1 H, septet, J = 7.0 Hz), 3.27 ( 1 H, q, J = 7.0 Hz), 3 3.07 (1H, s), 1.23 (6H, d, J = 7.0 Hz), 1.13 (2H, m), 1.03 (3H, t, J = 7.0 Hz), 4 0.85 (2H, m).
Ethyl 4 f4 ~I ethox c~yclopropyll-3-isopropy-1-phenylethynyll-benzoate 6 (Compound 99, General Formula 2) 7 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-8 isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo 9 benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 11 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 12 mmol) was added and the reaction mixture was stirred overnight at room 13 temperature. Column chromatography (1-2% EtOAc - hexanes) afforded 28.0 14 mg (34%) of the title compound.
1H NMR (CDC13) b: 8.01 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.51 16 ( 1 H, d J = 1.7 Hz), 7.2 8 ( 1 H, dd, J = 1.7, 7.9 Hz), 7.21 ( 1 H, d, J =
7.9 Hz), 17 4.38 (2H, q, J = 7.1 Hz), 3.83 (1H, septet, J = 6.7 Hz), 3.29 (2H, q, J =
7.0 Hz), 18 1.40 (3H, t, J = 7.1 Hz), 1.26 (6H, d, J = 6.7 Hz), 1.14 (2H, m), 1.04 (3H, t, J =
19 7.0 Hz), 0.87 (2H, m).
Methyl ~4-[4-(1-ethox~cyclopropyl)-3-isonropyl-phen~ethynyll-phenyl~-21 acetate (Compound 100, General Formula 2) 22 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-23 isopropylbenzene (Intermediate I03, 120.0 mg, 0.52 mmol) arid methyl-(4-24 iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with 26 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 27 0.17 mmol) was added and the reaction mixture was stirred overnight at room 28 temperature. Column chromatography (2-5% EtOAc - hexanes) afforded 1 140.0 mg (71 %) of the title compound as a pale-yellow oil.
2 1H NMR (CDCI3) 8: 7.53 (3H, m), 7.31-7.23 (4H, m), 3.86 (1H, septet, J = 6.7 3 Hz), 3.73 (3H, s), 3.67 (2H, s), 3.33 (2H, q, J = 7.0 Hz), 1.30 (6H, d, J =
6.7 4 Hz), 1.15 (2H, m), 1.08 (3H, t, J = 7.0 Hz), 0.90 (2H, m).
S 4 f4 (1 EthoxXcyclonropyll-3-isopropyl-phenylethynyll-benzoic acid 6 (Compound 101, General Formula 2) 7 Using General Procedure I; A solution of ethyl 4-[4-(1-8 ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-benzoate (Compound 99, 9 28.0 mg, 0.07 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) 11 and stirred overnight at room temperature. Work-up afforded 24 mg (92%) 12 the title compound as a pale-yellow solid.
13 1H NMR (d6-acetone) 8: 8.06 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 14 7.58 (1H, s), 7.33 (2H, m), 3.87 (1H, m), 2.27 (2H, q, J = 7.0 Hz), 1.26 (6H, d, J = 6.7 Hz), 1.09 (2H, m), 0.99 (3H, t, J = 7.0 Hz), 0.88 (2H, m).
16 ~4-[4-(1-Ethox c~ycloprop~)-3-isoprop_y-1-phenylethyn~l-phenyl~-acetic acid 17 (Compound 102, General Formula 2) 18 Using General Procedure I; a solution of methyl f 4-[4-(1-19 ethoxycyclopropyl)-3-isopropyl-phenylethynyl]-phenyl-acetate (Compound 100, 130.0 mg, 0.35 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was 21 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) 22 and stirred at 50 °C for 4h. Work-up and isolation by HPLC (Partisil 10-pac, 23 10% H20/CH3CN) afforded 88.0 mg (70%) of the title compound.
24 1H NMR (CDC13) 8: 7.50 (3H, m), 7.28-7.19 (4H, m), 3.82 (1H, m), 3.65 (2H, s), 3.29 (2H, q, J = 7.0 Hz), 1.25 (6H, d, J = 6.7 Hz), 1.14 (2H, rn), 1.04 (3H, t, 26 J = 7.0 Hz), 0.86 (2H, m).
27 4-Bromo-3-tent-but~phenol (Intermediate 104) 28 To a mixture of 3-tent-butyl-methoxy benzene (1.00 g, 6.09 mmols) in 1 CC14 (20 mL), molecular sieves, and silica gel was added N bromosuccinimide 2 (1.19 g, 6.70 mmols). This mixture was stirred at 55 °C for 48h. The resulting 3 mixture was cooled to room temperature, filtered to remove the solids, and the 4 filtrate diluted with EtOAc. This solution was washed with HZO, 10%
aqueous HCl, HaO, saturated aqueous NaHC03 and saturated aqueous NaCl 6 before being dried (MgS04) and concentrated under reduced pressure.
7 Column chromatography (2.5% EtOAc-hexanes) afforded 1.15 g (78%) of a 3 8 to 1 mixture of 1-bromo-2-tent-butyl methoxy benzene and 1-bromo-2-9 methoxy-4-tent-butyl benzene as a colorless oil.
A solution of the isomeric methoxy compounds in 10 mL of CHZC12 11 was cooled to 0 °C and treated with a solution (18.5 mL) of BBr3 in 12 (4.63 g, 18.5 mmols). After I O minutes the solution was warmed to room 13 temperature, stirred for 1h, and then quenched with HZO. The mixture was 14 extracted with EtOAc and the combined organic layers washed with saturated aqueous NaCI, dried (MgS04), and concentrated under reduced pressure. The 16 title compound was isolated, 1.17 g (59%), by column chromatography (2.5-17 5% EtOAc-hexanes).
18 'H NMR (CDC13) ~: 7.39 (1H, d, J = 8.5 Hz), 6.96 (1H, d, J = 2.9 Hz), 6.54 19 ( 1 H, dd, J = 2.9, 8. S Hz), 1.46 (9H, s).
~4-Bromo-3-test-butyl-phenoxyl-triisopropyl-silane (Intermediate I05) 21 To a solution of 4-bromo-3-tent-butylphenol (Intermediate 104, 1.17 g, 22 5.10 mmols) and imidazole (520.0 mg, 7.65 mmols) in 10 mL DMF was added 23 chloro-triisopropylsilane (1.18 g, 6.10 mmols). After stirring overnight at 24 room temperature the solution was diluted wirth H20 and extracted with EtOAc. The combined organic layers were washed with H20 and saturated 26 aqueous NaCl before being dried (MgS04) and concentrated under reduced 27 pressure. The title compound, 1.80 g (92%), was isolated by column 28 chromatography (0-1.5% EtOAc-hexanes) as a colorless oil.
1 'H NMR (CDC13) 8: 7.38 (1H, d, J = 8.0 Hz), 6.97 (1H, d, J = 2.9 Hz), 6.56 2 (1H, dd, J = 2.9, 8.5 Hz), 1.47 (9H, s), 1.29-1.24 (3H, m), 1.09 (18H, d, J
= 6.7 3 Hz).
4 Eth~l 2 tent-butyl-4-triisopropylsilanyloxv-benzoate (Intermediate 106) To a solution of (4-bromo-3-tent-butyl-phenoxy)-triisopropyl-silane b (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et20 cooled to -78 °C
was 7 added 3.6 mL of test-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols).
8 After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was 9 added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with 11 EtOAc and the combined organic layers dried (MgS04) concentrated under 12 reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) 13 to give 1.23 g (88%) of the title compound as a colorless oil.
14 'H NMR (CDC13) b: 7.24 (1H, d, J = 8.2 Hz), 6.97 (1H, d, J = 2.6 Hz), 6.69 I S (1H, dd, J = 2.6, 8.2 Hz), 4.33 (2H, q, J = 7.1 Hz), 1.39 (9H, s), 1.37 (3H, t, J =
16 7.1 Hz), 1.29-1.21 (3H, m), 1.10 (18H, d, J = 6.7 Hz).
17 [4-(1-Ethox~vin~l-3-test-butyl-phenoxy]-triisopropyl-silane (Intermediate 18 107) I9 Using General Procedure 1; ethyl 2-test-butyl-4-triisopropylsilanyloxy-benzoate (Intermediate 106, 1.30 g, 3.44 mmols) and 7.2 mL of Tebbe's 21 Reagent (1.03 g, 3.61 mmols) were reacted. The reaction required 7 days at 22 room temperature to go to completion. The standard work-up afforded 1.29 g 23 (78%) of the title compound after column chromatography (1-2% EtOAc-24 hexanes).
1H NMR (CDC13) 8: 7.05 (1H, d, J = 8.2 Hz), 6.94 (1H, d, J = 2.6 Hz), 6.63 26 (1H, dd, J = 2.6, 8.2 Hz), 4.20 (1H, d, J = 1.7 Hz), 4.08 (IH, d, J = 1.7 Hz), 27 3.83 (2H, q, J = 7.1 Hz), 1.37 (9H, s), 1.36 (3H, t, J = 7.1 Hz), 1.27-1.20 (3H, 28 m), 1.10 (18H, d, J = 6.7 Hz).
1 ~4 (1 Ethoxycyclonropyll 3 tent butyl-phenoxyl-triisoprobyl-silane 2 (Intermediate 108) 3 Using General Procedure 2; [4-(1-ethoxyvinyl)-3-tent-butyl-phenoxy]-4 triisopropyl-silane (Intermediate 107, 320. 0 mg, 0.85 mmols), Et2Zn (325.0 mg, 2.63 mmols), and CHzI2 (704.0 mg, 2.63 mmols) in 5.0 mL EtZO afforded 6 257.0 mg (66%) of the title compound as a colorless oil after chromatography 7 (1-2.5% EtOAc - hexanes).
8 1H NMR (CDC13) 8: 7.24 (1H, d, J = 8.5 Hz), 7.06 (1H, d, J = 2.6 Hz), 6.60 9 (1H, dd, J = 2.6, 8.5 Hz), 3.24 (2H, q, J = 7.1 Hz), 1.50 (9H, s), 1.29-1.21 (3H, m), 1.11 (18H, d, J = 6.7 Hz), 1.04 (3H, t, J = 7.1 Hz).
11 4-(1-Ethoxyc~lo~ro~~ -3-test-butxl-phenol (Intermediate 109) 12 To a solution of [4-(1-ethoxycyclopropyl)-3-tent-butyl-phenoxy]-13 triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 14 0 °C was added tetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols;
3.1 mL of a 1 M solution in THF). The solution was stirred at 0 °C for 30 16 minutes and then quenched by the addition of HZO. The mixture was extracted 17 with EtOAc and the combined organic layers were washed with HZO and 18 saturated aqueous NaCl before being dried (MgSOø) and concentrated under 19 reduced pressure. The title compound (400 mg, 88%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless 21 solid.
22 'H NMR (CDC13) 8: 7.29 (1H, d, J = 8.2 Hz), 7.01 (1H, d, J = 2.6 Hz), 6.57 23 (1H, dd, J = 2.6, 8.2 Hz), 3.29 (2H, q, J = 7.1 Hz), 1.59 (9H, s), 1.08-1.04 (7H, 24 m).
4-(1-Ethox cyclopropyll-3-tent-butt'-1-phenyl 1 1 1-trifluoromethansulfonate 26 (Intermediate 110) 27 A solution of 4-(1-ethoxycyclopropyl)-3-tent-butyl-phenol 28 (Intermediate 109, 400.0 mg, 1.71 mmol) in 10 mL of CH2C12 was cooled to 1 0 °C and to it was added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-2 chloropyridine (705.0 mg, 1.79 mmol) and triethylamine (522.0 mg, 5.1 3 mmols). The resulting solution was warmed to room temperature and stirred 4 overnight. The reaction was quenched by the addition of H20 and the mixture extracted with EtOAc and the combined organic layers were washed with 10%
6 aqueous HCl, saturated aqueous NaHC03, H20, and saturated aqueous NaCI.
7 The solution was dried (MgS04) and concentrated under reduced pressure.
8 The title compound was isolated by column chromatography (2-4% EtOAc-9 hexanes) as a colorless oil, 542.0 mg (87%).
'H NMR (CDC13) 8: 7.48 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 2.6 Hz), 7.01 11 (1H, dd, J = 2.6, 8.5 Hz), 3.26 (2H, q, J = 7.1 hz), 1.52 (9H, s), 1.12 (2H, bs), 12 1.08-1.04 (5H, m).
13 [~1-Ethox~~prop~l-3-test-butyl-phen~eth~yl-1-trimethylsilane 14 (Intermediate 111) Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tent-butyl-16 phenyl 1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 17 mmol) in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5 18 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added 19 followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 95 °C for 18 hours.
The 21 title compound, 215.0 mg (96%), was isolated by chromatography (0 - 2%
22 EtOAc - hexanes) as an orange oil.
23 1H NMR (CDC13) 8: 7.63 (1H, d, J = 1.7 Hz), 7.32 (1H, d, J = 7.9 Hz), 7.19 24 (1H, dd, J = 1.7, 7.9 Hz), 3.24 (2H, q, J = 7.1 Hz), 1.51 (9H, s), 1.10 (2H, bs), 1.06-1.01 (5H, m), 0.25 (9H, s).
26 1- 1-Ethox~~prop~~4-eth~yl-2-tent-butylbenzene (Intermediate 112) 27 Using General Procedure E; [4-(1-ethoxycyclopropyl)-3-tent-butyl-28 phenylethynyl]-trimethylsilane (Intermediate 1l1, 215.0 mg, 0.69 mmol) in 1 methanol (10 mL) was treated with potassium carbonate (80.0 mg, 0.58 mmol) 2 and stirred overnight at ambient temperature. The crude alkyne, 169 mg, was 3 used directly in the next reaction.
4 1H NMR (CDC13) 8: 7.68 (1H, d, J =1.8 Hz), 7.36 (1H, d, J = 7.9 Hz), 7.23 ( 1 H, dd, J = 1.8, 7.9 Hz), 3 .26 (2H, q, J = 7.1 Hz), 3 .06 ( 1 H, s), 1.51 (9H, s), 6 1.11 (2H, bs), 1.07-1.02 (5H, m).
7 Ether 4 f 4 ( 1 ethoxXcyclopropyll-3-tent-butyl-phen~ethynyll-benzoate 8 (Compound 103, General Formula 2) 9 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tey°t-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo 11 benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was 12 treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 13 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 14 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc - hexanes) afforded 70.0 16 mg (73%) of the title compound.
17 'H NMR (CDC13) 8: 8.02 (2H, d, J = 8.8 Hz), 7.72 (1H, d, J = 1.7 Hz), 7.59 18 (2H, d, J = 8. 8 Hz), 7.40 ( 1 H, d, J = 7.9 Hz), 7.2 8 ( 1 H, dd, J = 1.7, 7.9 Hz), 19 4.39 ( 2H, q, J = 7.1 Hz), 3.28 (2H, q, J = 7.1 Hz), 1.55 (9H, s), 1.40 (3H, t, J =
7.1 Hz), 1.12 (2H, bs), 1.08-1.04 (5H, m).
21 Meth~l~4-[4-(1-ethoxxcyclopropyll-3-tent-butyl-phenylethynyll-phenyll-22 acetate (Compound 104, General Formula 2) 23 Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tef°t-24 butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylamine (8 26 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with 27 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 28 0.13 mmol) was added and the reaction mixture was stirred overnight at room 1 temperature. Column chromatography (2-5% EtOAc - hexanes) afforded 2 100.0 mg (72%) of the title compound.
3 'H NMR (CDCl3) 8: 7.70 (1H, d, J = 1.5 Hz), 7.50 (2H, d, J = 7.9 Hz), 7.38 4 (1H, d, J = 7.9 Hz), 7.27 (3H, m), 3.70 (3H, s), 3.64 (2H, s), 3.28 (2H, q, J =
7.1 Hz), 1.54 (9H, s), 1.12 (2H, bs), 1.08-1.03 (5H, m).
6 4 f 4 ( 1 EthoxXcvclonropyl~ 3-teat-butyl-nhenylethynyll-benzoic acid 7 (Compound 105, General Formula 2) 8 Using General Procedure I; a solution of ethyl 4-[4-(1-9 ethoxycyclopropyl)-3-tent-butyl-phenylethynyl]-benzoate (Compound 103, 70.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 11 treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) 12 and stirred overnight at room temperature. Work-up afforded 40 mg (62%) 13 the title compound as a pale-yellow solid.
14 1H NMR (d6-acetone) ~: 8.06 (2H, d, J = 8.7 Hz), 7.76 (1H, d, J =1.8 Hz), 7.67(2H,d,J=8.7Hz),7.50(lH,d,J=7.9Hz),7.33(lH,dd,J=1.8,7.9 16 Hz), 3.28 (2H, q, J = 7.3 Hz), 1.54 (9H, s), 1.13 (2H, bs), 1.10 (2H, m), I
.02 17 (3H, t, J = 7.3 Hz).
