CA2238274C - Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4-tetrahydroquinoline carboxylic acids having retinoid-like biological activity - Google Patents

Abstract

Compounds of formula (I) where X is S, O, NR' where R' is H or alkyl of 1 to 6 carbons, or X is [C(R1)2]n where n is an integer between 0 and 2; 1; Y is a phenyl or naphthyl group, or heteroaryl group; W is a substituent selected from the group consisting of F, Br, Cl, I, C1-6alkyl, fluoro substituted C1-5 alkyl, NO2, N3, OH, OCH2OCH3, OC1-10alkyl, tetrazol, CN, SO2C1-6-alkyl, SO2C1-6-fluoro substituted alkyl, SO-C1-6 alkyl, CO-C1-6alkyl, COOR8, phenyl, phenyl itself substituted with a W group other than with phenyl or substitut ed phenyl; L is -(C-Z)-NH- or -HN-(C=Z)-; Z is O or S; A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, where R1 -R13 and o, p, m, n, r are as defined in claim 1, have retinoid-like biological activity.

Description

ARYL OR HETEROARYL AMIDES OF TETRAHYDRONAPHTHALENE, CHROMAN, THIOCHRO-MAN AND 1,2.3,~T6TRAHYDROQUINOLINE CARBOXYLIC ACIDS HAVING RETINOID-LIKE
BIOLOGICAL ACTTVITY' ~

7 1. Field of the Invention 8 The present invention relates to novel compounds 9 having retinoid-like biological activity. More specifically, the present invention relates to 11 amides formed between aryl or heteroryl amines and 12 tetrahydronaphthalene, chroman, thiochroman and 13 1,2,3,4-tetrahydroquinoline carboxylic acids where 14 at least one of the aromatic or heteroaromatic is moieties of the amide bears an electron withdrawing 16 substituent. The compounds are agonists of RAR
17 retinoid receptors.
ys 2. Background Art 19 Compounds which have retinoid-like activity are well known in the art, and are described in numerous 21 United States and other patents and in scientific 22 publications. It is generally known and accepted in 23 the art that retinoid-like activity is useful for 24 treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and 26 conditions of numerous diseases and conditions. In 27 other words, it is generally accepted in the art .L L
y~n~.+ ti~}- i/111 Q ~ a[~Tii'9Pfa 28 ti.11aL t L EJilar La. '1ia1 1 :o.1niaarv~... a...a.v~a~ y lLaCeli 29 retinoid-like compound or compounds as the active = 30 ingredient are useful as regulators of cell 31 proliferation and differentiation, and particularly 32 as agents for treating skin-related diseases, 33 including, actinic keratoses, arsenic keratoses, 34 inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and 1 hyperproliferative disorders of the skin, eczema, 2 atopic dermatitis, Darriers disease, lichen planus, 3 prevention and reversal of glucocorticoid damage 4 (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and 6 reverse the effects of age and photo damage to the 7 skin. Retinoid compounds are also useful for the s prevention and treatment of cancerous and g precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as 11 cancers of the breast, skin, prostate, cervix, 12 uterus, colon, bladder, esophagus, stomach, lung, 13 larynx, oral cavity, blood and lymphatic system, 14 metaplasias, dysplasias, neoplasias, leukoplakias 1s and papillomas of the mucous membranes and in the 16 treatment of Kaposi's sarcoma. In addition, 17 retinoid compounds can be used as agents to treat 18 diseases of the eye, including, without limitation, 19 proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well 21 as in the treatment and prevention of various aa cardiovascular diseases, including, without 23 limitation, diseases associated with lipid 24 metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to 26 increase the level of circulating tissue plasminogen 27 activator (TPA). Other uses for retinoid compounds 28 include the prevention and treatment of conditions 29 and diseases associated with human papilloma virus (HPV), including warts and genital warts, various 31 inflammatory diseases such as pulmonary fibrosis, 32 ileitis, colitis and Krohn's disease, 33 neurodegenerative diseases such as Alzheimer's 1 disease, Parkinson's disease and stroke, improper 2 pituitary function, including insufficient 3 production of growth hormone, modulation of 4 apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, 6 restoration of hair growth, including combination 7 therapies with the present compounds and other 8 agents such as MinoxidilR, diseases associated with 9, the imm.une system, including use of the present compounds as immunosuppressants and 11 immunostimulants, modulation of organ transplant 12 rejection and facilitation of wound healing, 13 including modulation of chelosis.
14 United States Patent Nos. 4,740,519 (Shroot et al.), 4,826,969 (Maignan et al.), 4,326,055 16 (Loeliger et al.), 5,130,335 (Chandraratna et al.), 17 5,037,825 (Klaus et al.), 5,231,113 (Chandraratna et Is al.), 5,324,840 (Chandraratna), 5,344,959 19 (Chandraratna), 5,130,335 (Chandraratna et al.), Published European Patent Application Nos. 0 170 105 21 (Shudo), 0 176 034 A (Wuest et al.), 0 350 846 A
22 (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176 23 033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 24 0 303 915 A (Bryce et al.), UK Patent Application GB
2190378 A (Klaus et al.), German Patent Application 26 Nos. DE 3715955 Al (Klaus et al.), DE 3602473 Al 27 (Wuest et al., and the articles J. Amer. Acad. Derm.
28 15: 756 - 764 (1986) (Sporn et al.), Chem. Pharm.
29 Bull. 33: 404-407 (1985) (Shudo et al.), J. Med Chem. 1988 31, 2182 - 2192 (Kagechika et al.), 31 Chemistry and Biology of Synthetic Retinoids CRC
32 Press Inc. 1990 p 334 - 335, 354 (Dawson et al.), 33 describe or relate to compounds which include a 1 tetrahydronaphthyl moiety and have retinoid-like or 2 related biological activity. United States Patent 3 No. 4,391,731 (Boller et al.) describes 4 tetrahydronaphthalene derivatives which are useful in liquid crystal compositions.
6 United States Patent Nos. 4,980,369, 5,006,550, 7 5,015,658, 5,045,551, 5,089,509, 5,134,159, a 5,162,546, 5,234,926, 5,248,777, 5,264,578, 9 5,272,156, 5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972, 5,348,975, 5,380,877, 11 5,399,561, 5,407,937, (assigned to the same assignee 12 as the present application) and patents and 13 publications cited therein, describe or relate to 14 chroman, thiochroman and 1,2,3,4-tetrahydroquinoline 1s derivatives which have retinoid-like biological 16 activity. Still further, several co-pending 17 applications and recently issued patents which are 18 assigned to the assignee of the present application, 19 are directed to further compounds having retinoid-like activity.
21 it is now general knowledge in the art that two 22 main types of retinoid receptors exist in mammals 23 (and other organisms). The two main types or 24 families of receptors respectively designated the RARs and RXRs. Within each type there are subtypes;
26 in the RAR family the subtypes are designated RARa227 RARA and RARr, in RXR
the subtypes are: RXRa, RXB, and 28 RXRr. It has also been established in the art that 29 the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform 31 in the various tissues and organs of mammalian 32 organisms. Accordingly, among compounds having 33 agonist-like activity at retinoid receptors, 1 specificity or selectivity for one of the main types 2 or families, and even specificity or selecti.vity for 3 one or more subtypes within a family of receptors, 4 is considered a desirable pharmacological property.
5 The present invention provides compounds having 6 retinoid-like biological activity and specifically 7 compounds which are agonists of one or more RAR

8 retinoid receptor subtypes.

The present invention covers compounds of 11 Formula 1 13 Ri tRa)m S-f 1 s R 0~~ ;nrvL y__ r A B
16 17 ~M
\='/~

21 Formula 1 22 wherein X is S, 0, NR' where R' is H or alkyl of 23 1 to 6 carbons, or 24 X is [ C(Rl ) 2 l n where n is an integer between 0 and 2;
26 Rl is independently H or alkyl of 1 to 6 27 carbons;
28 R2 is hydrogen, or lower alkyl of 1 to 6 29 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or 31 F ;
32 m is an integer having the value of 0 - 2;
33 o is an integer having the value of 0 - 4;

1 p is an integer having the value of 0 - 2;
2 r is an integer having the value 0 - 2 with the 3 proviso that when Z is 0 the sum of p and r is at 4 least 1;
s Y is a phenyl or naphthyl group, or heteroaryl 6 selected from a group consisting of pyridyl, 7 thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, 8 thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said 9 phenyl, naphthyl and heteroaryl groups being io optionally substituted with one or two R2 groups;
11 W is a substituent selected from the group 12 consisting of F, Br, Cl, I, C1_6alkyl, fluoro 13 substituted Cl_6 alkyl, NO21 N31 OH, OCH2OCH31 14 OC1_loalkyl, tetrazol, CN, S02C1_6-alkyl , S02C1_6-alkyl, 1s S02C1_6-fluoro substituted alkyl, SO-C1_6 alkyl, 16 CO-C1_6alkyl, COOR8, phenyl, phenyl itself substituted 17 with a W group other than with phenyl or substituted 18 phenyl;
19 L is -(C=Z)-NH- or -NH-(C=Z)-20 Z is 0 or S;
21 A is (CHa)q where q is 0-5, lower branched chain az alkyl having 3-6 carbons, cycloalkyl having 3-6 23 carbons, alkenyl having 2-6 carbons and 1 or 2 24 double bonds, alkynyl having 2-6 carbons and 1 or 2 25 triple bonds, and 26 B is COOH or a pharmaceutically acceptable salt 27 thereof, COORS, CONR9R10, -CH2OH, CH20R11, CH2OCOR11, 28 CHO, CH ( OR1Z ) 2, CHOR130, -COR7, CR7( OR12 ) 2, CR70Ri30, 29 where R7 is an alkyl, cycloalkyl or alkenyl group 30 containing 1 to 5 carbons, R8 is an alkyl group of 1 31 to 10 carbons or trimethylsilylalkyl where the alkyl 32 group has 1 to 10 carbons, or a cycloalkyl group of 33 5 to 10 carbons, or R. is phenyl or lower 1 alkyiphenyl, R9 and Rlo independently are hydrogen, 2 an alkyl group of 1 to 10 carbons, or a cycloalkyl 3 group of 5-10 carbons, or phenyl or lower 4 alkylphenyl, R11 is lower alkyl, phenyl or lower s alkylphenyl, R1z is lower alkyl, and R13 is divalent 6 alkyl radical of 2-5 carbons.
7 In a second aspect, this invention relates to 8 the use of the compounds of Formula 1 for the 9 treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic 11 keratoses, inflammatory and non-inflammatory acne, 12 psoriasis, ichthyoses and other keratinization and 13 hyperproliferative disorders of the skin, eczema, 14 atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage 16 (steroid atrophy), as a topical anti-microbial, as 17 skin anti-pigmentation agents and to treat and 18 reverse the effects of age and photo damage to the 19 skin. The compounds are also useful for the prevention and treatment of cancerous and 21 precancerous conditions, including, premalignant and 22 malignant hyperproliferative diseases such as 23 cancers of the breast, skin, prostate, cervix, 24 uterus, colon, bladder, esophagus, stomach, lung, 26 larynx, oral cavity, blood and lymphatic system, 26 metaplasias, dysplasias, neoplasias, leukoplakias 27 and papillomas of the mucous membranes and in the 28 treatment of Kaposi's sarcoma. In addition, the 29 present compounds can be used as agents to treat diseases of the eye, including, without limitation, 31 proliferative vitreoretinopathy (PVR), retinal 32 detachment, dry eye and other corneopathies, as well 33 as in the treatment and prevention of various 1 cardiovascular diseases, including, without 2 limi.tation, diseases associated with lipid 3 metabolism such as dyslipidemias, prevention of 4 post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen 6 activator (TPA). Other uses for the compounds of 7 the present invention include the prevention and 8 treatment of conditions and diseases associated with a human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as 11 pulmonary fibrosis, ileitis, colitis and Krohn's 12 disease, neurodegenerative diseases such as 13 Alzheimer's disease, Parkinson's disease and stroke, 14 improper pituitary function, including insufficient is production of growth hormone, modulation of is apoptosis, including both the induction of apoptosis 17 and inhibition of T-Cell activated apoptosis, 18 restoration of hair growth, including combination 19 therapies with the present compounds and other agents such as MinoxidilR, diseases associated with 21 the immune system, including use of the present 22 compounds as immunosuppressants and 23 ai.mmunostimulants, modulation of organ transplant 24 rejection and facilitation of wound healing, including modulation of chelosis.
26 This invention also relates to a pharmaceutical 27 formulation comprising a compound of Formula 1 in 28 admixture with a pharmaceutically acceptable 29 excipient.
In another aspect, this invention relates to 31 processes for making a compound of Formula 1 which s2 processes comprise reacting, in the presence of an 33 acid acceptor or water acceptor, a compound of 1 Formula 2 with a compound of Formula 3 or a compound 2 of Formula 2a with a compound of Formula 3a where Xi 3 is OH, halogen, or other group which renders the 4-COXf group reactive for amide formation, and where the remaining symbols are defined as in connection 6 with Formula 1.

R1 R1 (R2)rn 9 ~
nnrCOXi H21c""_y A B
11 (R3)0'rvv!

13 (W)p IFormula 2 Formula 3 1s R, Ri (R2)m SSS Y A B
21 ,, t~}~ XtCO-(~M
~NI 2 f (R3)0 N

24 (mP

27 Formula 2a Formula 3a 28 Still further, the present invention relates to 29 such reactions performed on the compounds of Formula 1 which cause transformations of the B group while 31 the reaction product still remains within the scope 32 of Formula 1.
33 General EmbodimentsDefinitions 1 This invention also relates to a compound of the formula (FQ
Z

M-A
w, Ry W:

3 wherein R1 is independently H or alkyl of 1 to 6 carbons;
4 R2 is hydrogen, or lower alkyl of 1 to 6 carbons;

R3 is hydrogen, lower alkyl of 1 to 6 cabons or F;
6 o is an integer having the value of 0 - 4;

7 Wl, W2, W3 and W41each is independently selected from the 8 group consisting of H, F, Br, Cl, I, CF3, NOz, N3, OH, OCH2OCH3, 9 OC1_10alkyl and C1_6alkyl, with the proviso that when Z is 0 then at least one of the W1, W2, groups is not H nor alkyl and at 11 least one of the W3, and W4 groups is not H nor alkyl;

12 Z is 0 or S;

13 A is (CH2)q where q is 0-5, lower branched chain alkyl 14 having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 16 carbons and 1 or 2 triple bonds, and 17 B is COOH or a pharmaceutically acceptable salt thereof, 18 COOR8, CONR9Rlo,- CH2OH, CH20R11, CH2OCOR11, CHO, 19 CH (OR12) 2, CHOR130, -COR7, CR7 (OR12) 2, CR70R130, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, 21 R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl 22 where the alkyl group has 1 to 10 carbons, or a cycloalkyl 1 group of 5 to 10 carbons, or RB is phenyl or lower alkylphenyl, 2 R9 and Rlo independently are hydrogen, an alkyl gorup of 1 to 3 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl 4 or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl 6 radical of 2-5 carbons.

7 This invention also relates to the formula w, RS ~~ Z

~=. = ~ 1 fl ~ ~ W
x --' ~, w2 wherein R1 is independently H or alkyl of 1 to 6 carbons;

11 R2 is hydrogen, or lower alkyl of 1 to 6 carbons;

12 Wl, W2, W3, and W4, each is independently selected from the 13 group consisting of H, F, Br, Cl, I, CF3, NO2, N3, OH, OCH2OCH3, 14 OCl_loalkyl and C1_6alkyl, with the proviso that when Z is 0 then at least one of the W1, W2, W3, and W4 groups is not H nor 16 alkyl, with the further proviso that when Z is 0 and X is 0 17 then W2 is not Cl;

18 X is O or S;
19 Z is O or S;

A is (CH2)q where q is 0-5, lower branched chain alkyl 21 having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl 1 having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 2 carbons and 1 or 2 triple bonds, and 3 B is COOH or a pharmaceutically acceptable salt thereof, 4 COOR8, CONRyRla, - CH2OH , CH20R11, CH2OCOR11, CHO, CH ( OR12 ) 2, CHOR130, -COR7, CR7 (OR12) 2, CR70R130, where R7 is an alkyl, 6 cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an 7 alkyl group of 1 to 10 carbons or trimethysilylalkyl where the 8 alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 9 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rlo independently are hydrogen, an alkyl group of 1 to 10 carbons, 11 or a cycloalkyl group of 5-10 carbons, or phenyl or lower 12 alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, 13 R12 is lowser alkyl, and R13 is divalent alkyl radical of 2-5 14 carbons.

1 The term alkyl refers to and covers any and all 2 groups which are known as normal alkyl, 3 branched-chain alkyl and cycloalkyl. The term 4 alkenyl refers to and covers normal alkenyl, branch s chain alkenyl and cycloalkenyl groups having one or s more sites of unsaturation. Similarly, the term 7 alkynyl refers to and covers normal alkynyl, and s branch chain alkynyl groups having one or more 9 triple bonds.

