WO2014203132A1 - Substituted benzopyran compounds, compositions and uses thereof - Google Patents

Substituted benzopyran compounds, compositions and uses thereof Download PDF

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Publication number
WO2014203132A1
WO2014203132A1 PCT/IB2014/062183 IB2014062183W WO2014203132A1 WO 2014203132 A1 WO2014203132 A1 WO 2014203132A1 IB 2014062183 W IB2014062183 W IB 2014062183W WO 2014203132 A1 WO2014203132 A1 WO 2014203132A1
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substituted
compound
unsubstituted
alkyl
group
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PCT/IB2014/062183
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French (fr)
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David C. Myles
Peter J. Kushner
Cyrus L. Harmon
Leslie Hodges GALLAGHER
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Olema Pharmaceuticals, Inc.
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Publication of WO2014203132A1 publication Critical patent/WO2014203132A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • This invention is in the field of pharmaceuticals, and in particular novel benzopyran compounds, and salts, prodrugs and derivatives thereof and their medical uses, including as estrogen receptor modulators and for medical conditions that would benefit from an anti-estrogenic drug, and pharmaceutical compositions thereof.
  • Estrogen receptor modulators are a class of compounds that act on the estrogen receptor. These compounds can be pure agonists (mimicking estrogen), pure antagonists, or mixed agonist-antagonists (sometimes referred to as Selective Estrogen Receptor Modulators (SERMs)). For example, estradiol (A) is a pure agonist, fulvestrant (B) is a complete antagonist, and tamoxifen (C) and raloxifene (D) are SERMs.
  • ER estrogen receptors
  • Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • fulvestrant is substantially superior to the aromatase inhibitor anastrozole in treating metastatic breast cancer (Robertson et al. J Clin Oncol (2009) 27(27):4530-5).
  • Estradiol is a naturally-occuring female estrogenic hormone.
  • Raloxifene was disclosed by Eli Lilly in 1981 (U.S. Patent No. 4,418,068; 5,478,847; 5,393,763; and 5,457,117) for prevention of breast cancer and treatment of osteoporosis. Fulvestrant was disclosed by Imperial Chemical Industries (ICI) in 1983 (U.S. Patent No. 4,659,516, expired in 2007 with a patent term extension; U.S. Patent Nos. 6,774, 122 and 7,456, 160). Tamoxifen was also disclosed by ICI in the '516 patent. Tamoxifen was developed for the treatment of breast cancer on the basis of strong antagonism of estrogen action in mammary tissue (Jordan, J. Cell. Biochem. 51 (1995
  • ovariectomized rodents to test doses of the compound both in the absence (agonist mode) and presence (antagonist mode) of estrogen.
  • Tamoxifen and other partial anti-estrogens stimulate uterine weight gain in the agonist mode and only partly block estrogen-driven uterine weight gain in the antagonist mode.
  • Fulvestrant and other complete anti-estrogens do not stimulate uterine weight gain in the agonist mode and completely block estrogen-driven weight gain in the antagonist mode.
  • the induction of estrogen-regulated alkaline phosphatase expression in human uterine cancer cell growth in culture can be used to distinguish partial and complete anti-estrogenicity and correlates well with the rodent weight gain assay.
  • Tamoxifen and fulvestrant both inhibit cultured human breast cancer cell proliferation provoked by estrogen.
  • fulvestrant more fully inhibits the proliferation when provoked with growth factors, especially of the insulin/insulin-like growth factor family.
  • growth-factor driven breast cancer cell proliferation and the effect on uterine weight provide two assays which can distinguish between complete and partial anti- estrogens.
  • Tamoxifen binding stabilizes the estrogen receptor whereas fulvestrant and chemically related antiestrogens, such as ICI-164384 and RU-58668, cause degradation of the estrogen receptor.
  • fulvestrant and chemically related antiestrogens such as ICI-164384 and RU-58668, cause degradation of the estrogen receptor.
  • some compounds like GW-5638 (Wu et al, Mol Cell.,18,413 (2005), and OP1075, described below, degrade the receptor but are partial estrogens- that is, not complete anti-estrogens.
  • the ability to degrade the estrogen receptor does not ensure complete antiestrogenicity.
  • the ability to induce degradation of the receptor is nonetheless a factor that differentiates the behavior of tamoxifen and fulvestrant and may be desirable in a drug to treat breast cancer.
  • Fulvestrant which degrades the estrogen receptor, incorporates a core of 17-beta estradiol. It has a long flexible aliphatic side chain that blocks oral absorption. The estradiol core blocks oral absorption and the long flexible aliphatic side chain makes the drug very insoluble which worsens the problem. Fulvestrant must be injected because of the poor oral bioavailability. Two 5 ml intramuscular depot injections, one into each buttock, must be administered monthly by a health professional. Furthermore, it is unclear whether these two injections provide sufficient drug exposure for optimal action. The drug does not seem to work in pre-menopausal women.
  • Patent No. 5,395,842 (see claim 29) which taught that EM-343 (H), showed superior binding to the estrogen receptor with no loss of anti-estrogen action.
  • EM-343 differed from the Saeed compounds by including the hydroxyl at the 4'-position of a 4-methyl, 7-hydroxyl benzopyran.
  • Labrie et al. filed a continuation-in-part patent application, which issued in 2000 as U.S. Patent No. 6,060,503, disclosing prodrugs and optically active species of EM- 343.
  • Labrie et al. disclosed a pure isomer of EM-343, EM-652, referred to as acolbifene (I), which is (S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-(2-(piperidin-l- yl)ethoxy)phenyl)-2H-chromen-7-ol.
  • D is -OCH 2 CH 2 N(R3)R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound together being a ring structure selected from the group consisting of pyrrolidino, dimethyl- 1-pyrrolidino, methyl- 1-purrolidinyl, piperidino, hexamethyleneimino and morpholino); and wherein Ri and R 2 are independently selected from the group consisting of hydrogen, hydroxyl and a moiety converted in vivo in to hydroxyl, and
  • Ri and R 2 are independently selected from the group consisting of hydroxyl and a moiety converted in vivo in to hydroxyl;
  • R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen- containing cyclic moiety, nitrogen-containing polycyclic moiety, and RaRb (Ra and Rb being independently hydrogen, straight or branched Ci-C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight of branched C 2 -C 6 alkynyl.
  • Acolbifene binds to the estrogen receptor alpha with three times the affinity of 17- beta estradiol, the native ligand (Katzenellenbogen (2011) J Med Chem 54(15):5271-82). Since anti-estrogens must compete with estradiol for binding to the estrogen receptor, high affinity binding is an important drug virtue.
  • EM-800, a pivalate prodrug of EM-652, and HC1 salts of EM-652 were also described in the '503 patent.
  • Acolbifene was initially thought to be a complete anti-estrogen.
  • careful studies with the rodent uterine assay and human uterine cell alkaline phosphatase assays revealed that it retained some estrogen-like action, about 12% that of estradiol (Labrie et al. "The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?" Endocrinology. 2003 144(11):4700-6). This contrasts with fulvestrant where the residual estrogen-like action is almost unmeasurable.
  • fulvestrant binding induces dramatic degradation of the estrogen receptor, while acolbifene induces either no or modest receptor degradation.
  • Raloxifene and apeledoxifene don't degrade the receptor, but stabilize the receptor to a much lesser degree than tamoxifen.
  • Acolbifene is orally bioavailable and is currently being positioned for Phase III clinical trials for the treatment of breast cancer by the Canadian company Endoceutics (Founded by Dr. Labrie).
  • a daily oral dose of 40 mg of acolbifene or EM800 in women produces mean drug exposures of 8.3 and 15 ng/ml of circulating acolbifene, respectively.
  • both forms of the drug are effective against tamoxifen-resistant human breast cancer xenografts growing on immunocompromised mice.
  • the 40mg dose of EM800 was numerically as effective as anastrozole in preventing progression of metastatic estrogen receptor positive breast cancer.
  • the Merck chromane core differs from the acolbifene core by the absence of a double bond in the oxane ring. These structures also had a hydroxyl at position 6 (not 7) of the fused benzene ring.
  • a chromane core with a 2-m ethyl pyrrolidine (but not a 3 -methyl) with a methyl on the linker created a nearly complete anti-estrogen, (see compound 12 of the Blizzard et al. paper).
  • Blizzard et al. commented on the differences among anti-estrogenic activities of variously substituted cores, and noted that the size and stereogenic placement of substituents is crucial for receptor potency and selectivity.
  • Blizzard et al. again studied the dihydrobenzoxathiin core and reported that their studies have resulted in the discovery that addition of a methyl group to the side chain at the appropriate position and with the right stereochemistry, either on the pyrrolidine ring or on the linker substantially increased estrogen antagonist activity in uterine tissue. Blizzard et al. also reported that the best estrogen antagonist activity in this dihydrobenzoxathiin series was determined to have a methyl group on the pyrrolidine and a methyl group on the linker, with the hydroxyl in the 6-position of the fused benzene ring. Blizzard et al.
  • SEMs Selective Estrogen Receptor Modulators
  • Kushner et al. (US 2013/0178445 and WO 2013/090921, both filed Dec. 17, 2012 and both assigned to Olema Pharmaceuticals) describe OP-1038 (3-(4-hydroxyphenyl)-4-methyl- 2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol) and OP-1074 ((2S)-3- (4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H- chromen-7-ol), as well as pharmaceutical compositions and methods of use.
  • Bazedoxifene is a SERM, under development for prevention and treatment of postmenopausal osteoporosis (Biskobing, D. M. (2007) Clinical interventions in aging 2 (3): 299-303).
  • Lasofoxifene is another SERM under development for the treatment of postmenopausal osteoporosis and vaginal atrophy (Gennari et al. (2006), Expert Opin Investig Drugs 15 (9): 1091-103).
  • U.S. Patent 5,254,568 discloses benzopyrans as anti-estrogenic agents.
  • WO2010/145010 discloses a combination of SERM and sex steroid precursor for treating hot flashes and other symptoms.
  • WO2004/091488 discloses benzopyrans as estrogen receptor modulators.
  • U.S. Patent 5,840,735 discloses benzopyrans as sex steroid activity inhibitors.
  • U.S. Patent 6,262,270 discloses a method for the enantiomeric synthesis of acolbifene derivatives.
  • the present invention is related to benzopyran compounds of Formula I, II, III,
  • the active compounds can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or Ri and/or R 2 -substituted derivative optionally in a pharmaceutically acceptable composition to treat a disorder that is modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic.
  • X, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII and their prodrugs are anti-estrogens useful to treat locally advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer).
  • the compounds are used to treat estrogen or progesterone receptor negative breast cancer.
  • the compounds can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer, either by itself or in combination with one or more other anti-cancer agents, including targeted therapies.
  • a targeted therapy such as an mTOR inhibitor such as everolimus or a CDK 4/6 inhibitor such as palbociclib (PD- 0332991).
  • the compounds of the invention are also useful as adjuvant therapy after surgery to prevent recurrence. Such adjuvant use is often administered for several years, for instance 5 years, or 10 years after surgery and associated chemotherapy and radiotherapy have been concluded.
  • the compounds of the invention are also useful for the prevention of breast cancer in women at high risk and can be taken for any desired time period, including indefinitely.
  • a patient typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRCAl or BRCA2 or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention.
  • the compounds described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence.
  • these compounds are useful to treat other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis. Besides these reproductive tissues the compounds are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
  • SERMs selective estrogen receptor modulators
  • a compound of the present invention is used in combination with an estrogen, SERM or partial anti-estrogen such that the anti-estrogen prevents adverse action of the total or partial estrogen on the uterus and other tissues.
  • the present invention is related to specific benzopyrans (in the form of a C2 equal mix of diastereomers and their pure S-diastereomers) that are useful for the treatment of medical disorders that are mediated, modulated or affected by an estrogen receptor, including breast cancer.
  • the compounds can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or Ri and/or R 2 -substituted derivative or a pharmaceutically acceptable composition thereof to treat a disorder that is mediated, modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic compound.
  • a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or Ri and/or R 2 -substituted derivative or a pharmaceutically acceptable composition thereof to treat a disorder that is mediated, modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic compound.
  • Ri and R 2 are independently either:
  • R can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring.
  • Ri or R 2 is an ester, amide, carbonate or phosphate.