18 ~4-[4-(1-Ethox cv yclopropyll-3-test-butyl-phenylethynyl]-phen~~acetic acid 19 (Compound 106, General Formula 2) Using General Procedure I; a solution of methyl f 4-[4-(1-21 ethoxycyclopropyl)-3-tent-butyl-phenylethynyl]-phenyl-acetate (Compound 22 104, 100.0 mg, 0.26 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) was 23 treated with NaOH (240.0 mg, 6.0 mmols, 3.0 mL of a 2N aqueous solution) 24 and stirred at 50 °C for 4h. Work-up and isolation by HPLC (Partisil 10-pac, 10% H20/CH3CN) afforded 70.0 mg (73%) of the title compound.
26 'H NMR (CDCl3) 8: 7.73 (1H, d, J = I .3 Hz), 7.53 (2H, d, J = 7.9 Hz), 7.41 27 (1H, d, J = 7.9 Hz), 7.28 (3H, m), 3.69 (2H, s), 3.31 (2H, q, J = 7.1 Hz), 1.56 28 (9H, s), 1.15 (2H, bs), 1.11-1.05 (5H, m).
1 1 (4 Bromophenyll-cyclopropanecarbonitrile (Intermediate 113) 2 To a 50% aqueous NaOH solution (40.0 g, wt/wt) was added benzyl 3 triethylammonium chloride ( 1.0 g, 4.4 mrnols), 4-bromobenzonitrile ( 19.6 g, 4 0.10 mol), and 1,2-dibromoethane (56.4 g, 0.30 mol). The mixture was stirred overnight at room temperature and then diluted with 100 mL of H20. This 6 mixture was extracted with EtOAc and the combined extracts were washed 7 with saturated aqueous NaHS203, HZO, and saturated aqueous NaCl before 8 being dried (MgS04) and concentrated under reduced pressure. Bulb-to-bulb 9 distillation afforded 18.8 g (85%) of the title compound as a colorless solid.
1H NMR (CDCl3) 8: 7.48 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 1.75 11 (2H, dd, J = 5.2, 7.6 Hz), 1.39 (2H, dd, J = 5.2, 7.6 Hz).
12 1-(4-Bromophenyl~c~lopropanecarbox~ic acid (Intermediate 114) 13 To a solution of KOH (6.06 g, 0.11 mol) in 10 mL of HZO was added 14 40 mL of ethylene glycol and 1-(4-bromophenyl)-cyclopropanecarbonitrile (Intermediate 113, 10.0 g, 0.45 mol). This solution was heated to 135-140 °C
16 for 4h, cooled to room temperature, and then poured into a mixture of 100 mL
I7 ice and I O% aqueous HCl. The resulting mixture was allowed to stand 18 overnight at 5 °C, the solid was collected by filtration and washed with HZO.
19 The colorless solid was dried under reduced pressure to give 10.6 g (97%) of the title compound.
21 1H NMR (CDC13) 8: 7.43 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 1.68 22 (2H, dd, J = 4.0, 7.1 Hz), I .24 (2H, dd, J = 4.0, 7.1 Hz).
23 Test-butt(I-~4-bromo~henyll-cycloprop~]'-carbamate (Intermediate 115) 24 A solution of 1-(4-bromophenyl)-cyclopropanecarboxylic acid (Intermediate 114, 2.32 g, 9.62 mmols), diphenylphosphoryl azide (2.65 g, 26 9.62 mmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL teYt-BuOH
27 (distilled from Na°) was heated to reflux for 17h. The solution was 28 concentrated under reduced pressure and the residue dissolved in EtOAc and 1 washed with 5% aqueous HC1, H20, saturated aqueous NaHC03, and saturated 2 aqueous NaCI before being dried over MgS04. Concentration of the dry 3 solution under reduced pressure and column chromatography (5-10% EtOAc -4 hexanes) afforded 2.01 g (67%) of the title compound as a colorless solid.
1H NMR (CDCl3) 8: 7.39 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.3 Hz), 5.35 6 (1H, bs), 1.43 (9H, s), 1.26 (2H, m), 1.17 (2H, m).
7 1-~4-Bromophen l~yclopropylamine (Intermediate 116) 8 To a solution of test-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate 9 (Intermediate 115, 1.08 g, 3.40 mmols) in 20 mL MeOH and 20 mL THF was added 20 mL of 3M aqueous HCl. The solution was warmed to 35 °C for 3 11 hours and then stirred for 17h at 25 °C. The reaction was quenched by 12 adjusting the pH of the solution to 12 with 3M aqueous NaOH. The mixture 13 was extracted with EtzO and the combined organic layers were washed with 14 HZO and saturated aqueous NaCl before being dried (MgS04) and concentrated under reduced pressure. The title compound 613 mg (85%) was 16 used without further purification.
17 1H NMR (CDCl3) 8: 7.43 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz), 1.89 18 (2H, bs), 1.07 (2H, m), 0.95 (2H, m).
19 N [ 1 ~4-bromophenyl~cyclopropyl]-propionamide (Intermediate 117) To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 21 116, 84 mg, 0.4 mmol) in 4 mL CH2Cl2 at room temperature was added 22 propionyl chloride (43.0 mg, 0.47 mmol) and pyridine (5.6.0 mg, 0.71 mmol).
23 After stirring 17 hours at room temperature the reaction was quenched by the 24 addition of H20 and extracted with EtOAc. The combined extracts were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and saturated 26 aqueous NaCl before being dried (MgS04) and concentrated under reduced 27 pressure. The title compound 85.0 mg (67%), was isolated by column 28 chromatography (20-50% EtOAc-hexanes) as a colorless solid.
1 1H NMR (CDC13) ~: 7.48 (2H, d, J = 8.S Hz), 7.09 (2H, d, J = 8.S Hz), 6.40 2 (1H, s), 2.19 (2H, q, J = 7.2 Hz), 1.18-1.24 (4H, m), 1.12 (3H, t, J = 7.2 Hz).
3 j1 (4 Bromophenxll-c~clopropyll-~ famine (Intermediate 118) 4 To a solution of N [1-(4-bromophenyl)-cyclopropyl]-propionamide S (Intermediate 117, 85.0 mg, 0.32 mmol) in THF (S mL) at 0 °C was added 6 BH3-Me2S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). The 7 solution was heated to SS °C for 17 hours, cooled to room temperature, 8 saturated aqueous NaHC03 was added and the resulting mixture was stirred 9 for 2 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with HZO and saturated aqueous NaCI before being dried 11 (MgS04) and concentrated under reduced pressure. The title compound was 12 isolated by column chromatography (10-30% EtOAc-hexanes).
13 1H NMR (CDC13) 8: 7.42 (2H, d, J = 8.S Hz), 7.19 (2H, d, J = 8.S Hz), 2.46 14 (2H, t, J = 7.3 Hz), 1.40 (2H, m), 0.98 (2H, m), 0.86 (SH, m).
1 S Pronyl-f 1- 4-trimeth ls~~ethynyl-phenyl-c~propyl_]-amine 16 (Intermediate 119) 17 Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-18 propylamine (Intermediate 118, 100.0 mg, 0.39 mmol) in triethylamine (8 19 mL) was treated with copper(I)iodide ( 13.0 mg, 0.06 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was 21 then added followed by dichlorobis(triphenylphosphine)palladium(II) (48.0 22 mg, 0.06 mmol). The resulting reaction mixture was heated to 70 °C
for 23 Sdays. The title compound (80.0 mg, 7S%) was isolated by chromatography 24 (0 - 10% EtOAc - hexanes) as an orange oil.
1H NMR (CDCl3) 8: 7.41 (2H, d, J = 8.S Hz), 7.21 (2H, d, J = 8.S Hz), 2.45 26 (2H, t, J = 7.3 Hz), 1.39 (2H, m), 0.98 (2H, m), 0.87 (2H, m), 0.84 (3H, t, J =
27 7.3 Hz), 0.24 (9H, s).
28 j~4-Ethyn~phenyll-cycloaropyll-nro~wlamine (Intermediate 120) 1 Using General Procedure E; propyl-[1-(4-trimethylsilanylethynyl-2 phenyl)-cyclopropyl]-amine (Intermediate 119, 80.0 mg, 0.30 mmols) in 3 methanol (8 mL) was treated with potassium carbonate (80.0 mg, 0.59 mmol) 4 and stirred overnight at ambient temperature. The crude alkyne (58 mg, 100%) was used directly in the next reaction.
6 1H NMR (CDC13) ~: 7.44 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz), 3.05 7 ( 1 H, s), 2.46 (2H, t, J = 7.3 Hz), 1.41 (2H, m), 1.00 (2H, m), 0.90 (2H, m), 8 0.86 (3H, t, J = 7.3 Hz).
9 Eth~l4-~4-(1-propylamino-c~cloprop~2phenylethynyll-benzoate (Compound 107, General Formula 2) 11 Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-12 propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo 13 benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was 14 treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) 16 was added and the reaction mixture was stirred overnight at room temperature.
17 Column chromatography (5-15% EtOAc - hexanes) afforded 40.0 mg (61%) 18 of the title compound as an orange oil.
19 'H NMR (CDCl3) 8: 8.01 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz), 4.39 (2H, q, J = 7.1 Hz), 2.49 21 (2H, t, J = 7.3 Hz), 1.46 (2H, m), 1.41 (3H, t, J = 7.1 Hz), 1.0l (2H, m), 0.89 22 (2H, m), 0.87 (3H, t, J = 7.3 Hz).
23 4-(4-~(1-Propylamino-e.~prop,~phen,~eth~,Yll-benzoic acid (Compound 24 108, General Formula 2) Using General Procedure I; a solution of ethyl 4-[4-(1-propylamino-26 cyclopropyl)-phenylethynyl]-benzoate (Compound 107, 40.0 mg, 0.12 mmol) 27 in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 28 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at 1 room temperature. Work-up afforded 25.0 mg (69%) of the title compound as 2 a solid.
3 'H NMR (d6-DMSO) ~: 7.97 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.50 4 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.37 (2H, m), 1.00 (2H, m), 0.93 (2H, m), 0.84 (3H, t, J = 7.3 Hz).
6 ~1 (4 Bromophenvl)-cyclonrop~]-dipropylamine (Intermediate 121) 7 To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 8 116) in CH3CN / HOAc (5 mL, 9:1, v/v) and THF 3 mL at 0 °C was added 9 propionaldehyde (277.0 mg, 4.95 mmols) and NaCNBH3 (153.0 mg, 2.47 mmols). The reaction was warmed to room temperature and after Shours 11 quenched with HZO. The pH of the solution was adjusted to 8-9 using aqueous 12 NaOH and extracted with EtOAc. The combined extracts were washed with 13 H20 and saturated aqueous NaCl, dried (MgS04) and concentrated under 14 reduced pressure. The title compound, 190.0 mg (56%), was isolated by column chromatography (2-5% EtOAc-hexanes).
16 'H NMR (CDC13) ~: 7.42 (2H, d, J = 8.3 Hz), 7.18 (2H, d, J = 8.3 Hz), 2.39 17 (4H, t, J = 7.3 Hz), 1.62-1.40 (4H, m), 0.96 (2H, m), 0.86 (6H, t, J = 7.3 Hz), 18 0.80 (2H, m).
19 Dipropyl-f 1-(4-trimeth lsy ilan~lethynyl-phenyll-cycloarop~l]-amine (Intermediate 122) 21 Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-22 dipropylamine (Intermediate 121, 150.0 mg, 0.50 mmol) in triethylamine (5 23 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged 24 with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 26 mg, 0.05 mmol). The resulting reaction mixture was heated to 70 °C
for Sd.
27 The title compound was isolated by chromatography (0 - 3% EtOAc -28 hexanes).
1 'H NMR (CDC13) 8: 7.35 (2H, d, J = 8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 2.39 2 (4H, t, J = 7.3 Hz), 1.55-1.42 (4H, m), 0.96 (2H, m), 0.88-0.79 (8H, m), 0.25 3 (9H, s).
4 [1 (4 Ethynvlphenyll-cyclonropYll-dipropylamine (Intermediate 123) Using General Procedure E; dipropyl-[1-(4-trimethylsilanylethynyl-6 phenyl)-cyclopropyl]-amine (Intermediate 122, 45.0 mg, 0.14 inmols) in 7 methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) 8 and. stirred overnight at ambient temperature. The crude alkyne (34 mg, 9 100%) was used directly in the next reaction.
1H NMR (CDCl3) 8: 7.42 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 11 2.40(4H, t, J = 7.3 Hz), 1.53-1.40 (4H, m), 0.96 (2H, m), 0.90-0.79 (8H, m).
12 Eth 1Y 4-f4-(1-dipropylamino-cycloprop~l~phenylethynyll-benzoate 13 (Compound 109, General Formula 2) 14 Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0 mg, 0.16 mmol) and ethyl-4-iodo 16 benzoate (Reagent A, 59.0 mg, 0.21 mmol) in triethyl amine (6 mL) was 17 treated with copper(I)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 18 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) 19 was added and the reaction mixture was stirred overnight at room temperature.
Column chromatography (2-4% EtOAc - hexanes) afforded the title compound 21 as a yellow oil.
22 'H NMR (CDCl3) 8: 8.03 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.49 23 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 4.39 (2H, q, J = 7.1 Hz), 2.43 24 (4H, t, J = 7.3 Hz), 1.52-1.42 (4H, m), 1.41 (3H, t, J = 7.1 Hz), 0.99 (2H, m), 0.88-0.83 (8H, m). .
26 4-[4-(1-Dipropylamino-c~lo~ropyll-phenylethyn~]-benzoic acid 27 (Compound 110, General Formula 2) 28 Using General Procedure I; a solution of ethyl 4-[4-(1-dipropylamino-1 cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) 2 in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 3 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at 4 room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
6 1H NMR (d6-DMSO) 8: 7.98 (2H, d, J = 8.3 Hz), 7.67 (6H, m), 3.05-2.89 (4H, 7 m), 1.98 (2H, m), 1.72 (4H, m), 1.23 (2H, m), 0.88 (6H, t, J = 7.3 Hz).
8 Benzxl f 1 t4 bromobhen~)-c~propyl]-amine Intermediate 124) and 9 Dibenzyl-[ 1-f 4-bromophenyll-cyclopropyl]-amine (Intermediate 125) A solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116, 11 244.0 mg, 1.15 mmols) and benzyl bromide (255.0 mg, 1.50 mmols) in 4 mL
12 DMF was stirred at 85 °C for 6 hours, cooled to room temperature and stirred 13 overnight. The solution was diluted with H20 and the pH adjusted to 8-9 with I4 aqueous NaOH. The solution was extracted with EtOAc and the combined organic layers were washed with H20 and saturated aqueous NaCI, dried 16 (MgS04) and concentrated under reduced pressure. Column chromatography 17 (5-10% EtOAc-Hexanes) afforded 110 mg (32%) of the N benzyl amine.
I8 1H NMR (CDC13) 8: 7.48 (2H, d, J = 8.4 Hz), 7.30-7.23 (7H, m), 3.68 (2H, s), 19 1.07 (2H, m), 0.93 (2H, m); and 100 mg (22%) of the N,N dibenzyl amine, 1H
NMR (CDC13) 8: 7.55 (2H, d, J = 8.3 Hz), 7.40-7.19 (12H, m), 3.61 (4H, s), 21 0.87 (2H, m), 0.71 (2H, m).
22 Benzyl-[1-(4-trimeth~silanyleth~nyl-phenyl-cycloprop~]-amine 23 (Intermediate I26) 24 Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 110.0 mg, 0.36 mmol) in triethylamine (8 mL) was 26 treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with 27 argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then 28 added followed by dichlorobis(triphenylphosphine)palladium(II) (38.0 mg, 1 0.05 mmol). The resulting reaction mixture was heated to 70 °C for Sd. The 2 title compound 85 mg (74%) was isolated by chromatography (1 - 10% EtOAc 3 - hexanes).
4 'H NMR (CDC13) 8: 7.46 (2H, d, J = 8.3 Hz), 7.31-7.22 (7H, m), 3.67 (2H, s), 1.06 (2H, m), 0.94 (2H, m), 0.26 (9H, s).
6 Benzyl-f 1-(4-ethynylphenyl~-cycloprop~ll-amine (Intermediate 127) 7 Using General Pocedure E; benzyl-[1-(4-trimethylsilanylethynyl-8 phenyl)-cyclopropyl]-amine (Intermediate 126, 85.0 mg, 0.27 mmol) in 9 methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) I O and stirred overnight at ambient temperature. The crude alkyne (65 mg, 11 100%) was used directly in the next reaction.
12 'H NMR (CDCl3) 8: 7.49 (2H, d, J = 7.9 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.23 13 (5H, m), 3.68 (2H, s), 3.08 (1H, s), 1.07 (2H, m), 0.95 (2H, m).
14 Eth;~ 4-(4-(1-benzylamino-cXclopropyl)-phenyleth~yl]-benzoate (Compound 111, General Formula 2) 16 Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-17 amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate 18 (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with 19 copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes.
Dichlorobis (triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added 21 and the reaction mixture was stirred overnight at room temperature. Column 22 chromatography (2-5% EtOAc - hexanes) afforded 90 mg (90%) of the title 23 compound as an orange solid.
24 1H NMR (CDC13) b: 8.05 (2H, d, J = 8.3 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.43 (2H, d, J = 8.1 Hz), 7.32-7.22 (5H, m), 4.40 (2H, q, J
26 = 7.1 Hz), 3.72 (2H, s), 1.42 (2H, t, J = 7.1 Hz), 1.01 (2H, m), 0.99 (2H, m).