10 Lower alkyl means the above-defined broad 11 definition of alkyl groups having 1 to 6 carbons in 12 case of normal lower alkyl, and as applicable 3 to 6 13 carbons for lower branch chained and cycloalkyl 14 groups. Lower alkenyl is defined similarly having 2 Is to 6 carbons for normal lower alkenyl groups, and 3 16 to 6 carbons for branch chained and cyclo- lower 17 alkenyl groups. Lower alkynyl is also defined 1s similarly, having 2 to 6 carbons for normal lower 19 alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.
21 The term "ester" as used here refers to and 22 covers any compound falling within the definition of 23 that term as classically used in organic chemistry.
24 It includes organic and inorganic esters. Where n of Formula 1 is -COOH, this term covers the products 26 derived from treatment of this function with 27 alcohols or thioalcohols preferably with aliphatic 28 alcohols having 1-6 carbons. Where the ester is 29 derived from compounds where B is -CH2OH, this term so covers compounds derived from organic acids capable' 31 of forming esters including phosphorous based and 32 sulfur based acids, or compounds of the formula 33 -CH2OCORli where Rli is any substituted or 1 unsubstituted aliphatic, aromatic, heteroaromatic or 2 aliphatic aromatic group, preferably with 1-6 3 carbons in the aliphatic portions.
4 Unless stated otherwise in this application, preferred esters are derived from the saturated 6 aliphatic alcohols or acids of ten or fewer carbon 7 atoms or the cyclic or saturated aliphatic cyclic 8 alcohols and acids of 5 to 10 carbon atoms.
9 Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also 11 preferred are the phenyl or lower alkyl phenyl 12 esters.
13 Amides has the meaning classically accorded that 14 term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic 16 and aromatic mono- and di- substituted amides.
17 Unless stated otherwise in this application, 18 preferred amides are the mono- and di-substituted 19 amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or 21 saturated aliphatic-cyclic radicals of 5 to 10 22 carbon atoms. Particularly preferred amides are 23 those derived from substituted and unsubstituted 24 lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the substituted 26 and unsubstituted phenyl or lower alkylphenyl 27 amines. Unsubstituted amides are also preferred.
28 Acetals and ketals include the radicals of the 29 formula-CK where K is (-OR)a. Here, R is lower alkyl. Also, K may be -OR70- where R. is lower alkyl 31 of 2-5 carbon atoms, straight chain or branched.
32 A pharmaceutically acceptable salt may be 33 prepared for any compounds in this invention having WO 97/19052 PC'd'/US96/18580 1 a functionality capable of forming such-salt, for 2 example an acid functionality. A pharmaceutically 3 acceptable salt is any salt which retains the 4 activity of the parent compound and does not impart s any deleterious or untoward effect on the subject to 6 which it is administered and in the context in which 7 it is administered. Pharmaceutically acceptable a salts may be derived from organic or inorganic 9 bases. The salt may be a mono or polyvalent ion.
Of particular interest are the inorganic ions, 11 sodium, potassium, calcium, and magnesium. Organic 12 salts may be made with amines, particularly ammonium 13 salts such as mono-, di- and trialkyl amines or 14 ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where 16 there is a nitrogen sufficiently basic as to be 17 capable of forming acid addition salts, such may be 18 formed with any inorganic or organic acids or 119 alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as 21 hydrochloric acid, sulfuric acid or phosphoric acid.
22 Any of a number of simple organic acids such as 23 mono-, di- or tri- acid may also be used.
24 Some of the compounds of the present invention may have trans and cis (E and Z) isomers. In 26 addition, the compounds of the present invention may 27 contain one or more chiral centers and therefore may 28 exist in enantiomeric and diastereomeric forms. The 29 scope of the present invention is intended to cover all such isomers per se, as well as mixtures of cis 31 and trans isomers, mixtures of diastereomers and 32 r a cemi c mixtu re s of en a nt i omer s (opt i c a l i s ome r s) as 33 well.

1 With reference to the symbol Y in Formula 1, the 2 preferred compounds of the invention are those where 3 Y is phenyl, pyridyl, 2-thiazolyl, thienyl, or 4 furyl, more preferably phenyl. As far as substitutions on the Y (phenyl) and Y(pyridyl) 6 groups are concerned, compounds are preferred where 7 the phenyl group is 1,4 (para) substituted by the L
8 and A-B groups, and where the pyridine ring is 2,5 9 substituted by the L and A-B groups. (Substitution in the 2,5 positions in the "pyridine" nomenclature 11 corresponds to substitution in the 6-position in the 12 "nicotinic acid" nomenclature.) In the preferred 13 compounds of the invention there is no optional R2 14 substituent on the Y group.
As far as the amide or carbamoyl function "L" is 16 concerned which links the two cyclic portions of the 17 molecule, L i.s preferably -CZ-NH-; in other words 18 amide or carbamoyl compounds are preferred in 19 accordance with the present invention where the carbonyl (CO-) or thiocarbonyl (CS-) group is linked 21 to the condensed cyclic moiety.
22 With reference to the symbol X in Formula 1, 23 compounds are preferred in accordance with the 24 invention where X is [ C( Rl ) Z] a and n is 1, and also where X is 0 or S (chroman and thiochroman 26 derivatives).
27 The Rl groups are preferably H or CH3. The R3 28 group is preferably hydrogen.
29 The A-B group of the preferred compounds is ( CH2 ) n-COOH or ( CH2 ) a-COORg , where n and R. are def ined 31 as above. Even more preferably n is zero and R. is 32 lower alkyl, or n is zero and B is COOH or a 33 pharmaceutically acceptable salt thereof.

1 Referring now to the W group in Formula 1, this 2 group is, generally speaking, an electron s withdrawing group, which is present in the compounds 4 of the invention either in the aromatic portion of the condensed ring system, or as a substituent of s the aryl or heteroaryl group Y. Preferably the W
7 group is present in the Y group, or both in the Y
s group and also in the aromatic portion of the 9 condensed ring system. When the Z group is S
(thioamides) a W group does not necessarily have to 11 be present in the compounds of the invention, 12 although preferably at least one W group is 13 nevertheless present. In the aryl or heteroaryl Y
14 moiety the W group is preferably located in the position adjacent to the A-B group; preferably the 16 A-B group is in para position in the phenyl ring 17 relative to the "amide" moiety, and therefore the W
18 group is preferably in meta position relative to the 19 amide moiety. Where the W group is also present in the aromatic portion of the condensed ring system, 21 it preferably occupies the 8 position of the chroman 22 or thiochroman nucleus with the Z=C-NH- group 23 occupyi.ng the 6 position. In tetrahydronaphthalene 24 compounds of the invention the Z=C-NH- group is preferably in the 2-position, and the W group is in 26 the 3 or 4 position. Preferred W groups are F, NO2, 27 Br, I, CF3, N31 and OH. The presence of one or two 28 fluoro substituents in the Y group is especially 29 preferred. When the Y group is phenyl, the fluoro 3o substituents preferably are in the ortho and ortho' 31 positions relative to the A-8 group, which is 32 preferably COOH or COOR8.
33 The most preferred compounds of the invention 1 are shown i.n Table 1, with reference to Formulas 4 2 and S.

G+O2~lp8s 9 \ N
F{ Wa 11 ~
W, 16 Formula 4 C02R8' Z

22 \ ~ \

R1' I

24 X W, R~~

28 Formula 5 y TABLE 1 2 Compound s No. Formula R1' X Wl W2 Z W3 W4 R8*
4 1 4 -- -- H H 0 F H Et s 2 4 -- -- H H 0 F H H
6 3 4 -- -- F H 0 H H Et 8 5 4 -- -- H Br 0 F H Et 9 6 4 -- -- H Br 0 F H H
7 4 -- -- OH H 0 F H Et 12 9 5 H 0 H Br 0 F H Et 13 10 5 H 0 H Br 0 F H H
14 11 5 CH3 O H Br 0 F H Et is 12 5 CH3 O H Br 0 F H H
16 13 5 CH3 O H CF3 0 F H Et 18 15 5 CH3 0 H N3 0 F H Et 22 19 5 CH3 0 H I 0 F H Et 24 21 5 CH3 O H CH3 0 F H Et 26 23 5 CH3 S H H 0 F H Et 27 24 5 CH3 s H H 0 F H H
28 25 4 -- -- H H S H H Et 27 4 -- -- H H S F H Et 32 29 4 -- -- H Br 0 NO2 H CH3 33 30 4 -- -- H Br 0 NO2 H H

1 31 5 CH3 0 H H 0 F H Et 3 33 4 -- -- OH Br 0 F H Et 4 34 4 -- -- OH Br 0 F H H
35 4 -- -- OH Br 0 F F CH3 6 36 4 -- -- OH Br 0 F F H

Modes of Administration 11 The compounds of this invention may be 12 administered systemically or topically, depending on 13 such considerations as the condition to be treated, 14 need for site-specific treatment, quantity of drug is to be administered, and numerous other 16 considerations.
17 In the treatment of dermatoses, it will ys generally be preferred to administer the drug 19 topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral 21 administration may also be used. Any common topical 22 formulation such as a solution, suspension, gel, 23 ointment, or salve and the like may be used.
24 Preparation of such topical formulations are well described in the art of pharmaceutical formulations 26 as exemplified, for example, Remington's 27 Pharmaceutical Science, Edition 17, Mack Publishing 28 Company, Easton, Pennsylvania. For topical 29 application, these compounds could also be administered as a powder or spray, particularly in 31 aerosol form. If the drug is to be administered 32 systemically, it may be confected as a powder, pill, 33 tablet or the like or as a syrup or elixir suitable 1 for oral administration. For intravenous or 2 intraperitoneal administration, the compound will be 3 prepared as a solution or suspension capable of 4 being administered by injection. in certain cases, it may be useful to formulate these compounds by 6 injection. In certain cases, it may be useful to 7 formulate these compounds in suppository form or as a extended release formulation for deposit under the s skin or intramuscular injection.
Other medicaments can be added to such topical 11 formulation for such secondary purposes as treating 12 skin dryness; providing protection against light;
13 other medications for treating dermatoses;
14 medicaments for preventing infection, reducing irritation, inflammation and the like.
16 Treatment of dermatoses or any other indications 17 known or discovered to be susceptible to treatment 18 by retinoic acid-like compounds will be effected by 19 administration of the therapeutically effective dose of one or more compounds of the instant invention.
21 A therapeutic concentration will be that 22 concentration which effects reduction of the 23 particular condition, or retards it expansion. In 24 certain instances, the compound potentially may be used in prophylactic manner to prevent onset of a 26 particular condition.
27 A useful therapeutic or prophylactic 28 concentration will vary from condition to condition 29 and in certain instances may vary with the severity of the condition being treated and the patient's 31 susceptibility to treatment. Accordingly, no single 32 concentration will be uniformly useful, but will 33 require modification depending on the 1 particularities of the disease being treated. Such 2 concentrations can be arrived at through routine 3 experimentation. However, it is anticipated that in 4 the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 6 0.01 and 1.0 milligrams per mililiter of formulation 7 will constitute a therapeutically effective 8 concentration for total application. If s administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be 11 expected to effect a therapeutic result in the 12 treatment of many disease for which these compounds 13 are useful.
14 Assay of Retinoi.d-like Biological Activity The retinoid-like activity of the compounds of 16 the invention can be confirmed in assays wherein 17 ability of the compound to bind to retinoid 18 receptors is measured. As it is noted in the 19 introductory section of this application for patent two main types of retinoic acid receptors (RAR and 21 RXR) exist in mammals (and other organisms). Within 22 each type there are sub-types (RARa1 RARj3, RARr, RXRa1 23 RXR, and RXRr) the distribution of which is not 24 uniform in the various tissues and organs of mammalian organisms. Selective binding of only one 26 or two retinoid receptor subtypes within one 27 retinoid receptor family can give rise to beneficial 28 pharmacological properties because of the varying 29 distribution of the sub-types in the several mammalian tissues or organs. For the 31 above-summarized reasons, binding of any or all of 32 the retinoid receptors, as well as specific or 33 selective activity in a receptor family, or 1 selective or specific activity in any one of.the 2 receptor subtypes, are all considered desirable 3 pharmacological properties.
4 in light of the foregoing the prior art has 5 developed assay procedures for testing the agonist 6 like activity of compounds in the RAR ,, RARA i, RARr il 7 RXR, RXR, and RXRr receptor subtypes. For example, s a chimeric receptor transactivation assay which 9 tests for agonist-like activity in the RAR , RARn, 10 RARr, and RXRa receptor subtypes, and which is based 11 on work published by Feigner P. L. and Hoim M.
12 (1989) Focus, 11 2 is described in detail in U.S.
13 Patent No. 5,455,265.

ts 16 A holoreceptor transactivation assay and a 17 ligand binding assay which measure the ability of is the compounds of the invention to bind to the 19 several retinoid receptor subtypes, respectively, 20 are described in published PCT Application No. WO
W093/11755 (particularly on pages 30 - 33 and 37 -22 41) published on June 24, 1993.

24 description of the ligand binding assay is also 26 provided below.
2s BINDING ASSAY
27 All binding assays were performed in a similar 2o fashion. All six receptor types were derived from 29 the expressed receptor type (RAR a, B. t and RXR a, 3o B, z) expressed in Baculovirus. Stock solutions of 31 all compounds were prepared as 10mM ethanol 32 solutions and serial dilutions carried out into 1:1 33 DMSO; ethanol. Assay buffers consisted of the 1 following for all six receptor assays: 8% glycerol, 2 120mM KC1, 8mM Tris, 5mM CHAPS 4mM DTT and 0.24mM
3 PMSF, pH - 7.4@ room temperature.
4 All receptor biding assays were performed in the s same manner. The final assay volume was 250}1l and 6 contained from 10-40ug of extract protein depending 7 on receptor being assayed along with 5 nM of [3H]
8 all-trans retinoic acid or lOnM [3H] 9-cis retinoic s acid and varying concentrations of competing ligand at concentrations that ranged from 0 - 10-5 M. The 11 assays were formatted for a 96 well minitube system.
12 Incubations were carried out at 4 C until 13 equilibrium was achieved. Non-specific binding was 14 defined as that binding remaining in the presence of 1000nM of the appropriate unlabeled retinoic acid 16 isomer. At the end of the incubation period, 50ul 17 of 6.25% hydroxyapitite was added in the appropriate 18 wash buffer. The wash buffer consisted of 100mM
19 KC1, 10mM Tris and either 5mM CHAPS (RXR a, !3, z) or 0.5% Triton X-100 (RAR a, !3, z). The mixture was 21 vortexed and incubated for 10 minutes at 4 C, 22 centrifuged and the supernatant removed. The 23 hydroxyapitite was washed three more times with the 24 appropriate wash buffer. The receptor-ligand complex was adsorbed by the hydroxyapitite. The 26 amount of receptor-ligand complex was determined by 27 liquid scintillation-countirig-of hydroxyapita.te 28 pellet.
29 After correcting for non-specific binding, IC50 so values were determined. The ICso value is defined as 31 the concentration of competing ligand needed to 32 reduce specific binding by 50%. The IC50 value was 33 determined graphically from a loglogit plot of the 1 data. The Kd values were determined by application 2 of the Cheng-Prussof equation to the IC50 values, the 3 labeled ligand concentration and the Kd of the 4 labeled ligand.
The results of ligand binding assay are expressed 6 in Kd numbers. (See Cheng et al. Biochemical 7 Pharmacology Vol. 22 pp 3099-3108).
s s Table 2 shows the results of the ligand binding assay for certain exemplary compounds of the 11 invention.