  • Examples of useful metabolically cleavable prodrug groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups
  • the compounds of the invention can be administered in a pharmaceutical composition suitable for oral delivery to the patient, typically a human.
  • the compounds can be delivered in a carrier suitable for topical, transdermal (including by patch), intravenous, parenteral, intraortal, subcutaneous or other desired delivery route, including any method of controlled delivery, for example, using degradable polymers, or with nano or microparticles, liposomes, layered tablets or other structural frameworks which slow delivery.
  • the compounds of the invention can be used to prevent a disorder modulated through the estrogen receptor, which comprises administering to a patient in need of such prevention, a prophylactically effective amount of a compound or pharmaceutical composition.
  • the compounds of the invention can be in the form of a salt. They can be administered as a pharmaceutically acceptable salt, for example, a pharmaceutically acceptable acid addition salt, including a hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.
  • the compounds are used to treat or prevent a disorder modulated by the estrogen receptor in an animal, typically a mammal, and most typically a human.
  • the present invention provides a combination of a compound of the instant invention, and another pharmacologically active agent.
  • the compounds can also be used as adjunctive therapy or combination therapy with another active agent.
  • a therapeutically effective amount of the compound can be used in combination with another anti-cancer agent, especially for estrogen receptor positive breast cancer, but in some embodiments, for estrogen receptor negative breast cancer.
  • the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of the present invention and a
  • the compounds provided herein are administered for medical therapy in a therapeutically effective amount.
  • the amount of the compounds administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions provided herein can be administered by a variety of routes including oral, topical, parenteral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal with a pharmaceutical carrier suitable for such administration.
  • the compounds are administered in a controlled release formulation.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders.
  • the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (as a nonlimiting example, from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • a minor component as a nonlimiting example, from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), for example in an amount ranging from about 0.01 to about 20%) by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10%) by weight, and more preferably from about 0.5 to about 15%> by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a suitable delivery polymeric composition, or a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • the compounds provided herein can be administered by a transdermal device.
  • Transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. In certain embodiments, the formulation comprises hexapropyl-P-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-P-cyclodextrin (10-50% in water).
  • the present invention also includes pharmaceutically acceptable acid addition salts of compounds of the compounds of the invention.
  • the acids which are used to prepare the pharmaceutically acceptable salts are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
  • a compound of the invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.
  • a compound of the invention can be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press. In other embodiments, there is between 10 and 500 mg of active compound in the oral tablet.
  • a compound of the invention can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5, or 10, or 15, or 20, or 30 or 50 mg/mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets (5-1000 mg of active compound per tablet) in a tablet press.
  • XI, XII, XIII, XIV, XV, XVI, XVII and XVIII and their prodrugs are anti-estrogens useful to treat any disorder modulated, mediated or affected by the estrogen receptor.
  • the compounds are used in combination or alternation with another anti-cancer agent for the treatment of cancer, as described more fully below.
  • the compound in combination or alternation with estrogen or a partial estrogen receptor antagonist for the treatment of a postmenopausal disorder also described below.
  • a compound of the present invention is used to treat local, advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer).
  • the compound is used to treat estrogen or progesterone receptor negative breast cancer.
  • the compound can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer, either by itself or in combination with one or more other anti-cancer agents described below or otherwise known to those skilled in the art.
  • a targeted therapy such as an mTOR inhibitor such as everolimus or a CDK 4/6 inhibitor such as palbociclib (PD-0332991).
  • the compounds of the invention are also useful as adjunctive therapy after or instead of chemotherapy, radiation or surgery. Such adjuvant use is often used for several years, perhaps 5 years, after chemotherapy or other therapies have been concluded, but may optimally be continued for additional years.
  • the compounds of the invention are also useful for the prevention of breast cancer in women at high risk and can be taken for any desired time period, including indefinitely.
  • a patient typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRCAl or BRCA2 or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention.
  • the compounds described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence.
  • these compounds are useful in treating other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis. Besides these reproductive tissues the compounds are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
  • SERMs Selective estrogen receptor modulators
  • a compound of the present invention is used in combination with an estrogen, SERM or partial anti-estrogen whereby the anti-estrogen prevents adverse action of the total or partial estrogen on the uterus and other tissues.
  • the present compounds are used as therapeutic or prophylactic agents for the treatment of conditions in mammals, particularly humans whose conditions are modulated by estrogen receptors.
  • An oral anti-estrogen is useful for treating locally advanced or metastatic breast cancer, preventing recurrence or early breast cancer after surgery, and preventing breast cancer in women at high risk. It is useful for treating estrogen-dependent cancers of the reproductive tract including endometrial and ovarian cancers. It has potential uses in the treatment of lung and bronchial cancers that express estrogen receptors.
  • Selective estrogen receptor modulators such as tamoxifen, raloxifene, lasofoxifene, and apeledoxifene additionally have application as hormone replacement therapy to prevent osteoporosis and other disorders such as hot flashes, etc. in post-menopausal women, a use that depends on their partial estrogen like action, for example, on bone.
  • the compounds described herein can be employed in combination with an estrogen or a selective estrogen receptor modulator to block the unwanted estrogenic activity of the therapy.
  • the anti-estrogen is dosed in the amount to prevent the adverse action of the estrogen or estrogen receptor modulator on the uterus and mammary gland yet allowing the beneficial action of estrogen on bone and vasomotor symptoms.
  • the compounds of the present invention can be administered for the treatment of cancer, and in particular breast cancer in combination or association with Herceptin, Tykerb, CDK 4/6 inhibitor such as palbociclib (PD-0332991), mTOR inhibitor such as Novartis' everolimus and other rapamycin analogs such rapamycin and temsirolimus, Millennium's MLN0128 TORCl/2 inhibitor, an EFGR-family inhibitor such as trastuzumab, pertuzumab, emtansine, erlotinib, gefitinib, neratinib and similar compounds, a PI3 Kinase Inhibitor such as perifosene, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145, a histone deacetylase inhibitor such as vorinostat, romidepsin, panobinostat, valproic acid, etinostat, and be
  • provided herein is a method of treating a mammal susceptible to or afflicted with a condition related to estrogen receptor.
  • the compounds of the present invention are provided for use in medical therapy, including for any of the conditions described herein.
  • the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases is also provided.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • any dose is appropriate that achieved the desired goals.
  • suitable daily dosages are between about 0.1-4000 mg, more typically between 5 mg and 1 gram, more typically between 10 mg and 500 mg, and administered orally once-daily, twice-daily or three times-daily, continuous (every day) or intermittently (e.g., 3-5 days a week).
  • the dose of the compounds of this invention usually ranges between about 0.1 mg, more usually 10, 50, 100, 200.250, 1000 or up to about 2000 mg per day.
  • the regimen for treatment usually stretches over many months or years. Oral dosing may be preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, nonlimiting dosages might range from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds provided herein When used to prevent the onset of cancer, a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column
  • the diastereomerically or enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate or mixture of diastereomers by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer or diastereomer. See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H.
  • a diastereomerically pure compound of formula (1) may be obtained by reaction of the racemate or mix of diastereomers with a suitable optically active acid or base.
  • suitable acids or bases include those described in Bighley et al.., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, the contents of which are hereby incorporated by reference in their entireties.
  • Enantiomerically or diastereomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer or diastereomer used.
  • the identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art.
  • the diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer or diastereomer regenerated by treatment with an appropriate base or acid.
  • the other enantiomer or diasteromer may be obtained from the racemate or mix of diastereomers in a similar manner or worked up from the liquors of the first separation.
  • enantiomerically or diastereomerically pure compound can be separated from racemic compound or a mixture of diastereomers by chiral
  • chiral columns and eluents for use in the separation of the enantiomers or diastereomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art.
  • Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to
  • CHIRALPACK® IC CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
  • the solid was transferred to a 2 L Erlenmeyer flask. Isopropyl alcohol (IPA) was used to rinse the flask. The solid was recrystallized from IPA (1.4 L). The suspension was cooled in an ice bath for 30 minutes and the solid collected by vacuum filtration. The solid was rinsed with ice cold IPA until the filtrate was colorless and dried in a vacuum oven to give a white powder (162.24 g). The mother liquor and washes were combined and concentrated to an orange oil (38.09 g).
  • IPA isopropyl alcohol
  • the oil bath was cooled to 90 °C and 380 mL of isopropyl alcohol was added in one portion.
  • the reaction mixture became a cloudy white suspension and redissolved to give a solution in less than a minute at 90 °C.
  • the heating to the bath was set to 50 °C and the flask was allowed to gradually cool to 50 °C.
  • a precipitate started to form at 60 °C and gave a suspension at 50 °C.
  • a thick oily mass falls out of solution ⁇ 55-53 °C.
  • Vigorous agitation with overhead stirrer 300 rpm was required to prevent the oily mass from solidifying into one solid as seen with small scale reactions equipped with stir bar. The reaction was left to stir until the mixture cooled to room temperature.
  • the mother liquor was decanted and fresh isopropanol (100 mL) was added to the flask to rinse the solid.
  • the liquid was decanted and combined with the mother liquor.
  • the mother liquor was concentrated to a dark red oil (27.13 g) and DCM (150 mL) was added to the flask to give a red solution.
  • Silica gel 55 g was added to solution and concentrated to dryness.
  • the silica gel mixture was poured into a 600 mL sintered glass funnel filled with silica gel (50 g). The solids were washed with ethyl acetate (1.2 L) and the filtrate concentrated to an orange oil (137.61 g crude).
  • the oil was dissolved into boiling 80 % IP A/water (1.2 L) and the solution allowed to cool to room temperature and stand overnight to give a cake.
  • the cake was filtered and washed with cold IPA (100 mL).
  • the mother liquor was partially concentrated on a rotovap to give a tan powder. This process was repeated until an oil could not be washed away from the powder.
  • the product was pooled and dried in a vacuum oven to give an impure tan powder (118.25 g, 85.6 %).
  • the red oil was dissolved into ethyl acetate (500 mL) and washed with saturated sodium bicarbonate solution (3 x 1 L). The organic layers was washed with brine (1 L), filtered and concentrated to give a red oil (109.32 g, crude). The oil was loaded onto 100 g of silica gel and chromatographed in 40 g portions on silica gel (100 g cartridge, 5-30 % EA/Hex). Fractions containing spots with Rf 0.55 (33 % EA/Hex) were pooled and concentrated to a light red glass (53.37 g). The glass was mixed with DCM (200 mL) and sonicated to give a pink suspension.
  • the solid was filtered through a sintered glass funnel washed with a 20 % DCM in Hexanes solution (250 mL) and dried in a vacuum oven overnight (32.41 g). The mother liquor was concentrated to a glass and the process repeated a second time to give a pink solid (4.2784 g).
  • the impure mixed fractions were pooled and concentrated to a glass (16.71 g).
  • the glass was dissolved into DCM (75 mL) and pink crystals formed on standing (7.0862 g). This process was repeated to give a second crop of pink crystals (2.3643).
  • the mother liquors from both the pure and impure fractions were combined and chromatographed with the same method (2 x 100 g cartridges). The fractions with Rf 0.55 were pooled and concentrated to give a red oil (17.388 g) which did not solidify. The oil was not combined with previous batches but reprotected in a separate reaction.
  • the reaction was diluted with DCM (200 mL), washed with saturated NaHC03 (200 mL), water (200 mL), brine (200 mL), dried over Na2S04, filtered and concentrated to give a red viscous residue.
  • the residue adsorbed onto silica gel (75 g) was purified on a silica gel column (4 x 100 g, 0 - 20 % EA/Hex) to give a white solid which was triturated with methanol and dried in a vacuum oven at 40° C for 16 h to afford the titled compound as a white powder (51.67 g 90.2 %).
  • the reaction mixture was heated in an oil bath at 120 °C. After 91 h of heating the reaction was cooled to room temperature and the mixture filtered through a pad of Celite (3 cm) which was successively washed with DCM (200 mL), EA (200 mL) and MeOH (200 mL). The filtrate was collected and concentrated. The residue was adsorbed onto silica gel (25 g) purified with silica gel (100 g cartridge, 0 - 30% MeOH/DCM) [TLC: 5 % MeOH/DCM, 4 major spots, Rf (SM:0.95), 0.9, 0.83, (prod. 0.43)]. The fractions containing product were pooled and concentrated to give a brown foam (13.64 g, 81.0 %).