27 4-(~1-Benzylamino-c~clopro~yl~phenylethxn~]-benzoic acid (Compound 28 112, General Formula 2) 1 Using General Procedure I; a solution of ethyl 4-[4-(1-benzylamino-2 cyclopropyl)-phenylethynyl]-benzoate (Compound 111, 75.0 mg, 0.19 mmol) 3 in ethanol (4 mL) and tetrahydrofuran (4 mL) was treated with NaOH (80.0 4 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (50%) of the title compound as 6 a colorless solid.
7 1H NMR (CD30D) 8: 7.93 (2H, d, J = 8.3 Hz), 7.61-7.51 (6H, m), 7.32-7.23 8 (5H, m), 3.98 (2H, s), 1.33(2H, m), 1.19 (2H, m).
9 Dibenzyl-[1-(,4-trimeth;~silanylethynyl-phenyl-c~prop~]-amine (Intermediate 128) 11 Using General Procedure D; dibenzyl-[1-(4-bromophenyl)-12 cyclopropyl]-amine (Intermediate 125, 45.0 mg, 0.11 mmol) in triethylamine 13 (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then 14 sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.35 g, 3.6 mmols) was then added followed by 16 dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The 17 resulting reaction mixture was heated to 70 °C for Sd. The title compound 40 18 mg (88%) was isolated by chromatography (hexanes).
19 'H NMR (CDC13) 8: 7.52 (2H, d, J = 8.3 Hz), 7.36-7.24 (12H, m), 3.60 (4H, s), 0.87 (2H, m), 0.67 (2H, m), 0.29 (9H, s).
21 Dibenzyl-[1-(4-eth;~n~phenyl)-c~clopropyl]-amine (Intermediate 129) 22 Using General Procedure E; dibenzyl-[1-(4-trimethylsilanylethynyl-23 phenyl)-cyclopropyl]-amine (Intermediate 128, 100.0 mg, 0.26 mmol) in 24 methanol (5 mL) was treated with potassium carbonate (60.0 mg, 0.44 mmol) and stirred overnight at ambient temperature. The crude alkyne (80 mg, 99%) 26 was used directly in the next reaction.
27 'H NMR (CDC13) ~: 7.53 (2H, d, J = 7.9 Hz), 7.36 (2H, d, J = 7.9 Hz), 7.28-28 7.25 (10H, m), 3.62 (4H, s), 3.11 (1H, s), 0.88 (2H, m), 0.68 (2H, m).
1 Ethvl 4 f 4 ( 1 dibenzylamino cyclopronyll-phenylethynyll-benzoate 2 (Compound 113, General Formula 2) 3 Using General Procedure F; dibenzyl-[1-(4-ethynylphenyl)-4 cyclopropyl]-amine (Intermediate 129, 40.0 mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was 6 treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 7 minutes. Dichlorobis (triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) 8 was added and the reaction mixture was stirred overnight at room temperature.
9 Column chromatography (2-5% EtOAc - hexanes) afforded the title compound as an oil.
11 1H NMR (CDC13) ~: 8.04 (2H, d, J = 8.5 Hz), 7.79 (4H, m), 7.42 (2H, d, J =
12 7.9 Hz), 7.29-7.17 (10H, m), 4.40 (2H, q, J = 7.1 Hz), 3.63 (4H, s), 1.42 (3H, t, 13 J = 7.1 Hz), 0.88 (2H, m), 0.73 (2H, m).
14 4-f4-(1-Dibenzylamino-cvclopropyll-phenylethynyl]-benzoic acid (Compound 114, Formula 2) 16 Using General Procedure I; a solution of ethyl 4-[4-(1-dibenzylamino-17 cyclopropyl)-phenylethynyl]-benzoate (Compound I13, 48.0 mg, 0.10 mmol) 18 in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with NaOH (80.0 19 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 42.0 mg (93%) of the title compound as 21 a colorless solid.
22 1H NMR (d6-DMSO) 8: 7.98 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 7.64 23 (2H, d, J = 7.9 Hz), 7.47 (2H, d, J = 7.9 Hz), 7.28-7.20 (10H, m), 3.57 (4H, s), 24 0.84 (2H, m), 0.69 (2H, m).
Benzvl-f 1-(4-bromo~henYll-c~clopropyl]-methylamine (Intermediate 130) 26 To a solution of benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine 27 (Intermediate 124, 100.0 mg, 0.33 mmol) in 5 mL of acetone was added 28 KZCO3 (91 mg, 0.66 mmol) and iodomethane (2.28 g, 16.1 mmols). The 1 resulting mixture was stirred at 25 °C for 20 hours, diluted with EtzO, and 2 washed with H20 and saturated aqueous NaCl. The solution was dried 3 (MgS04) and concentrated under reduced pressure to give 90 mg (86%) of the 4 title compound.
1H NMR (CDCl3) S: 7.47 (2H, d, J = 8.5 Hz), 7.29-7.18 (7H, m), 3.53 (2H, s), 6 2.07 (3H, s), 1.07 (2H, m), 0.86 (2H, m).
7 Benzyl f 1 (4 trimethXlsilanylethynyl-phenyl-cyclonronyll-methylamine 8 (Intermediate 131) 9 Using General Procedure D; benzyl-[I-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130, 90.0 mg, 0.28 mmol) in triethylamine (8 11 mL) was treated with copper(I)iodide (6.0 mg, 0.03 mmol) and then sparged 12 with argon for S minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was 13 then added followed by dichlorobis(triphenylphosphine)palladium(II) (20.0 14 mg, 0.03 mmol). The resulting reaction mixture was heated to 70 °C
for 5 days. The title compound 80 mg (84%) was isolated by chromatography (0-16 2% EtOAc-hexanes).
17 'H NMR (CDCl3) ~: 7.46 (2H, d, J = 8.2 Hz), 7.32-7.18 (7H, m), 3.52 (2H, s), 18 2.06 (3H, s), 1.06 (2H, m), 0.87(2H, m), 0.26 (9H, s).
19 Benzvl-(1-(4-ethyn~phen~l-c~prop~]-rnethylamine (Intermediate 132) Using General Procedure E; benzyl-[I-(4-trimethylsilanylethynyl-21 phenyl)-cyclopropyl]-methylamine (Intermediate 131, 80.0 mg, 0.24 mmol) 22 in methanol (5 mL) was treated with potassium carbonate (80.0 mg, 0.59 23 mmol) and stirred overnight at ambient temperature. The crude alkyne (60 24 mg, 99%) was used directly in the next reaction.
IH NMR (CDC13) 8: 7.49 (2H, d, J = 8.2 Hz), 7.33-7.21 (7H, m), 3.55 (2H, s), 26 3.08 (1H, s), 2.08 (3H, s), 1.07 (2H, m), 0.89 (2H, m).
27 Eth,~l 4-~4-f 1-(bent 1-~ylamino~-cycloaroyyl]~phenylethyn~~-benzoate 2~ (Compound 115, General Formula 2) 1 Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-2 methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo 3 benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (S mL) was 4 treated with copper(I)iodide ( 18.0 mg, 0.10 mmol) and sparged with argon for S S minutes. Dichlorobis (triphenylphosphine)palladium(II) (6S mg, 0.10 mmol) 6 was added and the reaction mixture was stirred overnight at room temperature.
7 Column chromatography (2-S% EtOAc - hexanes) afforded 86 mg (7S%) of 8 the title compound as an oil.
9 1H NMR (CDCl3) 8: 8.03 (2H, d, J = 8.S Hz), 7.59 (2H, d, J = 8.S Hz), 7.53 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.25 (SH, m), 4.39 (2H, q, J =
7.1 11 Hz), 3.57 (2H, s), 2.10 (3H, s), 1.41 (3H, t, J = 7.1 Hz), 1.10 (2H, m), 0.92 12 (2H, m).
13 4-f4~1-Benz l~xlamino-cycloprop~ll-phenyleth~~]-benzoic acid 14 (Compound 1I6, General Formula 2) 1 S Using General Procedure I; a solution of ethyl 4- f 4-[1-(benzyl-16 methylamino)-cyclopropyl]-phenylethynyl~-benzoate (Compound 115, 65.0 17 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated 18 with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and 19 stirred overnight at room temperature. Work-up afforded 45.0 mg (7S%) of the title compound as a solid.
21 'H NMR (d6-DMSO) 8: 7.96 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 7.58 22 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.29-7.18 (SH, m), 3.52 (2H, s), 23 2.00 (3H, s),1.02 (2H, m), 0.87 (2H, m).
24 ~4-Bromo-2-meth 1-y phen,~~l)-methanol (Intermediate 133) 2S A solution of methyl 4-bromo-2-methyl-benzoate (1.0S g, 4.58 mmols) 26 in 10 mL of Et20 was cooled to 0 °C and treated with LiAIH4 (177.0 mg, 4.58 27 mmols), stirred for 3 hours, and then carefully quenched with HZO. The 28 mixture was extracted with Et20 and the combined organic layers were 1 washed with HZO and saturated aqueous NaCl, dried (MgS04), and 2 concentrated under reduced pressure. The title compound, 830.0 mg (90%), 3 was isolated by column chromatography (10-30% EtOAc-hexanes) as a 4 colorless oil.
1H NMR (CDC13) 8: 7.30 (2H, m), 7.18 (1H, d, J = 8.8 Hz), 4.57 (2H, d, J =
6 5.5 Hz), 2.27 (3H, s), 2.13 (1H, t, J = 5.5 Hz).
7 (4-Bromo-2-methyl-benz~oxyl-trimethylsilane (Intermediate 134) 8 To a solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 9 133, 500.0 mg, 2.48 mmols), in 10 mL THF was added triethylamine (374.0 mg, 3.70 mmols) and chlorotrimethylsilane (297.0 mg, 2.70 mmols). The 11 resulting solution was stirred for 17 hours at 25 °C and then treated with H20 12 and extracted with Et20. The combined organic layers were washed with HZO, 13 10% aqueous HCI, saturated NaHC03, and saturated NaCI before being dried 14 (MgS04) and concentrated under reduced pressure. The title compound, 550.0 I S mg (81 %), was isolated by column chromatography (5% EtOAc-hexanes) as a 16 colorless oil.
17 1H NMR (CDC13) b: 7.35-7.28 (3H, m), 4.64 (2H, s), 2.29 (3H, s), 0.20 (9H, 18 s).
19 2-Methyl-4-trimethylsilanylethxnyl-1-trimeth~lsilanyloxymethxl-benzene (Intermediate 135) 21 Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-22 trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 23 mL) was treated with copper(I)iodide (3 8.0 mg, 0.20 mmol) and then sparged 24 with argon for 5 minutes. Trimethylsilyl acetylene ( 1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 26 mg, 0.20 mmol). The resulting reaction mixture was heated to 70 °C
for 5 27 days. The title compound (380.0 mg, 65%) was isolated by chromatography 28 (0 - 2% EtOAc - hexanes) as an orange oil.
1 'H NMR (CDC13) 8: 7.31 (3H, m), 4.64 (2H, s), 2.24 (3H, s), 0.24 (9H, s), 0.15 2 (9H, s).
3 (4-Ethvn~-2-meth T~l-phenyll-methanol (Intermediate 136) 4 Using General Procedure E; 2-methyl-4-trimethylsilanylethynyl-1-trimethylsilananyloxymethyl-benzene (Intermediate 135, 380.0 mg, 1.30 6 mmols) in methanol (10 mL) was treated with potassium carbonate (180.0 mg, 7 1.3 mmol) and stirred overnight at ambient temperature. The crude alkyne 8 was purified by column chromatography (5-20% EtOAc-hexanes) to give 9 100.0 mg (34%) of the title compound.
'H NMR (CDCI3) 8: 7.06 (3H, m), 4.42 (2H, d, J = 5.2 Hz), 2.81 (1H, s), 2.05 11 (3H, s), 1.59 ( 1 H, t, J = 5.2 Hz).
12 Eth,~(4-hydxox~meth,~-3-meth 1-y phen~eth~n~ -benzoate (Compound 13 117, General Formula 6) _ 14 Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate 16 (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with 17 copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes.
18 Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added 19 and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc - hexanes) afforded 130.0 mg (99%) of the 21 title compound as an orange solid.
22 'H NMR (CDCI3) 8: 7.98 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.36 23 (3H, m), 4.65 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 2.40 (1H, s), 2.30 (3H, s), 1.39 24 (3H, t, J = 7.1 Hz).
Ethyl 4-(4-bromomethyl-3-meth ~~l-phen~leth~n~l-benzoate (Intermediate 26 137) 27 A solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-28 benzoate (Compound 117, 130.0 mg, 0.44 mmol) and triphenylphosphine 1 (150.0 mg, 0.57 mmol) in 5 mL CH2C12 was cooled to 0 °C and N
2 bromosuccinimide (101.0 mg, 0.57 mmol) was added in 5 portions over 20 3 minutes. The solution was warmed to 25 °C and stirred for 17 hours.
The 4 reaction was quenched by the addition of dilute aqueous NaHC03. The resulting mixture was extracted with EtzO and the combined organic layers 6 were washed with HZO and saturated aqueous NaCl before being dried 7 (NaZS04) and concentrated under reduced pressure. The title compound, 120.0 8 mg (76%), was isolated by column chromatography (2-5% EtOAc-hexanes) as 9 a colorless solid.
'H NMR (CDC13) 8: 8.01 (2H, d, J = 8.1 Hz), 7.56 (2H, d, J = 8.1 Hz), 7.32 11 (3H, m), 4.48 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 2.40 (3H, s), 1.39 (3H, t, J =
12 7.1 Hz).
13 Ethyl4-(4-imidazol-1-yl-meths-3-methvl-phenyleth~~l-benzoate 14 (Compound 118, General Formula 6) A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF was 16 treated with NaH (11.0 mg, 0.44 mmol) and heated to 90 °C. After 1h a 17 solution of ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate 18 (Intermediate 137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added and 19 stirnng at 90 °C continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 21 90.0 mg (71 %) was isolated by column chromatography (20-100% EtOAc-22 hexanes) as a colorless solid.
23 1H NMR (CDC13) ~: 8.02 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.51 24 (lH,s),7.40(lH,s),7.36(lH,dd,J=1.2,7.9Hz),7.10(lH,s),6.93(lH,d,J
= 7.9 Hz), 6.88 (1H, t, J = 1.7 Hz), 5.12 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 2.27 26 (3H, s), 1.40 (3H, t, J = 7.1 Hz).
27 ~4-Imidazol-1- 1-methXl-3-methyl-phenyleth~nyl)-benzoic acid 28 (Compound 119, General Formula 6) 1 Using General Procedure I; a solution of ethyl 4-(4-imidazol-1-2 ylmethyl-3-methyl-phenylethynyl)-benzoate (Compound 1I8, 82.0 mg, 0.24 3 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH
4 (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight S at room temperature. Work-up afforded S 1.0 mg (68%) of the title compound 6 as a solid.
7 'H NMR (d6-DMSO) S: 9.20 (1H, s), 7.97 (2H, d, J = 8.2 Hz), 7.73 (2H, m), 8 7.65 (2H, d, J = 8.2 Hz), 7.52 (1H, s), 7.46 (1H, d, J = 7.9 Hz), 7.13 (1H, d, J =
9 7.9 Hz), S.SO (2H, s), 2.32 (3H, s).
4-Bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138) 11 A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 12 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in S mL
13 CH2Clz was cooled to 0 °C and N bromosuccinimide (309.0 mg, 1.74 mmol) 14 was added in S portions over 20 minutes. The solution was warmed to 2S
°C
and stirred for 17 hours. The reaction was quenched by the addition of dilute 16 aqueous NaHC03. The resulting mixture was extracted with Et20 and the 17 combined organic layers were washed with H20 and saturated aqueous NaCI
18 before being dried (NazS04) and concentrated under reduced pressure. The 19 title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil.
21 1 H NMR (CDC13) 8: 7.32 ( 1 H, d, J = 2.0 Hz), 7.29 ( 1 H, dd, J = 2.0, 7.9 Hz), 22 7.15 (1H, d, J = 7.9 Hz), 4.43 (2H, s), 2.37 (3H, s).
23 1-(4-Bromo-2-meth 1-~yl)-1H imidazole (Intermediate 139) 24 A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was 2S treated with NaH (20.0 mg, 0.86 mmol) and heated to 90 °C. After 1h a 26 solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 27 190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90 °C
28 continued for lhour. The solution was cooled to room temperature and 1 concentrated under reduced pressure. The title compound, 160.0 mg (88%) 2 was isolated by column chromatography (5% MeOH-EtOAc) as a colorless 3 solid.
4 'H NMR (CDC13) ~: 7.46 (1H, s), 7.34 (1H, dd, J = 1.8 Hz), 7.30 (1H, dd, J =
1.8,8.2Hz),7.08(lH,t,J=1.2Hz),6.83(lH,t,J=l.2Hz),6.80(lH,d,J=
6 8.2 Hz), 5.03 (2H, s), 2.23 (3H, s).