13 Ligand Binding Assay Compound # Rd (nanomolar) 16 RARa RARB RARI' RXRa RXR13 RXRI' 17 2 1.90 480.0 0.00 0.00 0.00 0.00 18 4 23.00 23.00 96.0 0.00 0.00 0.00 19 6 1.3 0.00 0.00 0.00 0.00 0.00 8 3.00 0.00 0.00 0.00 0.00 0.00 21 12 24.0 0.00 0.00 0.00 0.00 0.00 22 14 14.0 0.00 0.00 0.00 0.00 0.00 23 16 52.0 0.00 0.00 0.00 0.00 0.00 24 18 51.0 0.00 0.00 0.00 0.00 0.00 20 16.0 0.00 0.00 0.00 0.00 0.00 26 22 57.0 0.00 0.00 0.00 0.00 0.00 27 24 126.0 584 0.00 0.00 0.00 0.00 28 26 15 0.00 0.00 0.00 0.00 0.00 29 28 7.5 0.00 0.00 0.00 0.00 0.00 30 245.0 0.00 0.00 0.00 0.00 0.00 31 32 162.0 0.00 0.00 0.00 0.00 0.00 32 34 4.00 0.00 0.00 0.00 0.00 0.00 33 36 2.30 0'.00 0.00 0.00 0.00 0.00 34 38 9.00 0.00 0.00 0.00 0.00 0.00 0.00 indicates value greater than 1000nM (nanomolar) 1 As it can be seen from the test results 2 summarized in Table 2, the therein indicated 3 exemplary compounds of the invention bind 4 specifically or selectively to RARa receptors.
CANCER CELL LINE ASSAYS

7 Hormones 8 All trans-Retinoic acid (t-RA) (Sigma Chemicals g Co., St. Louis, MO) was stored at -70 C. Prior to each experiment the compound was dissolved in 100%
11 ethanol at 1 mM and diluted in culture medium 12 immediately before use. All experiments were 13 performed in subdued light. Controls were assayed 14 using the same concentration of ethanol as present in the experimental plates and this concentration of 16 diluent had no effect in either assay.
17 Cells and Cell Culture 18 All cell lines, RPMI 8226, ME-180 and AML-193 19 were obtained from the American Type Culture Collection (ATCC, Rockville, MD). RPMI 8226 is a 21 human hematopoietic cell line obtained from the 22 peripheral blood of a patient with multiple myeloma.
23 The cells resemble the lymphoblastoid cells of other 24 human lymphocyte cell lines and secrete a-type light chains of immunoglobulin. RPMI-8226 cells are grown 26 in RPMI medium (Gibco) supplemented with 10% fetal 27 bovine serum, glutamine and antibiotics. The cells 28 were maintained as suspension cultures grown at 37 C
29 in a humidified atmosphere of 5% CO2 in air. The cells were diluted to a concentration of 1 x 105/ml 31 twice a week.
32 ME-180 is a human epidermoid carcinoma cell line 33 derived from the cervix. The tumor was a highly 34 invasive squamous cell carcinoma with irregular cell clusters and no significant keratinization. ME-180 36 cells were grown and maintained in McCoy's 5a medium 1(Gibco) supplemented with 10% fetal bovine serum, 2 glutamine and antibiotics. The cells were =
3 maintained as monolayer cultures grown at 37 C in a 4 humidified atmosphere of 5% C02 in air. The cells were diluted to a concentration of 1 x 10'/ml twice a 6 week.
7 AML-193 was established from the blast cells 8 classified as M5 Acute Monocyte Leukemia. The s growth factor, granulocyte colony-stimulation factor (GM-CSF) was required to establish this cell line 11 and growth factors are necessary for its continuous 12 proliferation in chemically defined medium. AML-193 13 cells were grown and maintained in Iscove's modifi.ed 14 Dulbecco's medium supplemented with 10% fetal bovine serum, glutamine and antibiotics with 5ug/ml insulin 16 (Sigma Chemical Co.) and 2 ng/ml rh GM-CSF (R and D
17 Systems). The cells were di.luted to a concentration 1s of 3 x 105/ml twice a week.
19 Incorporation of 3H-Thymidine The method used for determination of the 21 incorporation of radiolabeled thymidine was adapted 22 from the procedure described by Shrivastav et al.
23 RPMI-8226 cells were plated in a 96 well round 24 bottom microtiter plate (Costar) at a density of 1,000 cells/well. To appropriate wells, reta.noid 26 test compounds were added at the final 27 concentrations indicated for a final volume of 150 28 pl/well. The plates were incubated for 96 hours at 29 37 C in a humidified atmosphere of 5% COZ in air.
so Subsequently, 1 pCi of [5'-3H]-thymidine (Amersham, 31 U.K. 43 Ci./mmol specific activity) in 25 ul culture 32 medium was added to each well and the cells were 33 incubated for an additional 6 hours. The cultures 34 were further processed as described below.
ME-180 wells, harvested by trypsinization were 36 plated in a 96 well flat bottom microtiter plate 1(Costar) at a density of 2,000 cells/well. The 2 cultures were treated as described above for RPMI
3 8226 with the following exceptions. After 4 incubation with thymidine the supernatant was 5 carefully removed, and the cells were washed with a 6 0.5 mM solution of thymidine in phosphate buffered 7 saline. ME180 cells were briefly treated with 50pl 8 of 2.5% trypsin to dislodge the cells from the s plate. AML-193 cells were plated in a 96 well 10 round bottom microtiter plate (Costar) at a density 11 of 1,000 cells/well. To appropriate wells, retinoid 12 test compounds were added at the final 13 concentrations indicated for a final volume of 150 14 p1/well. The plates were incubated for 96 hours at 16 3 7 C in a humidified atmosphere of 5% COZ in air.
16 Subsequently, 1 pCi of [5'-3H]-thymidine (Amersham, 17 U.K., 43 Ci/mmol specific activity) in 25 pl culture 78 medium was added to each well and the cells were 19 incubated for an additional 6 hours.
20 All cells lines were then processed as follows:
21 the cellular DNA was precipitated with 10%
22 trichloroacetic acid onto glass fiber filter mats 23 using a SKATRON multi-well cell harvester (Skatron 24 Instruments, Sterling VA). Radioactivity 25 incorporated into DNA, as a direct measurement of 26 cell growth, was measured by liquid scintillation 27 counting. The numbers represent the mean 28 disintegrations per minute of incorporated thymidine 29 from triplicate wells SEM.
In the above noted in vitro cell lines exemplary 31 compounds 6, 8, 12, 14 and 20 of the invention 32 caused significant decrease in the proliferation of 33 the tumor cell lines (as measured by incorporation 34 of radioactive labeled thymidine) in the 10-11 to 10-6 molar concentration range of the respective test 36 compound.

26 ' 2 The compounds of this invention can be made by s the synthetic chemical pathways illustrated here.
4 The synthetic chemist will readily appreciate that the conditions set out here are specific embodiments 6 which can be generalized to any and all of the 7 compounds represented by Formula 1. Generally a speaking the process of preparing compounds of the g invention involves the formation of an amide by the reaction of a compound of the general Formula 2 with yi a compound of general Formula 3, or by the reaction 12 of a compound of general Formula 2a with a compound 13 of general Formula 3a as these formulas are defined 14 in the Summary section of the present application for patent. Thus, as is noted above, a compound of 16 Formula 2 is an acid or an "activated form" of a 17 carboxylic acid attached to the aromatic portion of is a tetrahydronaphthalene, (X =[ C( R,. ) 2] n and n is 1), 19 dihydroindene ([ C( Rl ) z] a where n is 0), chroman (X is 0), thiochroman (X is S), or tetrahydroquinoline (X
21 is NR') nucleus. The carboxylic acid, or its 22 "activated form" is attached to the 2 or 3 position 23 of the tetrahyronaphthalene, and to the 6 or 7 24 position of the chroman, thiochroman or tetrahydroquinoline moieties. In the preferred 26 compounds of the invention the attachment is to the 27 2 position of tetrahydronaphthalene and to the 6 28 position of chroman, thiochroman or 29 tetrahydroquinoline.
The term "activated form" of the carboxylic acid 31 should be understood in this regard as such 32 derivative of the carboxylic acid which is capable 33 of forming an amide when reacted with a primary 34 amine of Formula 3. In case of the "reverse amides"
the activated form of a carboxylic acid is a 36 derivative (Formula 3a) that is capable of forming 1 an amide when reacted with a primary amine of 2 Formula 2a. This, generally speaking, means such 3 derivatives of a carboxylic acid which are normally 4 known and used in the art to form amide linkages s with an amine. Examples of suitable forms or 6 derivatives for this purpose are acid chlorides, 7 acid bromides, and esters of the carboxylic acid, 8 particularly active esters, where the alcohol moiety s of the ester forms a good leaving group. Presently 1o- most preferred as reagents in accordance with 11 Formula 2 (or Formula 3a) are acid chlorides (X,, is 12 Cl). The acid chlorides of Formula 2 (or of Formula 13 3a) can be prepared by traditional methods from the 14 corresponding esters (X1 is for example ethyl) by 15 hydrolysis and treatement with thionyl chloride 16 (SOC12). The acid chlorides of Formula 2 (or of 17 Formula 3a) can also be prepared by direct treatment 1s of the carboxylic acids with thionyl chloride, where 19 the carboxylic acid, rather than an ester thereof is 20 available commercially or by a known synthetic 21 procedure. The acid chlorides of Formula 2 (or of 22 Formula 3a) are typically reacted with the amine of 23 Formula 3 (or amine of Formula 2a) in an inert 24 solvent, such as methylene chloride, in the presence 25 of an acid acceptor, such as pyridine.
26 The carboxylic acids themselves in accordance 27 with Formula 2 (or Formula 3a) are also suitable for 28 amide formation when reacted with an amine, a 29 catalyst (4-dimethylaminopyridine) in the presence 30 of a dehydrating agent, such as 31 dicyclohexylcarbodiimide (DCC) or more pereferably 32 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 33 hydrochloride (EDC).
34 The carboxylic acids or the corresponding esters 35 of Formula 2, are generally speaking, prepared as 36 described in the chemical scientific or patent 1 literature and the literature procedures for their 2 preparation may be modified, if necessary, by such 3 chemical reactions or processes which per se are 4 known in the art.-= For example, generally speaking, 2,2, 4,4 and/or 2,2,4,4-substituted chroman 6 6-carboxylic acids and chroman 7-carboxylic acids 7 are available in accordance with the teachings of e United States Patent Nos. 5,006,550, 5,314,159, 9 5,324,744, and 5,348,,975.
11 2,2,'4,4 and/or 2,2,4,4-substituted 12 thiochroman 6-carboxylic acids are available in ta accordance with,the teachings of United States 14 Patent No. 5,015,658.
!5 16 5,6,7,8-Tetrahydronaphthalene-2-carboxylic acids 17 are, generally speaking, available in accordance 18. with the teachings of United States Patent No.
ta 5,130,335.

COZEL C02Et HI'tOg/H2SO4 T'iClg/HC1 6 / HOAcJH2O/I~
NOz 9 Compound A Compound B

12 CO2Et CO2Et NO
1)~ z i Br2IHOAc 13 2) H3PO2 14 NH2 NHz Sr 16 Compound C
Compound D

19 CO2Et CO2H
1 i Ftol-vrraox _ Br sr Compound E Compound F

28 C02Et CO2Et COZEt N~~ Toluene 32 Compound C Compound G

36 Reaction Scheme Z

OH OH \ Br2, HOAc CH30CH20 11 Bu4NBr CH202 13 14 Krause, J. G. Compound I Compouad J
Synnceris 1972, p140 Compound H

1)tBuli,THF
18 _78 C H+ Bro_/HOAc 19 2) C02 (8) C02H OH
21 Cnmpound K Compound L

26 (i-Pr)2EtN

28 Br Br 29 Compound M Compound N

36 Reaction Scheme 2 1 Reaction Schemes 1 and 2 provide examples for 2 the synthesis of derivatives of 3 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-4 carboxylic acid, which are within the scope of Formula 2 and which are reacted with an amine of 6 Formula 3 to provide 7 (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-8 2-yl)carbamoyl derivatives within the scope of s Formula 1. Thus, as is shown in Reaction Scheme 1, ethyl 11 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-12 carboxylate (Compound A) is nitrated to provide the 13 corresponding 3-nitro compound (Compound B). The 14 nitro group of Compound B is reduced to provide the corresponding 3-amino compound (Compound C) which is 16 described in the publication Lehmann et al. Cancer 17 Research, 1991, 51, 4804. Ethyl is 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphth 19 alene-2-carboxylate (Compound C) is brominated to yield the corresponding 4-bromo derivative (Compound 21 D), which is converted by treatment with 22 isoamylnitrite and reduction with H3PO2, to ethyl 23 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphth 24 alene-2-carboxylate (Compound E). Saponification of Compound E yields 26 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphth 27 alene-2-carboxylic acid (Compound F) which is used 28 as a reagent in accordance with Formula 2. Ethyl 29 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphth alene-2-carboxylate (Compound C) is also diazotized 31 and reacted with HBF4 to provide ethyl 32 5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-3-fluoronaph 33 thalene-2-carboxylate (Compound G) which serves 34 either per se or after saponification as a reagent in accordance with Formula 2.

1 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-hydroxy-2 naphthalene (Compound H, available in accordance 3 with the publication Krause Synthesis 1972 140), is 4 the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to 6 provide the corresponding 3-bromo compound (Compound 7 I) which is thereafter protected in the hydroxyl 8 function by treatment with methoxymethyl chloride 9 (MOMC1) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymet-11 hoxy-2-bromonaphthalene (Compound J). Compound J is 12 reacted with t-butyllithium and carbon dioxide to 13 provide the corresponding carboxylic acid (Compound 14 K) from which the methoxymethyl protecting group is is removed by acid to give 16 5,6,7,8-tetrahydro-5,5,8,8-tetra-17 methyl-2-hydroxynaphthalene-3-carboxylic acid 18 (Compound L). Compound L is brominated to yield 19 5,6,7,8-tetrahy-dro-5,5,8,8-tetramethyl-l-bromo-2-hydroxynaphthalene 21 -3-carboxylic acid (Compound M). Compound L and 22 Compound M serve as reagents in accordance with 23 Formula 2. The hydroxy group of Compound M is 24 protected for further transformations with methoxymethyl chloride (MOMC1) in the presence of 26 base, yielding 27 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-bromo-2-met 28 hoxymethoxynaphthalene-3-carboxylic acid (Compound N).

8 CO2H CO2H -11 I ~ Br~. HOAc 1) SOC13 9 2) CH3OH. TEA
7O CH1Cl, Compound 0 Br 12 Compound P

1) F3CCONa 16 O CuI, NMP, 180 C
O
17 2) NaOH/HtOH
Sr 7r 19 Compound R Compound S

22 1) SOC12 1) HNO3, HZSO4 23 2) CHzOH 2) NaOH/EtOH

Compound 0 Compound T

O

NOz 32 Compound V

36 Reaction Scheme 3 Q
11 1) soC,'32 ~2~2.H5 CO2H 2) C2H50H
12 3) HN03/H2S0j O

16 Compound 0 Compound W

22 1 fiOAc O
O

24 Compound 0 Compound X

36 Reaction Scheme 3 -continued-4 \ f \
5everal Stops 8 Compound Y

10 8r COpFi 11 1)tBuLi=/-78 C
12 Bri/EiOAc 2}CO2 15 Compound Z Compound Al 1s 19 Reaction Scheme 4 CO2H C02F{
BrZ/HOAc 2s Sfiroot, B. Br 29 U. S. Patent 5,059,621 Compound B 1 36 Reaction Scheme 5 1 Reaction Schemes 3, 4 and 5 provide examples for 2 the synthesis of derivatives of 2,2,4,4 and 3 4,4-substituted chroman-6-carboxylic acids which can 4 serve as reagents in accordance with Formula 2 for the synthesis of the carbamoyl (amide) compounds 6 within the scope of the present invention. Thus, 7 referring now to Reaction Scheme 3, s 2,2,4,4-tetramethylchroman-6-carboxylic acid g(Compound 0, see U. S. Patent No. 5,006,550) is brominated with bromine in acetic acid to yield the 11 corresponding 8-bromo derivative (Compound P).
12 Compound P is converted to the acid chloride by 13 treatment with thionyl chloride, and the resulting 14 acid chloride is suitable for reaction with an amine of Formula 3 to provide the carbamoyl (amide) 16 compounds of the invention. The acid chloride is 17 also reacted with an alcohol (methanol) in the 18 presence of base to yield the corresponding ester, 19 methyl 20_ 2,2,4,4-tetramethyl-8-bromochroman-6-carboxylate 21 (Compound R). The bromo function of Compound R is 22 converted to a trifluoromethyl function by treatment 23 with sodium trifluoroacetate in the presence of 24 cuprous iodide catalyst and l-methyl-2-pyrrolidinone (NMP), and the carboxylate ester group is saponified 26 to yield 27 2,2,4,4-tetramethyl-8-trifluoromethylchroman-6-carbo 28 xylic acid (Compound S). Compound S is within the 29 scope of Formula 2 and is suitable per se or as the acid chloride or in other "activated" form to react 31 with the amines of Formula 3 to yield the carbamoyl 32 (amide) compounds of the invention.
33 2,2,4,4-Tetramethylchro-man-6-carboxylic acid 34 (Compound 0) is also converted to the methyl ester (Compound T) which is then nitrated to yield 36 2,2,4,4-tetramethyl-8-nitrochroman-6-carboxylic acid 1 (Compound V), still another reagent within the scope 2 of Formula 2. Moreover, in the example further 3 shown in Reaction Scheme 3, 4 2,2,4,4-tetramethylchroman- 6-carboxylic acid (Compound 0) is converted to the ethyl ester and 6 nitrated thereafter to yield ethyl 7 2,2,4,4-tetramethyl-8-nitrochroman-6-carboxylate 8 (Compound W). Still further, Compound 0 is-reacted 9 with IC1 to yield 2,2,4,4-tetramethyl-8-iodochroman-6=carboxylic acid 11 (Compound X).
12 In accordance with the example shown in Reaction 13 Scheme 4, 2-methylphenol is subjected to a series of 14 reactions in accordance with the teachings of United is States Patent No. 5,045,551 16 to yield 2,2,4,4,8-pentamethylchroman (Compound Y). Compound Y is brominated with bromine 1s in acetic acid to give 19 2,2,4,4,8-pentamethyl-6-bromochroman (Compound Z) 2o which is reacted with t-butyl lithium and thereafter 21 with carbon dioxide to give 22 2,2,4,4,8-pentamethylchroman-6-carboxylic acid 23 (Compound Al ) .
24 Reaction Scheme 5 illustrates the synthesis of 25 4,4-dimethyl-8-bromochroman-6-carboxylic acid 26 (Compound 81) by bromination of 27 4,4,-dimethyl-chroman-6-carboxylic acid which is 28 available in accordance with the teachings of United 29 States Patent No. 5,059,621.