  • OP-1038 was separated into its diastereomers (2S)-3-(4-hydroxyphenyl)-4- methyl-2-(4- ⁇ 2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol (OP-1074; Reference Compound 2) and (2R)-3-(4-hydroxyphenyl)-4-methyl-2-(4- ⁇ 2-[(3R)-3- methylpyrrolidin-l-yl]ethoxy ⁇ phenyl)-2H-chromen-7-ol (OP-1075; Reference Compound 3) using a Diacel, Chiralpak IC column at room temperature in isocratic mode with 80 % hexanes, 20 % 2-propanol with 0.1 % dimethylethylamine or 0.1% diethyl amine as a modifier. This method was used at analytical and preparative scale.
  • the mixture was filtered through a pad of Celite (4 cm). The solids were washed with DCM (5 x 500 mL). The filtrate was poured into a separatory funnel and the layers separated (-200 mL aqueous layer recovered). The aqueous layer was extracted with DCM (3 x 100 mL). The organic layers were combined and washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a yellow liquid (33.43 g).
  • the oil was taken up in methanol (50 mL) and 25 % sodium methoxide in methanol (9.9 mL, 45.5 mmol, 1 equiv) was added to the methanolic solution to give a white suspension.
  • the mixture was concentrated to dryness and taken up into anhydrous DCM (35 mL).
  • the suspension was centrifuged at 3K rpm for 5 minutes.
  • the clear solution was collected and the solid resuspended into DCM (35 mL). This process was repeated a total of 4 times.
  • the combined solution was concentrated to a yellow liquid (5.6341 g, 95.6 %).
  • the reaction mixture was heated in an oil bath at 120 °C. After 78 h of heating the reaction was cooled to room temperature and the mixture filtered through a pad of Celite (2 cm) which was successively washed with DCM (20 mL), EA (20 mL) and MeOH (20 mL). The filtrate was collected and concentrated. The residue was adsorbed onto silica gel (3 g) purified with silica gel (12 g cartridge, 0 - 30% MeOH/DCM) [TLC: 5 % MeOH/DCM, 4 major spots, R f (SM:0.95), 0.9, 0.83, (prod.
  • the oil was suspended into ethyl acetate (100 mL) and washed with saturated NaHC0 3 (2 x 50 mL). The combined aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a red glass (0.12 g, crude). The compound was dissolved into methanol and loaded onto silica gel (2 g) and concentrated to dryness. The silica gel containing the compound was purified on silica (4 g cartridge) with 0- 10 % MeOH in DCM.
  • the aqueous phase is washed with diethyl ether.
  • the combined organic phases are dried over anhydrous sodium sulfate or similar drying agent, filtered, concentrated in vacuo and carried on in the following procedure.
  • the products are purified via silica gel chromatography. Reduction of the amide is achieved with borane DMS complex in THF under standard conditions.
  • an estrogen- responsive reporter gene (ERE-tkl09-Luc) is transiently transfected into MCF-7 cells and treated with anti-estrogens in triplicate in the presence of 100 pM 17P-estradiol (E2) for 18-22 hours. Luciferase activity is normalized to activity of E2 alone and IC50's were calculated using the least squares fit method.
  • Proliferation in MCF-7 is measured using a fluorescent DNA binding dye 6-8 days after treatment in triplicate with anti-estrogens in the presence of 100 pM E2.
  • ERa expression is detected in MCF-7 cell lysates treated with 100 nM anti- estrogens in serum-free medium for 22-24 hours and immunoblotted with an antibody specific to ERa.
  • a tumor xenograft study is to examine the ability of compounds of the present invention, to slow or shrink a tamoxifen resistant tumor (MCF-7 HER2/neu Clone 18) xenograft growing on ovariectomized athymic nude mice under stimulation from exogenous estrogen.
  • Clone 18 cells grown in culture are implanted along with 0.18 mg estradiol/ 90 day release pellets (Innovative Research, Sarasota Florida) into mice to initiate the experiment. When the tumors have reached 250 cubic millimeters the mice are divided into groups of mice and dosing initiated. The groups are:
  • a positive control such as fulvestrant lOOmg/kg delivered daily by
  • the oral bioavailabilty in rats of compounds of the present invention are determined in the following study. 3 rats (female Sprague Dawley, non-fasted) are dosed by oral gavage (5 mg/kg body weight) in 0.5% CMC in water with a comparison to intravenous dosing (3 mg/kg body weight). Plasma is collected at the following hourly time points from rats in both groups (0, 0.08, 1.0, 2.0, 4.0, 8.0, 16.0, 24.0, 48.0 and 96.0 hours post dosing). Plasma concentrations of compounds of the present invention are determined by HPLC.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Ci_ 6 alkyl is intended to encompass, Ci, C 2 , C 3 , C 4 , C 5 , C 6 , Ci-6, Ci_5, Ci_3, Ci_2, C 2 -6, C2-5, C2-4, C2-3, C 3 _6, C 3 _5, C 3 _ 4 , C 4 _6, C 4 _5, and Cs_6 alkyl.
  • analogue means one analogue or more than one analogue.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group which in one embodiment has from 1 to 20 carbon atoms ("Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci_i 2 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("Ci_i 0 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms ("Ci_ 6 alkyl", also referred to herein as "lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“Ci_ 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci_ 4 alkyl”). In some
  • an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci_ 2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 _6 alkyl”).
  • Ci_ 6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci-10 alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is substituted Ci_i 0 alkyl.
  • Alkylene refers to a substituted or unsubstituted alkyl group, as defined above, wherein two hydrogens are removed to provide a divalent radical.
  • exemplary divalent alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group which in one embodiment has from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2 - 20 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms ("C 2 _ 10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms ("C 2 -9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2 _8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms ("C 2 _ 6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2 _ 5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2 -4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C 2 _ alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 - 6 alkenyl groups include the aforementioned C 2 - 4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2 _ 10 alkenyl.
  • the alkenyl group is substituted C 2 - 10 alkenyl.
  • alkenylene refers a substituted or unsubstituted alkenyl group, as defined above, wherein two hydrogens are removed to provide a divalent radical.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group which in one embodiment has from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2 _ 2 o alkynyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2 _i 0 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2 _ 9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2 _ 8 alkynyl").
  • an alkynyl group has 2 to 7 carbon atoms ("C 2 _7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2 - 6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2 _ 5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2 - 4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkynyl").
  • an alkynyl group has 2 carbon atoms ("C 2 alkynyl").
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 - 4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1- butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2 -6 alkenyl groups include the aforementioned C 2 _ 4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2 _ 10 alkynyl.
  • the alkynyl group is substituted C 2 -io alkynyl.
  • Alkynyl ene refers a substituted or unsubstituted alkynyl group, as defined above, wherein two hydrogens are removed to provide a divalent radical.
  • exemplary divalent alkynylene groups include, but are not limited to, ethynylene, propynylene, and the like.
  • Naturally occurring or non-naturally occurring "amino acids” can be used in the preparation of compounds of the invention as described herein.
  • natural amino acids include valine, leucine, isoleucine, methionine, phenylalanine, asparagine, glutamic acid, glutamine, histidine, lysine, arginine, aspartic acid, glycine, alanine, serine, threonine, tyrosine, tryptophan, cysteine, proline, 4-hydroxyproline, g-carboxyglutamic acid, selenocysteine, desmosine, 6-N-methyllysine, e-N,N,N-trimethyllysine, 3-methylhistidine, O-phosphoserine, 5- hydroxylysine, e-N-acetyllysine, s-N-methylarginine, N-acetyl serine, g-aminobutyric acid, citrulline, orni
  • Non- limiting examples of non-naturally occurring amino acids include phenyl glycine, meta-tyrosine, para-amino phenylalanine, 3-(3-pyridyl)-L-alanine, 4-(trifluoromethyl)-D-phenylalanine, and the like.
  • an L-amino acid is used.
  • Aryl refers to a radical of a monocyclic or polycyclic ⁇ e.g., bicyclic or tricyclic
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms ("C 14 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • Particularly aryl groups include pheny
  • the aryl group is unsubstituted C 6 -i4 aryl. In certain embodiments, the aryl group is substituted C 6 -i4 aryl.
  • R and R may be hydrogen and at least one of R and R is each independently selected from Ci-C 8 alkyl, Ci-C 8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, R 58 COR 59 , R 58 SOR 59 R 58 S0 2 R 59 , COOalkyl, COOaryl, CO R 58 R 59 , CO R 58 OR 59 , R 58 R 59 ,
  • S0 2 R 58 R 59 S-alkyl, SOalkyl, S0 2 alkyl, Saryl, SOaryl, S0 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S.
  • R 60 and R 61 are independently hydrogen, Ci-C 8 alkyl, C 1 -C4 haloalkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Ci 0 aryl, substituted C 6 -Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
  • fused aryl refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
  • Alkyl is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl").
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrol yl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, tnazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
  • benzothiophenyl isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl,
  • benzthiadiazolyl indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • each Y is selected from carbonyl, N, R , O, and S; and R is independently hydrogen, Ci-C 8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • R is independently hydrogen, Ci-C 8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • each W is selected from C(R ) 2 , R , O, and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, Ci-C 8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, and 5-10 membered heteroaryl.
  • Heteroaralkyl is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
  • Carbocyclyl or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C 3 _ 10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 - 6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 - 6 carbocyclyl").
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5 _i 0 carbocyclyl").
  • Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _i 0 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3 _i 0 carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _i 0 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3 _ 10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5 _ 6 cycloalkyl").
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5 _i 0 cycloalkyl").
  • C 5 _6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
  • C 3 _ 6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _ 6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3 _ 10 cycloalkyl.
  • the cycloalkyl group is substituted C 3 _i 0 cycloalkyl.
  • Heterocyclyl or “heterocyclic” refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thioranyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • each W is selected from CR , C(R ) 2 , NR , O, and S; and each Y is selected from R 67 , O, and S; and R 67 is independently hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, 5-10 membered heteroaryl.
  • heterocyclyl rings may be optionally substituted with one or more substituents selected from the group consisting of the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(0)-alkyl ,-S(0)-aryl, -S(0) 2 -alkyl, and -S(0) 2 - aryl.
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g, heteroaryl, cycloalkenyl, e.g,.cycloheteroalkenyl, and the like having from 1 to 5, and
  • Acyl refers to a radical -C(0)R 20 , where R 20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • R 21 is Ci-C 8 alkyl, substituted with halo or hydroxy; or C 3 -Cio cycloalkyl, 4-10 membered heterocyclyl, C 6 -Ci 0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroaryl alkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
  • Acylamino refers to a radical - R 22 C(0)R 23 , where each instance of R 22 and R23 is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R 22 is an amino protecting group.
  • acylamino groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • acylamino groups are - R 24 C(0)-Ci-C 8 alkyl, - R 24 C(O)-(CH 2 ) t (C 6 -Ci 0 aryl), - R 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), - R 24 C(O)-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and - R 24 C(O)-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R 24 independently represents H or Ci-C 8 alkyl.
  • R 24 independently represents H or Ci-C 8 alkyl.
  • R 25 is H, Ci-C 8 alkyl, substituted with halo or hydroxy
  • C 3 -Cio cycloalkyl 4-10 membered heterocyclyl, C 6 -Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and
  • R 26 is H, Ci-C 8 alkyl, substituted with halo or hydroxy
  • C 3 -Cio cycloalkyl 4-10 membered heterocyclyl, C 6 -Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided at least one of R 25 and R 26 is other than H.
  • Acyloxy refers to a radical -OC(0)R 27 , where R 27 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl,
  • R 28 is Ci-C 8 alkyl, substituted with halo or hydroxy; C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted Ci- C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Alkoxy refers to the group -OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl.
  • Particular alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • R 29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Cio aryl, aryloxy, carboxyl, cyano, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0) 2 - and aryl- S(0) 2 -.
  • substituents for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Cio aryl, aryloxy, carboxyl, cyano, C 3 -C 10
  • Exemplary 'substituted alkoxy' groups include, but are not limited to, -0-(CH 2 ) t (C 6 -Cio aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 OH, and -OCH 2 CH 2 Me 2 .
  • Amino refers to the radical - H 2 .
  • Substituted amino refers to an amino group of the formula -N(R 38 ) 2 wherein R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R 38 is not a hydrogen.