7 1-~2-MethXl-4-trimethvlsilanyleth~nyl-benzyl)-1H imidazole (Intermediate 8 I40) 9 Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H
imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) 11 was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with 12 argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then 13 added followed by dichlorobis(triphenylphosphine)palladium(II) (45.0 mg, 14 0.07 mmol). The resulting reaction mixture was heated to 70 °C for 5 days.
The title compound (140.0 mg, 82%) was isolated by chromatography (5%
16 MeOH-EtOAc ) as an orange oil.
17 1H NMR (CDCl3) 8: 7.53 (1H, s), 7.38 (1H, s), 7.34 (1H, d, J = 8.0 Hz), 7.15 18 ( 1 H, s), 6.94 ( 1 H, s), 6.91 ( 1 H, d, J = 8.0 Hz), 5.14 (2H, s), 2.29 (3H, s), 0.31 19 (9H, s).
1-(4-Ethynyl-2-meth,1-~yl)-1H imidazole (Intermediate 141) 21 Using General Procedure E; I-(2-methyl-4-trimethylsilanylethynyl-22 benzyl)-11I imidazole (Intermediate 140, 140.0 mg, 0.53 mmols) in methanol 23 (5 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and 24 stirred overnight at ambient temperature. The crude alkyne (105 mg, 100%) was used directly in the next reaction.
.26 1H NMR (CDC13) 8: 7.49 (1H, s), 7.35 (1H, s), 7.31 (1H, dd, J = 1.7, 7.9 Hz), 27 7.10 ( 1 H, s), 6.69 ( 1 H, d, J = 7.9 Hz), 6. 85 ( 1 H, t, J =1.2 Hz), 5.14 (2H, s), 28 3.08 (1H, s), 2.26 (3H, s).
1 Methyl [4 ~4 imidazol 1 y1 methyl 3 methyl-uhenylethY_nyll-phenyll-acetate 2 (Compound 120, General Formula 6) 3 Using General Procedure F; 1-(4-ethynyl-2-methyl-benzyl)-1H
4 imidazole (Intermediate 141, 101.0 mg, 0.53 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 145.0 mg, 0.53 mmol) in triethylamine (5 6 mL) was treated with copper(I)iodide (34.0 mg, 0.18 mmol) and sparged with 7 argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (124 mg, 8 0.18 mmol) was added and the reaction mixture was stirred overnight at room 9 temperature. Column chromatography (5% MeOH-EtOAc) afforded 45.0 mg (25%) of the title compound as an orange oil.
11 1H NMR (CDCl3) b: 7.47 (3H, m), 7.35 (3H, m), 7.27 (3H, m), 6.91 (1H, d, J
=
12 7.3 Hz), 5.11 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 2.26 (3H, s).
13 f4~(4-Imidazol-1-yl-meth,~-3-methyl-phenylethynyl)-phenyl]-acetic acid 14 (Compound 121, General Formula 6) Using General Procedure I; a solution of methyl [4-(4-imidazol-1-16 ylmethyl-3-methyl-phenylethynyl)-phenyl]-acetate (Compound 120, 45.0 mg, 17 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with 18 NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred 19 overnight at room temperature. Work-up afforded 30.0 mg (70%) of the title compound as a pale-orange solid.
21 1H NMR (d4-MeOH) 8: 8.97 (1H, s), 7.60 (2H, d J = 8.8 Hz), 7.47 (3H, m), 22 7.41 ( 1 H, d, J = 7.9 Hz), 7.3 0 (2H, d, J = 7.9 Hz), 7.23 ( 1 H, d, J =
7.9 Hz), 23 5.51 (2H, s), 3.64 (2H, s), 2.33 (3H, s).
24 1-Isopropyl-3-methox~-benzene (Intermediate 142) To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL of 26 acetone was added K.ZC03 (7.50 g, 54.3 mmols) and iodomethane (10.3 g, 72.5 27 mmols). The resulting solution was heated to 50 °C and stirred for 18 hours, 28 cooled to room temperature, and concentrated under reduced pressure. The 1 residual oil was dissolved in Et20 and washed with HZO, saturated aqueous 2 NaHC03, and saturated aqueous NaCI before being dried (MgS04) and 3 concentrated under reduced pressure. The crude methyl ether was used 4 without further purification.
S 'H NMR (CDC13) 8: 7.22 (1H, t, J = 8.1 Hz), 6.84-6.72 (3H, m), 3.81 (3H, s), 6 2.88 (1H, septet, J = 7.0 Hz), 1.25 (6H, d, J = 7.0 Hz).
7 1-Bromo-2-iso~rop~l-4-methoxy-benzene (Intermediate 143) 8 A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 9 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CC14 was treated with N bromosuccinimide (4.98 g, 28.0 mmols) at 35 °C for 18 hours. An 11 additional portion of N bromosuccinimide (830.0 mg, 4.46 mmols) was added 12 and stirring continued for 6 hours. The mixture was cooled to room 13 temperature, H20 was added, and the mixture was filtered to remove the 14 solids. The mixture was extracted with Ea0 and the combined organic layers were washed with 10% aqueous HCl, HZO, saturated aqueous NaHC03, and 16 saturated NaCl before being dried (MgS04) and concentrated under reduced 17 pressure. Column chromatography (2.5% EtOAc-hexanes) afforded 4.34 g 18 (81 %) of the title compound as a pale-yellow oil.
19 'H NMR (CDC13) S: 7.4I ( I H, d, J = 8.8 Hz), 6.82 ( 1 H, d, J = 2.6 Hz), 6.61 (1H, dd, J = 2.6, 8.8 Hz), 3.79 (3H, s), 3.31 (1H, septet, J = 6.7 Hz), 1.23 (6H, 21 d,J=6.7Hz).
22 4-Bromo-3-isoprop.~~l-phenol (Intermediate 144) 23 To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene 24 (Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CHZC12 at -78 °C was added BBr3 (4.81 g, 19.2 mmols; 19.2 mL of a 1M solution in CH2Clz). After stirring 26 for 3 hours at -78 °C the solution was warmed to 0 °C for 3 hours and then at 27 25 °C for 1 hour before being quenched with H20. The mixture was diluted 28 with Et20 and washed with H20 and saturated aqueous NaCl, dried (NaZSO~) 1 and concentrated under reduced pressure. Column chromatography (2.5-10%
2 EtOAc-hexanes) afforded the title compound as a colorless oil.
3 'H NMR (CDC13) b: 7.38 (1H, d, J = 8.5 Hz), 6.79 (1H, d, J = 2.9 Hz), 6.57 4 ( 1 H, dd, J = 2.9, 8.5 Hz), 3 .31 ( 1 H, septet, J = 7.0 Hz), 1.22 (6H, d, J = 7.0 Hz).
6 (4-Bromo-3-iso~ropyl-phenoxxl-tent-butyl-dimeth~-silane (Intermediate 7 145) 8 A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 9 5.25 mmols), chloro-tent-butyl-dimethylsilane (0.95 g, 6.30 mmols), and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25 °C for 3 11 hours. The solution was diluted with H20 and extracted with Et20 and the 12 combined organic layers were washed with HzO, saturated aqueous NaCI, and 13 dried (MgS04) before being concentrated under reduced pressure. Column 14 chromatography (1-2% EtOAc-hexanes) afforded 1.50 g (87%) of the title compound as a colorless oil.
16 1H NMR (CDC13) ~: 7.32 (1H, d, J = 8.8 Hz), 6.73 (1H, d, J = 3.0 Hz), 6.52 17 ( 1 H, dd, J = 3 .0, 8 . 8 Hz), 3 .26 ( 1 H, septet, J = 6.7 Hz), 1.19 (6H, d, J = 6.7 18 Hz), 0.96 (9H, s), 0.17 (6H, s).
19 4-(Tent-butyl-dimeth 1-y silan~loxyl-2-isopropyl-benzaldehyde (Intermediate 146) 21 A solution of (4-bromo-3-isopropyl-phenoxy)-tent-butyl-dimethyl-22 silane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E20 was cooled to -23 78 °C and treated with tent-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a 24 1.7M solution in pentane). After 30 minutes the reaction was quenched with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. The solution 26 was diluted with HzO, extracted with Et20 and the combined organic layers 27 washed with H20 and saturated aqueous NaCl before being dried (MgS04) and 28 concentrated under reduced pressure. Column chromatography (2% EtOAc-1 hexanes) afforded 480.0 mg (SS%) of the title compound as a colorless oil.
2 1H NMR (CDC13) 8: 10.19 (1H, s), 7.72 (1H, d, J = 8.5 Hz), 6.85 (1H, d, J =
3 2.3 Hz), 6.77 (1H, dd, J = 2.3, 8.5 Hz), 3.97 (1H, septet, J = 6.7 Hz), 1.27 (6H, 4 d, J = 6.7 Hz), 1.00 (9H, s), 0.25 (6H, s).
4-Hydrox -~isopronyl-benzaldehyde (Intermediate 147) 6 To a solution of 4-(test-butyl-dimethyl-silanyloxy)-2-isopropyl-7 benzaldehyde (Intermediate 146, 880.0 mg, 3.17 mmols) in 6 mL THF at 0 8 °C was added tetrabutylammonium fluoride (1.66 g, 6.33 mmols; 6.3 mL
of a 9 1M solution in THF). The pale-yellow solution was stirred for 30 minutes and quenched by the addition of ice cold H20. The mixture was extracted with 11 EtaO and the combined organic layers were washed with H20 and saturated 12 aqueous NaCl before being dried (NaZS04) and concentrated under reduced 13 pressure. Column chromatography (20% EtOAc-hexanes) afforded 500.0 mg 14 (96%) of the title compound as a colorless solid.
IS 1H NMR (CDCl3) 8: 10.15 (1H, s), 7.79 (1H, d, J = 8.S Hz), 6.95 (1H, d, J =
16 2.3 Hz), 6.86 ( 1 H, dd, J = 2.3, 8.5 Hz), 3.96 ( 1 H, septet, J = 6.7 Hz), 1.29 (6H, 17 d,J=6.7Hz).
18 4-Form,1-~pro~~phenyl 1,1 1-trifluoro-methansulfonate (Intermediate 19 148) A solution of 4-hydroxy-2-isopropyl-benzaldehyde (Intermediate 147, 21 300.0 mg, 1.83 mmol) in 10 mL of CH2C12 was cooled to 0 °C and to it was 22 added 2-[N,N-bis(trifluoromethylsulfonyl)amino]-S-chloropyridine (754.0 mg, 23 1.92 mmol) and triethylamine (592.0 mg, 5.85 mmols). The resulting solution 24 was warmed to room temperature and stirred for 4.5 hours. The reaction was quenched by the addition of HBO and the mixture extracted with EtOAc and 26 the combined organic layers were washed with 10% aqueous HCI, saturated 27 aqueous NaHC03, H20, and saturated aqueous NaCI. The solution was dried 28 (MgS04) and concentrated under reduced pressure. The title compound was 1 isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless 2 oil, 470.0 mg (87%).
3 'H NMR (CDCl3) 8: 10.37 (1H, s), 7.94 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J =
4 2.3 Hz), 7.26 ( 1 H, dd, J = 2.3, 8 . 5 Hz), 4.00 ( 1 H, septet, J = 6.7 Hz), 1.3 3 (6H, d, J = 6.7 Hz), 6 4 Hydroxymeth~l-3-isonro~yl-phenyl 1,,1,1-trifluoro-methansulfonate 7 (Intermediate 149) 8 To a solution of 4-formyl-3-isopropyl-phenyl 1,1,1-trifluoro-9 methansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL MeOH
at 0 °C was added NaBH4 (72.0 mg, 1.91 mmols). After stirring 2 hours at 0 11 °C the reaction was carefully quenched with HZO and extracted with Et20.
12 The combined organic layers were washed with Ha0 and saturated aqueous 13 NaCl, dried (MgS04), and concetrated under reduced pressure. The title 14 compound was isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless oil, 355.0 mg (90%).
16 iH NMR (CDC13) 8: 7.45 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 2.7 Hz), 7.08 17 ( 1 H, dd, J = 2.7, 8.5 Hz), 4.74 (2H, d, J = 5.3 Hz), 3 .21 ( 1 H, septet, J = 7.0 18 Hz), 2.12 ( 1 H, t, J = 5.3 Hz), 1.24 (6H, d, J = 7.0 Hz).
19 4-(Tent-but 1-~dim_eth 1-y silan~loxxmethyll-3-isopropyl-phenyl 1 1 1-trifluoro-methansulfonate (Intermediate 150) 21 A solution of 4-hydroxymethyl-3-isopropyl-phenyl 1,1,1-trifluoro-22 methansulfonate (Intermediate 149, 760.0 mg, 2.55 mmols), chloro-tert-23 butyl-dimethylsilane (470.0 mg, 3.18 mmols), and imidazole (225.0 mg, 3.25 24 mmols) in 6 mL DMF was stirred at 25 °C for 17 hours. The solution was 2S diluted with H20 and extracted with Et20 and the combined organic layers 26 were washed with 10% aqueous HCI, saturated aqueous NaHC03, HZO, and 27 saturated aqueous NaCl, and dried (MgS04) before being concentrated under 28 reduced pressure. Column chromatography (2-5% EtOAc-hexanes) afforded 1 970.0 mg (92%) of the title compound as a colorless oil.
2 1H NMR (CDC13) 8: 7.49 (1H, d, J = 8.5 Hz), 7.10 (1H, d, J = 2.3 Hz), 7.06 3 (1H, dd, J = 2.3, 8.5 Hz), 4.75 (2H, s), 3.10 (1H, septet, J = 6.7 Hz), 1.21 (6H, 4 d, J = 6.7 Hz), 0.93 (9H, s), 0.10 (6H, s).
1-~Ter~t-butyl-dimethxl-silanXlox~lnethyll-2-isoaropyl-4-6 trimeth. l~~ethynyl-benzene (Intermediate 151) 7 To a solution of 4-(te~~t-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-8 phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 150, 970.0 mg, 2.35 9 mmols) in triethylamine (2 mL) and 6 mL DMF was sparged with argon for 15 minutes. Trimethylsilyl acetylene (1.00 g, 10.6 mmols) was then added 11 followed by dichlorobis(triphenylphosphine)palladium(II) (66.0 mg, 0.09 12 mmol). The resulting reaction mixture vvas heated to 95 °C for 20 hours. The 13 solution was cooled to room temperature and concentrated under reduced 14 pressure. The title compound (200.0 mg, 78%) was isolated by chromatography (0-25% EtOAc-hexanes) as an orange oil.
16 1H NMR (CDC13) 8: 7.37-7.25 (3H, m), 4.75 (2H, s), 3.08 (1H, septet, J =
7.0 17 Hz), 1.21 (6H, d, J = 7.0 Hz), 0.92 (9H, s), 0.25 (9H, s), 0.09 (6H, s).
18 Test-but ~~1-(4-ethynyl-2-isoprop 1-b~enz_~~l-dimethyl-silane (Intermediate 19 152) Using General Procedure E; 1-(test-butyl-dimethyl-silanyloxymethyl)-21 2-isopropyl-4-trimethylsilanylethynyl-benzene (Intermediate 151, 850.0 mg, 22 2.36 mmols) in methanol (25 mL) was treated with potassium carbonate 23 (250.0 mg, 1.81 mmols) and stirred overnight at ambient temperature. The 24 crude alkyne (650 mg, 95%) was used directly in the next reaction.
1H NMR (CDCl3) 8: 7.41-7.25 (3H, m), 4.77 (2H, s), 3.07 (1H, septet, J = 7.0 26 Hz), 3.05 (1H, s), 1.22 (6H, d, J = 7.0 Hz), 0.94 (9H, s), 0.11 (6H, s).
27 Ethyl 4-[4 ~tert-butyl-dimethyl-silanxlox~methyl~-3-isopropyl-28 phen~lethynyl]-benzoate (Intermediate 153) 1 Using General procedure F; test-butyl-(4-ethynyl-2-isopropyl-2 benzyloxy)-dimethyl-silane (Intermediate 152, 300.0 mg, 1.04 mmols) and 3 ethyl-4-iodo benzoate (Reagent A, 287.0 mg, 1.04 mmols) in triethylamine 4 (8mL) was treated with copper(I)iodide (50.0 mg, 0.26 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (182 6 mg, 0.26 mmol) was added and the reaction mixture was stirred overnight at 7 room temperature. Column chromatography (2-4% EtOAc - hexanes) 8 afforded 310.0 mg (68%) of the title compound as an orange solid. .
9 'H NMR (CDC13) b: 8.03 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.48-7.37 (3H, m), 4.80 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 3.14 (1H, septet, J =
6.8 11 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.27 (6H, d, J = 6.8 Hz), 0.96 (9H, s), 0.12 (6H, 12 s).
13 Meth.~~4-f4- test-butyl-dimethxl-silanyloxymethyl)-3-isopropy-1-14 phen, l~yn~ll-phenyl-acetate (Intermediate 154) Using General Procedure F; test-butyl-(4-ethynyl-2-isopropyl-16 benzyloxy)-dimethyl-silane (Intermediate 152, 355.0 mg, 1.26 mmols) and 17 methyl-(4-iodophenyl)-acetate (Reagent B, 349.0 mg, 1.26 mmols) in 18 triethylamine (8 mL) was treated with copper(I)iodide (60.0 mg, 0.32 mmol) 19 and sparged with argon for 5 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (222 mg, 0.32 mmol) was added 21 and the reaction mixture was stirred overnight at room temperature. Column 22 chromatography (2-5% EtOAc-hexanes) afforded 288.0 mg (66%) of the title 23 compound as an orange oil.