31 2,2,4,4,8-Pentamethylchroman-6-carboxylic acid 32 (Compound Al ) and 33 4,4,-dimethyl-8-bromochroman-6-carboxylic acid 34 (Compound 81) serve as reagents, either per se, or as the corresponding acid chlorides (or other 36 "activated form), in accordance with Formula 2 for WO 97/19052 PC'1'/US96/18580 1 the synthesis of the carbamoyl (amide) compounds of 2 the present invention.
3 Referring back now to the reaction between the 4 reagent of Formula 2 with an amine compound of Formula 3 it is noted that the amine compounds are, s generally speaking, available in accordance with the 7 state-of-the-art. as described in the scientific and 8 patent literature. More specifically, the amine 9 compounds of Formula 3 can be prepared as described in the scientific and patent literature, or from 11 known compounds of the literature, by such chemical 12 reactions or transformations which are within the 13 skill of the practicing organic chemist. Reaction 14 Scheme 6 illustrates examples for the preparation of ys amine compounds of Formula 3 (where Y is phenyl) 16 from commercially available starting materials 17 (Aldrich Chemical Company, or Research Plus, Inc.
18 The illustrated compounds of Formula 3 are used for rs the synthesis of several preferred compounds of the invention.

C0~ 2C2H5 24 ~ 1) Na2Cr2O7, HOAc, HSO4, 90 C
2) SOC12 N02 ~ F 3) EtOH/Py. CH,Cl, 26 4) H2. Pd/C H2N F
27 Compound C1 CO H
31 1) Na~Cr~O7, HOAc. HISO4, 90 C ~ 2C2 s 2) SOC1y 32 N02 Br 3) EtOH/Py, CH~Ch 4) H,. Pd/C H2N CB33 34 Compound D1 36 Reaction Scheme 6 4 1) Na,Cr,O7, HOAc. H,S04, 90 C ' 2) SOC12 i 3) EtOHlPy, CH_Cl_ H2N Ci 2 Cl 4) H,, Pd/C

7 Compound El ~ ~ 1) SOC12 2) MeOHlTE.i/ CH2C1_ 16 Compound Fl 21 EDC, DMAP {
22 EtOH

Compound G1 F F
26 1) SOCI:
27 2H 2) CHgOH/Py C02CH3 ~ 3)NaN3/CH3CN

4) H2, Pd/C ( 29 F ~ F H2N I F
31 Compound Hl 36 Reaction Scheme 6 -continued-1 Thus, in accordance with Reaction Scheme 6, 2 3-nitro-6-methyl-fluorobenzene (Aldrich) is s subjected to oxidation, conversion of the resulting 4 carboxylic acid to an acid chloride and thereafter 5 to an ethyl ester, followed by reduction of the 6 nitro group, to yield ethyl 7 2-fluoro-4-amino-benzoate (Compound C1).
a 3-Nitro-6-methyl-bromobenzene (Aldrich) and a 3-nitro-6-methyl-chlorobenzene (Aldrich) are so subjected to essentially to the same series of 11 reactions to yield ethyl 2-bromo-4-amino-benzoate 12 (Compound D1) and ethyl 2-chloro-4-amino-benzoate 13 (Compound E1), respectively. 2-Nitro-4-aminobenzoic 14 acid (Research Plus) is converted to its methyl 15 ester (Compound F1) through the corresponding acid 16 chloride. 2,3,5,6-Tetrafluoro-4-amino-benzoic acid (Aldrich) is esterified by treatment with ethanol in 1s the presence of 19 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 20 hydrochloride (EDC) and 4-dimethylaminopyridine in 21 CH2C12 to give ethyl 22 2,3,5,6-tetrafluoro-4-amino-benzoate (Compound G1).

23 2,4,6-Trifluorobenzoic acid (Aldrich) is converted 24 to the methyl ester through the acid chloride, and 25 the 4-f luoro atom is displaced by reaction with 26 sodium azide, followed by hydrogenation, to yield 27 methyl 2,6-difluoro-4-amino benzoate (Compound HI).

28 Compounds Cl, Dl, E1, Fi, G,, and H, serve as amine 29 reagents in accordance with Formula 3. Further 3a examples of reagents in accordance with Formula 3 31 are nitro, fluoro, chZoro, bromo and trifluoromethyl 32 derivatives of amino substituted heteroaryl 33 carboxylic acids, or their lower alkyl esters, such 34 as ethyl 2-amino-4-chloropyridine 2-carboxylate, 35 ethyl 5-amino-3-chloropyridine 5-carboxylate, and 3s 3,4-dibromo-5-aminothiophene-2-carboxylic acid. The WO 97/19052 PCT/t1S96/18580 1 latter examples can be prepared by respective 2 chlorination or bromination of a 2-aminopyridine-5-carboxylic acid or of its ester, 4 3-aminopyridine-6-carboxylic acid or of its ester (described in WO 93/06086) and of 6 2-aminothiophene-5-carboxylic acid (described in 7 WO 93/06086).
$ The reaction between the compounds of Formula 2 9 and Formula 3 or between compounds of Formula 2a and 3a, described above, com.pris.es the actual synthesis 11 of the carbamoyl (amide)'compounds of the invention.
12 Numerous examples of this reaction are described in 13 detail in the experimental section below. The 14 carbamoyl (amide) compounds of the invention can be is converted into thiocarbamoyl (thioamide) compounds 16 of the invention where with reference to Formula 1 Z
17 is S, by reacting the carbamoyl (amide) compound is with' 19 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan e-2,4-disulfide (Lawesson's reagent). This reaction =21 is illustrated in Reaction Scheme 7 for two specific 22 examples for the compounds of the invention.

2 C02Et cazEt S

Lawensson N
N H
g I H benzene, 80 C

8 Compound 11 Compound 25 COZEt /
11 CO2Et s O / ~

13 ~ N ~ E Laweasson H \ E
~ H benzene. 80 C

16 Compound 1 Compound 27 19 Reaction Scheme 7 In Reaction Scheme 7 one starting material ethyl 21 4-[5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnap 22 hthalen-2-yl)carbamoyl]benzoate (Compound I,.) is 23 obtained in accordance with the teachings of 24 Kagechika et al. J. Med Chem. 1988 31, 2182 - 2192.
The other starting material, ethyl 26 2-fluoro-4-[5',6',7',8'-tetrahydro-5',5',8',8'-tetra 27 methylnaphthalen-2-yl)carbamoyl]benzoate (Compound 28 1) is obtained in accordance with the present 29 invention.

= 2 C02 02Hs O
9 ~
COyH H
FDC. DMAP
11 Etbyt 4-amin-2-[luoro banzoate 13 \ Compound K1 14 Compound K

/

17 ioQhmol k F K+COglacetnne 18 ~ - I C7HISI
19 BF3' O(C2H5)2 OH

Compound 7 N F
k-I

OC-lHis 28 Compound Ll 36 Reaction Scheme 8 F

~~ Ca~'1 p õ ~

72 c'CO2H DMAP 13 Methyl4-amino-2.6-difluorobenzoatc 14 OMOM pMOM
Br Br Compound A4t 16 Compound N

,8 CpZH
XF
2, N \ 1) NaOH/EtOH H
22 2) HCl/MeOH
ON

Br Compoond 36 36 Reaction Scheme 9 Ca:C.iHS
2 0 ~ ~
3 CCzH \
I)SOCh k F
4 ~ ( H
2) Ethy14-amino-2-IIuoro ro C benmate. Py O
6 3) H2, Pd/C

7 Compound V Compound Nl COZC_HS

12 1)~~ko2 N H
13 2) NaN3 16 Compound 15 1s Reaction Scheme 10 19 Reaction Schemes 8, 9 and 10 disclose examples 20 for the preparation of carbamoyl (amide) compounds 21 of the invention, first by a coupling reaction of a 22 compound of Formula 2 with a compound of Formula 3, 23 followed by one or more reactions performed on the 24 carbamoyl (amide) compound that has been first 25 obtained directly in the coupling reaction. Thus, 26 as is shown in Reaction Scheme 8, 27 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-28 3-methoxymethoxynaphthalene-2-carboxylic acid 29 (Compound K) is coupled with ethyl 30 4-amino-2-fluorobenzoate (Compound C1) in CH2C12 in 31 the presence of 32 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 33 hydrochloride (EDC) and dimethylaminopyridine (DMAP) 34 to gs.ve ethyl 35 2-f luoro-4-[5',6',7',8'-tetrahydro-5',5',8',8'-tetra 36 meth-1 yl-2'-methoxymethoxy-naphthalen-3'-yl)carbamoyl]benz 2 oate (Compound K1). The methoxymethyl protecting 3 group is removed from Compound K,, by treatment with 4 thiophenol and borontrifluoride ethereate resulting in ethyl 6 2-fluoro-4-[5',6',7',8'-tetrahydro-5',5',8',8'-tetra 7 methyl-2'-hydroxy-naphthalen-3'-yl)carbamoyl]-8 benzoate (Compound 7). The hydroxy function of 9 Compound 7 is converted into an n-hexyl ether by treatment with hexyl iodide in the presence of mild base.
12 In accordance with Reaction Scheme 9 13 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-l-bromo-2-met 14 hoxymethoxynaphthalene-3-carboxylic acid (Compound N) is coupled with methyl 16 4 -amino- 2, 6 -di f luorobenz oate (Compound H1) in CH2C12 17 solvent in the presence of ethylcarbodiimide 18 hydrochloride (EDC) and DMAP to provide methyl 19 2,6-difluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-2o tetramethyl-1'-bromo-2'-methoxymethoxy-naphthalen-3' 21 -yl)carbamoyl]benzoate (Compound MI), from which the 22 esterifying methyl group and the methoxymethyl 23 protecting group are removed by treatement with base 24 and acid, respectively.
Reaction Scheme 10 discloses the example of 26 converting 2,2,4,4-tetramethyl-8-nitrochroman-6-27 carboxylic acid (Compound V) into the corresponding 28 acid chloride by treatment with thionyl chloride, 29 followed by coupling with ethyl 4-amino-2-fluorobenzoate (Compound C2) and 31 hydrogenation to yield ethyl 32 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-amino-6'-chr 33 omanyl)carbamoyl]benzoate (Compound Nl). Compound N,.
34 is converted to the corresponding 8-azido compound, ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azido-36 6'-chromanyl)carbamoyl]benzoate (Compound 15) by 1 treatment of isoamyl nitrate and NaN3.

R1 R1 R m 6 R1 R1 (R~m ~ ~

NaN3 \.nCON
~'iOX (R3)6'M!' nr 3 9 (~o.,,,.
l /J acotonc \X ~ (mP
11 (W)P
12 Formula 2 Formula 6 t-BuOH

16 R, R, (R2)m is .nn~N=C=O
(R3)o-1 \
1s X
21 (W)p Formula 7 26 R, R, (R2)m 28 (R3)O~~~i' t -NH2 29 l 11 t, 31 Formula 2a (mp 36 Reaction Scheme 11 1 Reaction Scheme 11 illustrates the synthesis of 2 the primary amine compounds of Formula 2a from the 3 acid chlorides (X1 = Cl) or other form of activated 4 acids of Formula 2 where the primary amine of s Formula 2a is not available by a published 6 literature procedure. Thus, substantially in 7 accordance with the step of a Curtius rearrangement, 8 the acid chloride of Formula 2 is reacted with 9 sodium azide in acetone to yield the azide compound of Formula 6. The azide of Formula 6 is heated in a 11 polar high boiling solvent, such as t-butanol, to 12 provide the intermediate isocyanate of Formula 7, 13 which is hydrolyzed to yield a compound of Formula 14 2a.

n F C02H F ' C~
18 1) FxO~il~i2SO4 ~ ~
19 ~ 2) B,~ flz ~
BT / F HQzC F

tmd T

Sugawara, S; Ishilrawa, N.
23 Kogyo Kaguku Zasshi 24 1970, 73, 972-979 F
F
26 F COZH F C02Et 27 1) BtOH/H2S04 28 2) BuLi/C02 29 Br F HC~,C