  • each R is independently selected from: hydrogen, Ci-C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 6 -Cio aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3 -Ci 0 cycloalkyl; or Ci-C 8 alkyl, substituted with halo or hydroxy; C 3 -C 8 alkenyl, substituted with halo or hydroxy; C 3 -C 8 alkynyl, substituted with halo or hydroxy, or -(CH 2 ) t (C 6 -Cio aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -Ci 0 cycloalkyl), or -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substitute
  • Exemplary ' substituted amino' groups are - R 39 -Ci-C 8 alkyl, - R 39 -(CH 2 ) t (C 6 -
  • each R 39 independently represents H or Ci-C 8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstit
  • substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below.
  • Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
  • Carbamoyl or “amido” refers to the radical -C(0) H 2 .
  • Substituted carbamoyl or “substituted amido” refers to the radical -C(0)N(R 62 ) 2 wherein each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R 62 is not a hydrogen.
  • R 62 is selected from H, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocyclyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or Ci-C 8 alkyl substituted with halo or hydroxy; or C 3 -Cio cycloalkyl, 4-10 membered heterocyclyl, C 6 -Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy
  • Exemplary 'substituted carbamoyl' groups include, but are not limited to, -C(O) R 64 -Ci-C 8 alkyl, -C(O) R 64 -(CH 2 ) t (C 6 -Ci 0 aryl), -C(O)N 64 -(CH 2 ) t (5-10 membered heteroaryl), -C(0) R 64 -(CH 2 ) t (C 3 -Cio cycloalkyl), and -C(O) R 64 -(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, each R 64 independently represents H or Ci-C 8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsub
  • Cyano refers to the radical -CN.
  • Halo or "halogen” refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I).
  • the halo group is either fluoro or chloro. In further embodiments, the halo group is iodo.
  • Haldroxy refers to the radical -OH.
  • Niro refers to the radical -N0 2 .
  • Cycloalkylalkyl refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group.
  • Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropyl ethyl, cyclobutyl ethyl, cyclopentylethyl, cyclohexyl ethyl, cycloheptyl ethyl, and cyclooctylethyl, and the like.
  • Heterocyclylalkyl refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group.
  • Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
  • Cycloalkenyl refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation.
  • Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
  • Fused cycloalkenyl refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
  • Ethylene refers to substituted or unsubstituted -(C-C)-.
  • Neitrogen-containing heterocyclyl means a 4- to 7- membered non- aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piped dine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine.
  • morpholine e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl
  • pyrrolidine e.g. 2- pyrrolidinyl and 3-pyrrolidinyl
  • azetidine pyrrolidone
  • imidazoline imidazolidinone
  • 2- pyrazoline
  • Particular examples include azetidine, piperidone and piperazone.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, -CN,
  • each instance of Raa is, independently, selected from Cl-10 alkyl, Cl-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
  • each instance of Rcc is, independently, selected from hydrogen, Cl-10 alkyl, Cl- 10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered
  • heterocyclyl C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
  • each instance of Ree is, independently, selected from Cl-6 alkyl, Cl-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, Cl-6 alkyl, Cl-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, al
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or "unsubstituted” alkyl,
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.
  • exemplary counterions include halide ions (e.g., F “ , CI “ , Br “ , ⁇ ), N0 3 “ , C10 4 “ , OH “ , H 2 P0 4 “ , HS0 4 “ , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,
  • benzenesulfonate 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).
  • carboxylate ions e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R , R cc and R dd are as defined above.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-( 10, 10-dioxo-l 0, 10,10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methyl
  • Ts
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-
  • methoxybenzylideneamine N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, ⁇ , ⁇ '- isopropylidenedi amine, N- ?-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, TV- copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,
  • diphenylphosphinamide Dpp
  • dimethylthiophosphinamide Mpt
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps)
  • 2,4-dinitrobenzenesulfenamide pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • benzisothiazolyl S,S-dioxido trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri- ⁇ -xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,/?-chlorophen
  • the substituent present on a sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group).
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66(1): 1-79 (Jan.'77).
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • “Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule of the structural Formula indicated herein.
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions a compound of the invention that are pharmaceutically active in vivo.
  • Solvate refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline or liquid form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans ⁇ i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • the term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight.
  • the term may refer to more than 96% by weight, more than 97% by weight, more than 98%) by weight, more than 98.5%> by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term “enantiomerically pure R- compound” refers to at least 95% by weight R-compound and at most about 5% by weight S- compound. In alternative embodiments, when specified, the term can refer to at least about 99% by weight R-compound and at most about 1% by weight S-compound or at least about 99.9% by weight R-compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
  • the term “enantiomerically pure S- compound” or “S-compound” refers to at least about 95% by weight S-compound and at most about 5% by weight R-compound. In alternative embodiments, when specified, the term can refer to at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.

Abstract

Benzopyran compounds with anti-estrogenic activity are provided as Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII. These compounds are useful for the treatment or prevention of a variety of conditions that are modulated through the estrogen receptor in mammals including humans.

Description

SUBSTITUTED BENZOPYRAN COMPOUNDS,
COMPOSITIONS AND USES THEREOF
FIELD
[0001] This invention is in the field of pharmaceuticals, and in particular novel benzopyran compounds, and salts, prodrugs and derivatives thereof and their medical uses, including as estrogen receptor modulators and for medical conditions that would benefit from an anti-estrogenic drug, and pharmaceutical compositions thereof.
BACKGROUND
[0002] Estrogen receptor modulators are a class of compounds that act on the estrogen receptor. These compounds can be pure agonists (mimicking estrogen), pure antagonists, or mixed agonist-antagonists (sometimes referred to as Selective Estrogen Receptor Modulators (SERMs)). For example, estradiol (A) is a pure agonist, fulvestrant (B) is a complete antagonist, and tamoxifen (C) and raloxifene (D) are SERMs.
[0003] Most breast cancers express estrogen receptors (ER), and their growth is driven by the action of estrogen at its receptors, primarily at ER alpha. This type of cancer is treated with an estrogen antagonist, which competes with estrogen for binding to the receptor, but does not activate it, preventing estrogen driven growth. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors. A recent study also suggests that fulvestrant is substantially superior to the aromatase inhibitor anastrozole in treating metastatic breast cancer (Robertson et al. J Clin Oncol (2009) 27(27):4530-5).
[0004] Estradiol is a naturally-occuring female estrogenic hormone. Raloxifene was disclosed by Eli Lilly in 1981 (U.S. Patent No. 4,418,068; 5,478,847; 5,393,763; and 5,457,117) for prevention of breast cancer and treatment of osteoporosis. Fulvestrant was disclosed by Imperial Chemical Industries (ICI) in 1983 (U.S. Patent No. 4,659,516, expired in 2007 with a patent term extension; U.S. Patent Nos. 6,774, 122 and 7,456, 160). Tamoxifen was also disclosed by ICI in the '516 patent. Tamoxifen was developed for the treatment of breast cancer on the basis of strong antagonism of estrogen action in mammary tissue (Jordan, J. Cell. Biochem. 51 (1995
Figure imgf000003_0001
tamoxifen raloxifene
C D
[0005] The degree of anti-estrogenicity is often assayed by exposing female, immature
(preferably ovariectomized) rodents to test doses of the compound both in the absence (agonist mode) and presence (antagonist mode) of estrogen. Tamoxifen and other partial anti-estrogens stimulate uterine weight gain in the agonist mode and only partly block estrogen-driven uterine weight gain in the antagonist mode. Fulvestrant and other complete anti-estrogens do not stimulate uterine weight gain in the agonist mode and completely block estrogen-driven weight gain in the antagonist mode. The induction of estrogen-regulated alkaline phosphatase expression in human uterine cancer cell growth in culture can be used to distinguish partial and complete anti-estrogenicity and correlates well with the rodent weight gain assay.
[0006] Tamoxifen and fulvestrant both inhibit cultured human breast cancer cell proliferation provoked by estrogen. However, fulvestrant more fully inhibits the proliferation when provoked with growth factors, especially of the insulin/insulin-like growth factor family. Thus the inhibition of growth-factor driven breast cancer cell proliferation and the effect on uterine weight provide two assays which can distinguish between complete and partial anti- estrogens.
[0007] Tamoxifen binding stabilizes the estrogen receptor whereas fulvestrant and chemically related antiestrogens, such as ICI-164384 and RU-58668, cause degradation of the estrogen receptor. (Dodge et al, J. Bone Miner. Res., 8 (Suppl 1, S278 (1993); Wakeling, Breast Cancer Res. Treat. 25, 1 (1993); Baer et al, Calcified Tissue Int., 55, 338 (1994). However, some compounds, like GW-5638 (Wu et al, Mol Cell.,18,413 (2005), and OP1075, described below, degrade the receptor but are partial estrogens- that is, not complete anti-estrogens. Thus the ability to degrade the estrogen receptor does not ensure complete antiestrogenicity. The ability to induce degradation of the receptor is nonetheless a factor that differentiates the behavior of tamoxifen and fulvestrant and may be desirable in a drug to treat breast cancer.
[0008] Fulvestrant, which degrades the estrogen receptor, incorporates a core of 17-beta estradiol. It has a long flexible aliphatic side chain that blocks oral absorption. The estradiol core blocks oral absorption and the long flexible aliphatic side chain makes the drug very insoluble which worsens the problem. Fulvestrant must be injected because of the poor oral bioavailability. Two 5 ml intramuscular depot injections, one into each buttock, must be administered monthly by a health professional. Furthermore, it is unclear whether these two injections provide sufficient drug exposure for optimal action. The drug does not seem to work in pre-menopausal women.
[0009] In 1990, an important step in oral anti-estrogen development came with the discovery of a family of high-affinity benzopyran anti-estrogens by Kapil and coworkers.
(Sharma et al. (1990) J Med Chem, 33(12):3222-9; Sharma et al. (1990) J Med Chem,
33(12):3216-22). The numbering scheme of benzopyrans is typically:
Figure imgf000004_0001
F [0010] Sharma et al. showed that the combination of 7-hydroxyl and 4' -hydroxyl groups conferred high-affinity binding of the benzopyran core to the estrogen receptor (Compound G; see Compound 25 of Sharma -9 where R1 and R2 are OH).
Figure imgf000005_0001
G
[0011] Further, Sharma et al. reported that the presence of a methyl group at the 4 position of the benzopyran core enhanced receptor binding affinity, without a hydroxyl group at the 4' -position.
[0012] In 1991, Labrie and coworkers filed a patent application which issued as U.S.
Patent No. 5,395,842 (see claim 29) which taught that EM-343 (H), showed superior binding to the estrogen receptor with no loss of anti-estrogen action. EM-343 differed from the Saeed compounds by including the hydroxyl at the 4'-position of a 4-methyl, 7-hydroxyl benzopyran.
Figure imgf000005_0002
EM-343 H
[0013] In 1995, Labrie et al. filed a continuation-in-part patent application, which issued in 2000 as U.S. Patent No. 6,060,503, disclosing prodrugs and optically active species of EM- 343. Particularly, Labrie et al. disclosed a pure isomer of EM-343, EM-652, referred to as acolbifene (I), which is (S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-(2-(piperidin-l- yl)ethoxy)phenyl)-2H-chromen-7-ol.
Figure imgf000006_0001
I
[0014] Labrie et al. in WO 01/54699 (see Figure 4a and 4b) also presented several broad generic Markush formulae of benzopyran-containing compounds, including acolbifene analogs, in which the side chain terminates in various substituted ring systems including pyrrolidinyl, piperidinyl, and methyl- 1 -pyrrolidinyl and dimethyl- 1 -pyrrolidinyl.
[0015] U.S. Patent Nos. 7,005,428 and 6,465,445 to Labrie, which claim priority to a
June 1998 application describe the following generic formulas for use as anti-estrogenic compounds:
Figure imgf000006_0002
wherein D is -OCH2CH2N(R3)R4 (R3 and R4 either being independently selected from the group consisting of C1-C4 alkyl, or R3, R4 and the nitrogen atom to which they are bound together being a ring structure selected from the group consisting of pyrrolidino, dimethyl- 1-pyrrolidino, methyl- 1-purrolidinyl, piperidino, hexamethyleneimino and morpholino); and wherein Ri and R2 are independently selected from the group consisting of hydrogen, hydroxyl and a moiety converted in vivo in to hydroxyl, and
Figure imgf000006_0003
wherein Ri and R2 are independently selected from the group consisting of hydroxyl and a moiety converted in vivo in to hydroxyl;
wherein R3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen- containing cyclic moiety, nitrogen-containing polycyclic moiety, and RaRb (Ra and Rb being independently hydrogen, straight or branched Ci-C6 alkyl, straight or branched C2-C6 alkenyl, and straight of branched C2-C6 alkynyl.