24 1H NMR (CDC13) b: 7.49 (2H, d, J = 8.5 Hz), 7.43-7.35 (3H, m), 7.25 (2H, d, J
= 8.5 Hz), 4.77 (2H, s), 3.69 (3H, s), 3.63 (2H, s), 3.11 (1H, septet, J = 6.7 26 Hz), 1.25 (6H, d, J = 6.7 Hz), 0.94 (9H, s), 0.10 (6H, s).
27 Ethyl f4-(4-hydroxymethyl-3-isopropyl-phen~lethyn~l-benzoate 28 (Compound 122, General Formula 6) 1 To a solution of ethyl 4-[4-(test butyl-dimethyl-silanyloxymethyl)-3-2 isopropyl-phenylethynyl]-benzoate (Intermediate 153, 310.0 mg, 0.71 mmol) 3 in 4 mL THF at 0 °C was added tetrabutylammonium fluoride (371.0 mg, 1.42 4 mmols; 1.4 mL of a 1M solution in THF). The pale-yellow solution was stirred for 10 minutes and quenched by the addition of ice cold H20. The 6 mixture was extracted with Et20 and the combined organic layers were 7 washed with Ha0 and saturated aqueous NaCl before being dried (Na2S04) 8 and concentrated under reduced pressure. Column chromatography (20-30%
9 EtOAc-hexanes) afforded 200.0 mg (87%) of the title compound as a colorless solid.
11 'H NMR (CDC13) 8: 7.98 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.48 12 ( 1 H, s), 7.3 5 (2H, m), 4.71 (2H, s), 4.3 5 (2H, q, J = 7.1 Hz), 3 .19 ( 1 H, septet, J
13 = 7.0 Hz), 2.51 (1H, s), 1.39 (3H, t, J = 7.1 Hz), 1.25 (6H, d, J = 7.0 Hz).
14 Methyl f4- 4-h~droxymethyl-3-isopropyl-phen 1y ethyn~l-phenyll-acetate I S (Compound 123, General Formula 6) 16 To a solution of methyl f 4-[4-(test-butyl-dimethyl-silanyloxymethyl)-17 3-isopropyl-phenylethynyl]-phenyl-acetate (Intermediate 154, 288.0 mg, 18 0.66 mmol) in 5 mL THF at 0 °C was added tetrabutylammonium fluoride 19 (471.0 mg, 1.80 mmols; 1.8 mL of a 1M solution in THF). The pale-yellow solution was stirred for 15 minutes and quenched by the addition of ice cold 21 H20. The mixture was extracted with EtzO and the combined organic layers 22 were washed with HZO and saturated aqueous NaCI before being dried 23 (Na2S04) and concentrated under reduced pressure. Column chromatography 24 (5-10% EtOAc-hexanes) afforded 180.0 mg (85%) of the title compound as a colorless solid.
26 'H NMR (CDCl3) 8: 7.48 (3H, m), 7.32 (2H, m), 7.24 (2H, d, J = 8.5 Hz), 4.69 27 (2H, s), 3.68 (3H, s), 3.62 (2H, s), 3.18 (1H, septet, J = 7.0 Hz), 2.21 (1H, s), 28 1.25 (6H, d, J = 7.0 Hz).
1 Ethvl ~4 (4 bromomethyl 3 isopropyl-phenylethynyll-benzoate 2 (Intermediate 155) 3 A solution of ethyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-4 benzoate (Compound 122, 200.0 mg, 0.62 mmol) and triphenylphosphine S (211.0 mg, 0.81 mmol) in 5 mL CH2C12 was cooled to 0 °C and N
6 bromosuccinimide (144.0 mg, 0.81 mmol) was added in 5 portions over 20 7 minutes. The solution was warmed to 25 °C and stirred for 17 hours.
The 8 reaction was quenched by the addition of dilute aqueous NaHC03. The 9 resulting mixture was extracted with Et20 and the combined organic layers were washed with H20 and saturated aqueous NaCI before being dried 11 (NaZS04) and concentrated under reduced pressure. The title compound, 220.0 12 mg (93%), was isolated by column chromatography (5% EtOAc-hexanes) as a 13 pale-yellow solid.
14 1H NMR (CDC13) ~: 8.03 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.48 ( 1 H, s), 7.31 (2H, m) 4.5 5 (2H, s), 4.3 9 (2H, q, J = 7.1 Hz), 3 .29 ( 1 H, septet, J
16 = 7.0 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.30 (6H, d, J = 7.0 Hz).
17 Meth j~4-bromomethXl-3-iso~ropyl-phen~ethynYl)-phen~]-acetate 18 (Intermediate 156) 19 A solution of methyl [4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and 21 triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CHZC12 was cooled to 0 22 °C and N bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions 23 over 20 minutes. The solution was warmed to 25 °C and stirred for 17 hours.
24 The reaction was quenched by the addition of dilute aqueous NaHC03. The resulting mixture was extracted with Et20 and the combined organic layers 26 were washed with H20 and saturated aqueous NaCl before being dried 27 (NaZS04) and concentrated under reduced pressure. The title compound, 212.0 28 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) 1 as a pale-yellow oil.
2 1H NMR (CDC13) b: 7.48 (3H, m), 7.28 (4H, m), 4.55 (2H, s), 3.69 (3H, s), 3 3.63 (2H, s), 3.28 (1H, septet, J = 7.0 Hz), 1.30 (6H, d, J = 7.0 Hz).
4 Ethyl [4-(4-imidazol-1- 1-meth 1-~propyl-phenyleth~yll-phen~]-S benzoate (Compound 124, General Formula 6) 6 A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-7 benzoate (Intermediate 155, 120.0 mg, 0.31 mmol) and 1-acetylimidazole 8 (36.0 mg, 0.33 mmol) in S mL CH3CN was heated at 6S °C for 4 hours and 9 then at SS °C for 16 hours. The solution was cooled to room temperature, diluted with H20 and made basic by addition of NaZC03, and extracted with 11 EtOAc. The combined organic layers were washed with H20 and saturated 12 aqueous NaCI, dried (MgS04), and concentrated under reduced pressure.
13 Column chromatography (1% Et3N in S% MeOH-EtOAc) afforded 75.0 mg 14 (65%) of the title compound as a colorless solid.
1H NMR (CDC13) 8: 8.03 (2H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.S Hz), 7.53 16 (1H, d, J = 1.S Hz), 7.49 (1H, s), 7.35 (1H, dd, J = 1.5, 7.9 Hz), 7.09 (1H, bs), 17 6.98 (1H, d, J = 7.9 Hz), 6.85 (1H, bs), 5.19 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 18 3.08 (1H, septet, J = 6.8 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.20 (6H, d, J =
6.8 Hz).
19 Meths[4-(4-imidazol-1- 1-~~isopropyl-phen~leth~nyl)~henyl]=
acetate (Compound 125, General Formula 6) 21 A solution of methyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-22 phenyl]-acetate (Intermediate 156, 72.0 mg, 0.19 mmol) and 1-23 acetylimidazole (22.0 mg, 0.20 mmol) in S mL CH3CN was heated at 6S
°C
24 for 8h and then at SS °C for 16 hours. The solution was cooled to room 2S temperature, diluted with H20 and made basic by addition of Na2C03, and 26 extracted with EtOAc. The combined organic layers, were washed with H20 27 and saturated aqueous NaCI, dried (MgS04), and concentrated under reduced 28 pressure. Column chromatography (0.5% Et3N in S% MeOH-EtOAc) afforded " 1 40.0 mg (58%) of the title compound as a colorless solid.
2 'H NMR (CDCl3) 8: 7.49 (4H, m), 7.33 (1H, dd, J = 1.5, 7.9 Hz), 7.28 (2H, d, 3 J=8.SHz),7.08(lH,t,J=1.2Hz),6.95(lH,d,J=7.9Hz),6.84(lH,t,J=
4 1.2 Hz), 5.17 (2H, s), 3.70 (3H, s), 3.64 (2H, s), 3.06 (1H, septet, J = 6.8 Hz), 1.20 (6H, d, J = 6.8 Hz).
6 [4-(4-Imidazol-1-yl-methyl-3-isoaropyl-phenylethynyll-phenyl]-benzoic acid 7 (Compound 126, General Formula 6) 8 ~Tsing General Procedure I; a solution of ethyl [4-(4-imidazol-1-9 ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-benzoate (Compound 124, 75.0 mg, 0.20 mmol) in ethanol (4 mL) and tetrahydrofuran ( 1 mL) was treated 11 with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and 12 stirred overnight at room temperature. Work-up afforded 68.0 mg (88%) of 13 the title compound as a colorless solid.
14 1H NMR (d4-MeOH) ~: 9.01 (1H, s), 8.01 (2H, d, J = 8.2 Hz), 7.63-7.57 (5H, 1S m), 7.44 (IH, d, J = 7.9 Hz), 7.29 (1H, d, J = 7.9 Hz), S.S9 (2H, s), 3.I7 (1H, 16 septet, J = 6.8 Hz), 1.20 (6H, d, J = 6.8 Hz).
17 [~4-Imidazol-1-yl-meth,~isopropyl-phenXlethynyll~phenyl]-acetic acid 18 (Compound 127, General Formula 6) 19 lJsing General Procedure I; a solution of methyl [4-(4-imidazol-I-ylmethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 125, 40.0 21 mg, 0.11 mmol) in ethanol (4 mL) and tetrahydrofuran ( 1 mL) was treated 22 with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and 23 stirred overnight at room temperature. Work-up afforded 22.0 mg (S2%) of 24 the title compound as a colorless solid.
'H NMR (d4-MeOH) S: 9.02 (1H, bs), 7.62 (1H, t, J = 1.4 Hz), 7.58 (2H, m), 26 7.49 (2H, d, J = 8.2 Hz), 7.43 (1H, dd, J = 1.5, 7.9 Hz), 7.31 (3H, m), 5.58 27 (2H, s), 3.68 (2H, s), 3.16 (1H, septet, J = 6.7 Hz), 1.18 (6H, d, J = 6.7 Hz).
28 4-Bromo-N c~propyl-2-methyl-benzamide (Intermediate 157) 1 A solution of 4-bromo-2-methylbenzoic acid and SOC12 was refluxed 2 for 3 hours, cooled to room temperature and concentrated under reduced 3 pressure. The residue was dissolved in 30 mL CH2C12 and combined with 4 cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine (2.05 g, 26.0 mmols).
The solution was stirred for 18 hours and then diluted with EtOAc before 6 being washed with 5% aqueous HCI, saturated NaHC03, and saturated 7 aqueous NaCl. The solution was dried (MgS04) and concentrated under 8 reduced pressure leaving the title compound as a colorless solid.
9 1H NMR (CDCl3) ~: 7.34 ( 1 H, d, J = 2.3 Hz), 7.28 ( 1 H, dd, J = 2.3, 8.2 Hz), 7.13 (1H, d, J = 8.2 Hz), 6.10 (1H, bs), 2.85 (1H, m), 2.37 (3H, s), 0.85 (2H, 11 m), 0.59 (2H, m).
12 (4-Bromo-2-meth 1-~yl)-cycloprop~l-amine (Intermediate 158) 13 To a solution of 4-bromo-N cyclopropyl-2-methyl-benzamide 14 (Intermediate 157, 1.81 g, 7.12 mmols) in THF (12 mL) was added BH3~SMe2 (1.08 g, 14.24 mmols). The solution was heated to 60 °C
for 6 16 hours, cooled to room temperature and carefully treated with saturated 17 aqueous Na2C03 (30 mL) and stirred for 17 hours. This mixture was extracted 18 with EtOAc and the combined organic layers were washed with HZO, saturated 19 aqueous NaCI before being dried (MgS04) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-21 15% EtOAc-hexanes).
22 1H NMR (CDC13) 8: 7.26 (2H, m), 7.12 (1H, d, J = 7.9 Hz), 3.76 (2H, s), 2.31 23 (3H, s), 2.14 (1H, m), 0.44 (2H, m), 0.36 (2H, m).
24 (4-Bromo-2-meth 1-benz~~c~pro~yl-ether-amine (Intermediate 159) A mixture of (4-bromo-2-methyl-benzyl)-cyclopropyl-amine 26 (Intermediate 158, 600.0 mg, 2.49 mmols), ethyl iodide (1.56 g, 10.0 mmols), 27 and KZC03 (690.0 mg, 5.00 mmols) in 10 mL acetone was heated at 60 °C fox 28 18 hours. The mixture was cooled to room temperature, diluted with H20, and 1 extracted with EtOAc. The combined organic layers were washed with Hz0 2 and saturated aqueous NaCl before being dried (MgS04) and concentrated 3 under reduced pressure. The title compound was isolated by column 4 chromatography (2.5% EtOAc-hexanes).
'H NMR (CDC13) 8: 7.23 (2H, m), 7.12 (1H, d, J = 7.6 Hz), 3.62 (2H, s), 2.56 6 (2H, q, J = 7.3 Hz), 2.29 (3H, s), 1.75 (1H, m), 1.04 (3H, t, J = 7.3 Hz), 0.39 7 (2H, m), 0.30 (2H, m).
8 Cyclopropyl-ethyl-(2-methyl-4-trimeth, ls~. 1~,~.~benz,~~l~amine 9 (Intermediate 160) Using General Procedure D; (4-bromo-2-methyl-benzyl)-cyclopropyl-11 ethyl-amine (Intermediate 159, 620.0 mg, 2.31 mmols) in triethylamine (8 12 mL) was treated with copper(I)iodide (44.0 mg, 0.23 mmol) and then sparged 13 with argon for 15 minutes. Trimethylsilylacetylene ( 1.04 g, 10.6 mmols) was 14 then added followed by dichlorobis-(triphenylphosphine)palladium(II) (162.0 mg, 0.23 mmol). The resulting reaction mixture was heated to 70 °C for 16 days. The title compound (650.0 mg, 98%) was isolated by chromatography 17 (1-4% EtOAc - hexanes).
18 'H NMR (CDCl3) S: 7.32 (1H, s), 7.20 (2H, m), 3.65 (2H, s), 2.5S (2H, q, J
=
19 7.3 Hz), 2.28 (3H, s), 1.74 (1H, m), 1.03 (3H, t, J = 7.3 Hz), 0.36 (2H, m), 0.27 (2H, m), 0.24 (9H, s).
21 C~clopropyl-ether(4-ethynyl-2-methyl-benzvll-amine (Intermediate 161) 22 Using General Procedure E; cyclopropyl-ethyl-(2-methyl-4-23 trimethylsilanylethynyl-benzyl)-amine (Intermediate 160, 650.0 mg, 2.30 24 mmols) in methanol (lOmL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne 26 (495 mg, 99%) was used directly in the next reaction.
27 'H NMR (CDCl3) 8: 7.32 (1H, s), 7.21 (2H, m), 3.66 (2H, s), 3.01 (1H, s), 2.56 28 (2H, q, J = 7.3 Hz), 2.29 (3H, s), 1.76 (1H, m), 1.04 (3H, t, J = 7.3 Hz), 0.40 I (2H, m), 0.29 (2H, m).
2 Ethyl~4- ~4-((c~cloprop~yl-amino)-meths]-3-methyl-phen~~nyl~-3 benzoate (Compound 128, General Formula 6) 4 Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo 6 benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was 7 treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 8 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 9 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc - hexanes) afforded the 11 title compound.
12 1H NMR (CDC13) 8: 8.01 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.31-13 7.24 (3H, m), 4.38 (2H, q, J = 7.1 Hz), 3.68 (2H, s), 2.58 (2H, q, J = 7.3 Hz), 14 2.32 (3H, s), 1.77 (1H, m), 1.39 (3H, t, J = 7.1 Hz), 1.05 (3H, t, J = 7.3 Hz), 0.39 (2H, m), 0.31 (2H, m).
16 Methyl (4-14-[(c~~cloprop~~l-amino)-methyll-3-methyl-phenyleth~n~)-17 phenyl)-acetate) (Compound 129, General Formula 6) I8 Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-19 benzyl)-amine (Intermediate 161, 300.0 mg, 1.41 mmols) and methyl-(4-iodophenyl)-acetate (Reagent B, 388.0 mg, 1.41 mmols) in triethylamine (8 21 mL) was treated with copper(I)iodide (67.0 mg, 0.35 mmol) and sparged with 22 argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (246 mg, 23 0.35 mmol) was added and the reaction mixture was stirred overnight at room 24 temperature. Column chromatography (5-7% EtOAc - hexanes) afforded 270.0 mg (53%) of the title compound as a pale-yellow oil.
26 'H NMR (CDC13) 8: 7.47 (2H, d, J = 7.9 Hz), 7.30-7.22 (5H, m), 3.70 (3H, s), 27 3.68 (2H, s), 3.63 (2H, s), 2.58 (2H, q, J = 7.3 Hz), 2.32 (3H, s), 1.77 (1H, m), 28 1.05 (3H, t, J = 7.3 Hz), 0.39 (2H, m), 0.30 (2H, m).