31 =
rrfichael Reuman er al 32 J. lltrd. Chem-33 1995, 38, 2531-25411 36 Reaction Scheme 12 1 Reaction Scheme 12 illustrates examples for 2 preparing compounds of Formula 3a where such 3 compounds are not available commercially or by a 4 published literature procedure. Thus, by way of example 2,5-difluoro-4-bromobenzoic acid (available 6 by the literature procedure of Sugawara et al. Kogyo 7 Kaguku Zasshi 1970, 73, 972-979) is first esterified s by treatment with ethyl alcohol and acid to yield 9 the corresponding ester, and thereafter is reacted io with butyl lithium followed by carbon dioxide to yy give the monoester of 2,5-difluoro terephthalic acid 12 (Compound T1). A similar sequence of reactions 13 performed on 2,3,5,6-difluoro-4-bromobenzoic acid 14 (available by the literature procedure of Reuman et al. J. Med. Chem. 1995, 38, 2531-2540) yields the 16 monoester of 2,3,5,6-tetrafluoroterephthalic acid.
17 The just illustrated sequence of reaction can be, 18 generally speaking, utilized for the synthesis of 19 all compounds of Formula 3a with such modification zo which will become readily apparent to those skilled 21 in the art, where such compounds are not available 22 by a known literature procedure.
23 Numerous other reactions suitable for preparing 24 compounds of the invention, and for converting compounds of Formula 1 within the scope of the 26 present invention into still further compounds of 27 the invention, and also for preparing the reagents 28 of Formula 2, Formula 3, Formula 2a and Formula 3a 29 will become readily apparent to those skilled in the art in light of the present disclosure. In this 31 regard the following general synthetic methodology, 32 applicable for conversion of the compounds of 33 Formula 1 into further homologs and/or derivatives, 34 and also for preparing the reagents of Formula 2 and 3, (as well as 2a and 3a) is noted.
36 Carboxylic acids are typically esterified by 1 refluxing the acid in a solution of the appropriate 2 alcohol in the presence of an acid catalyst such as 3 hydrogen chloride or thionyl chloride.
4 Alternatively, the carboxylic acid can be condensed 5 with the appropriate alcohol in the presence of s- di.cyclohexylcarbodiimide and dimethylaminopyridine.
7 The ester is recovered and purified by conventional 8 means. Acetals and ketals are readily made by the s method described in March, "Advanced Organic 10 Chemistry," 2nd Edition, McGraw-Hill Book Company, p 11 810). Alcohols, aldehydes and ketones all may be 12 protected by forming respectively, ethers and 13 esters, acetals or ketals by known methods such as 14 those described in McOmie, Plenum Publishing Press, 15 1973 and Protecting Groups, Ed. Greene, John Wiley &
16 Sons, 1981.
17 A means for making compounds where A is ( CH2 ) g 18 (q is 1 - 5) is to subject the compounds of Formula 19 1, where B is an acid or other function, to 20 homologation, using the well known Arndt-Eistert 121 method of homologation, or other known homologation 22 procedures. Similar homologations (and several of 23 the other herein mentioned synthetic 24 transformations) can be transformed on the reagent 25 of Formula 3. Compounds of the invention, where A
26 is an alkenyl group having one or more double bonds 27 can be made, for example, by having the requisite 28 number of double bonds incorporated into the reagent 29 of Formula 3. Generally speaking, such compounds so where A is an unsaturated carbon chain can be 31 obtained by synthetic schemes well known to the 32 practicing organic chemist; for example by Wittig 33 and like reactions, or by introduction of a double 34 bond by elimination of halogen from an 35 alpha-halo-carboxylic acid, ester or like 36 carboxaldehyde. Compounds of the invention where 1 the A group has a triple (acetylenic) bond can be 2 made by using the corresponding aryl or heteroaryl 3 aldehyde intermediate. Such intermediate can be 4 obtained by reactions well known in the art, for example, by reaction of a corresponding methyl 6 ketone with strong base, such as lithium diisopropyl 7 amide.
8 The acids and salts derived from compounds of 9 Formula 1 are readily obtainable from the corresponding esters. Basic saponification with an 11 alkali metal base will provide the acid. For 12 example, an ester of Formula 1 may be dissolved in a 13 polar solvent such as an alkanol, preferably under 14 an inert atmosphere at room temperature, with about a three molar excess of base, for example, potassium 16 or lithium hydroxide. The solution is stirred for 17 an extended period of time, between 15 and 20 hours, is cooled, acidified and the hydrolysate recovered by 19 conventional means.
The amide (in Formula 1 B is CONR9R,.o ) may be 21 formed by any appropriate amidation means known in 22 the art from the corresponding esters or carboxylic 23 acids. One way to prepare such compounds is to 24 convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an 26 appropriate amine.
27 Alcohols are made by converting the 28 corresponding acids to the acid chloride with 29 thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book 31 Company), then reducing the acid chloride with 32 sodium borohydride (March, Ibid, pg. 1124), which 33 gives the corresponding alcohols. Alternatively, 34 esters may be reduced with lithium aluminum hydride at reduced temperatures. Alkylat3.ng these alcohols 36 with appropriate alky halides under Williamson 1 reaction conditions (March, Ibid, pg. 357) gives the 2 corresponding ethers. These alcohols can be 3 converted to esters by reacting them with 4 appropriate acids in the presence of acid catalysts or dicyclohexylcarbodiimide and 6 dimethylaminopyridine.
7 Aldehydes can be prepared from the corresponding 8 primary alcohols using mild oxidizing agents such as 9 pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or 11 dimethyl sulfoxide/oxalyl chloride in methylene 12 chloride (Omura, K., Swern, D., Tetrahedron, 1978, 13 34, 1651).
14 Ketones can be prepared from an appropriate is aldehyde by treating the aldehyde with an alkyl 16 Grignard reagent or similar reagent followed by 17 oxidation.
18 Acetals or ketals can be prepared from the 19 corresponding aldehyde or ketone by the method described in March, Ibid, p 810.
21 Compounds of Formula 1 where B is H can be 22 prepared from the corresponding halogenated aromatic 23 compounds, preferably where the halogen is I.
24 Specific ExamplesEthyl 4-Amino-2-fluorobenzoate (Compound Cl ) 26 To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 27 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol ) in 28 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4, .
29 This mixture was slowly heated to 90 C for 1 h to so give a greenish heterogeneous solution. The mixture 31 was cooled to room temperature and diluted with 32 ethyl acetate. The PH of the solution was adjusted 33 to 4 with NaOH (aq.). The mixture was extracted 34 with more ethyl acetate. The organic layer was washed with NaHC03(sat.), then brine and dried over 36 Na2SO4. After filtration, the solution was 1 concentrated to dryness which then was dissolved in 2 6 ml of SOC121 and heated at 80 C for 1 h. The 3 excess of SOC12 was removed under reduced pressure 4 and the residue was dissolved in 5 ml of CH2C12, 2 ml of EtOH and 2 ml of pyridine. The mixture was 6 stirred at room temperature for 2 h and concentrated 7 to dryness. Ethyl 2-fluoro-4-nitrobenzoate was a obtained as a white solid after column s chromatography of the residue with ethyl 1o= acetate/hexane (1/9). This solid was then dissolved 11 in 10 ml of ethyl acetate, and Pd/C (50 mg) was 12 added. Hydrogenation with a hydrogen balloon 13 converted ethyl 2-fluoro-4-ni.trobenzoate into the 14 title compound.
is 1H NMR b 7.77 (t, J= 8.4 Hz, 1H), 6.41 (dd, J1 =
16 8.6, J2 = 2.2 Hz, 1H), 6.33 (dd, J1 = 13.0, J2 = 2.2 17 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.3 (b, 2H), 1.37 1a (t, J = 7.1 Hz, 3H).
19 Methyl 4-Amino-2,6-difluorobenzoate (Compound Hi) 20 A solution of trifluorobenzoic acid (150 mg, 21 0.85 nunol, Aldrich) in 0.5 ml of SOC12 was heated 22 under reflux for 2h. The reaction mixture was 23 cooled to room temperature, and excess of SOC12 was 24 removed under reduced pressure. The residue was 25 dissolved in 1 ml of pyridine and 0.2 ml of 26 methanol. After stirring at room temperature for 30 27 min, solvent was removed and the residue was 28 purified by column chromatography (ethyl 29 acetate/hexane 1/10) to give methyl trifluoro-30 benzoate as a colorless oil. This oil was then 31 dissolved in 1 ml of CH3CN, then a solution of NaN3 32 (100 mg, 1.54 mmol) in 0.5 ml of water was added.
33 The reaction mixture was refluxed for two days.
34 Salt was filtered and the remaining solution was 35 concentrated to an oil. This oil was then dissolved 36 in 1 ml of methanol, followed by a catalytic amount 1 of Pd/C (10%, w/w). The reaction mixture was 2_ hydrogenated under a hydrogen balloon for 12 h.
3 Catalyst was removed and the solution was 4 concentrated to an oil. After column chromatography (ethyl acetate/hexane 1/3), the title product was 6 obtained as colorless crystals.
7 'H NMR 6 6.17 (d, J = 10.44 Hz, 2H), 4.2 (b, 2H), 8 3.87 (s, 3H).
s 8-Bromo-2,2,4,4-tetramethyl-6-chromanoic acid (Compound P) 11 To a solution of 2,2,4,4-tetramethyl-6-12 chromanoic acid (200 mg, 0.85 mmol) in 0.5 ml of 13 AcOH was added Br2 (0.07 ml, 1.28 mmol). The 14 resulting dark-orange solution was stirred at room temperature for overnight. The excess bromine was 16 removed under reduced pressure. Then the solution 17 was poured into 5 ml of water and extracted with 18 ethyl acetate (3x3ml). The combined ethyl acetate 19 layers were further washed with NaHCO3 (sat.), brine and dried over MgSO4. After concentration, the 21 residue was purified by column chromatography 22 (silica gel, ethyl acetate/hexane 1/3) to yield the 23 desired product (170 mg, as white solids.
24 'H NMR 6 8.11 (d, J= 2.2 Hz, 1H), 8.00 (d, J= 2.2 Hz, 1H), 1.90 (s, 2H), 1.43 (s, 6H), 1.39 (s, 6H).
26 8-Iodo-2,2,4,4-tetramethyl-6-chromanoic Acid 27 (Compound X) 28 To a solution of 2,2,4,4-tetramethyl-6-29 chromanoic acid (66 mg, 0.28 mmol) in 0.8 ml of AcOH
was added IC1 (0.07 ml, 1.4 mmol). The resulting 31 colored solution was stirred at room temperature for 32 overnight. Following the same procedure as for the 33 synthesis of 8-bromo-2,2,4,4-tetramethyl-6-34 chromanoic acid (Compound P), the reaction gave the title compound (107 mg) as white solids.
36 'H NMR 6 8.35 (d, J= 2.2 Hz, 1H), 8.03 (d, J= 2.2 1 Hz, 1H), 1.87 (s, 2H), 1.43 (s, 6H), 1.38 (s, 6H).
2 2,2,4,4-Tetramethyl-8-trifluoromethylchroman-6-oic 3 acid (Compound S) 4 A solution of 8-bromo-2,2,4,4-tetramethyl-6-s chromanoic acid (Compound R, 150 mg, 0.48 mmol) in 1 6 ml of SOC12 was ref luxed for 2 h. After cooling to 7 room temperature, the excess of SOC12 was removed 8 under reduced pressure and the residue was dissolved 9 in 1 ml of pyridine and 0.2 ml of methanol. The 10 mixture was stirred at room temperature for 30 min.
11 Solvent was removed and the residue was passed 12 through a column (silica gel, ethyl acetate/hexane 13 1/10) to give the methyl 8-bromo-2,2,4,4-tetra-14 methylchromanoate (158 mg) as a colorless oil. To a 15 solution of this methyl ester in 3 ml of 16 N-methylpyrrolidone (NMP) was added NaCO2CF3 (502 mg, 17 3.7 mmol) and CuI (350 mg, 1.84 mmol). The 18 resulting mixture was heated to 175 C (bath temp) 19 for 2 h. The resulting mixture was cooled to room 20 temperature and poured into ice-water. The product 21 was extracted into ethyl acetate (3x3ml). The 22 combined organic layers were dried and concentrated 23 to dryness. The crude material was purified by 24 column chromatography (ethyl acetate/chloroform 25 1/10) to give the title compound as a colorless oil 26 (120 mg). This was hydrolyzed under standard 27 conditions to give the title compound.
28 1H NMR b 8.21 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.1 29 Hz, 1H), 1.92 (s, 2H), 1.41 (s, 12H).
30 Ethyl 8-Nitro-2,2,4,4-tetramethyl-6-chromanoate 31 (Compound W) 32 Ethyl 2,2,4,4-tetramethyl-6-chromanoate (150 mg, 33 0.57 mmol) was slowly added to 0.3 ml of conc. H2SO4 34 at 0 C. To this mixture was added very slowly 0.03 35 ml of HN03. The reaction mixture was stirred at 0 C
36 for 30 min and poured into ice-water. The product 1 was extracted into 5 ml of ethyl acetate, washed 2 with NaHCO3 (sat.), brine and dried over MgSO4.
a After concentration, the product was purified by 4 column chromatography (ethyl acetate/hexane 1/10) to s yield 74 mg of light-yellow oil.
6 1H NMR 6 8.24 (d, J 2.1 Hz, 1H), 8.17 (d, J = 2.1 7 Hz, 1H), 4.38 (q, J 7.1 Hz, 2H), 1.95 (s, 2H), 8 1.43 (s, 6H), 1.42 (s, 6H), 1.40 (t, J = 7.1 Hz, 9 3H).
2-Oxo-4.4.8-trimethylchroman (Compound P1) 11 In a 500 ml of round bottom flask, NaH (1.66 g, 12 60% suspension in oil, 0.046 mol) was washed with 13 dry hexane. Then, dry THF (22 ml) was added 14 followed by o-cresol (5 g, 0.046 mol) in 10 ml of 1s dry THF. The reaction mixture was stirred at 0 C
16 for 30 min followed by addition of 3,3-dimethyl 17 acryloyl chloride in 10 ml of THF. The resulting 1s white slurry was stirred at room temperature for 12 19 h, then slowly quenched with water. The mixture was then extracted with ethyl acetate. The organic 21 layer was washed with brine, water and dried over az MgSO4. After filtration and removal of the solvent, 23 a yellow oil was obtained (10.44 g). This oil was 24 then dissolved in 50 ml of dry CH2C12, and was canulated into a solution of A1C13 (10.8 g, 0.069 26 mmol ) in 10 ml of CHaC12 . The reaction mixture was 27 stirred at room temperature for 12 h. Then 28 ice-water was carefully added and the organic layer 29 was separated, and washed with NaHCO3 (sat), brine, water and finally dried over MgSO4, After removal of 31 the drying agent and solvent, the residue was 32 purified by column chromatography (silica gel, ethyl 33 acetate/hexane 1/9) to yield the title compound 34 (4.408 g) as an oil.
lIH NMR 6 7.1 (m, 3H), 2.62 (s, 2H), 2.33 (s, 3H), 36 1.36 (s, 6H).

WO 97/19052 PCTlUS96/18580 1 2,4-Dimethyl-4-(2'-hydroxy-3'-methylphenyl)pentan-2-2 ol (Compound R,) 3 To a solution of 2-oxo-4,4,8-trimethylchroman 4(Compound P1, 2.20 g, 11.5 mmol) in 40 ml of dry ethyl ether was added methyl magnesium bromide 6(12.67 ml, 38 mmol, 3 M solution in THF). The 7 reaction mixture was stirred at room temperature for 8 12 h, then quenched with NH4C1 (sat.) until all 9 precipitate dissolved. The mixture was extracted with diethyl ether and the combined organic layers 11 were separated and washed with brine, water and 12 dried over MgSO4. After filtration and removal of 13 the solvent, the title compound was obtained as a 14 tan solid (2.215 g).
is 1H NMR 6 7.16 (d, J= 7.88 Hz, 1H), 7.00 (d, J = 6.72 16 Hz, 1H), 6.81 (t, J 7.6 Hz, 1H), 5.89 (b, 1H), 17 2.21 (s, 3H), 2.17 (s, 2H), 1.48 (s, 6H), 1.10 (s, 18 6H).
19 2, 2, 4, 4, 8-Pentamethyl-6-bromochroman (Compound Z) 21 A solution of 2,4-dimethyl-4-(2'-hydroxy-3'-22 methylphenyl)pentan-2-ol (Compound R,., 2.215 g, 9.98 2.3 mmol ) in 30 ml of 15% of H2SO4 was heated to 110 C .
24 After cooling to room temperature, the reaction mixture was extracted with diethyl ether. The 26 organic layer was washed with NaHCO3 (sat.), brine 27 and water. After filtration and removal of solvent, 28 the residue was passed through a column (silica gel, 29 pure hexane) to give the title compound as a clear oil (1.636 g). This oil was then dissolved in 1.5 31 ml of HOAc, then Br2 (0.4113 ml, 7.98 mmol) was 32 added. The reaction mixture was stirred at room 33 temperature for 12 h. Solvent was removed under 34 reduced pressure and to the residue was added ethyl acetate, and the resulting mixture was washed with 36 NaHCO3 (sat.), brine, water and dried over MgSO4.