[0016] Acolbifene binds to the estrogen receptor alpha with three times the affinity of 17- beta estradiol, the native ligand (Katzenellenbogen (2011) J Med Chem 54(15):5271-82). Since anti-estrogens must compete with estradiol for binding to the estrogen receptor, high affinity binding is an important drug virtue. Both the Labrie '842 and the Labrie '503 patents disclosed benzopyran compounds that can contain an unsubstituted pyrrolidine in the "tail" or R3 position as depicted in Compound F. EM-800, a pivalate prodrug of EM-652, and HC1 salts of EM-652 were also described in the '503 patent.
[0017] Acolbifene was initially thought to be a complete anti-estrogen. However, careful studies with the rodent uterine assay and human uterine cell alkaline phosphatase assays revealed that it retained some estrogen-like action, about 12% that of estradiol (Labrie et al. "The combination of a novel selective estrogen receptor modulator with an estrogen protects the mammary gland and uterus in a rodent model: the future of postmenopausal women's health?" Endocrinology. 2003 144(11):4700-6). This contrasts with fulvestrant where the residual estrogen-like action is almost unmeasurable. Furthermore, fulvestrant binding induces dramatic degradation of the estrogen receptor, while acolbifene induces either no or modest receptor degradation. Raloxifene and bazedoxifene don't degrade the receptor, but stabilize the receptor to a much lesser degree than tamoxifen.
[0018] Acolbifene is orally bioavailable and is currently being positioned for Phase III clinical trials for the treatment of breast cancer by the Canadian company Endoceutics (Founded by Dr. Labrie). A daily oral dose of 40 mg of acolbifene or EM800 in women produces mean drug exposures of 8.3 and 15 ng/ml of circulating acolbifene, respectively. In preclinical studies both forms of the drug are effective against tamoxifen-resistant human breast cancer xenografts growing on immunocompromised mice. In clinical studies the 40mg dose of EM800 was numerically as effective as anastrozole in preventing progression of metastatic estrogen receptor positive breast cancer. [0019] Starting in 2005, Blizzard and coworkers at Merck published a series of papers on estrogen receptor ligands. They first focused on using a dihydrobenzoxathiin core (J) with alkyl substituted pyrrolidine side chains and linkers as SERAMs (Selective Estrogen Receptor Alpha Modulators) (Blizzard et al. (2005) Bioorg Med Chem Lett. 15(1): 107-13).
Figure imgf000008_0001
Merck Dihydrobenzoxathiin Core
J
[0020] The group tried to maximize the estrogen receptor α/β selectivity ratio and minimize uterine activity (e.g., maximize antagonism of uterine activity). They reported that the unbranched linker with 3 -methyl pyrrolidinyl and 3,4-methyl pyrrolidinyl as well as the a-m ethyl (i.e., a methyl on the a-position of the ethylene) linker with an unsubstituted pyrrolidinyl side chains were noteworthy. Blizzard et al. concluded that minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
[0021] Blizzard et al. also studied a chromane core (Blizzard et al. (2005) Bioorg Med
Chem Lett. 15(6): 1675-81) (Compound K).
Figure imgf000008_0002
Merck Chromane Core
K
[0022] The Merck chromane core differs from the acolbifene core by the absence of a double bond in the oxane ring. These structures also had a hydroxyl at position 6 (not 7) of the fused benzene ring. A chromane core with a 2-m ethyl pyrrolidine (but not a 3 -methyl) with a methyl on the linker created a nearly complete anti-estrogen, (see compound 12 of the Blizzard et al. paper). Blizzard et al. commented on the differences among anti-estrogenic activities of variously substituted cores, and noted that the size and stereogenic placement of substituents is crucial for receptor potency and selectivity.
[0023] In the third publication of this series (Blizzard et al. (2005) Bioorg Med Chem
Lett. 15(17):3912-6); Blizzard et al. again studied the dihydrobenzoxathiin core and reported that their studies have resulted in the discovery that addition of a methyl group to the side chain at the appropriate position and with the right stereochemistry, either on the pyrrolidine ring or on the linker substantially increased estrogen antagonist activity in uterine tissue. Blizzard et al. also reported that the best estrogen antagonist activity in this dihydrobenzoxathiin series was determined to have a methyl group on the pyrrolidine and a methyl group on the linker, with the hydroxyl in the 6-position of the fused benzene ring. Blizzard et al. also noted that to their knowledge, their optimized side chain with two methyl groups represented the first example where a relatively small structural modification of an existing SERM resulted in a conversion of a SERM to a SERAM/SERD (Selective Estrogen Receptor alpha Modulator and Down- regulator).
[0024] The Merck team then investigated whether the optimized side chain modification reported for the dihyrobenzoxathiin core was "portable" and could confer strong anti- estrogenicity when appended to different cores (Blizzard et al. (2005) Bioorg Med Chem Lett. 15(23):5214-8). Merck demonstrated that none of the three cores tested (raloxifene,
bazedoxifene, or lasofoxifene) became more anti-estrogenic with either the 3-methyl pyrrolidine or the chiral side chain modifications. Blizzard et al. concluded that "The lack of a dramatic effect on the uterine profile upon incorporation of side chains A and B clearly indicates that the side chain Structure Activity Relationship of the dihydrobenzoxathiin SERAMs is not transferable to other platforms."
[0025] In yet another 2005 research publication, Gauthier, Labrie and colleagues reported the synthesis and structure-activity relationships of analogs of acolbifene (Gauthier et al. (2005) J Enzyme Inhib Med Chem, 20(2): 165-77). They attempted to improve on the anti-estrogenicity of acolbifene by creating analogs in which the terminal piperidine was either replaced by pyrrolidine or substituted in various ways. All of these analogs proved to be more estrogenic than acolbifene as revealed by the rodent uterus assay. This experience suggests that improvement of the anti-estrogenicity of acolbifene will be a challenge and modifications provide unpredictable results. [0026] Blizzard reviewed the Merck research on anti-estrogens in 2008 (Curr Top Med
Chem. 8(9):792-812). He noted that:
[0027] "Selective Estrogen Receptor Modulators (SERMs) have been the subject of extensive medicinal chemistry efforts at several pharmaceutical companies, including
Merck The Merck SERM project involved a large number of talented and dedicated chemists and biologists who worked for several years to discover novel classes of SERMs with a range of selectivities....no drugs have yet reached the market as a result of this effort."
[0028] Indeed, the Merck effort began in the early 1990's and continued well into the
2000' s, reflecting impressive science but no commercial products. Their most promising compounds, which included side chains in which the piperidine ring was replaced with a mono- or di-substituted pyrrolidine ring appended to a benzoxathiin core, especially with a 3-R methyl pyrrolidine terminus, showed anti-estrogenicity, although not as complete as fulvestrant in the rodent uterus assay. A chiral methyl on atom 2 of the flexible linker also conferred improved anti-estrogenicity. The two features together in a doubly substituted side chain conferred anti- estrogenicity that was similar to fulvestrant. Unfortunately the Merck core had problematic reactive metabolites when investigated in primates, which halted clinical development.
[0029] Aragon Pharmaceuticals filed PCT/US2011/039669 (published December 15,
2011 as WO2011/156518), which claimed priority to U.S. Provisional Application 61/353,531 titled "Estrogen Receptor Modulators and Uses Thereof filed in June 2010. Aragon disclosed large genuses of benzopyran derivatives and at least 71 acolbifene analogs intended for treatment of tamoxifen resistant breast cancer. Aragon appears to have taken the prior art teachings of Merck regarding how to optimize the dihydrobenzoxathiin core, and applied the teachings to the acolbifene benzopyran core. Aragon is considering advancing a drug to the clinic for late stage progressive metastatic disease.
[0030] Kushner et al. (US 2013/0178445 and WO 2013/090921, both filed Dec. 17, 2012 and both assigned to Olema Pharmaceuticals) describe OP-1038 (3-(4-hydroxyphenyl)-4-methyl- 2-(4-{2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H-chromen-7-ol) and OP-1074 ((2S)-3- (4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H- chromen-7-ol), as well as pharmaceutical compositions and methods of use.
[0031] Bazedoxifene is a SERM, under development for prevention and treatment of postmenopausal osteoporosis (Biskobing, D. M. (2007) Clinical interventions in aging 2 (3): 299-303). Lasofoxifene is another SERM under development for the treatment of postmenopausal osteoporosis and vaginal atrophy (Gennari et al. (2006), Expert Opin Investig Drugs 15 (9): 1091-103).
[0032] U.S. Patent 5,254,568 discloses benzopyrans as anti-estrogenic agents.
[0033] WO2010/145010 discloses a combination of SERM and sex steroid precursor for treating hot flashes and other symptoms.
[0034] WO2004/091488 discloses benzopyrans as estrogen receptor modulators.
[0035] U.S. Patent 5,840,735 discloses benzopyrans as sex steroid activity inhibitors.
[0036] U.S. Patent 6,262,270 discloses a method for the enantiomeric synthesis of acolbifene derivatives.
[0037] Thus, there is a need to provide a new anti-estrogenic compound for the treatment of medical disorders that are mediated or affected by an estrogen receptor and pharmaceutical compositions and uses thereof.
SUMMARY OF THE INVENTION
[0038] The present invention is related to benzopyran compounds of Formula I, II, III,
IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII (in the form of a mixture of S-C2 and R-C2 diastereomers and also its pure S-diastereomer) that have unexpected and improved properties for the treatment of medical disorders that are modulated or affected by an estrogen receptor.
[0039] The active compounds can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or Ri and/or R2-substituted derivative optionally in a pharmaceutically acceptable composition to treat a disorder that is modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic.
Figure imgf000011_0001
- 11 -
Figure imgf000012_0001
- 12-
Figure imgf000013_0001
Figure imgf000014_0001
[0040] The specific benzopyran compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX,
X, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII and their prodrugs (including esters, carbonates and phosphates), derivatives and their salts are anti-estrogens useful to treat locally advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer). In an alternative embodiment, the compounds are used to treat estrogen or progesterone receptor negative breast cancer. The compounds can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer, either by itself or in combination with one or more other anti-cancer agents, including targeted therapies. They are also useful for second line therapy for treatment after a previous hormonal therapy has failed, either by itself or in combination with another anticancer agent, for example, a targeted therapy such as an mTOR inhibitor such as everolimus or a CDK 4/6 inhibitor such as palbociclib (PD- 0332991).
[0041] The compounds of the invention are also useful as adjuvant therapy after surgery to prevent recurrence. Such adjuvant use is often administered for several years, for instance 5 years, or 10 years after surgery and associated chemotherapy and radiotherapy have been concluded.
[0042] The compounds of the invention are also useful for the prevention of breast cancer in women at high risk and can be taken for any desired time period, including indefinitely. For example, a patient, typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRCAl or BRCA2 or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention. The compounds described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence. In addition to breast cancer these compounds also are useful to treat other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis. Besides these reproductive tissues the compounds are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
[0043] Selective estrogen receptor modulators (SERMs) are useful for hormonal therapy for postmenopausal women in particular to treat or prevent osteoporosis. In one embodiment, a compound of the present invention is used in combination with an estrogen, SERM or partial anti-estrogen such that the anti-estrogen prevents adverse action of the total or partial estrogen on the uterus and other tissues.
[0044] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description. All variations and modifications of the disclosed invention are considered within the scope of this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0045] The present invention is related to specific benzopyrans (in the form of a C2 equal mix of diastereomers and their pure S-diastereomers) that are useful for the treatment of medical disorders that are mediated, modulated or affected by an estrogen receptor, including breast cancer.