1 4-~4-[(CYcloprop~yl-aminol-methXl]-3-methyl-phen l~~yl -benzoic 2 acid: (Compound 130, General Formula 6) 3 Using General Procedure I; a solution of ethyl 4-~4-[(cyclopropyl-4 ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoate (Compound 128, 130.0 mg, 0.36 mmol) in ethanol (5 mL) and tetrahydrofuran {5 mL) was 6 treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) 7 and stirred overnight at room temperature. Work-up afforded 115.0 mg (96%) 8 of the title compound as a colorless solid.
9 'H NMR (d6-acetone) 8: 8.05 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.2 Hz), 7.32 (3H, m), 3.73 (2H, s), 2.59 (2H, q, J = 7.3 Hz), 2.35 (3H, s), 1.83 (1H, m), 11 1.05 (3H, t, J = 7.3 Hz), 0.38 (2H, m), 0.27 (2H, m).
12 (4- i4-[(C~loprop~yl-amino)-meths]-3-methyl-phenyleth~yl~phen~)-13 acetic acid (Compound 131, General Formula 6) 14 Using General Procedure I; a solution of methyl (4- f 4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl~-phenyl)-acetate (Compound 16 129, 140.0 mg, 0.39 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was 17 treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) 18 and stirred overnight at room temperature. Work-up followed by HPLC
19 (Partisil-10 pac 10% Ha0-CH3CN) afforded the title compound.
1H NMR (CDC13) 8: 7.45 (2H, d, J = 8.2 Hz), 7.25 (5H, m), 4.16 (2H, m), 3.82 21 (2H, s), 3.56 (2H, s), 2.75 (2H, q, J = 7.3 Hz), 2.30 (3H, s), 1.86 (1H, m), 1.14 22 (3H, t, J = 7.3 Hz), 0.54 (2H, m), 0.46 (2H, m).
23 Ethyl~~4-cyclopropylaminometh 1-3~-iso_propyl-then l~~n~ -benzoate 24 (Compound 132, General Formula 6) A solution of ethyl [4-(4-bromomethyl-3-isopropyl-phenylethynyl)-26 benzoate (Intermediate 155, 110.0 mg, 0.29 mmol) and cyclopropylamine 27 (420.0 mg, 7.4 mmols) in EtOH (5 mL) was stirred at 25 °C for 6 hours and 28 then concentrated under reduced pressure. The residue was dissolved in 1 EtOAc and washed with saturated aqueous NaHC03, H20 and saturated 2 aqueous NaCI. The solution was dried (MgS04) and concentrated under 3 reduced pressure to give 103 mg (99%) of the title compound as an orange oil.
4 1H NMR (CDCl3) 8: 8.01 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.5 Hz), 7.47 ( 1 H, s), 7.3 0 (2H, m), 4.3 8 (2H, q, J = 7.1 Hz), 3.89 (2H, s), 3.26 ( 1 H, septet, J
6 = 7.0 Hz), 2.17 ( 1 H, m), 1.40 (3H, t, J = 7.1 Hz), 1.26 (6H, d, J = 7.0 Hz), 0.45 7 (2H, m), 0.39 (2H, m).
8 Eth~f4-[(c ~cloprop~yl-amino)-meths]-3-isoprop~phen~lethyn~~-9 benzoate (Compound 133, General Formula 6) To a solution of ethyl {4-(4-cyclopropylaminomethyl-3-isopropyl-11 phenylethynyl~-benzoate (Compound 132, 103.0 mg, 0.29 mmol) in 6 mL of 12 acetone was added ethyl iodide (67.0 mg, 0.43 mmol) and K2C03 (79.0 mg, 13 0.57 mmol). The mixture was stirred at 60 °C for 6 hours, cooled to room 14 temperature and quenched by the addition of H20. The mixture was extracted with EtOAc and the combined organic layers were washed with H20 and 16 saturated aqueous NaCI before being dried (MgS04) and concentrated under 17 reduced pressure. Column chromatography (4-5% EtOAc - hexanes) afforded 18 . 68.0 mg (59%) of the title compound.
19 IH NMR (CDC13) S: 8.01 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.44 (1H, s), 7.28 (2H, m), 4.39 (2H, q, J = 7.1 Hz), 3.73 (2H, s), 3.55 (1H, septet, J
21 = 6.6 Hz), 2.57 (2H, q, J = 7.3 Hz), 1.75 (1H, m), 1.40 (3H, t, J = 7.1 hz), 1.22 22 (6H, d, J = 6.6 Hz), 1.05 (3H, t, J = 7.3 Hz), 0.37 (2H, m), 0.28 (2H, m).
23 4-~4-[~CyclopropYl-ethyl-amino)-methyl]-3-isoprop 1-~phen~eth~~~-24 benzoic acid (Compound 134, General Formula 6) Using General Procedure I; a solution of ethyl 4-~4-[(cyclopropyl-26 ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 27 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 28 treated with NaOH (600.0 mg,15.0 mmols, 3.0 mL of a SN aqueous solution) 1 and stirred overnight at room temperature and then at 55 °C for 9 hours.
2 Work-up followed by crystallization of the solid residue from hot CH3CN
3 afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
4 'H NMR (d6-acetone) $: 8.05 (2H, d, J = 8.1 Hz), 7.66 (2H, d, J = 8.1 Hz), 7.49 (1H, s), 7.32 (2H, m), 3.78 (2H, s), 3.44 (1H, septet, J = 6.7 Hz), 2.59 6 (2H, q, J = 7.3 Hz), 1.80 (1H, m), 1.21 (6H, d, J = 6.7 Hz), 1.05 (3H, t, J
= 7.3 7 Hz), 0.40 (2H, m), 0.26 (2H, m).
8 Meth[4-(8,8-dimethXl-5-oxo-SY6,7,8-tetrahydro-naphthalen-2- ~~l-eth~yl),~
9 phenyl-acetate (Compound 4, General Formula 8) Using General Procedure F; 6-ethynyl-4,4-dimethyl-3,4-dihydro-2H
11 naphthalen-1-one (Intermediate 13, 190.0 mg, 0.96 mmol) and methyl-(4-12 iodophenyl)-acetate (Reagent B, 245.0 mg, 0.96 mmol) in triethyl amine (8 I3 mL) was treated with copper(I)iodide (46 mg, 0.24 mmol) and sparged with 14 argon for 1S minutes. Dichlorobis(triphenylphosphine)palladium(II) (168 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight at room 16 temperature. Column chromatography (10-20% EtOAc - hexanes) afforded 17 250.0 mg (75%) of the title compound as a pale-yellow solid.
18 'H NMR (CDC13) 8: 7.99 (1H, d, J = 7.9 Hz), 7.57 (1H, d, J = 1.5 Hz), 7.51 19 (2H, d, J = 8.5 Hz), 7.43 ( 1 H, dd, J = 1.5, 7.9 Hz), 7.29 (2H, d, J = 8.5 Hz), 3.70 (3H, s), 3.65 (2H, s), 2.73 (2H, t, J = 7.0 Hz), 2.04 (2H, t, J = 7.0 Hz), 21 1.41 (6H, s).
22 Meth[~5-h~~,8-dimeth~l-5,6,7,8-tetrahydro-naphthalen-2-23 ethyn~~phenyl]t-acetate (Compound 135, General Formula 4) 24 To a solution of methyl [4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 4) in 5 mL MeOH at 0 26 °C was added NaBH4 (18.0 mg, 0.48 mmol). The reaction was stirred at 0 °C
27 for 2 hours and then quenched by the addition of H20. The solution was 28 diluted with Et20 and washed with H20 and saturated aqueous NaCI before 1 being dried (MgS04) and the solvents were removed under reduced pressure.
2 Column chromatography (20-40% EtOAc-hexanes) afforded 140.0 mg (87%) 3 of the title compound as a colorless oil.
4 1H NMR (CDC13) b: 7.49 (3H, m), 7.39 (1H, d, J = 7.9 Hz), 7.31 (1H, dd, J =
1.5, 7.9 Hz), 7.25 (2H, d, J = 8.2 Hz), 4.58 (1H, bs), 3.68 (3H, s), 3.62 (2H, s), 6 2.05 (1H, m), 1.79 (2H, m), 1.60 (1H, m), 1.33 (3H, s), 1.26 (3H, s).
7 Meth[4-(5-imidazol-1-~,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-8 Xlethyn~~phen,~T1]-acetate (Compound 136, General Formula 4) 9 A solution of methyl [4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 11 mmol) and carbonyldiimidazole (136.0 mg, 0.84 mmol) in 5 mL THF was 12 heated to 65 °C for 48 hours. The solution was cooled to room temperature 13 and concentrated under reduced pressure. The residue was dissolved in EtzO
14 and washed with 5% aqueous NaOH, HZO, and saturated aqueous NaCI before being dried (NaaS04) and concentrated under reduced pressure. Column 16. chromatography (5% MeOH-CHZCla) afforded 50.0 mg (31%) of the title 17 compound as a colorless solid.
18 1H NMR (CDC13) 8: 7.57 (1H, d, J = 1.5 Hz), 7.52-7.45 (3H, m), 7.27 (3H, m), 19 7.08 (1H, s), 6.81 (2H, m), 5.30 (1H, t, J = 5.8 Hz), 3.71 (3H, s), 3.65 (2H, s), 2.20 (2H, m), 1.75 (2H, m), 1.40 (3H, s), 1.36 (3H, s).
21 [~5-Imidazol-1-~l-,8-dimeth~ 6 7.8-tetrahydro-naphthalen-2-~~yl)-22 phenyl]-acetic acid (Compound 137, General Formula 4) 23 Using General Procedure I; a solution of methyl [4-(5-imidazol-1-yl-24 8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated with 26 NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred 27 overnight at room temperature. Work-up afforded 40.0 mg (83%) of the title 28 compound as a pale-orange solid.
29 'H NMR (d4-MeOH) 8: 8.93 (1H, s), 7.68 (1H, s), 7.61 (1H, s), 7.54 (1H, s), 1 7.47 (2H, d, J = 8.2 Hz), 7.31 (3H, m), 6.95 ( 1 H, d, J = 8.2 Hz), 5.83 ( 1 H, t, J
2 = 5.8 Hz), 3.68 (1H, s), 3.63 (1H, s), 2.38 (1H, m), 2.26 (1H, m), 1.76 (2H, m), 3 1.45 (3H, s), 1.36 (3H, s).
4 Ethyl [4-(5-imidazol-1-yl-8,8-dimeth~l-5 6,7,8-tetrah d~ronaphthalen-2- ~~1-ethyn~l)-benzoate (Compound 138, General Formula 4) 6 A solution of ethyl [4-(S-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-7 naphthalen-2-yl-ethynyl)-benzoate (180.0 mg, 0.52 mmol) and 8 carbonyldiimidazole (176.0 mg, 1.08 mmol) in 5 mL THF was heated to 65 °C
9 for 21 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in Et20 and washed with 11 55 aqueous NaOH, H20, and saturated aqueous NaCI before being dried 12 (NaZSO~) and concentrated under reuced pressure. Column chromatography 13 (5% MeOH-CHZC12) afforded 50.0 mg (24%) of the title compound as a I4 colorless solid.
1H NMR (CDC13) 8: 8.03 (2H, d, J = 7.9 Hz), 7.59 (3H, m), 7.46 (1H, s), 7.29 16 ( 1 H, dd, J = 1. 5, 8.3 Hz), 7.09 ( 1 H, s), 6. 82 ( I H, d, J = 8 .2 Hz), 6. 81 ( 1 H, s), 17 5.31 (1H, t, J = 5.8 Hz), 4.39 (2H, q, J = 7.1 Hz), 2.20 (2H, m), 1.75 (2H, m), 18 1.40 (9H, m).
19 [4-(S-Imidazol-I ;yl-88,~-dimethyl-55,6,7,8-tetrahydro-naphthalen-2-Xl-ethynyll-benzoic acid (Compound 139, General Formula 4) 21 Using General Procedure I; a solution of ethyl [4-(5-imidazol-1-yl-8,8-22 dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoate (Compound 23 138, 50.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (1 mL) was 24 treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (87%) 26 of the title compound as a colorless solid.
27 1H NMR (d4-MeOH) 8: 8.92 ( 1 H, s), 8.04 (2H, d, J = 8.2 Hz), 7.74 ( 1 H, d, J =
28 1.5 Hz), 7.62 (3H, m), 7.57 ( 1 H, t, J = 1.5 Hz), 7.3 8 ( 1 H, dd, J =1.5, 7.9 Hz), 29 6.97 (1H, d, J = 7.9 Hz), 5.83 (IH, t, J = 5.8 Hz), 2.33 (2H, m), 1.78 (2H, m), 1 1.47 (3H, s), 1.39 (3H, s).
2 2-Isopr~yl-4-trifluoromethanesulfonXloxy-benzyl acetate (Intermediate 3 162) 4 To a solution of 4-hydroxymethyl-3-isopropylphenyl 1,1,1-trifluoromethanesulfonate (Intermediate 149, 190.0 mg, 0.64 mmol) in 5 mL
6 CH2C12 was added acetyl chloride (75.0 mg, 0.9b mmol) and pyridine(101.0 7 mg, 1.38 mmols). After stirnng for 3 hours at 25 °C the reaction was 8 quenched by the addition of HZO and the resulting mixture extracted with 9 EtOAc. The combined organic layers were washed with Hz0 and saturated aqueous NaCl, dried (lVIgSO4) and concentrated under reduced pressure. The 11 title compound, 182 mg (84%), was isolated from the residual oil by column 12 chromatography (5 - 10% EtOAc-hexanes) as a colorless oil.
13 ' H NMR (CDCl3) 8: 7.43 ( 1 H, d, J = 8. 7 Hz), 7.19 ( 1 H, d, J = 2. 7 Hz), 7.09 14 ( 1 H, dd, J = 2.7, 8.5 Hz), 5.17 (2H, s), 3.18 ( 1 H, septet, J = 6.7 Hz), 2.10 (3H, s), 1.26 (6H, d, J = 6.7 Hz).
16 4-Isopropen~lox meth 1-prop 1-phenyl 1-trifluoromethanesulfonate 17 (Intermediate 163) 18 Using General Procedure 1; 2-isopropyl-4-19 trifluoromethanesulfonyloxy-benzyl acetate (Intermediate 162, 182.0 mg, 0.54 mmols), and 1.1 mL of Tebbe's Reagent ( 159.0 mg, 0.56 mmols) afforded 21 130.0 mg (72%) of the title compound as a colorless oil after column 22 chromatography (2-5% EtOAc-hexanes).
23 1H NMR (CDC13) 8: 7.43 (1H, d, J = 8.S Hz), 7.18 (1H, d, J = 2.6 Hz), 7.09 24 ( 1 H, dd, J = 2.6, 8.5 Hz), 4.75 (2H, s), 3 .98 (2H, s), 3 .12 ( 1 H, septet, J = 6.7 Hz), 1.88 (3H, s), 1.25 (6H, d, J = Hz).
26 3-Isopropyl-4-(1-methyl-cyclopropox~meth~l-phen~ 1 27 trifluoromethanesulfonate (Intermediate 164) 28 Using General Procedure 2; 4-isopropenyloxymethyl-3-isopropylphenyl 1 1,1,1-trifluoromethanesulfonate (Intermediate 163, 130. 0 mg, 0.39 mmol), 2 Et2Zn (272.0 mg, 2.2 mmols), and CH2I2 (702.0 mg, 2.6 mmols) in 3.0 mL
3 Et~O afforded 120.0 mg (89%) of the title compound as a colorless oil after 4 column chromatography (4-5% EtOAc - hexanes).
'H NMR (CDC13) 8: 7.39 (1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 2.7 Hz), 7.05 6 (1H, dd, J = 2.7, 8.5 Hz), 4.54 (2H, s), 3.16 (1H, septet, J = 6.7 Hz), 1.47 (3H, 7 s), 1.24 (6H, d, J = 6.7 Hz), 0.86 (2H, m), 0.48 (2H, m).
8 (3-Isoprop~-4-(1-methyl-c~propoxymeth~l-phenyleth~yl]-9 trimeth. ls~ (Tntermediate 165) Using General Procedure D; 3-isopropyl-4-( 1-methyl-11 cyclopropoxymethyl)-phenyl l,l,l-trifluoromethanesulfonate (Intermediate 12 164, 120.0 mg, 0.34mmo1) in triethylamine (2 mL) and anhydrous DMF (5 13 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 14 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (24.0 mg, 0.03 mmol). The 16 resulting reaction mixture was heated to 95 °C for 60 hours. The title 17 compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc -18 hexanes).
19 IH NMR (CDC13) ~: 7.36 (1H, s), 7.24 (2H, bs), 4.53 (2H, s), 3.11 (1H, septet, J = 6.7 Hz), 1.45 (3H, s), 1.22 (6H, d, J = 6.7 Hz), 0.85 (2H, m), 0.44 (2H, m), 21 0.25 (9H, s).