WO 97/19052 PCT/bJS96/18580 1 After filtration and removal of solvent, the residue 2 was passed through a column (silica gel, pure 3 hexane) to give the title compound as a white solid 4 (2.227 g).
6 'H NMR 6 7.21 (s, 1H), 7.06 (s, 1H), 2.14 (s, 3H), 6 1.79 (s, 2H), 1.32 (s, 6H), 1.31 (s, 6H).
7 2.2,4,4,8-PentamethYl-6-chromanoic Acid (Compound A,) 8 To a solution of 2,2,4,4, 8-pentamethyl-6-bromo-9 chroman (Compound Z) (1.2 g, 4.24 mmol) in 18 ml of dry THF at -78 C under argon gas was added slowly ii 5.48 ml of t-BuLi (1.7 M in hexane, 9.33 mmol). The 12 reaction mixture was stirred at -78 C for 1 h. Then 13 CO2 was bubbled through the solution for 1 h. After 14 removal of CO2 stream, the reaction mixture was stirred for an additional hour at -78 C. Then 10%
16 of HC1 was added. After warming up to room 17 temperature, the reaction mixture was extracted with 18 ethyl acetate. The organic layer was further washed 19 with brine and dried over Na2SO4 . After concentration, the residue was purified by column 21 chromatography (ethyl acetate/hexane 5/95) to yield 22 the title compound as a white solid (774 mg).
23 'H NMR 6 7.96 (s, 1H), 7.75 (s, 1H), 2.23 (s, 3H), 24 1.88 (s, 2H), 1.39 (s, 6H).
8-Bromo-4,4-dimethyl-6-chromanoic Acid (Compound B,) 26 Using the same procedure as for the synthesis of 27 8-bromo-2,2,4,4-tetramethylchromanoic acid (Compound 28 P) but using 4,4-dimethylchromanoic acid (100 mg, 29 0.49 mmol), the title compound was obtained as a white solid.
31 'H NMR 6 8.10 (d, J 2.1 Hz, 1H), 7.98 (d, J = 2.1 32 Hz, 1H), 4.39 (t, J 5.44 Hz, 2H), 1.89 (t, J = 5.4 33 Hz, 1H), 1.38 (s, 6H).
34 Ethyl 2-Amino-l-bromo-5,5.8,8-tetrahydro-5.5,8,8-tetramethylnaphthalene-3-carboxylate 36 (Compound D) 1 To a solution of ethyl 5,6,7,8-tetrahydro-2 5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate 3 (Compound C, 58 mg, 0.21 mmol) in 2 ml of HOAc was 4 added Br2 (0.02 ml, 0.42 mmol). The orange solution was stirred at room temperature for 2 days. The 6 excess Br2 and HOAc were removed under reduced 7 pressure and the residue was passed through a column s(silica gel, ethyl acetate/hexane 1/10) to yield the 9 title compound as a light-orange oil (59 mg, 79.5%).
'H NMR 6 7.90 (s, 1H), 6.41 (b, 2H), 4.36 (q, J 7.2 >> Hz, 2H), 1.70 (m, 4H), 1.58 (s, 6H), 1.40 (t, J=
12 7.2 Hz, 3H), 1.28 (s, 6H).
13 Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl 14 -4-bromonaphthalene-2-carboxylate (Compound E) is Ethyl 2-Amino-l-bromo-5,5,8,8-tetrahydro-16 5,5,8,8-tetramethylnaphthalene-3-carboxylate 17 (Compound D, 59 mg, 0.17 mmol) was dissolved in 2 ml ys of EtOH at 0 C. To this solution was added iml of 19 trifluoroacetic acid and 1 ml of isoamylnitrite.
The reaction mixture was stirred at 0 C for 30 mi.n 21 then H3P0Z (0.325 ml, 3.14 mmol) was added. The 22 reaction mixture was allowed to warm to room 23 temperature and stirred for 12 h. NaHCO3 (sat.) was 24 added and the reaction mixture was extracted with ethyl acetate, dried over MgSO41 filtered and 26 concentrated to give an oil. The product was 27 purified by column chromatography (silica gel, ethyl 28 acetate/hexane 1/10) to give the title compound as a 29 colorless oil.
'H NMR 6 8.02 (d, J 2.0 Hz, 1H), 7.95 (d, J = 2.0 31 Hz, 1H), 4.35 (q, J= 7.1 Hz, 2H), 1.71 (m, 4H), 32 1.56 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.31 (s, 33 6H).
34 Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-fluoronaphthalen-2-yl-carboxylate (Compound G) 36 In an ice bath, ethyl 5,6,7,8-tetrahydro-WO 97/19052 1'CT/US96/18580 1 5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate 2 (Compound C, 150 mg, 0.55 nunol) was added 0.24 ml of 3 HBF4 (48% solution in water), followed by a solution 4 of NaNO2 (81 mg, 1.16 mmol) in 1 ml of water. The 5 slurry was left in a refrigerator for 3 days. The 6 reaction mixture was washed successively with ethyl 7 acetate until TLC showed no UV visible spot at the s baseline. The ethyl acetate layer was dried with 9 MgSO4 and the solution was concentrated to an oil.
10 The oil was further dissolved in 1 ml of toluene and the mixture was heated under reflux for 2 h. After 12 the reaction cooled to room temperature, solvent was 13 evaporated and the residue was passed through a 14 column (silica gel, ethyl acetate/hexane 1/10) to 15 give the title compound as an oil.
16 1H NMR 6 7.85 (d, J 7.8 Hz, 1H), 7.04 (d, J = 12.3 17 Hz, 1H), 4.38 (q, J 7.1 Hz, 2H), 1.69 (s, 4H), is 1.38 (t, J = 7.1 Hz, 3H), 1.30 (s, 6H), 1.28 (s, 19 6H).
20 2-Bromo-3-hydroxy-5,5,8,8-tetrahydro-5,5,8,8-tetrame 21 thylnaphthalene (Compound I) 22 Using the same procedure as for the synthesis of 23 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid 24 (Compound P) but using 2-hydroxy-5,5,8,8-tetrahydro-26 5,5,8,8-tetramethyltetralin (700 mg, 3.43 nunol) and 26 Br2 (0.177 ml, 3.43 mmol) in 1.5 ml of HOAc, the 27 title compound was obtained as a white solid (747 28 mg).
29 1H NMR 6 7.36 (s, 1H), 6.96 (s, 2H), 5.32 (b, 1H), 30 1.66 (s, 4H), 1.25 (s, 12H).
31 5 6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-methoxymet-32 hoxy-2-bromonaphthalene (Compound J) 33 To a solution of 2-bromo-3-hydroxy-5,5,8,8-tet-34 rahydro-5,5,8,8-tetramethylnaphthalene (Compound I, 35 600 mg, 2.12 ntmol ) and catalytic amount of Bu4NBr in 36 20 ml of dry CH2C12 at 0 C was added 1 diisoproylethylamine (1.138 ml, 12.75 mmol), 2 followed by methoxymethyl chloride (0.484 ml, 6.39 3 mmol). The reaction mixture was heated at 45 C for 4 12 h. The reaction mixture was washed with 10% of citric acid, then NaHCO3 (sat.), brine and dried over 6 MgSO4. After filtration and removal of the solvent, 7 the residue was purified by column chromatography a(ethyl acetate/hexane 1/9) to yield the title 9 compound (722 mg) as a white solid.
'H NMR 6 7.43 (s, 1H), 7.06 (s, 1H), 5.21 (s, 2H), 11 3.54 (s, 3H), 1.66 (s, 4H), 1.26 (s, 6H), 1.25 (s, 12 6H).
13 3-Methoxymethoxy-5,5,8,8-tetramethyZ-5,6,7,8-tetrah 14 ydronaphthalen-2-vl carboxylic acid (Compound K) Using the same procedure as for the synthesis of 16 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound A,) 17 but using 5,6,7,8-tetrahydro-5,5,8,8-18 tetramethyl-3-methoxymethoxy-2-bromonaphthalene 19 (Compound J, 722 mg, 2.21 mmol) and 2.86 ml of t-BuLi (4.87 mmol, 1.7 M solution in hexane), the 21 title compound was obtained as a white solid (143 22 mg).
23 'H NMR S 8.12 (s, 1H), 7.19 (s, 1H), 5.40 (s, 2H), 24 3.58 (s, 3H), 1.70 (s, 4H), 1.30 (s, 12H).
Ethyl 2-Fluoro-4-[(5',6',7',8'-tetrahydro-26 5',5',8',8'-tetramethylnalphthalen-2'-yl)carbamoyl]be 27 nzoate (Compound 1) 28 To 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-29 2-naphthoic acid (46 mg, 0.2 mmol) was added 1 ml thionyl chloride. This mixture was refluxed for 2 31 h. Excess thionyl chloride was removed under 32 reduced pressure and the residue was dissolved in 2 33 ml of CH2C12. To this solution was added ethyl 34 4-amino-2-fluorobenzoate ((Compound C,, 37 mg, 0.2 mmol) followed by 0.5 ml of pyridine. The reaction 36 mixture was stirred at room temperature for 4 h and 1 was concentrated under reduced pressure. The 2 residue was purified by column chromatography (ethyl 3 acetate/hexane 1/10) to give the title compound as 4 white solids.
'H NMR 6 8.06 (b, 1H), 7.93 (t, J= 8.4 Hz, 1H), 7.85 s(d, J= 2.0 Hz, 1H), 7.78 (dd, J, = 2.0 Hz, Ja = 12.9 7 Hz, 1H), 7.55 (dd, J1 = 2.0 Hz, J2 = 8.2 Hz, 1H), 8 7.40 (d, J= 8.3 Hz, 1H), 7.32 (dd, Jl = 2.02 Hz, J2 9 = 8.8 Hz, 1H), 4.38 (q, J= 7.2 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J= 7.2 Hz), 1.32 (s, 6H), 1.30 (s, 11 6H).
12 Ethyl 4-[(3'-f luoro-5',6',7',8'-tetrahydro-13 5',5',8',8'-tetramethylnaphthalen-2'-y1)carbamoyl]be 14 nzoate (Compound 3) Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-16 3-fluoronaphthalene-2-carboxylate (Compound G, 75 17 mg, 0.27 mmol) was dissolved in a mixture of 3 ml of 18 EtOH and 1 ml of NaOH (1 M in water). The reaction 19 mixture was left overnight at room temperature. The reaction was neutralized with 5% of HC1. Water 21 (2ml) was added and the mixture was extracted with 22 ethyl acetate (3x3m1). The combined layers were 23 washed once with 3 ml of brine and dried over MgSO4.
24 After filtration, the clear organic solution was 26 concentrated to give 3-fluoro-5,5,8,8-tetrahydro-26 5,5,8,8-methylnaphthalen-2-yl carboxylic acid.
27 Using the same procedure as for ethyl 28 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetr 29 amethylnaphthalen-2'-yl)carbamoyl]benzoate (Compound 1), except using ethyl 4-amino benzoate (45 mg, 0.27 31 mmol), the carboxylic acid was converted to the 32 title compound (white solid).
33 'H NMR b 8.66 (b, 1H), 8.13 (d, J= 7.8 Hz, 1H), 8.05 34 (d, J= 8.3 Hz, 2H), 7.76 (d, J= 8.3 Hz, 2H), 7.07 (d, J'= 12.3 Hz, 1H), 4.36 (q, J= 7.1 Hz, 2H), 1.70 36 (s, 4H), 1.49 (t, J= 7.1 Hz, 3H), 1,32 (s, 6H), 1 1.30 (s, 6H).
2 Ethyl 2-Fluoro-4- L(5',6',7',8'-tetrahydro-4'-3 bromo-5',5',8',8'-tetramethylnazahthalen-2'-vl)carbam 4 oyllbenzoate (Compound 5) Using the same procedure as for the synthesis of 6 ethyl 2-f luoro-4-[-5',6',7',8'-tetrahydro-7 5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be 8 nzoate (Compound 1), but using 5,6,7,8-tetrahydro-9 5,5,8,8-tetramethyl-4-bromonaphthalene-2-carboxylic acid (Compound F), the title compound was obtained 11 as a white solid.
12 1H NMR 6 8.30 (b, 1H), 7.92 (t, J = 8.4 Hz, 1H), 7.84 13 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 2.1 Hz, IH), 7.74 14 (dd, J, = 2.1 Hz, J2 = 12.8 Hz, 1H) , 7.35 (dd, J, =
2.0 Hz, J2 = 8.4 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 16 1.67 (m, 4H), 1.55 (s, 6H), 1.39 (t, J = 7.2 Hz, 17 3H), 1.31 (s, 6H).
18 Ethyl 2-Fluoro-4-f(3'-methoxymethoxy-5',6',7',8'-1a tetrahvdro-5', 5',8',8'-tetramethyl-naphthalen-2'-yl)carbamoyllbenzoate (Compound Kl) 21 Using the same procedure as for the synthesis of 22 ethyl 2-fluoro-4-[(3'-methoxymethoxy-4'-bromo-23 5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphth 24 alen-2'-yl)carbamoyl]benzoate (Compound S,), but using 3-methoxymethoxy-5,5,8,8-tetramethyl-26 5,6,7,8-tetrahydronaphthalen-2-y1 carboxylic acid 27 (Compound K, 143 mg, 0.49 mmol) and 28 4-amino-2-fluorobenzoate (Compound C,, 98.5 mg, 0.54 29 mmol), the title compound was obtained as a white so solid.
31 1H NMR 6 10.1 (b, 1H), 8.20 (s, 1H), 7.93 (t, J= 8.8 32 Hz, 1H), 7.83 (d, J= 13.4 Hz, 1H), 7.29 (d, J= 8.0 33 Hz, 1H), 5.41 (s, 2H), 4.39 (q, J= 7.1 Hz, 2H), 34 3.59 (s, 3H), 1.70 (s, 4H), 1.31 (s, 12H), 1.26 (t, J= 7.1 Hz, 3H).
36 Ethyl 2-Fluoro-4-f(3'-hydroxy-5',6',7',8'-tetra-1 hydro-5',51,8', 8'-tetramethyl-2-naphthalenyl)-2 carbamoyl]benzoate (Compound 7) 3 A solution of ethyl 2-fluoro-4-[(3'-methoxymet-4 hoxy-5',6',7',8'-tetrahydro-5', 5',8',8'-tetramethyl-6 naphthalen-2'-yl)carbamoyl]benzoate (Compound K1, 7 50.7 mg, 0.11 mmol ) in 2 ml of CH2C12 was added 8 thiophenol (0.061 ml, 0.55 mmol). The reaction a mixture was stirred at 0 C for 5 min, then BF3. Et2O
(0.027 ml, 0.22 mmol) was added. The reaction 11 mixtrue was stirred at 0 C for 2 h, then NaHCO3 12 (sat.) was added. The organic layer was separated, 13 and washed with brine, water and dried over MgSO4.
14 After filtration and removal of solvent, the residue was passed through a column (silica gel, ethyl 16 acetate/hexane 1/3) to give the title compound as 17 white solid (44.2 mg).
ia 1H NMR 6 8.61 (b, 1H), 7.94 (t, J = 8.42 Hz, 1H), 19 7.71 (dd, J = 10.8, 2.0 Hz, 1H), 7.53 (s, 1H), 7.35 (dd, J = 6.4, 2.0 Hz, 1H), 6.96 (s, 1H), 4.39 (q, J
21 = 7.1 Hz, 2H), 1.69 (s, 4H), 1.40 (t, J= 7.1 Hz, 22 3H), 1.29 (s, 6H), 1.27 (s, 6H).
23 Ethyl 24 2-Fluoro-4-f(4',4'-dimethyl-8'-bromochroman-6'-yl)ca rbamoyllbenzoate (Compound 9) In a 10 ml of round 26 bottom flask, 4,4-dimethyl-8-bromo-6-chromanoic acid 27 (Compound Bl, 139 mg, 0.485 mmol) was added SOC12 (1 28 ml, large excess). The resulting solution was 29 heated at 90 C for 2 h and let cooled to room temperature. The excess of SOC12 was evaporated 31 under reduced pressure. The residue was dissolved 32 in CH2C12 (3 ml). Ethyl 4-amino-2-fluorobenzoate 33 (Compound Cl, 90 mg, 0.49 mmol) was added followed by 34 pyridine (0.5 ml, large excess). The reaction mixture was stirred for overnight and then 36 concentrated to dryness. The residue was purified 1 by column chromatography with ethyl acetate/hexane 2 (1/5) to yield the title compound as a white solid 3 (190 mg).
4 'H NMR 5 7.95 (t, J= 8.31 Hz, 1H), 7.88 (b, 1H), 5 7.83 (d, J= 2.2 Hz, 1H), 7.80 (d, J= 2.2 Hz, 1H), 6 7.75 (dd, J= 12.89, 2.0 Hz, 1H), 7.30 (dd, J=
7 8.55, 2.0 Hz, 1H), 4.37 (m, 5H), 1.89 (t, J= 5.49 8 Hz, 2H), 1.40 (t, J= 7.1 Hz, 3H), 1.39 (s, 6H).
9 Ethyl 2-Fluoro-4-[(2',2',4',4'-tetramethyl-8'-bromo-10, chroman-6'-yl)carbamoyl]benzoate (Compound il) 11 Using the same procedure as for ethyl 12 2-f luoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 13 rbamoyl]benzoate (Compound 9), but using 14 2,2,4,4-tetramethyl-8-bromo-6-chromanoic acid 15 (Compound P, 70 mg, 0.22 minol) and ethyl 16 4-amino-2-fluorobenzoate (Compound C1, 38 mg, 0.22 17 mmol), the title compound was obtained as a white is solid (80 mg, 76%).
19 'H NMR 6 8.25 (b, 1H), 7.92 (t, J= 8.4 Hz, 1H), 20 7.83 (s, 2H), 7.74 (dd, J1 = 2.0, J2 = 13.0 Hz, 1H), 21 7.34 (dd, J2 = 2.0, J2 = 8.7 Hz, 1H), 4.37 (q, J=
22 7.1 Hz, 2H), 1.88 (s, 2H), 1.41 (s, 6H), 1.39 (t, J
23 = 7.1 Hz, 3H), 1.37 (s, 6H).
24 Ethyl 25 2-Fluoro-4-T(2',2',4',4'-tetramethyl-8'-trifluoromet 26 hylchroman-6'-yl)carbamoyll benzoate (Compound 13) 27 Using the same procedure as for ethyl 28 2-f luoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 29 rbamoyl]benzoate (Compound 9), but using 30 2,2,4,4-tetramethyl-8-trifluoromethyl-6-chromanoic 31 acid (Compound S, 57 mg, 0.19 mmol) and ethyl 32 4-amino-2-fluorobenzoate (Compound C1, 35 mg, 0.19 33 mmol), the title compound was obtained as white 34 solids.
35 'H NMR 6 8.06 (d, J= 2.2 Hz, 1H), 7.99 (b, 1H), 7.95 36 (t, J= 8.55 Hz, 1H), 7.81 (d, J= 2.2 Hz, 1H), 7.76 1 (dd, J = 12.8, 2.1 Hz, 1H), 7.33 (dd, J = 8.55, 1.9 2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.93 (s, 2H), 3 1.41 (s, 12H), 1.40 (t, J = 7.2 Hz, 3H).
4 Ethyl 2-Fluoro-4-f(2',2',4',4'-tetramethyl-8'-amino-chroman-6'-yl)carbamoyllbenzoate (Compound N1) 6 Using 8-nitro-2, 2, 4, 7 4-tetramethylchroman-6-carboxylic acid (Compound V) 8 and following the same procedure as for the 9 synthesis of ethyl 2-fluoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 11 rbamoyl]benzoate (Compound 9), ethyl 12 2-fluoro-4-[2',2',4',4'-tetramethyl-8'-nitrochroman-13 6'-yl)]carbamoylbenzoate was obtained as a white 14 solid. This compound (50 mg, 0.12 mmol) was dissolved in 2 ml of methanol. A catalytic amount 16 of Pd/C was added to the solution and the solution 17 was maintained under H2 atmosphere (hydrogen balloon) 18 for overnight. The catalyst was removed by 19 filtration and the solvent was evaporated to give the title compound as a white solid.
21 1H NMR 6 7.93 (t, J= 8.43 Hz, 1H), 7.90 (b, 1H), 22 7.73 (dd, J = 12.9, 2.0 Hz, 1H), 7.29 (dd, J = 8.43, 23 1.96 Hz, 1H), 7.23 (d, J 2.14 Hz, 1H), 7.01 (d, J
24 = 2.2 Hz, 1H), 4.35 (q, J 7.1 Hz, 2H), 1.88 (s, 2H), 1.39 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.37 26 (s, 6H).
27 Ethyl 2-Fluoro-4-[(2',2'.4',4'-tetramethyl-8'-azido-28 chroman-6'-yl)carbamoylibenzoate (Compound 15) 29 To a solution of ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-aminochroman 31 -6'-yl)carbamoyl]benzoate (Compound N1, 32 mg, 0.077 32 mmol) in 3 ml of EtOH was added 0.5 ml of 33 trifluoroacetic acid (TFA) and 0.5 ml of 34 isoamylnitrite at 0 C. The reaction was stirred for 2 h when a solution of NaN3 (5 mg, ) in 0.2 ml of 36 water was added. The reaction mixture was allowed i to warm to room temperature and stirred for 2 overnight. The solvent was removed and the residue 3 was purified by column chromatography ( silica gel, 4 ethyl acetate/ hexane 1/10) to give the title compound as a colorless oil.
6 'H NMR 6 8.0 (b, 1H), 7.94 (t, J= 7.8 Hz, 1H), 7.73 7 (d, J= 12.1 Hz, 1H), 7.64 (s, 1H), 7.31 (dd, J=
8 8.5, 2.0 Hz, 1H), 7.21 (d, J= 2.0 Hz, 1H), 4.37 (q, 9 J= 7.1 Hz, 2H), 1.90 (s, 2H), 1.39 (t, J= 7.1 Hz, 3H), 1.45 (s, 6H), 1.40 (s, 6H).
11 Methyl 2,6-Difluoro-4-[(2',2',4',4'-tetramethyl-12 8'-trifluoromethylchroman-6'-yl)carbamoyllbenzoate 13 (Compound 17) 14 Using the same procedure as for ethyl 2-f luoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 16 rbamoyl]benzoate (Compound 9), but using 17 2,2,4,4-tetramethyl-8-trifluoromethylchromanoic acid is (Compound S, 11.2 mg, 0.037 mmol) and methyl 19 4-amino-2,6-difluorobenzoate (Compound H,, 6.6 mg, 0.035 mmol), the title compound was obtained as 21 white crystals.
22 'H NMR 6 8.21 (b, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 23 7.36 (d, J= 10.20 Hz, 1H), 3.93 (s, 3H), 1.92 (s, 24 2H), 1.40 (s, 12H). Ethyl 2-Fluoro-4-[(2', 2', 4', 4'-tetramethyl-8'-iodo-26 chroman-6'-yl)carbamoyl]benzoate (Compound 19) 27 Using the same procedure as for ethyl 28 2-fluoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca 29 rbamoyl]benzoate (Compound 9), but using 2,2,4,4-tetramethyl-8-iodochromanoic acid (Compound 31 X, 81 mg, 0.25 mmol) and ethyl 32 4-amino-2-fluorobenzoate ((Compound C,, 55 mg, 0.30 33 mmol), the title compound was obtained as a white 34 solid.
'H NMR 6 8.05 (b, 1H), 8.01 (d, J= 2.2 Hz, 1H), 7.94 36 (t, J= 8.4 Hz, 1H), 7.86 (d, J= 2.2 Hz, 1H), 7.75 WO 97/19052 PCT/gJS96/18580 y(dd, J= 12.88, 2.1 Hz, 1H), 7.33 (dd, J= 8.8, 2.1 2 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 1.89 (s, 2H), 3 1.42 (s, 6H), 1.38 (s, 6H).
4 tE hyl 2-Fluoro-4-[(2',2',4',4',8'-pentamethylchroman-6 6'-yl)carbamoyl]benzoate (Compound 21) 7 Using the same procedure as for ethyl 8 2-f luoro-4-[(4',4'-dimethyl-8'-bromochroman-6'-yl)ca s rbamoyl]benzoate (Compound 9), but using 10= 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound it A,, 92 mg, 0.37 mmol) and ethyl 12 4-amino-2-f luorobenzoate (Compound C,,, 75 mg, 0.41 13 mmol), the title compound was obtained as a white 14 solid (100 mg).
IH NMR 6 8.31 (b, 1H), 7.90 (t, J= 8.24 Hz, 1H), 16 7.76 (dd, J= 14.29, 1.7 Hz, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 7.35 (dd, J= 8.67, 1.7 Hz, 1H), 4.32 (q, J
is = 7.1 Hz, 2H), 2.18 (s, 3H), 1.84 (s, 2H), 1.38 (t, 19 J= 7.1 Hz, 3H), 1.35 (s, 6H), 1.34 (s, 6H).
Ethyl 21 2-Fluoro-4-[(2',2',4',4'-tetramethylthiochroman-6'-y 22 1)carbamoyl]benzoate (Compound 23) 23 Using the same procedure as for the synthesis of 24 ethyl 2-fluoro-4-[(41,4'-dimethyl-8'-bromochroman-26 6'-yl)carbamoyl]benzoate (Compound 9) but using 26 2,2,4,4-tetramethyl-6-thiochromanoic acid (15 mg, 27 0.06 mmol) and ethyl 2-fluoro-4-aminobenzoate 28 (Compound C1, 11.2 mg, 0.06 mmol), the title compound 29 was obtained as colorless oil.
'H NMR 6 7.95 (m, 2H), 7.75 (d, J= 12.75 Hz, 1H), 31 7.58 (m, 2H), 7.50 (d, J= 8.8 Hz, 1H), 7.28 (dd, J
32 =10.6, 1.9 Hz, 1H), 4.38 (q, J= 7.1 Hz, 2H), 1.99 33 (s, 2H), 1.44 (s, 6H), 1.42 (s, 6H), 1.40 (t, J=
34 7.1 Hz, 3H).
Ethyl 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-3s tetramethyl-2-naphthalenyl)thiocarbamoyl lbenzoate 1 (Compound 25) 2 To a solution of ethyl 3 4-[(5',6',7',8'-tetrahydro-5',5',8', 4 8'-tetramethylnaphthalen-2-yl)carbamoyl]benzoate 5(Compound I1, 61 mg, 0.16 mmol) in 2 ml of anhydrous 6 benzene was added Lawesson's reagent (45 mg, 0.112 7 mmol). The resulting yellow solution was refluxed 8 under N2 for 2 h. The solvent was removed and the g residue was purified by column chromatography (silica gel, ethyl acetate/hexane 1/5) to give the 11 title compound as a yellow solid (55 mg, 87%).
12 1H NMR 6 9.04 (b, 1H), 8.11 (d, J = 8.70 Hz, 2H), .13 7.85 (b, 2H), 7.75 (b, 1H), 7.55 (dd, J= 8.2, 1.9 14 Hz, 1H), 7.36 (d, J= 8.3 Hz, 1H), 4.38 (q, J= 7.1 Hz, 2H), 1.71 (s, 4H), 1.40 (t, J= 7.1 Hz, 3H), 16 1.30 (s, 12H).
17 Ethyl 2-Fluoro-4-j(5',6',7',8'-tetrahydro-18 5',5',8',8'-tetramethylnaphthalen-2'-yl)thiocarbamov 19 llbenzoate (Compound 27) Using the same procedure as for the synthesis of 21 ethyl 22 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetrameth-23 yl-2-naphthalenyl)thiocarbamoyl]benzoate (Compound 24 25) but using ethyl 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetr 26 amethylnaphthalen-2'-yl)carbamoyl]benzoate (Compound 27 1, 167 mg, 0.42 mmol) in 8 ml of benzene and 28 Lawensson's reagent (220 mg, 0.544 mmol), the title 29 compound was obtained as a bright yellow solid (127.5 mg).
31 1H NMR 6 9.30 (b, 1H), 8.05 (b, 1H), 7.95 (t, J=
32 8.37 Hz, 1H), 7.77 (d, J= 1.89 Hz, 1H), 7.53 (dd, J
33 = 8.24, 2.1 Hz, 1H), 7.49 (b, 1H), 7.35 (d, J= 8.24 34 Hz, 1H), 4.33 (q, J= 7.1 Hz, 1H), 1.71. (s, 4H), 1.32 (s, 6H), 1.30 (s, 6H).
36 3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronap 1 hthalen-2-vl carboxylic acid (Compound L) 2 To a solution of 3 2-bromo-3-methoxymethoxy-5,5,8,8-tetrahydro-5,5,8,8-4 tetramethylnaphthalene (Compound J, 722 mg, 2.2 5 mmol) in 10 ml of dry THF at -78 C under argon was 6 added slowly 2.86 ml of t-BuLi (1.7 M in hexane, 4.8 7 mmol). The reaction mixture was stirred at -78 C
a for 1 h. Then CO2 was bubbled through the solution 9 for 1 h. After removal of CO2 stream, the reaction 10 mixture was stirred for an additional hour at -78 C.
11 Then 10% of HC1 was added. After warming up to room 12 temperature, the reaction mixture was left overnight 13 then extracted with ethyl acetate. The organic 14 layer was washed with brine and dried over Na2SO4.
1s After concentration, the residue was purified by 16 column chromatography (ethyl acetate/hexane 1/3) to 17 yield the title compound as a white solid.
is 1H NMR d 7.85 (s, 1H), 6.93 (s, 1H), 1.68 (s, 4H), 19 1.28 (s, 12H).
20 4-Bromo-3-hydroxy-5.5,8,8-tetramethyl-5,6,7,8-tetrah 21 ydronaphthalen-2-yl carboxylic acid (Compound M) 22 3-Hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetra-23 hydronaphthalen-2-yl acid (Compound L, 155 mg, 0.62 24 mmol) was dissolved in 1 ml of HOAc. To this 25 solution was added Br2 (0.033 ml, 0.62 mmol). The 26 reaction mixture was left at room temperature for 27 over night. A stream of air was passed through the 28 reaction mixture to remove the unreacted Br2. The 29 remaining solid was dissolved in small amount of THF
30 and purified by column chromatography (ethyl 31 acetate/hexane 1/1) to yield the desired product as 32 a cream colored solid.
33 'H NMR d 7.91 (s, 1H), 1.75 (m, 2H), 1.64 (m, 2H), 34 1,62 (s, 6H), 1.30 (s, 6H).
35 4-Bromo-3-methoxymethoxy-5,5,8,8-tetramethYl-5,6,7,8 36 -tetrahydronaphthalen-2-yl carboxylic acid (Compound i N) 2 To a solution of 3 4-bromo-3-hydroxy-5,5,8,8-tetra-4 methyl-5,6,7,8-tetrahydronaphthalen-2-yl acid s(Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2C12 6 was added chloromethyl methyl ether (0.162 ml, 2.1 7 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) 8 and a catalytic amount of tetrabutylammouimn 9 bromide. The reaction mixture was heated to 45 C
for 2 h. The reaction mixture was concentrated and 11 the residue was purified by column chromatography 12 (ethyl acetate/hexane 1/9) to yield the 13 methoxymethyl ester of the title compound as a white 14 solid (200 mg). This white solid was further dissolved in 20 ml of EtOH. An aqueous solution of 16 NaOH (0.5 ml, 1M) was added. The reaction mixture 17 was stirred at room temperature for over night. The is EtOH was removed and the residue was added 2 ml of 19 ethyl acetate and 3 ml of water. This mixture was very slowly acidified with 10% HC1 to PH = 7. The 21 ethyl acetate layer was separated and washed with 22 brine, dried over Na2SO4. After filtration of the 23 drying agent and removal of solvent, the reaction 24 yielded the title compound as a white solid (155 mg). 'H NMR d 7.99 (s, 1H), 5.20 (s, 2H), 3.66 (s, 26 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 27 (s, 6H). Ethyl 28 2-fluoro-4-f(3'-methoxymethoxy-4'-bromo-5',6',7',8'-2g tetrahydro-5'.51,8',8'-tetramethylnaphtha-len-2'-yl)carbamoyl]benzoate (Compound S1) 31 To a solution of 32 4-bromo-3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8 33 -tetrahydronaphthalen-2-yl acid (Compound N, 80 mg, 34 0.22 nunol) in 4 ml of CH2ClZ was added DMAP (60 mg, 0.26 mmol), ethyl 2-fluoro-4-aminobenzoate (Compound 36 Cl, 43 mg, 0.24 mmol ) and EDC (50 mg, 0.26 inmol ).