[0046] The compounds can be provided if desired as a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, N-oxide or Ri and/or R2-substituted derivative or a pharmaceutically acceptable composition thereof to treat a disorder that is mediated, modulated or affected by an estrogen receptor, including those treatable with an anti-estrogenic compound. - 15-
Figure imgf000016_0001
- 16-
Figure imgf000017_0001
Figure imgf000018_0001
wherein Ri and R2 are independently either:
(i) R9 which is independently selected from H, halogen (CI, Br, I or F), natural or non- naturally occurring amino acid (bound through either the OC(O)- or C(0)0- (an ester) or the amino (through either -C(0)-N- or -N-C(O)- (an amide linkage)), R10, -OR10, or -SR1( where R10 is -C(=0)RC1, -C(=0)0RC1, -C(=0)SRC1, -C(=0)N(RC1)2; or polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
-S(=0)2RC1, -S(=0)2ORcl, -S(=0)RC1, -S(=0)ORcl, -P(=0)2RC1, -P(=0)2ORcl, -P(=0)(ORcl)2, -P(=0)(RC1)2, or -P(RC1)(0RC1); or oxygen attached to an oxygen protecting group (to produce OH on administration), sulfur attached to a sulfur protecting group (to produce SH or a disulfide on administration), or nitrogen attached to a nitrogen protecting group (to produce - H- on administration);
and R can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring.
[0047] In certain embodiments either or both of Ri or R2 is an ester, amide, carbonate or phosphate.
[0048] Examples of useful metabolically cleavable prodrug groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups
[0049] The compounds of the invention can be administered in a pharmaceutical composition suitable for oral delivery to the patient, typically a human. Alternatively, the compounds can be delivered in a carrier suitable for topical, transdermal (including by patch), intravenous, parenteral, intraortal, subcutaneous or other desired delivery route, including any method of controlled delivery, for example, using degradable polymers, or with nano or microparticles, liposomes, layered tablets or other structural frameworks which slow delivery.
[0050] In yet another aspect, the compounds of the invention can be used to prevent a disorder modulated through the estrogen receptor, which comprises administering to a patient in need of such prevention, a prophylactically effective amount of a compound or pharmaceutical composition.
[0051] The compounds of the invention can be in the form of a salt. They can be administered as a pharmaceutically acceptable salt, for example, a pharmaceutically acceptable acid addition salt, including a hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like. [0052] The compounds are used to treat or prevent a disorder modulated by the estrogen receptor in an animal, typically a mammal, and most typically a human.
[0053] In yet another aspect, the present invention provides a combination of a compound of the instant invention, and another pharmacologically active agent.
[0054] The compounds can also be used as adjunctive therapy or combination therapy with another active agent. For example, a therapeutically effective amount of the compound can be used in combination with another anti-cancer agent, especially for estrogen receptor positive breast cancer, but in some embodiments, for estrogen receptor negative breast cancer.
[0055] Additional embodiments within the scope provided herein are set forth in non-limiting fashion elsewhere herein and in the examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting in any manner.
PHARMACEUTICAL COMPOSITIONS
[0056] In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of the present invention and a
pharmaceutically acceptable carrier.
[0057] The compounds provided herein are administered for medical therapy in a therapeutically effective amount. The amount of the compounds administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[0058] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, topical, parenteral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal with a pharmaceutical carrier suitable for such administration. In one embodiment, the compounds are administered in a controlled release formulation.
[0059] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. Typically, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (as a nonlimiting example, from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
[0060] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[0061] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
[0062] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), for example in an amount ranging from about 0.01 to about 20%) by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10%) by weight, and more preferably from about 0.5 to about 15%> by weight. When formulated as an ointment, the active ingredients will typically be combined with either a suitable delivery polymeric composition, or a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
[0063] The compounds provided herein can be administered by a transdermal device.
Transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[0064] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington 's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. [0065] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington 's Pharmaceutical Sciences.
[0066] In certain embodiments, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. In certain embodiments, the formulation comprises hexapropyl-P-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-P-cyclodextrin (10-50% in water).
[0067] The present invention also includes pharmaceutically acceptable acid addition salts of compounds of the compounds of the invention. The acids which are used to prepare the pharmaceutically acceptable salts are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
[0068] The following formulation examples illustrate non-limiting representative pharmaceutical compositions that may be prepared in accordance with this invention for the purpose of illustration only. The present invention is specifically not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets
[0069] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
Formulation 2 - Capsules
[0070] A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
Formulation 3 - Liquid
[0071] A compound of the invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL. Formulation 4 - Tablets
[0072] A compound of the invention can be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press. In other embodiments, there is between 10 and 500 mg of active compound in the oral tablet.
Formulation 5 - Injection
[0073] A compound of the invention can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5, or 10, or 15, or 20, or 30 or 50 mg/mL.
Formulation 6 - Tablets
[0074] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
Formulation 7 - Tablets
[0075] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.
Formulation 8 - Tablets
[0076] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.
Formulation 9 - Tablets
[0077] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.
Formulation 10 - Tablets
[0078] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets (5-1000 mg of active compound per tablet) in a tablet press.
USE OF COMPOUNDS IN MEDICAL THERAPY
[0079] Specific benzopyran compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X,
XI, XII, XIII, XIV, XV, XVI, XVII and XVIII and their prodrugs (including esters, carbonates and phosphates), derivatives and their salts as described herein are anti-estrogens useful to treat any disorder modulated, mediated or affected by the estrogen receptor.
[0080] In one embodiment, the compounds are used in combination or alternation with another anti-cancer agent for the treatment of cancer, as described more fully below. In another embodiment, the compound in combination or alternation with estrogen or a partial estrogen receptor antagonist for the treatment of a postmenopausal disorder, also described below.
[0081] In one embodiment, a compound of the present invention is used to treat local, advanced or metastatic breast cancer that is positive for expression of estrogen receptors, progesterone receptors or both (receptor positive advanced breast cancer). In an alternative embodiment, the compound is used to treat estrogen or progesterone receptor negative breast cancer. The compound can be used as the initial treatment of advanced breast cancer in patients who have never received previous hormonal therapy for advanced breast cancer, either by itself or in combination with one or more other anti-cancer agents described below or otherwise known to those skilled in the art. They are also useful for second line therapy for treatment after a previous hormonal therapy has failed, either by itself or in combination with another anticancer agent, for example, a targeted therapy such as an mTOR inhibitor such as everolimus or a CDK 4/6 inhibitor such as palbociclib (PD-0332991).
[0082] The compounds of the invention are also useful as adjunctive therapy after or instead of chemotherapy, radiation or surgery. Such adjuvant use is often used for several years, perhaps 5 years, after chemotherapy or other therapies have been concluded, but may optimally be continued for additional years.
[0083] The compounds of the invention are also useful for the prevention of breast cancer in women at high risk and can be taken for any desired time period, including indefinitely. For example, a patient, typically a woman, with a family history of breast cancer, or who has been determined to carry a mutation in the BRCAl or BRCA2 or other genes that predispose a patient to breast cancer may choose to use such preventative treatment instead of a mastectomy or other intervention. The compounds described herein are also useful as neoadjuvants to shrink large tumors prior to surgical removal, both to enable breast conservative surgery and to reduce the risk of recurrence. In addition to breast cancer these compounds also are useful in treating other cancers and other overgrowth diseases of the female reproductive tract including ovarian, endometrial, and vaginal cancer and endometriosis. Besides these reproductive tissues the compounds are useful in treating lung cancers that are positive for estrogen or progesterone receptors.
[0084] Selective estrogen receptor modulators (SERMs) are useful for hormonal therapy for postmenopausal women in particular to treat or prevent osteoporosis. In one embodiment, a compound of the present invention is used in combination with an estrogen, SERM or partial anti-estrogen whereby the anti-estrogen prevents adverse action of the total or partial estrogen on the uterus and other tissues.
[0085] The present compounds are used as therapeutic or prophylactic agents for the treatment of conditions in mammals, particularly humans whose conditions are modulated by estrogen receptors.
[0086] An oral anti-estrogen is useful for treating locally advanced or metastatic breast cancer, preventing recurrence or early breast cancer after surgery, and preventing breast cancer in women at high risk. It is useful for treating estrogen-dependent cancers of the reproductive tract including endometrial and ovarian cancers. It has potential uses in the treatment of lung and bronchial cancers that express estrogen receptors.
[0087] Selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, lasofoxifene, and bazedoxifene additionally have application as hormone replacement therapy to prevent osteoporosis and other disorders such as hot flashes, etc. in post-menopausal women, a use that depends on their partial estrogen like action, for example, on bone. The compounds described herein can be employed in combination with an estrogen or a selective estrogen receptor modulator to block the unwanted estrogenic activity of the therapy. The anti-estrogen is dosed in the amount to prevent the adverse action of the estrogen or estrogen receptor modulator on the uterus and mammary gland yet allowing the beneficial action of estrogen on bone and vasomotor symptoms.
[0088] The compounds of the present invention can be administered for the treatment of cancer, and in particular breast cancer in combination or association with Herceptin, Tykerb, CDK 4/6 inhibitor such as palbociclib (PD-0332991), mTOR inhibitor such as Novartis' everolimus and other rapamycin analogs such rapamycin and temsirolimus, Millennium's MLN0128 TORCl/2 inhibitor, an EFGR-family inhibitor such as trastuzumab, pertuzumab, emtansine, erlotinib, gefitinib, neratinib and similar compounds, a PI3 Kinase Inhibitor such as perifosene, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145, a histone deacetylase inhibitor such as vorinostat, romidepsin, panobinostat, valproic acid, etinostat, and belinostat.
[0089] In another method of treatment aspect, provided herein is a method of treating a mammal susceptible to or afflicted with a condition related to estrogen receptor.
[0090] In another embodiment, the compounds of the present invention are provided for use in medical therapy, including for any of the conditions described herein. The use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases is also provided.
[0091] Injection dose levels range are provided in any desired dosage, for example, from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. In one embodiment, a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
[0092] For oral dosing, any dose is appropriate that achieved the desired goals. In one example, suitable daily dosages are between about 0.1-4000 mg, more typically between 5 mg and 1 gram, more typically between 10 mg and 500 mg, and administered orally once-daily, twice-daily or three times-daily, continuous (every day) or intermittently (e.g., 3-5 days a week). For example, when used to treat any disorder described herein, the dose of the compounds of this invention usually ranges between about 0.1 mg, more usually 10, 50, 100, 200.250, 1000 or up to about 2000 mg per day.
[0093] For the prevention and/or treatment of long-term conditions, the regimen for treatment usually stretches over many months or years. Oral dosing may be preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, nonlimiting dosages might range from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
[0094] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[0095] When used to prevent the onset of cancer, a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[0096] The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
GENERAL SYNTHETIC PROCEDURES
[0097] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., Synthetic Schemes below. It will be appreciated that where typical or preferred process conditions {i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0098] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
[0099] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column
chromatography or FIPLC. The following schemes are presented with details as to the preparation of representative substituted benzopyrans that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
[00100] The diastereomerically or enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate or mixture of diastereomers by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer or diastereomer. See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); E.L. Eliel Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and S.H. Wilen Tables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972, Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, NY).
[00101] In certain embodiments, a diastereomerically pure compound of formula (1) may be obtained by reaction of the racemate or mix of diastereomers with a suitable optically active acid or base. Suitable acids or bases include those described in Bighley et al.., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, the contents of which are hereby incorporated by reference in their entireties.
[00102] Enantiomerically or diastereomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer or diastereomer used. The identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art. The diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer or diastereomer regenerated by treatment with an appropriate base or acid. The other enantiomer or diasteromer may be obtained from the racemate or mix of diastereomers in a similar manner or worked up from the liquors of the first separation.
[00103] In certain embodiments, enantiomerically or diastereomerically pure compound can be separated from racemic compound or a mixture of diastereomers by chiral
chromatography. Various chiral columns and eluents for use in the separation of the enantiomers or diastereomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art. Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to
CHIRALPACK® IC, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
[00104] General processes for preparing compounds of the instant invention are provided as further embodiments of the invention and are illustrated in the following Schemes.
SYNTHESIS OF INTERMEDIATES
[00105] The various intermediates useful for preparation of the compounds of the invention can be prepared in accordance with methods described in the art and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art.
Scheme 1
Synthesis of 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (OP-1038; Reference Compound 1) and Separation and Purification of Stereoisomers (OP-1074 and OP-1075; Reference Compound 2 and
Reference Compound 3 respectively)
Figure imgf000029_0001
Step 1:
Reaction to produce l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone
[00106] Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4-
Hydroxyphenyl acetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 °C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 °C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 % aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0 %).