22 4-Ethyn 1-2-isopropyl-1-(1-methyl-cyclopropoxymeth~)-benzene 23 (Intermediate 166) 24 Using General Procedure E; [3-isopropyl-4-( 1-methyl-cyclopropoxymethyl)-phenylethynyl]-trimethylsilane (Intermediate 165, 26 110.0 mg, 0.37 mmol) in methanol (6 mL) was treated with potassium 27 carbonate (80.0 mg, 0.58 mmol) and stirred overnight at ambient temperature.
28 The crude alkyne (84 mg, 100%) was used directly in the next reaction.
1 1H NMR (CDC13) 8: 7.55 (1H, s), 7.41 (2H, m), 4.68 (2H, s), 3.26 (1H, septet, 2 J = 6.8 Hz), 3.18 (1H, s), 1.60 (3H, s), 1.37 (6H, d, J = 6.8 Hz), 0.99 (2H, m), 3 0.59 (2H, m).
4 Methyl f4-~3-isopropyl-4~1-methyl-c~clopropox~~l-phen l~~nyll' phenyll-acetate (Compound 140, General Formula 6) 6 Using General Procedure F; 4-ethynyl-2-isopropyl-1-(1-methyl-7 cyclopropoxymethyl)-benzene (Intermediate 166, 78.0 mg, 0.34 mmol) and 8 methyl-(4-iodophenyl)-acetate (Reagent B, 94.0 mg, 0.34 mmol) in 9 triethylamine (8 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes.
11 Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol) was added 12 and the reaction mixture was stirred at room temperature for 3.5 hours.
13 Column chromatography (2-5% EtOAc - hexanes) afforded 77.0 mg (60%) of 14 the title compound as a yellow oil.
1H NMR (CDC13) 8: 7.49 (2H, d, J = 8.2 Hz), 7.43 (1H, d, J = 1.5 Hz), 7.33-16 7.24 (4H, m), 4.55 (2H, s), 3.70 (3H, s), 3.63 (2H, s), 3.14 (1H, septet, J
= 6.8 17 Hz), 1.47 (3H, s), 1.25 (6H, d, J = 6.8 Hz), 0.86 (2H, m), 0.46 (2H, m).
18 ~4-[3-Isopropyl-methyl-c~clopropox~meth~~-phen l~ethyn~]-phenyl}-19 acetic acid (Compound 141, Formula 6) Using General Procedure I; a solution methyl f 4-[3-isopropyl-4-(1-21 methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate (Compound 22 140, 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was 23 treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3N aqueous solution) 24 and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H20/CH3CN) afforded of the title compound as a 26 colorless solid.
27 'H NMR (CDC13) 8: 7.50 (2H, d, J = 8.2 Hz), 7.43 (1H, s), 7.33-7.24 (4H, m), 28 4.55 (2H, s), 3.65 (2H, s), 3.14 (1H, septet, J = 6.7 Hz), 1.47 (3H, s), 1.25 (6H, 1 d, J = 6.7 Hz), 0.87 (2H, m), 0.46 (2H, m).
2 2,6-Di-tert-butyl-4-trimeth, lsy ilan,~ethynyl-phenol: (Intermediate 167) 3 Following General Procedure D and using 4-bromo-2,6-di-t-butyl-4 phenol (1.438, Smmol), triethyl amine (lSmL), anhydrous tetrahydrofuran (lSmL), copper(I)iodide (0.06g., 0.31mmol), trimethylsilyl acetylene (4.9g, 6 SOmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.18g, 0.26mmol) 7 followed by flash column chromatography over silica gel (230-400 mesh) 8 using hexane as eluent, the title compound was obtained (1.35g, 90%).
9 1H NMR (300 MHz, CDCl3): 8 7.29 (s, 2H), 5.35 (s, 1H), 1.42 (s, 18H), 0.24 (s, 9H).
11 X3,5-Di-tent-but~methoxy-phen l~~n~)-trimeth~ilane: (Intermediate 12 168) 13 A solution 2,6-di-tert-butyl-4-trimethylsilanylethynyl-phenol 14 (Intermediate 167, 0.302g, lmmol) in acetone (SmL) was treated with potassium carbonate (0.138g, lmmol) and methyl iodide (0.142g, lmmol) and 16 stirred overnight at room temperature. The volatiles were distilled off in 17 vacuo and the residue was purified by flash column chromatography on silica 18 gel (230-400 mesh) using ethyl acetate as the eluent to afford the title 19 compound as a white solid (0.28g, 90%).
1H NMR (300 MHz, CDCl3): 8 7.41 (s, 2H), 3.70 (s, 3H), 1.49 (s, 18H), 0.30 21 (s, 9H).
22 1.3-Di-tert-bu 1-tY 5eth~nyl-2-methoxX-benzene: (Intermediate 169) 23 Following General Procedure E and (3,5-di-tert-butyl-4-methoxy-24 phenylethynyl)-trimethyl-silane (Intermediate 168, 0.28g, 0.9mmol), potassium carbonate (0.988, 7.lmmol) and methanol (lOmL) followed by flash 26 column chromatography over silica gel (230-400 mesh) using hexane as the 27 eluent, the title compound was obtained (0.238, 100%).
28 'H NMR (300 MHz, CDC13): b 7.46 (s, 2H), 3.75 (s, 3H), 3.05 (s, 1H), 1.49 (s, 1 18H).
2 [4-(3,5-Di-tert-butyl-4-methox -y_phen,~,~m, 11-~T phen~ll-acetic acid meth 3 ester: (Compound 142, General Formula 5) 4 Following General Procedure F and using 1,3-di-test-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.0948, 0.36mmo1), methyl-4-iodo 6 phenyl acetate (Reagent B, 0.098, 0.32mmo1), triethyl amine (SmL), 7 anhydrous tetrahydrofuran (SmL), copper(I)iodide (0.028, O.lmmol) and 8 dichlorobis(triphenylphosphine)palladium(II) (0.068, 0.085mmo1) followed by 9 flash column chromatography over silica gel (230-400 mesh) using 10 % ethyl acetate in hexane as the eluent, the title compound (0.1148, 81 %) was obtained 11 as an oil.
12 'H NMR (300 MHz, CDC13): 8 7.52 (d, 2H, J= 8.OHz), 7.46 (s, 2H), 7.28 (d, 13 2H, J= 8.2Hz), 3.72 (s, 3H), 3.71(s, 3H), 3.66 (s, 2H), 1.47 (s, 18H).
14 ~f4-(3,5-Di-tert-butyl-4-methoxy-phenyleth~yl)-phmyl]-acetic acid:
(Compound 143, General Formula 5) 16 Following General Procedure I and using [4-(3,5-di-test-butyl-4-17 methoxy-phenylethynyl)-phenyl]-acetic acid methyl ester (Compound 142, 18 0.1148, 0.29mmo1), SM aqueous sodium hydroxide solution (2mL) and 19 ethanol (4mL), followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white 21 solid (0.0978, 88%).
22 IH NMR (300 MHz, CDCl3): b 7.55(d, 2H, J= 8.OHz), 7.48 (s, 2H), 7.30 (d, 23 2H, J= 8.2Hz), 3.74 (s, 3H), 3.69 (s, 2H), 1.49 (s, 18H).
24 [4-(3,5-Di-test-butyl-4-methoxy-phenyleth~nyl)-2-fluoro-phen~]-acetic acid meth,1~: (Compound 144, General Formula 5) 26 Following General Procedure F and using 1,3-di-test-butyl-5-ethynyl-2-27 methoxy-benzene (Intermediate 169, 0.0878, 0.33mmo1), methyl-2-fluoro-4-28 iodo phenyl acetate (Reagent H, 0.0888, 0.30mmo1), triethyl amine (SmL), 29 anhydrous tetrahydrofuran (lOmL), copper(I)iodide (0.028, O.lmmol) and dichlorobis(triphenylphosphine)palladium(II) (0.068, 0.085mmol) followed by 1 flash column chromatography over silica gel (230-400 mesh) using 10 % ethyl 2 acetate in hexane as the eluent, the title compound (0.1228, 89%) was 3 obtained.
4 1H NMR (300 MHz, CDC13): 8 7.46 (s, 2H), 7.33-7.24 (m, 3H), 3.75 (s, 3H), 3.73(s, 3H), 3.72 (s, 2H), 1.48 (s, 18H).
6 [~3,5-Di-test-butyl-4-methox~phen l~yn~l-2-fluoro-pheny~-acetic acid:
7 (Compound 145, General Formula 5) 8 Following General Procedure I and using [4-(3,5-di-test-butyl-4-9 methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid methyl ester.
(Compound 144, 0.1228, 0.29mmol), SM aqueous sodium hydroxide solution 11 ( 1mL) and ethanol (4mL), followed preparative reverse phase HPLC using 12 10% water in acetonitrile as the mobile phase, the title compound was 13 obtained as a white solid (0.0778, 65%).
14 'H NMR (300 MHz, CDC13): S 7.42 (s, 2H), 7.29-7.19 (m, 3H), 3.71 (s, 2H), 3.69 (s, 3H), 1.43 (s, 18H).
Claims (87)
1. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-;
-CO-O-, -O-CO-, -CS-NR1-, NR1CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 2;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-;
-CO-O-, -O-CO-, -CS-NR1-, NR1CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 2;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
2. A method in accordance with Claim 1 wherein the compound has the formula where X is O or CH3N;
Y is H or cyclopropyl;
Z is -C.ident.C- or -CO-O-;
R2 is H or F;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
Y is H or cyclopropyl;
Z is -C.ident.C- or -CO-O-;
R2 is H or F;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
3. A method in accordance with Claim 2 wherein the compound is selected from the group consisting of:
benzoic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-, benzeneacetic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]- and 2-fluoro-benzoic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]- or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
benzoic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H 1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-, benzeneacetic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]- and 2-fluoro-benzoic acid, 4-[(3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]- or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
4. A method in accordance with Claim 2 wherein the compound is selected from the group consisting of:
benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneacetic acid , benzoic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]- and 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
benzeneacetic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneacetic acid , benzoic acid, 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]- and 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1'-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
5. A method in accordance with Claim 2 wherein the compound is spiro[2H-1-benzopyran-2,1'-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 4-(carboxymethyl)phenyl ester or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
6. A method in accordance with Claim 2 wherein the compound is spiro[2H-1-benzopyran-2,1'-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-, 3-(carboxymethyl)phenyl ester or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
7. A method in accordance with Claim 2 wherein the compound is benzoic acid, 4-[(1,4,4-trimethylspiro[2H-1-1,2,3,4-tetrahydroquinoline-2,1'-cyclopropane]-6-yl)ethynyl]- or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
8. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 4;
R5 is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 4;
R5 is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
9. A method in accordance with Claim 8 wherein the compound has the formula where X is O, NR where R is H, n-propyl or benzyl;
R3 is H or lower alkyl of 1 to 6 carbons;
R5 is benzyl or lower alkyl of 1 to 6 carbons;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
R3 is H or lower alkyl of 1 to 6 carbons;
R5 is benzyl or lower alkyl of 1 to 6 carbons;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
10. A method in accordance with Claim 9 wherein the compound is selected from the group consisting of 4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoic acid and 4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
11. A method in accordance with Claim 9 wherein the compound is selected from the group consisting of 4-[4-(1-dibenzylamino-cyclopropyl)-phenylethynyl]-benzoic acid and 4-[4-(1-benzylmethylamino-cyclopropyl)-phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
12. A method in accordance with Claim 9 wherein the compound is selected from the group consisting of 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoic acid, 4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoic acid and 4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
13. A method in accordance with Claim 9 wherein the compound is selected from the group consisting of {4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid, {4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetic acid and {4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
14. A method in accordance with Claim 9 wherein the compound is selected from the group consisting of 4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoic acid, 4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoic acid, 4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-benzoic acid, 4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoic acid and 4-[4-(1-ethoxycyclopropyl)-3-teat-butyl-phenylethynyl]-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
15. A method in accordance with Claim 9 wherein the compound is selected from the group consisting of {4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid, {4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-phenyl}-acetic acid, {4-[4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetic acid, {4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-phenyl}-acetic acid, {4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetic acid, {4-[4-(1-isopropoxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetic acid and {4-[4-(1-ethoxycyclopropyl)-3-tert-butyl-phenylethynyl]-phenyl}-acetic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
16. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or I;
Z is -C=C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base.
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or I;
Z is -C=C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base.
17. A method in accordance with Claim 16 wherein the compound has the formula where R2 is H or halogen;
n is 0 or 1 and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
n is 0 or 1 and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
18. A method in accordance with Claim 17 wherein the compound is [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-2-fluoro-phenyl]-acetic acid or a salt with a pharmaceutically acceptable base.
19. A method in accordance with Claim 17 wherein the compound is [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl-ethynyl)-phenyl]-acetic acid or a salt with a pharmaceutically acceptable base.
20. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X1 is 1-imidazolyl, or lower alkyl or halogen substituted 1-imidazolyl, OR, SR, NRR6 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C=C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
R6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that when Y is H, A is phenyl and X1 is OH then n is 1 to 4.
X1 is 1-imidazolyl, or lower alkyl or halogen substituted 1-imidazolyl, OR, SR, NRR6 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C=C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
R6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that when Y is H, A is phenyl and X1 is OH then n is 1 to 4.
21. A method in accordance with Claim 20 wherein the compound has the formula wherein X1 is 1-imidazolyl, or dialkyl-N or alkyl,cyclopropyl-N where the alkyl group has 1 to 6 carbons;
R2 is H or halogen;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
R2 is H or halogen;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
22. A method in accordance with Claim 21 where the compound is selected from the group consisting of 4-[(5-cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2yl-ethynyl]-benzoic acid and 4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl]-2-fluoro benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
23. A method in accordance with Claim 21 where the compound is selected from the group consisting of 4-[(5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-acetic acid and [4-(5-(cyclopropyl-methyl-amino)-8,8-dimethyl- 5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-2-fluoro-phenyl]-acetic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
24. A method in accordance with Claim 21 where the compound is 4-[5-(iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)]-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
25. A method in accordance with Claim 21 where the compound is [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-benzoic acid or a salt with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
26. A method in accordance with Claim 21 where the compound is [4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetic acid or a salt with a pharmaceutically acceptable base or a C1-alkyl ester of said compound.
27. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C1-6-trialkylsilyl or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons; cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons;
n is an integer having the values of 1 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C1-6-trialkylsilyl or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons; cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons;
n is an integer having the values of 1 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
28. A method in accordance with Claim 27 wherein the compound has the formula wherein Y is branched-chain alkyl of 3 to 6 carbons;
R2 is H or F;
R3 is branched-chain alkyl of 3 to 6 carbons;
R7 is lower alkyl of 1 to 6 carbons, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
R2 is H or F;
R3 is branched-chain alkyl of 3 to 6 carbons;
R7 is lower alkyl of 1 to 6 carbons, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
29. A method in accordance with Claim 27 where the compound is selected from the group consisting of [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acid and [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-2-fluoro-phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base.
30. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR7, SR7 or NRR7 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons or C1-6-trialkylsilyl.
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
X2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR7, SR7 or NRR7 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons or C1-6-trialkylsilyl.
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
31. A method in accordance with Claim 30 where the compound has the formula wherein R3 is alkyl of 1 to 6 carbons;
X2 is 1-imidazolyl, OR7, or NRR7 where R is alkyl of 1 to 6 carbons or cyclopropyl, and R7 is alkyl of 1 to 6 carbons, cyclopropyl or lower alkyl substituted cyclopropyl;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
X2 is 1-imidazolyl, OR7, or NRR7 where R is alkyl of 1 to 6 carbons or cyclopropyl, and R7 is alkyl of 1 to 6 carbons, cyclopropyl or lower alkyl substituted cyclopropyl;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
32. A method in accordance with Claim 31 wherein the compound is selected from the group consisting of 4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-benzoic acid and [4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
33. A method in accordance with Claim 31 where the compound is selected from the group consisting of [4-(4-imidazol-1-yl-methyl-3-methyl-phenylethynyl)-phenyl]-acetic acid and [4-(4-imidazol-1-yl-methyl-3-isopropyl-phenylethynyl)-phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
34. A method in accordance with Claim 31 where the compound is selected from the group consisting of 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-benzoic and 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
35. A method in accordance with Claim 31 where the compound is (4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
36. A method in accordance with Claim 31 where the compound is {4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
37. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal as effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or I;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
38. A method in accordance with Claim 37 where the compound has the formula wherein R2 is hydrogen, alkyl of 1 to 6 carbons, or halogen n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base.
39. A method in accordance with Claim 38 where the compound is 4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
40. A method in accordance with Claim 38 where the compound is [4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-yl-ethynyl)phenyl] acetic acid methyl ester.
41. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound of the formula wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X3 is S, or O, C(R1)2, or CO;
Y1 is H, lower alkyl of 1 to 3 carbons, cycloalkyl of 3 to 6 carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of:
Y1 is cycloalkyl, when Y1 is not cycloalkyl then X3 is O or S and n is 1, when Y1 is not cycloalkyl then X3 is CO, and n is 1, when Y1 is not cycloalkyl then X3 is CO and the moiety A is substituted with at least one F group.