1 The reaction mixture was stirred at room temperature 2 for overnight and then concentrated to dryness. The 3 residue was purified by column chromatography (ethyl 4 acetate/hexane 1/3) to yield the title compound as a clear oil (45 mg).
6 1H NMR d 9.92 (b, 1H), 8.10 (s, 1H), 7.94 (t, J = 8.4 7 Hz, 1H), 7.81 (dd, J = 12.9; 1.9 Hz, 1H), 7.35 (dd, 8 J= 8.5; 1.8 Hz, 1H), 5.20 (s, 2H), 4.39 (q, J=
g 7.1 Hz, 2H), 3.61 (s, 3H), 1.74 (m, 2H), 1.64 (m, 2H), 1.60 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 11 ( s , 6H).
12 Methyl 2,6-Difluoro-4-j(3'-methoxymethoxv-4'-bromo-13 5' 6',7',8'-tetrahvdro-5'.5',8',8'-tetramethvlnaphth 14 alen-2'-vl)carbamoylibenzoate (Compound M,=) Using the same procedure as for the synthesis of 16 compound ethyl 2-fluoro-4-[(3'-methoxymethoxy-4'-17 bromo-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl 1s naphthalen-2'-yl)carbamoyl]benzoate (Compound S,.) but 19 using 4-bromo-3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound N, 21 80 mg, 0.22 mmol), DMAP (60 mg, 0.26 mmol), methyl zz 2,6-difluoro-4-aminobenzoate (Compound HZ , 52 mg, 23 0.24 mmol) and EDC (50 mg, 0.26 mmol), the title 24 compound was obtained as a clear oil.
1H NMR d 10.01 (b, 1H), 8.11 (s, 1H), 7.42 (d, J
26 10.0 Hz, 2H), 5.2 (s, 2H), 3.95 (s, 3H), 3.63 (s, 27 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.35 28 ( s , 6H).
29 General procedure for the syntheses of benzoi.c acid derivatives by hydrolyzing the corresponding 31 methyl or ethyl esters.
32 To a solution of ester (3.0 mmol) in 20 ml of 33 EtOH was added 5 ml of 1 N NaOH in water. The 34 reaction mixture was stirred at room temperature for overnight and neutralized with 10% HC1 to PH=5. The 36 alcohol was removed by evaporation and the aqueous 1 layer was extracted with ethyl acetate (3x10ml).
2 The combined ethyl acetate layers were washed with 3 NaHCO3 ( sat .), brine and dried over MgSO4 . After 4 concentration, the desired acid was obtained which could be recrystallized in ethyl acetate or in 6 acetonitrile.
7 2-Fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetr a amethylnaphthalen-2'-yl)carbamoyllbenzoic Acid 9 (Compound 2) 1H NMR 6(acetone-D6) 9.86 (b, 1H), 7.95 (m, 3H), 11 7.75 (dd, J= 7.9, 2.2 Hz, 1H), 7.62 (dd, J= 8.5, 12 1.6 Hz, 1H), 7.50 (d, J= 8.3 Hz, 1H), 1.73 (s, 4H), 13 1.32 (s, 6H), 1.30 (s, 6H).
14 4- L(3'-Fluoro-5',6',7',8'-tetrahydro-5',5',8',8'-tet ramethylnaghthalen-2'-yl)carbamoyllbenzoic Acid 16 (Compound 4) 17 'H NMR 6 (acetone-D6) 9.50 (b, 1H), 8.04 (b, 2H), 18 7.90 (b, 2H), 7.78 (d, J= 7.81 Hz, 1H), 7.19 (d, J
19 = 12.3 Hz, 1H), 1.72 (s, 4H), 1.30 (s, 12H).
2-Fluoro-4-f(4'-bromo-5',6',7',8'-tetrahydro-5',5',8 21 ',8'-tetramethylnaphthalen-2'-yl)carbamoyllbenzoic 22 Acid (Compound 6) 23 IH NMR 6(acetone-D6) 9.97 (b, 1H), 8.04 (d, J= 1.89 24 Hz, 1H), 8.01 (d, J= 1.90 Hz, 1H), 7.95 (t, J=
8.55 Hz, 1H), 7.90 (dd, J= 12.28, 2.0 Hz, 1H), 7.59 26 (dd, J= 8.67, 1.50 Hz, 1H), 1.76 (m, 4H), 1.58 (s, 27 6H), 1.35 (s, 6H).
28 2-Fluoro-4-[(3'-hydroxy-5',6',7',8'-tetrahydro-5',5' 29 ,8',8'-tetramethvlnaphthalen-2'-yl)carbamoyllbenzoic so Acid (Compound 8) 31 'H NMR (acetone-D6) S 11.3 (b, 1H), 10.2 (b, 1H), 32 7.94 (m. 2H), 7.85 (dd, J= 11.4, 1.95 Hz, 1H), 7.53 33 (dd, J= 6.59, 2.08 Hz, 1H), 6.94 (s, 1H), 2.85 (b, 34 1H), 1.70 (s, 4H), 1.29 (s, 6H), 1.28 (s, 12H).
2-Fluoro-4-f(8'-bromo-4',4'-dimethylchroman-6'-vl)ca 36 rbamoyljbenzoic Acid (Compound 10) 1 1H NMR (acetone-d6) S 9.87 (b, 1H), 8.04 (d, J= 2.1 2 Hz, 1H), 8.03 (d, J= 2.1 Hz, 1H), 7.94 (t, J= 8.66 3 Hz, 1H), 7.91 (dd, J= 13.8, 2.0 Hz, 1H), 7.57 (dd, 4 J= 8.6, 2.0 Hz, 1H), 4.37 (t, J= 5.44 Hz, 2H), s 1.92 (t, J= 5.44 Hz, 2H), 1.40 (s, 6H).
6 2-Fluoro-4-j(2',2',4',4'-tetramethyl-8'-bromochroman 7 - 6'=yl)carbamoyllbenzoic Acid (Compound 12) 8 1H NMR S(acetone-d6) 9.87 (b, 1H), 8.06 (d, J= 2.2 s Hz, 1H), 8.04 (d, J= 2.1 Hz, 1H), 7.94 (t, J= 8.54 Hz, ZH), 7.91 (dd, J= 14.0, 2.0 Hz, 1H), 7.59 (dd, 11 J= 8.5, 2.3 Hz, 1H), 1.96 (s, 2H), 1.42 (s, 6H), 12 1.41 (s, 6H).
13 2-Fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoro-14 methylchroman-6'-yl)carbamoyl] benzoic Acid (Compound 14) 16 'H NMR (acetone-d6) S 10.02 (b, 1H), 8.31 (s, 1H), 17 8.09 (s, 1H), 7.92 (m, 2H), 7.56 (d, J= 7.69 Hz, is 1H), 2.00 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H).
19 2-Fluoro-4-f(2',2',4',4'-tetramethyl-8'-azidochroman - 6'-yl)carbamoyl]benzoic Acid (Compound 16) 21 'H NMR 6 8.03 (t, J= 8.4 Hz, 1H), 7.87 (b, 1H), 7.79 22 (dd, J= 13, 2.0 Hz, 1H), 7.64 (d, J= 2.2 Hz, 1H), 23 7.32 (dd, J= 8.66, 1.9 Hz, 1H), 7.22 (d, J= 2.1 24 Hz, 1H), 1.91 (s, 2H), 1.45 (s, 6H), 1.41 (s, 6H).
2, 6-Difluoro-4-f(2',2',4',41-tetramethyl-8'-26 tr.ifluoromethylchroman-6'-yl)carbamoyllbenzoic acid 27 (Compound 18) 28 1H NMR (acetone-d6) 6 8.30 (d, J= 2.3 Hz, 1H), 8.06 29 (d, J= 2.2 Hz, 1H), 7.59 (d, J= 10.32 Hz, 2H), 1.954 (s, 2H), 1.44 (s, 6H), 1.41 (s, 6H).
31 2-Fluoro-4-[(2',2',4',4'-tetramethyl-8'-iodochroman-32 6'-yl)carbamoyl]benzoic Acid (Compound 20) 33 'H NMR b(acetone-d6) 10.0 (b, 1H), 8.24 (s, 1H), 34 8.07 (s, 1H), 7.94 (m, 2H), 7.57 (d, J= 8.67 Hz, 1H), 1.95 (s, 2H), 1.41 (s, 12H).
36 2-Fluoro-4-[(2',2',4',4',8'-pentamethylchroman-6'-yl 1 )carbamoyllbenzoic Acid (Compound 22) 2'=H NMR b(acetone-d6) 9.77 (b, 1H), 7.90 (m, 3H), 3 7.65 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.61, 2.0 4 Hz, 1H), 2.19 (s, 3H), 1.90 (s, 2H), 1.38 (s, 6H), 5 1.37 (s, 6H).
6 2-Fluoro-4-[(2',2',4',4'-tetramethylthiochroman-6'-y 7 1)carbamoyl3benzoic acid (Compound 24) 8 1H NMR 6 7.95 (m, 2H), 7.75 (d, J = 12.75 Hz, 1H), g 7.58 (m, 2H), 7.50 (d, J= 8.8 Hz, 1H), 7.28 (dd, J
10 = 10.6, 1.9 Hz, 1H), 1.99 (s, 2H), 1.44 (s, 6H), 11 1.42 (s, 6H).
12 4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylna 13 phthalen-2'-yl)thiocarbamoyl]benzoic Acid (Compound 14 26) 15 'H NMR S 9.08 (b, 1H), 8.17 (d, J = 8.61, 2H), 7.95 16 (b, 2H), 7.77 (b, 1H), 7.57 (dd, J = 8.1, 2.1 Hz, 17 1H), 7.37 (d, J = 8.2 Hz, 1H), 1.72 (s, 4H), 1.32 18 (s, 6H), 1.31 (s, 6H).
19 2-Fluoro-4- L(5', 6', 7', 8'-tetrahydro-5', 5', 8', 20 8'-tetramethylnaphthalen-2'-yl)thiocarbamoyllbenzoic 21 Acid (Compound 28) 22 'H NMR S(acetone-d6) 11.1 (b, 1H), 8.27 (b, J = 13.2 23 Hz, 1H), 8.02 (t, J = 8.3 Hz, 1H), 7.89 (s, 1H), 24 7.86 (d, J = 10.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 25 7.41 (d, J= 8.37 Hz, 1H), 1.72 (s, 4H), 1.30 (s, 26 12H).
27 2-Fluoro-4-[(3'-hydroxy-4'-bromo-5', 6', 7', 8'-tet-2e rahydro-5', 5', 8', 29 8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic 30 Acid (Compound 34) 31 A solution of ethyl 32 2-fluoro-4-[(3'-methoxymet-hoxy-4'-bromo-5',6',7',8' 33 -tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl) 34 carbamoyl]benzoate (Compound S,, 45 mg, 0.084 mmol) 35 in 1 ml of EtOH was added 1 ml of aqueous solution 36 of NaOH (1M). The reaction mixture was stirred at 1 room temperature for overnight and acidified to PH =
2 1 with 10% HCl. EtOH was removed and ethyl acetate 3 and more water were added to the solution. The 4 organic layer was separated and washed with NaHCO3, brine and dried over MgSO4. After filtration and 6 concentration, the reaction yielded 7 2-fluoro-4-[(3'-methoxymethoxy-4'-bromo-5', 6', 7', 8 8'-tetrahydro-5', 5', 8', 9 8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic acid as a white solid. The methoxymethyl group was 11 removed by dissolving the white solid in 2 ml of 12 MeOH and 3 drops of HC1 (con.). After stirring for 13 overnight, the reaction mixture was concentrated to 14 dryness. The residue was partitioned between ethyl is acetate and water. The organic layer was separated, 16 washed with NaHCO31 brine and dried over MgSO4.
17 After filtration and concentration, the residual 18 solid was purified in a mini (pipette) column with 19 ethyl acetate /hexane (1/1) to give the title compound as a white solid (5.0 mg).
21 'H NMR d (acetone-d6) 10.19 (b, 1H), 8.01 (s, 1H), 22 7.96 (t, J= 8.6 Hz, 1H), 7.76 (dd, J = 11.2; 2.0 23 Hz, 1H), 7.54 (dd, J = 8.8; 2.0 Hz, 1H), 1.75 (m, 24 2H), 1.65 (m, 2H), 1.61 (s, 6H), 1.32 (s, 6H).
2,6-Difluoro-4-[(3'-hydroxy-4'-bromo-5', 6', 7', 26 8'-tetrahydro-5', 5', 8', 27 8'-tetramethylnaphthalen-2'-yl)carbamoyllbenzoic 28 Acid (Compound 36) 29 Using the same procedure as for the synthesis of 2-fluoro-4-[(3'-hydroxy-4'-bromo-5', 6', 7', 8'-tet-31 rahydro-5', 5', 8', 32 8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic 33 acid (Compound 34) the title compound was obtained 34 as a white solid.
1H NMR d(acetone-d6) 10.23 (b, 1H), 8.01 (s, 1H), 36 7.52 (d, J = 10.2 Hz, 2H), 4.8 (b, 1H), 1.75 (m, 1 2H), 1.65 (m, 2H), 1.60 (s, 6H), 1.31 (s, 6H).
2 2,6-Difluoro-4-[(5', 6', 7', 8'-tetrahydro-5', 5', 3 8', 8'-tetramethylnanhthalen-2'-yl)carbamovllbenzoic 4 Acid (Compound 38) s To 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-6 naphthoic acid (43 mg, 0.19 mmol) was added 1 ml of 7 thionyl chloride. This mixture was refluxed for 2 8 h. Excess thionyl chloride was removed under 9 reduced pressure and the residue was dissolved in 2 io ml of CH2C12 . To this solution was added methyl 11 4-amino-2,6-difluorobenzoate (Compound H,, 7 mg, 0.2 12 mmol) followed by 0.5 ml of pyridine. The reaction 13 mixture was stirred at room temperature for 4 h and 14 was concentrated under reduced pressure. The 15 residue was purified by column chromatography (ethyl 16 acetate/hexane 1/5) to give the methyl ester of the 17 desired product as a colorless oil.
is 'H NMR d 8.11 (d, J = 1.9 Hz, 1H), 8.05 (b, 1H), 7.86 19 (dd, J = 6.2, 2.2 Hz, iH), 7.41 (m, 3H), 3.93 (s, 20 3H), 1.69 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H). This 21 colorless oil was hydrolyzed to the desired product 22 with NaOH/H20/EtOH according to the general 23 procedure.
24 1H NMR d(acetone-db) 9.74 (b, 1H), 7.95 (s, 1H), 25 7.70 (d, J = 6.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 3H), 26 1.71 (s, 4H), 1.29 (s, 6H), 1.28 (s, 6H).
27 Methyl 28 2-nitro-4-j(4'-bromo-5',6',7',8'-tetrahydro-5',5',8' 29 L8'-tetramethylnaphthalen-2'-yl)carbamoylibenzoate 30 (Compound 29) 31 Using the same procedure as for the synthesis of 32 Compound 1, but using Compound F and Compound F,, the 33 desired product was obtained as a white solid.
34 1H NMR 6 9.24 (b, 1H), 9.23 (d, J = 1.8 Hz, 1H), 7.92 35 (dd, J = 8.4, 2.4, Hz, 1H), 7.87 (d, J = 2.1 Hz, 36 iH), 7.84 (d, 3 2.1 Hz, 1H), 7.80 (d, J = 8.7 Hz, WO 97/19052 PCT/iJS96J18580 ~ 1H), 3.91 (s, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.58 2 (s, 3H), 1.33 (s, 3H).
3 2-Ni.tro-4-f(4'-bromo-5',6',7',8'-tetrahydro-5',5',8' 4 l8',-tetramethylnaphthalen-2'-yl)carbamoyllbenzoic s acid (Compound 30) 6 1H NMR b(acetone-d6): 10.16 (b, 1H), 8.42 (d, J
7 2.0 Hz, 1H), 8.09 (dd, J = 8.6; 2.1 Hz, 1H), 8.06 s(d, J= 2.2 Hz, 1H), 8.04 (d, J= 2.2 Hz, 1H), 7.93 e(d, J= 8.6 Hz, 1H), 1.75 (m, 2H), 1.65 (in, 2H), 1.57 (s, 3H), 1.34 (s, 3H).
y~