Step 2:
Reaction to produce l-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(4- ((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone
[00107] l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone (119.000 g, 487.2 mmol,
1.0 equiv.) and ethyl acetate (400 mL) was added to a 2 L 3 neck round bottomed flask equipped with a stir bar a thermometer, a condenser and a nitrogen inlet. The flask was flushed with nitrogen for 2 minutes and 3,4-dihydro-2H-pyran (222.252 ml, 2436.1 mmol, 5.0 equiv.) was added from a graduated cylinder. The suspension was flushed with nitrogen for 2 minutes and p- toluenesulfonic acid (0.378 g, 2.2 mmol, 0.0 equiv.) was added to the reaction. An exothermic reaction took place and the temperature rose from 20 to 33 °C over 5 minutes. The yellow suspension became a red solution within 1 minute of PTSA addition. The reaction was stirred for 66 h at room temperature. The reaction was monitored by HPLC at 4, 5 and 6 hours. The chromatograms indicated the reaction was 74 %, 90 % and 100 % complete at the time indicated respectively. TEA (5 mL) was added to the cream colored slurry to stop the reaction. The slurry was transferred to a round bottomed flask (2 L) and the three neck flask rinsed with ethyl acetate. The slurry was concentrated on a rotovap to give a cream colored powdery solid. The solid was transferred to a 2 L Erlenmeyer flask. Isopropyl alcohol (IPA) was used to rinse the flask. The solid was recrystallized from IPA (1.4 L). The suspension was cooled in an ice bath for 30 minutes and the solid collected by vacuum filtration. The solid was rinsed with ice cold IPA until the filtrate was colorless and dried in a vacuum oven to give a white powder (162.24 g). The mother liquor and washes were combined and concentrated to an orange oil (38.09 g).
Step 3:
Reaction to produce 2-(4-iodophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro-
2H-pyran-2-yl)oxy)phenyl)chroman-4-one
[00108] l-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(4-((tetrahydro-2H- pyran-2-yl)oxy)phenyl)ethanone (16.228 g, 39.34 mmol) was added to a 3 neck 1 L RB flask. 2- Butanol (380 mL, 0.197 M) and 4-iodobenzaldehyde (51.700 g, 222.8 mmol, 1.0 equiv.) was added to the flask to give a suspension. Piperidine (7.300 ml, 73.9 mmol, 0.3 equiv.) and 1,8- Diazabicyclo[5.4.0]undec-7-ene (11.300 ml, 75.6 mmol, 0.3 equiv.) was added to the suspension. The flask was fitted with a Dean-Stark apparatus and condenser, a thermometer, a stirrer shaft and heated in an oil bath at 130 °C to give an orange solution (became a solution when the internal temperature was 80 °C). Half the solvent (190 mL) was collected over 1.5 hours. The Dean-Stark trap was removed and the condenser was placed on the flask the reaction heated for a further 1 hour. The solution gradually darkens to an orange color. The oil bath was cooled to 90 °C and 380 mL of isopropyl alcohol was added in one portion. The reaction mixture became a cloudy white suspension and redissolved to give a solution in less than a minute at 90 °C. The heating to the bath was set to 50 °C and the flask was allowed to gradually cool to 50 °C. A precipitate started to form at 60 °C and gave a suspension at 50 °C. A thick oily mass falls out of solution ~ 55-53 °C. Vigorous agitation with overhead stirrer (300 rpm) was required to prevent the oily mass from solidifying into one solid as seen with small scale reactions equipped with stir bar. The reaction was left to stir until the mixture cooled to room temperature. The oily mass solidified into a cake even with vigorous agitation. The mother liquor was decanted and fresh isopropanol (100 mL) was added to the flask to rinse the solid. The liquid was decanted and combined with the mother liquor. The mother liquor was concentrated to a dark red oil (27.13 g) and DCM (150 mL) was added to the flask to give a red solution. Silica gel (55 g) was added to solution and concentrated to dryness. The silica gel mixture was poured into a 600 mL sintered glass funnel filled with silica gel (50 g). The solids were washed with ethyl acetate (1.2 L) and the filtrate concentrated to an orange oil (137.61 g crude). The oil was dissolved into boiling 80 % IP A/water (1.2 L) and the solution allowed to cool to room temperature and stand overnight to give a cake. The cake was filtered and washed with cold IPA (100 mL). The mother liquor was partially concentrated on a rotovap to give a tan powder. This process was repeated until an oil could not be washed away from the powder. The product was pooled and dried in a vacuum oven to give an impure tan powder (118.25 g, 85.6 %).
Step 4a:
Reaction to produce 2-(4-iodophenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4- ((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-ol
[00109] To a solution of 90.0% 2-(4-iodophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-
((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one (104.891 g, 150.7 mmol, 1.0 equiv.) in THF (1.2 L) at 5°C, was added Methylmagnesium chloride 3.0 M solution in THF (160.000 ml, 480.0 mmol, 3.2 equiv.) by addition funnel over 30 minutes. The temperature did not rise about 8 °C during the addition. The reaction was removed from the ice bath and stirred at room temperature and stirred for another hour. TLC (20% ethyl acetate in hexanes) showed the reaction had no starting material. The solution was cooled in an ice bath, and carefully quenched with saturated ammonium chloride (35 mL). Ethyl acetate (1.2 L) and water (1.2 L) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EA (1 L). The combined organic layer was washed with brine (1 L), dried over anhydrous Na2S04, filtered and concentrated in vacuo to yield a pale yellow foam (111.26 g crude). This material was used without further purification.
Step 4b:
Reaction to produce 3-(4-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-7-ol
[00110] 2-(4-iodophenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-((tetrahydro- 2H-pyran-2-yl)oxy)phenyl)chroman-4-ol (96.820 g, 150.7 mmol, 1.0 equiv.) and 80% acetic acid in H20 (686 mL) was added to a 2 L RB flask. The suspension was degassed, flushed with nitrogen and heated at 90 °C for 1.5 hours. TLC analysis (1 :2 EA/Hex) of the reaction showed no starting material was present. The solvent was removed to give a red oil. The red oil was dissolved into ethyl acetate (500 mL) and washed with saturated sodium bicarbonate solution (3 x 1 L). The organic layers was washed with brine (1 L), filtered and concentrated to give a red oil (109.32 g, crude). The oil was loaded onto 100 g of silica gel and chromatographed in 40 g portions on silica gel (100 g cartridge, 5-30 % EA/Hex). Fractions containing spots with Rf 0.55 (33 % EA/Hex) were pooled and concentrated to a light red glass (53.37 g). The glass was mixed with DCM (200 mL) and sonicated to give a pink suspension. The solid was filtered through a sintered glass funnel washed with a 20 % DCM in Hexanes solution (250 mL) and dried in a vacuum oven overnight (32.41 g). The mother liquor was concentrated to a glass and the process repeated a second time to give a pink solid (4.2784 g). The impure mixed fractions were pooled and concentrated to a glass (16.71 g). The glass was dissolved into DCM (75 mL) and pink crystals formed on standing (7.0862 g). This process was repeated to give a second crop of pink crystals (2.3643). The mother liquors from both the pure and impure fractions were combined and chromatographed with the same method (2 x 100 g cartridges). The fractions with Rf 0.55 were pooled and concentrated to give a red oil (17.388 g) which did not solidify. The oil was not combined with previous batches but reprotected in a separate reaction.
[00111] Gradient method: (5-30 % EA/Hex) 5 % EA hold for 2 minutes, gradient to 15 % over 3 minutes and hold at 15 % EA/ Hex for 7 minutes, gradient to 30 % over 7 minutes and hold at 30 % EA/ Hex for 17 minutes. Fractions with Rf 0.55 (33 % EA/Hex) were pooled and concentrated to a light pink oil which was triturated with DCM.
Step 5:
Reaction to produce 2-(4-iodophenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4- ((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene
[00112] To a solution of 3-(4-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-7- ol (41.860 g, 91.7 mmol, 1.0 equiv.) and pyridinium para-toluene sulfonate (4.822 g, 19.3 mmol, 0.2 equiv.) in DCM (200 mL) was added 3,4-dihydro-2H-pyran (49.226 ml, 539.6 mmol, 5.9 equiv.). The reaction was stirred at room temperature overnight (17 h). TLC showed major desired product. The reaction was diluted with DCM (200 mL), washed with saturated NaHC03 (200 mL), water (200 mL), brine (200 mL), dried over Na2S04, filtered and concentrated to give a red viscous residue. The residue adsorbed onto silica gel (75 g) was purified on a silica gel column (4 x 100 g, 0 - 20 % EA/Hex) to give a white solid which was triturated with methanol and dried in a vacuum oven at 40° C for 16 h to afford the titled compound as a white powder (51.67 g 90.2 %).
[00113] 1H MR (300 MHz, CDC13 ): δ 7.53 (d, J = 5.4 Hz, 2H)), 7.18 (d, J = 8.7 Hz,
1H), 7.06 (parent t, J = 7.8 Hz, 4H), 6.71 (s, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 5.15 (s, 2H), 4.59 (s, 2H), 4.63 (d, J = 5.7 Hz, 2H), 3.98 (s, 3H), 3.84 (s, 3H). Step 6:
Reaction to produce -(3R)-3-methyl-l-(2-(4-(4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-
(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidine
[00114] A mixture of 2-(4-iodophenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-
((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene (16.800 g, 26.9 mmol, 1.0 equiv.), (R)~2- (3-methylpyrrolidin-l-yl)ethanol (10.416 g, 80.6 mmol, 3.0 equiv.), 1,10-Phenanthroline (0.970 g, 5.4 mmol, 0.2 equiv.), and Cesium carbonate (17.530 g, 53.8 mmol, 2.0 equiv.) in butyronitrile (84 mL) was charged into a 250 mL round bottom flask which was evacuated and backfilled with argon (3 x), Copper(I) iodide (5.123 g, 26.9 mmol, 1.0 equiv.) was added to the suspension and evacuated and backfilled with argon (3 x). The reaction mixture was heated in an oil bath at 120 °C. After 91 h of heating the reaction was cooled to room temperature and the mixture filtered through a pad of Celite (3 cm) which was successively washed with DCM (200 mL), EA (200 mL) and MeOH (200 mL). The filtrate was collected and concentrated. The residue was adsorbed onto silica gel (25 g) purified with silica gel (100 g cartridge, 0 - 30% MeOH/DCM) [TLC: 5 % MeOH/DCM, 4 major spots, Rf (SM:0.95), 0.9, 0.83, (prod. 0.43)]. The fractions containing product were pooled and concentrated to give a brown foam (13.64 g, 81.0 %).
[00115] Gradient method 0 % MeOH 4 minutes, gradient to 1 % MeOH/DCM over 3 minutes, hold at 1 % MeOH/DCM for 10 minutes, gradient to 5 % MeOH/DCM over 3 minutes, hold at 5 % MeOH/DCM for 12 minutes, gradient to 25 % MeOH/DCM over zero minutes, hold at 25 % MeOH/DCM for 15 minutes. Many fractions contained a mixture of the starting material and product all fractions were pooled, concentrated, and rechromatographed on silica gel (loaded onto 15 g and 100 g cartridge) and gradient eluted with this gradient method (0 % MeOH 4 minutes, gradient to 1 % MeOH/DCM over 3 minutes, hold at 1 % MeOH/DCM for 20 minutes, gradient to 5 % MeOH/DCM over 5 minutes, hold at 5 % MeOH/DCM for 20 minutes).
Fractions 74 to 126 were pooled and concentrated to a brown oil which solidified to foam (13.64 g, 81 %) (Late eluting fractions from the first column contained a spot which corresponded to the amino alcohol. These fractions were pooled and concentrated to give a red black liquid (6.38 g).
Step 7:
Reaction to produce 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (OP-1038; Reference Compound 1)
[00116] (3R)-3 -methyl- l-(2-(4-(4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3 -(4-
((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidine (15.130 g, 24.2 mmol, 1.0 equiv.) was dissolved into 80% acetic acid/water (150 mL). The solution was heated in an oil bath at 90 °C for 1 hour. HPLC analysis of the reaction mixture indicated the reaction was complete. The dark red solution was concentrated to a dark red oil. The oil was suspended into ethyl acetate (600 mL) and washed with saturated NaHC03 (3 x 300 mL). The combined aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (2 x 200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give a red oil (14.03 g, crude). The oil was adsorbed onto silica gel (30 g) and chromatographed on silica gel (2 x 100 g cartridge) with 0-10 % MeOH in DCM. Fractions containing the product were pooled and concentrated to give a red colored foam (6.68 g). Impure fractions were concentrated and repurified with the same conditions to give an additional 0.9496 g of red foam which was combined with the previous foam. Total yield 7.6296 g, 69.0 %.