X3 is S, or O, C(R1)2, or CO;
Y1 is H, lower alkyl of 1 to 3 carbons, cycloalkyl of 3 to 6 carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
Z is -C.ident.C-, -(CR1=CR1)n' where n' is an integer having the value 1 - 5, -CO-NR1-, NR1-CO-, -CO-O-, -O-CO-, -CS-NR1-, NR1-CS-, -CO-S-, -S-CO-, -N=N-;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of:
Y1 is cycloalkyl, when Y1 is not cycloalkyl then X3 is O or S and n is 1, when Y1 is not cycloalkyl then X3 is CO, and n is 1, when Y1 is not cycloalkyl then X3 is CO and the moiety A is substituted with at least one F group.
42. A method in accordance with Claim 41 where the compound has the formula wherein R2 is H or F;
R3 is H or lower alkyl of 1 to 6 carbons;
X3 is O or CO;
Y1 is H, alkyl of 1 to 6 carbons, or cyclopropyl;
Z is -C.ident.C- or -CO-O-;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of:
Y1 is cyclopropyl, when Y1 is not cyclopropyl then X3 is O and n is 1, when Y1 is not cyclopropyl then X3 is CO, and n is 1, when Y1 is not cyclopropyl then X3 is CO and the moiety A is substituted with at least one F group.
R3 is H or lower alkyl of 1 to 6 carbons;
X3 is O or CO;
Y1 is H, alkyl of 1 to 6 carbons, or cyclopropyl;
Z is -C.ident.C- or -CO-O-;
n is 0 or 1, and R8 is H, alkyl of 1 to 6 carbons, or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of:
Y1 is cyclopropyl, when Y1 is not cyclopropyl then X3 is O and n is 1, when Y1 is not cyclopropyl then X3 is CO, and n is 1, when Y1 is not cyclopropyl then X3 is CO and the moiety A is substituted with at least one F group.
43. A method in accordance with Claim 42 where the compound is 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
44. A method in accordance with Claim 42 where the compound is selected from the group consisting of 4-[(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)-phenyl]-acetic acid and [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl-ethynyl)phenyl]-acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
45. A method in accordance with Claim 42 where the compound is 2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
46. A method in accordance with Claim 42 where the compound is selected from the group consisting of [4-(2,2,4,4-tetramethyl-chxoman-6-yl-ethynyl) phenyl] acetic acid, [2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid and [4-(8-ethyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
47. A method in accordance with Claim 42 where the compound is 4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-benzoic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
48. A method in accordance with Claim 42 where the compound is selected from the group consisting of [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl] acetic acid and [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl] acetic acid or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
49. A method in accordance with Claim 42 where the compound is 8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid-4-(carboxymethyl)phenyl ester or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
50. A method in accordance with Claim 42 where the compound is 2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4-(carboxymethyl)phenyl ester or a salt of said compound with a pharmaceutically acceptable base or a C1-6 alkyl ester of said compound.
51. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
X5 is O, X6 is CH, n is 0 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 1 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 0 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base; and X5 is S, X6 is N, n is 0 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
X5 is O, X6 is CH, n is 0 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 1 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 0 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base; and X5 is S, X6 is N, n is 0 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
52. A method in accordance with Claim 51 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
X5 is O, X6 is CH, n is 0 and R8 is H or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 1 and R8 is H or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 2 and R8 is H or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 0 and R8 is H or a cation of a pharmaceutically acceptable base; and X5 is S, X6 is N, n is 0 and R8 is H or a cation of a pharmaceutically acceptable base.
X5 is O, X6 is CH, n is 0 and R8 is H or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 1 and R8 is H or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 2 and R8 is H or a cation of a pharmaceutically acceptable base;
X5 is S, X6 is CH, n is 0 and R8 is H or a cation of a pharmaceutically acceptable base; and X5 is S, X6 is N, n is 0 and R8 is H or a cation of a pharmaceutically acceptable base.
53. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
54. A method in accordance with Claim 53 wherein in the formula of the compound R8 is H or a cation of a pharmaceutically acceptable base.
55. A method of inhibiting the enzyme cytochrome E450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R10 is CH3, R11 is Cl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is cyclopropyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3CH2, R11 is Br, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Cl, R12 is F, X6 is N and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is phenyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is H, R11 is Br, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is OCH3, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is H, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base;
R10 is CH3, R11 is H, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Br, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3CF2, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3,CH2, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is iso-propyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (1-methyl)cyclopropyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is tertiary-butyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (2,2-difluoro)cyclopropyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base and R10 is CH3, R11 is (cyclopropyl)methyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
R10 is CH3, R11 is Cl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is cyclopropyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3CH2, R11 is Br, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Cl, R12 is F, X6 is N and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is phenyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is H, R11 is Br, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is OCH3, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is H, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base;
R10 is CH3, R11 is H, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Br, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3CF2, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3,CH2, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is iso-propyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (1-methyl)cyclopropyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is tertiary-butyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (2,2-difluoro)cyclopropyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base and R10 is CH3, R11 is (cyclopropyl)methyl, R12 is F, X6 is CH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
56. A method in accordance with Claim 55 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R10 is CH3, R11 is Cl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is cyclopropyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3CH2, R11 is Br, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Cl, R12 is F, X6 is N and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is phenyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is H, R11 is Br, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R is OCH3, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is H, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is H, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Br, R12 is F X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3CF2, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, CH2, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is iso-propyl, R12 is F, X6 is CH and is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (1-methyl)cyclopropyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is tertiary-butyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (2,2-difluoro)cyclopropyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base, and R10 is CH3, R11 is (cyclopropyl)methyl, R12 is F, X6 is CH and R8 is H
or a cation of a pharmaceutically acceptable base.
R10 is CH3, R11 is Cl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is cyclopropyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3CH2, R11 is Br, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Cl, R12 is F, X6 is N and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is phenyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is H, R11 is Br, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R is OCH3, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, R12 is H, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is H, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is Br, R12 is F X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CF3CF2, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is CH3, CH2, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is iso-propyl, R12 is F, X6 is CH and is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (1-methyl)cyclopropyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is tertiary-butyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base;
R10 is CH3, R11 is (2,2-difluoro)cyclopropyl, R12 is F, X6 is CH and R8 is H or a cation of a pharmaceutically acceptable base, and R10 is CH3, R11 is (cyclopropyl)methyl, R12 is F, X6 is CH and R8 is H
or a cation of a pharmaceutically acceptable base.
57. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R12 is H, the two R13 groups jointly represent an oxo (=O) function and R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is H, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is H and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is F, R13 is CH3, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is H, one of the R13 groups is H, the other is OH, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
R12 is H, the two R13 groups jointly represent an oxo (=O) function and R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is H, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is H and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is F, R13 is CH3, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is H, one of the R13 groups is H, the other is OH, R14 is CH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
58. A method in accordance with Claim 57 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R12 is H, the two R13 groups jointly represent an oxo (=O) function and R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is H, R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is H and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is F, R13 is CH3, R14 is CH3 and R8 is H or a cation at a pharmaceutically acceptable base, and R12 is H, one of the R13 groups is H, the other is OH, R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base.
R12 is H, the two R13 groups jointly represent an oxo (=O) function and R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is H, R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R13 is CH3, R14 is H and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is F, R13 is CH3, R14 is CH3 and R8 is H or a cation at a pharmaceutically acceptable base, and R12 is H, one of the R13 groups is H, the other is OH, R14 is CH3 and R8 is H or a cation of a pharmaceutically acceptable base.
59. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is Cl and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OCH3, R17 is tertiary-butyl and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is 1-adamantyl, R16 is OCH3, R17 is H and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is tertiary-butyl and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is F, R15 is tertiary-butyl, R16 is OH, R17 is H and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is Cl and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OCH3, R17 is tertiary-butyl and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is 1-adamantyl, R16 is OCH3, R17 is H and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is tertiary-butyl and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is F, R15 is tertiary-butyl, R16 is OH, R17 is H and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
60. A method in accordance with Claim 59 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is Cl and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OCH3, R17 is tertiary-butyl and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is 1-adamantyl, R16 is OCH3, R17 is H and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is tertiary-butyl and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is F, R15 is tertiary-butyl, R16 is OH, R17 is H and R8 is H or a cation of a pharmaceutically acceptable base.
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is Cl and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OCH3, R17 is tertiary-butyl and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is 1-adamantyl, R16 is OCH3, R17 is H and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, R15 is tertiary-butyl, R16 is OH, R17 is tertiary-butyl and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is F, R15 is tertiary-butyl, R16 is OH, R17 is H and R8 is H or a cation of a pharmaceutically acceptable base.
61. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R12 is F, R15 is tertiary-butyl, R16 is CH3CH2O, R17 is I and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is F, R15 is tertiary-butyl, R16 is CH3CH2O, R17 is Br and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
R12 is F, R15 is tertiary-butyl, R16 is CH3CH2O, R17 is I and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is F, R15 is tertiary-butyl, R16 is CH3CH2O, R17 is Br and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
62. A method in accordance with Claim 61 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R12 is F, R15 is tertiary-butyl, R16 is CH3CH2O, R17 is I and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is F, R15 tertiary-butyl, R16 is CH3CH2O, R17 is Br and R8 is H
or a cation of a pharmaceutically acceptable base.
R12 is F, R15 is tertiary-butyl, R16 is CH3CH2O, R17 is I and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is F, R15 tertiary-butyl, R16 is CH3CH2O, R17 is Br and R8 is H
or a cation of a pharmaceutically acceptable base.
63. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R12 is H, X6 is CH, X7 is (CH3)2C and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is CH2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is S and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is F, X6 is CH, X7 is CH2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is H, X6 is N, X7 is CH2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
R12 is H, X6 is CH, X7 is (CH3)2C and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is CH2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is S and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base;
R12 is F, X6 is CH, X7 is CH2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R12 is H, X6 is N, X7 is CH2 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
64. A method in accordance with Claim 63 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R12 is H, X6 is CH, X7 is (CH3)2C and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is CH2 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is S and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is F, X6 is CH, X7 is CH2 and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is H, X6 is N, X7 is CH2 and R8 is H or a cation of a pharmaceutically acceptable base.
R12 is H, X6 is CH, X7 is (CH3)2C and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is CH2 and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is H, X6 is CH, X7 is S and R8 is H or a cation of a pharmaceutically acceptable base;
R12 is F, X6 is CH, X7 is CH2 and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is H, X6 is N, X7 is CH2 and R8 is H or a cation of a pharmaceutically acceptable base.
65. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
66. A method in accordance with Claim 65 wherein in the formula of the compound R8 is H or a cation of a pharmaceutically acceptable base.
67. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R6 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6 alkyl), or a ration of a pharmaceutically acceptable base.
68. A method in accordance with Claim 67 wherein in the formula of the compound R8 is H or a canon of a pharmaceutically acceptable base.
69. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R12 is F, R18 is H, R19 is H and R8 is H, alkyl of 1 to 6 carbons, CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base, and R12 is H, R18 is OH, R19 is F and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base.
R12 is F, R18 is H, R19 is H and R8 is H, alkyl of 1 to 6 carbons, CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base, and R12 is H, R18 is OH, R19 is F and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a ration of a pharmaceutically acceptable base.
70. A method in accordance with Claim 69 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R12 is H,R18 is OH,R19 is F and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is H ,R18 is OH,R19 is F and R8 is H or a cation of a pharmaceutically acceptable base.
R12 is H,R18 is OH,R19 is F and R8 is H or a cation of a pharmaceutically acceptable base, and R12 is H ,R18 is OH,R19 is F and R8 is H or a cation of a pharmaceutically acceptable base.
71. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
72. A method in accordance with Claim 71 wherein in the formula of the compound R8 is H or a cation of a pharmaceutically acceptable base.
73. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
74. A method in accordance with Claim 73 wherein in the formula of the compound R8 is H or a canon of a pharmaceutically acceptable base.
75. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound selected from the group of compounds wherein the variables for each compound are defined as follows with reference to the formula below:
R15 is 1-adamantyl, R16 is OH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R15 is 1-adamantyl, R16 is OCH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base.
R15 is 1-adamantyl, R16 is OH and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and R15 is 1-adamantyl, R16 is OCH3 and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base.
76. A method in accordance with Claim 75 wherein the compound is selected from the group of compounds wherein the variables for each compound are defined as follows:
R15 is 1-adamantyl, R16 is OH and R8 is H or a cation of a pharmaceutically acceptable base, and R15 is 1-adamantyl, R16 is OCH3 and R8 is H or a cation of a pharmaceutically acceptable base.
R15 is 1-adamantyl, R16 is OH and R8 is H or a cation of a pharmaceutically acceptable base, and R15 is 1-adamantyl, R16 is OCH3 and R8 is H or a cation of a pharmaceutically acceptable base.
77. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a canon of a pharmaceutically acceptable base.
78. A method in accordance with Claim 77 wherein in the formula of the compound R8 is H or a cation of a pharmaceutically acceptable base.
79. A method of inhibiting the enzyme cytochrome P450RAI in a mammal by administering to said mammal an effective dose of a pharmaceutical composition comprising a compound shown by the formula wherein the variable R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
80. A method in accordance with Claim 79 wherein in the formula of the compound R8 is H or a cation of a pharmaceutically acceptable base.
81. A method of providing a compound which is an inhibitor of the enzyme cytochrome P450RAI, the method comprising:
identifying a compound that has activity as a retinoid in an art recognized assay which demonstrates retinoid-like activity, the retinoid compound having a formula such that it includes a benzoic acid, benzoic acid ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or ester moiety, with a partial structure of -A(R2)-(CH2)n-COOR8 where n is 0, A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R2 groups; R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and selecting a compound that is a homolog of the previously identified retinoid compound where in the formula of the homolog n is 1 or 2.
identifying a compound that has activity as a retinoid in an art recognized assay which demonstrates retinoid-like activity, the retinoid compound having a formula such that it includes a benzoic acid, benzoic acid ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or ester moiety, with a partial structure of -A(R2)-(CH2)n-COOR8 where n is 0, A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R2 groups; R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons and R8 is H, alkyl of 1 to 6 carbons, -CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, and selecting a compound that is a homolog of the previously identified retinoid compound where in the formula of the homolog n is 1 or 2.
82. A method in accordance with Claim 81 wherein a homolog is selected where in the formula of the homolog n is 1.
83. A method in accordance with Claim 81 further comprising the step of synthesizing the selected homolog.
84. A method in accordance with Claim 83 wherein a homolog is synthesized where in the formula of the homolog n is 1.
85. A method in accordance with Claim 83 wherein the step of synthesizing the homolog utilizes a homologation procedure wherein a chain of a carboxylic acid or of carboxylic ester of the partial formula -A(R2)-(CH2)n-COOR8 is lengthened by adding one or two (CH2) units.
86. A method in accordance with Claim 85 wherein the step of synthesizing the homolog utilizes Arndt-Eistert method of synthesis.
87. A method in accordance with Claim 84 where the step of synthesizing the homolog includes a reaction with a reagent selected from the formulas
Applications Claiming Priority (3)
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|---|---|---|---|
| US09/672,751 | 2000-09-28 | ||
| US09/672,751 US6313107B1 (en) | 2000-08-29 | 2000-09-28 | Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI |
| PCT/US2001/025465 WO2002026727A2 (en) | 2000-09-28 | 2001-08-14 | Methods of providing and using compounds (retinoids) having activity as inhibitors of cytochrome p450rai |
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| CA2423919A1 true CA2423919A1 (en) | 2002-04-04 |
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| CA002423919A Abandoned CA2423919A1 (en) | 2000-09-28 | 2001-08-14 | Methods of providing and using compounds (retinoids) having activity as inhibitors of cytochrome p450rai |
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| US (4) | US6313107B1 (en) |
| EP (1) | EP1322631A2 (en) |
| JP (1) | JP2004509955A (en) |
| AU (2) | AU8647801A (en) |
| CA (1) | CA2423919A1 (en) |
| WO (1) | WO2002026727A2 (en) |
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-
2001
- 2001-06-07 US US09/963,318 patent/US6495552B2/en not_active Expired - Fee Related
- 2001-06-07 US US09/875,967 patent/US6387892B1/en not_active Expired - Fee Related
- 2001-08-14 CA CA002423919A patent/CA2423919A1/en not_active Abandoned
- 2001-08-14 WO PCT/US2001/025465 patent/WO2002026727A2/en active Application Filing
- 2001-08-14 EP EP01965927A patent/EP1322631A2/en not_active Withdrawn
- 2001-08-14 AU AU8647801A patent/AU8647801A/en active Pending
- 2001-08-14 JP JP2002531111A patent/JP2004509955A/en active Pending
- 2001-08-14 AU AU2001286478A patent/AU2001286478B2/en not_active Ceased
-
2002
- 2002-08-05 US US10/212,533 patent/US6855512B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1322631A2 (en) | 2003-07-02 |
| US6855512B2 (en) | 2005-02-15 |
| US6313107B1 (en) | 2001-11-06 |
| US20020132796A1 (en) | 2002-09-19 |
| AU2001286478B2 (en) | 2007-11-01 |
| US6387892B1 (en) | 2002-05-14 |
| US6495552B2 (en) | 2002-12-17 |
| WO2002026727A3 (en) | 2002-05-16 |
| WO2002026727A2 (en) | 2002-04-04 |
| JP2004509955A (en) | 2004-04-02 |
| US20030078270A1 (en) | 2003-04-24 |
| AU8647801A (en) | 2002-04-08 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Dead |