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula wherein X is S, O, NR' where R' is H or alkyl of 1 to 6 carbons, or X is [C(R1)2]n where n is an integer between 0 and 2;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is hydrogen, or lower alkyl of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0 - 2;
o is an integer having the value of 0.- 4;
p is an integer having the value of 0 - 2;

r is an integer having the value 0 - 2 with the proviso that when Z is O p is at least 1 and r is at least 1;

Y 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;
W is a substituent selected from the group consisting of F, Br, Cl, I, fluoro substituted C1-6 alkyl, NO2, N3, OH, OC2OCH3, OC1-10alkyl, tetrazol, CN, SO2C1-6alkyl, SO2C1-6-alkyl, SO2C1-6-fluoro substituted alkyl, SO-C1-6 alkyl, CO-C1-6alkyl, COOR8, phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl;
L is -(C=Z)-NH- or -HN-(C=Z)-Z is O or S;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, or alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
2. A compound in accordance with Claim 1 where Y is phenyl.
3. A compound in accordance with Claim 2 where the phenyl group is 1,4 substituted by the L and the A-B groups.
4. A compound in accordance with Claim 1 where Y is pyridyl.
S. A compound in accordance with Claim 4 where Y is 2,5 substituted by the L and the A-B groups.
6. A compound in accordance with Claim 1 where X is (C(R1)2)n and n is 1.
7. A compound in accordance with Claim 1 where X is O
8. A compound in accordance with Claim 1 where X is S, 9. A compound in accordance with Claim 1 where A-B is (CH2)q-COOH or a pharmaceutically acceptable salt thereof, (CH2)q-COOR8, or (CH2)q-CONR9R10.

10. A compound in accordance with Claim 1 where the W substituent of the Y group is selected from the group consisting of F, NO2, Br, I, CF3, N3, and OH.

11. A compound in accordance with Claim 1 where the W substituent of the condensed ring is selected from the group consisting of F, NO2, Br, I, CF3, N3, and OH.

12. A compound in accordance with Claim 1 where Z is O.
13. A compound of the formula wherein R1 is independently H or alkyl of 1 to 6 carbons;
R2 is hydrogen, or lower alkyl of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
o is an integer having the value of 0 - 4;
W1, W2, W3, and W4, each is independently selected from the group consisting of H, F, Br, Cl, I, CF3, NO2, N3, OH, OCH2OCH3, OC1-10alkyl and C1-6alkyl, with the proviso that when Z is O then at least one of the W1, W2, groups is not H nor alkyl and at least one of the W3, and W4 groups is not H nor alkyl;
Z is O or S;
A is (CH3)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, or alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.
14. A compound in accordance with Claim 13 where A is (CH2)q and q is 0, and where B is COOH or a pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.

15. A compound in accordance with Claim 14 where R1 is CH3, R2 is H and R3 is H.
16. A compound in accordance with Claim 15 where Z is O.
17. A compound in accordance with Claim 16 where B is COOR8.

18. A compound selected from the group consisting of:
ethyl 2-fluoro-4-[(5',6',7', 8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoate;
ethyl 4-[(3'-fluoro-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoate;

ethyl 2-fluoro-4-[(4'-bromo-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2' yl)carbamoyl]benzoate;
ethyl 2-fluoro-4-((3'-hydroxy-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoate;
ethyl 2-fluoro-4-[(3'-hydroxy-4'-bromo-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoate;
ethyl 2,6-difluoro-4-[(3'-hydroxy-4'-bromo-5',6';7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]be nzoate; and ethyl 2,6-difluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoate.

19. A compound in accordance with Claim 16 where B is COOH or a pharmaceutically acceptable salt thereof.

20. A compound selected from the group consisting of 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8', 8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic acid;
4-[(3'-fluoro-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthaIen-2'-yl) carbamoyl]benzoic acid;
2-fluoro-4-[(4'-bromo-5',6',7',8'-tetra hydro-5',6',8',8'-tetramethylnaphtha len-2'-yl)carbamoyl]benzoic acid;
2-fluoro-4-[(3'-hydroxy-5', 6',7',8'-tetrahydro -5',5', 8',8'-tetramethylnaphth alen-2'-yl)carbamoyl]benzoic acid;
2-fluoro-4-[(3'-hydroxy-4'-bromo-5', 6',7',8'-tetrahydro-5',5', 8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic acid;
2,6-difluoro-4-[(3'-hydroxy-4'-bromo-5',6',7',8'-tet-rahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbarmoyl]benzoic acid;
and 2,6-difluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)carbamoyl]benzoic acid.

21. A compound in accordance with Claim 15 where Z is S.

22. A compound in accordance with Claim 21 which is:
ethyl 4-1(5',6,7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)thiocarba moyl)benzoate;
ethyl 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaphthalen-2'-yl)t hiocarbarmoyl]benzoate;
4-[(5',6',7',8'-tetrahydro-5',5',8',8'-tetramethylnaph-thalen-2'-yI)thiocarbamoyl]benzoic acid; or 2-fluoro-4-[(5',6',7',8'-tetrahydro-5',5',8', 8'-tetramethylnaphthalen-2'-yl)t hiocarbamoyl]benzoic acid.

23. A compound of the formula wherein R1 is independently H or alkyl of 1 to 6 carbons;
R2 is hydrogen, or lower alkyl of 1 to 6 carbons;
W1, W2, W3, and W4, each is independently selected from the group consisting of H, F, Br, Cl, Z, CF3, NO2, N3, OH, OCH2OCH3, OC1-10alkyl and C1-6alkyl, with the proviso that when Z is O then at least one of the W1, W2, W3, and W4 groups is not H nor alkyl, with the further proviso that when Z is O and X is O then W2 is not Cl;
X is O or S;
Z is O or S;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, or alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, or CR7OR13O, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons.

24. A compound in accordance with Claim 23 where A is (CH2)q and q is 0, and where B is COOH or a pharmaceutically acceptable salt thereof, COOR8, or CONR9R10.

25. A compound in accordance with Claim 24 where R1 is independently H or CH3, and R2 is H.

26. A compound in accordance with Claim 25 where Z is O.

27. A compound in accordance with Claim 26 where B is COOR8.

28. A compound selected from the group consisting of:
ethyl 2-fluoro-4-[(2', 2',4',4'-tetramethyl- 8'-bromochroman-6'-yl)carbamoyl]benzoate;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoro-methy]chroman-6'-yl)carbamoyl] benzoate;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azido-chroman-6'-yl) carbamoyl]benzoate;
ethyl 2,6-difluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoromethylchroman-6'-yl) carbamoyI]benzoate;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-iodochro-man-6'-yl)carbamoyl]benzoate;
ethyl 2-fluoro-4-[(2',2,4',4',8'- pentamethylchroman-6'-yl)carbamoyl]benzoate;
ethyl 2-fluoro-4-[(2',2',4',4'-tetramethylthiochroman-6'-yl)carbamoyl]benzoate , and ethyl 2-fluoro-4- [(8'-bromo-4',4'-dimethylchroman-6'-yl)carbamoyl]benzoate.

29. A compound in accordance with Claim 26 where B is COOH or a pharmaceutically acceptable salt thereof.

30. A compound selected from the group consisting of 2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-bromochroman-6'-yl)carbamoy]benzoic acid;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoro-methylchroman-6'-yl)carbamoyl] benzoic acid;
2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-azidochroman-6'-yl)carbamoyl] benzoic acid;
2,6-di-fluoro-4-[(2',2',4',4'-tetramethyl-8'-trifluoromethylchroman-6'-yI)ca rbamoyl]benzoic acid;

2-fluoro-4-[(2',2',4',4'-tetramethyl-8'-iodochroman-6'-yI)carbamoyl]benz oic acid;

2-fluoro-4-[(2',2',4',4',8'-pentamethylchroman-6'-yl) carbamoyl]benzoic acid;
2-fluoro-4- [(2',2',4',4'-tetramethylthiochroman-6'-yl) carbamoyl]benzoic acid, and 2-fluoro-4-[(8'-bromo-4',4'-dimethylchroman-6'-yl)+carbamoyl]benzoic acid.