[00117] Gradient method 0 % MeOH/DCM for 5 minutes, gradient to 10 % MeOH/DCM over 20 minutes, hold at 10 % MeOH/DCM for 10 minutes. TLC conditions (UV and 12): 10 % MeOH/DCM 5 spots 0.64, 0.48, (product) 0.31, 0.21, 0.07. HPLC: 100 % purity (0 - 90% acetonitrile/water). LC_MS: [M+l]+ = 458.3.
Step 8:
[00118] OP-1038 was separated into its diastereomers (2S)-3-(4-hydroxyphenyl)-4- methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H-chromen-7-ol (OP-1074; Reference Compound 2) and (2R)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3- methylpyrrolidin-l-yl]ethoxy}phenyl)-2H-chromen-7-ol (OP-1075; Reference Compound 3) using a Diacel, Chiralpak IC column at room temperature in isocratic mode with 80 % hexanes, 20 % 2-propanol with 0.1 % dimethylethylamine or 0.1% diethyl amine as a modifier. This method was used at analytical and preparative scale.
Step 9:
Reaction to produce (R)-2-(benzyloxy)-l-(3-methylpyrrolidin-l-yl)ethanone
[00119] (R)-3-methylpyrrolidine hydrochloride (20.000 g, 164.5 mmol, 1.0 equiv.) was added to a round bottom flask and dissolved into anhydrous DCM (45 mL). Freshly distilled Diisopropylethylamine (60.157 ml, 345.4 mmol, 2.1 equiv.) and freshly activated 4 A molecular sieves (- 21 g) was added to the solution and stirred for 10 minutes. 2-(Benzyloxy)acetyl chloride (31.881 g, 172.7 mmol, 1.1 equiv.) dissolved into DCM (50 mL) was added to the reaction at room temperature dropwise via syringe over 20 minutes with a room temperature water bath for cooling. After complete addition the reaction was stirred for 17 hours. TLC analysis (1 : 1, EA/Hex, Rf: 0.83, 0.33, 0.05) showed no presence of acid chloride. The reaction poured into a separatory funnel and the organic layer washed successively with 1 M HCl (2 x 200 mL), saturated sodium bicarbonate (200 mL) and brine (200 mL). The organic layer was dried over anhydrous MgS04, filtered and concentrated to an orange oil (42.40 g). The oil was loaded onto silica gel (30 g) and the mixture split into -18 g portions and chromatographed on silica gel (4 x 100 g cartridges) with a gradient method 10-80 % EA/Hex. Fraction with Rf 0.33 spot were pooled and concentrated to give a yellow oil (34.02 g, 88.7 %).
[00120] Gradient method: 10 % EA/Hex hold 5 minutes, gradient to 80 % EA/Hex over 15 minutes, hold at 80 % EA/Hex for 10 minutes. Fractions with Rf 0.33 were pooled and concentrated.
Step 10:
Reaction to produce (R)-l-(2-(benzyloxy)ethyl)-3-methylpyrrolidine
[00121] Aluminum trichloride (54.513 g, 408.8 mmol, 3.0 equiv.) was dissolved into anhydrous THF (750 mL) and cooled in an ice bath. Lithium aluminum hydride (35.688 g, 940.3 mmol, 6.9 equiv.) was added in small portions via a powder addition funnel to the above suspension over 35 minutes and stirred for an additional 10 minutes. The suspension was cooled to -78 °C for 15 minutes and a solution of (R)-2-(Benzyloxy)-l-(3-methylpyrrolidin-l- yl)ethanone (33.980 g, 136.3 mmol, 1.0 equiv.) in anhydrous THF (150 mL) was added drop wise to the cold suspension via a pressure equalizing addition funnel over 20 minutes. The reaction was kept at -78 °C for 1 hour and stirred at room temperature for 1 hours. The reaction was carefully quenched with 6 N HCl solution (100 mL) and stirred for 17 h to give grey suspension. A solution 6 N NaOH (216 mL) was added to the mixture to give a white suspension after stirring for 30 minutes. The mixture was filtered through a pad of Celite (4 cm). The solids were washed with DCM (5 x 500 mL). The filtrate was poured into a separatory funnel and the layers separated (-200 mL aqueous layer recovered). The aqueous layer was extracted with DCM (3 x 100 mL). The organic layers were combined and washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a yellow liquid (33.43 g). This liquid was loaded onto silica gel (25 g) and chromatographed through silica gel (2 x 100 g cartridge) with 50-100 % ethyl acetate in hexanes followed by 10-40 % methanol in dichloromethane to give a yellow oil (29.17 g, quant). [00122] Gradient method: 50 % EA/Hex 4 minutes, gradient to 100 % EA over 6 minutes, hold at 100 % EA for 5 minutes, Solvent change to 10 % MeOH in DCM hold for 0 minutes, gradient to 40 % MeOH in DCM over 1 minute, hold at 40 % MeOH in DCM for 8 minutes. The fractions were pooled and concentrated to a yellow oil (29.17 g, quant).
Step 11:
[00123] (R)-l-(2-(benzyloxy)ethyl)-3-methylpyrrolidine (10.000 g, 45.6 mmol, 1.0 equiv.)
(0.4822 g; 0.7137 g) was added to a 400 mL Parr flask, methanol (60 mL) was added and the solution cooled in an ice bath for 10 minutes. 20% Pd(OH)2 on Carbon, 50 % H20 (6.403 g, 45.6 mmol, 1.0 equiv.) was added to the cooled solution and flushed with nitrogen. Hydrochloric acid (6 M, 7.6 mL) was added to mixture. The flask was pressurized with hydrogen to 30 psi shaken for 1 minute and the hydrogen released. This was repeated twice more and pressurized to 100 psi with hydrogen. This suspension was shaken for 16 hours. A sample was taken and the TLC (10 % MeOH in DCM) indicated the reaction was incomplete and additional catalyst (2.0 g) was added to the mixture. The reaction was treated in a similar manner described above and shaken on the hydrogenator for an additional 30 hours. Celite (5 g) was added to the Parr flask and the mixture filtered through a pad of Celite (2 cm). The solid was washed with methanol (2 x 250 mL). The filtrate was concentrated on a rotovap to dryness to give a red oil (7.81 g). The oil was taken up in methanol (50 mL) and 25 % sodium methoxide in methanol (9.9 mL, 45.5 mmol, 1 equiv) was added to the methanolic solution to give a white suspension. The mixture was concentrated to dryness and taken up into anhydrous DCM (35 mL). The suspension was centrifuged at 3K rpm for 5 minutes. The clear solution was collected and the solid resuspended into DCM (35 mL). This process was repeated a total of 4 times. The combined solution was concentrated to a yellow liquid (5.6341 g, 95.6 %).
Synthesis of HC1 Salts of OP-1038 and OP-1074
[00124] 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (OP-1038; 0.020 g, 0.0 mmol, 1.0 equiv.) or (2S)-3-(4- hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy}phenyl)-2H-chromen- 7-ol (OP-1074; 0.020 g, 0.0 mmol, 1.0 equiv.) was placed into a 1 dram vial and dissolved into methanol (0.2 mL). 4 M HC1 in methanol (200 μΕ) was added to the solution and stirred for 15 minutes. The yellow solution was concentrated a yellow orange solid (0.022 g and 0.0206 respectively). Synthesis of of 2-(4-{2-[(3R,4R)-3,4-dimethylpyrrolidin-l-yl]ethoxy}ph hydroxyphenyl)-4-methyl-2H-chromen-7-ol (Formula I)
Figure imgf000038_0001
Reaction to produce (3R,4R)-3,4-dimethyl-l-(2-(4-(4-methyl-7-((tetrahydro-2H-pyran-2- yl)oxy)-3-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2- yl)phenoxy)ethyl)pyrrolidine
[00125] A mixture of 2-(4-iodophenyl)-4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-
((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene (0.216 g, 0.3 mmol, 1.0 equiv.), -2- ((3R,4R)-3,4-dimethylpyrrolidin-l-yl)ethanol (0.149 g, 1.0 mmol, 3.0 equiv.), 1,10- Phenanthroline (0.012 g, 0.1 mmol, 0.2 equiv.), and Cesium carbonate (0.225 g, 0.7 mmol, 2.0 equiv.) in butyronitrile (0.84 mL) was charged into a 10 mL microwave tube which was evacuated and backfilled with argon (3 x), Copper(I) iodide (0.066 g, 0.3 mmol, 1.0 equiv.) was added to the suspension and evacuated and backfilled with argon (3 x). The reaction mixture was heated in an oil bath at 120 °C. After 78 h of heating the reaction was cooled to room temperature and the mixture filtered through a pad of Celite (2 cm) which was successively washed with DCM (20 mL), EA (20 mL) and MeOH (20 mL). The filtrate was collected and concentrated. The residue was adsorbed onto silica gel (3 g) purified with silica gel (12 g cartridge, 0 - 30% MeOH/DCM) [TLC: 5 % MeOH/DCM, 4 major spots, Rf (SM:0.95), 0.9, 0.83, (prod.
0.43)]. The fractions containing product were pooled and concentrated to give a reddish-brown glass (0.150 g, 67.8 %, S0755). HPLC analysis showed the solid to be 97.5 % pure, MR showed an impurity in the product similar to the amino alcohol starting material. Product was used in next reaction without further purification. [00126] Gradient method 0 % MeOH 3 minutes, gradient to 1 % MeOH/DCM over 3 minutes, hold at 1 % MeOH/DCM for 8 minutes, gradient to 5 % MeOH/DCM over 3 minutes, hold at 5 % MeOH/DCM for 12 minutes. Fractions 16- 19 were pooled and concentrated to a reddish brown glass (0.1500 g, 67.8 %).
Reaction to produce 2-(4-(2-((3R,4R)-3,4-dimethylpyrrolidin-l-yl)ethoxy)phenyl)-3-(4- hydroxyphenyl)-4-methyl-2H-chromen-7-ol (Formula I)
[00127] (3R,4R)-3,4-dimethyl-l-(2-(4-(4-methyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4- ((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidine (0.150 g, 0.2 mmol, 1.0 equiv.) was dissolved into 80% acetic acid/water (2 mL). The solution was heated in a heat block at 90° C for 2 hour. LC/MS analysis of the reaction mixture indicated the reaction was complete. The dark red solution was concentrated to a dark red oil. The oil was suspended into ethyl acetate (100 mL) and washed with saturated NaHC03 (2 x 50 mL). The combined aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a red glass (0.12 g, crude). The compound was dissolved into methanol and loaded onto silica gel (2 g) and concentrated to dryness. The silica gel containing the compound was purified on silica (4 g cartridge) with 0- 10 % MeOH in DCM. The fractions containing the product were pooled and concentrated to give a dark pink solid which contained an impurity (232-84-1 HPLC 74 % pure, 0.020 g). Impure fractions were repurified and F25 to 29 were pooled (232-84B F25- 29, HPLC: 95.5 % pure, 0.031 g ) and F30-40 were pooled (232-84B F30-40, HPLC: 74 % pure, 0.028 g). Overall yield including impure portions (0.020+0.031+0.028) 71 %.
[00128] Gradient method 0 % MeOH/DCM for 5 minutes, gradient to 10 % MeOH/DCM over 20 minutes, hold at 10 % MeOH/DCM for 10 minutes. TLC conditions (UV and I2): 10 % MeOH/DCM 5 spots 0.64, 0.48, (product) 0.31, 0.21, 0.07.
Separation of the Diastereomers of Formula I
[00129] Separation of the diastereomers of Formula I, (2S)-2-(4-{2-[(3R,4R)-3,4- dimethylpyrrolidin-l-yl]ethoxy}phenyl)-3-(4-hydroxyphenyl)-4-m ethyl -2H-chromen-7-ol and (2R)-2-(4-{2-[(3R,4R)-3,4-dimethylpyrrolidin-l-yl]ethoxy}phenyl)-3-(4-hydroxyphenyl)-4- methyl-2H-chromen-7-ol, is achieved according to step 8 above. Alternative Synthesis of 3-(4-hydroxyphenyl)-4-methyl-2-(4-{3-[(3R)-3-methylpyrrolidin-l- -2H-chromen-7-ol (Formula VIII)
Figure imgf000040_0001
Figure imgf000040_0002
[00131] 3-methyl pyrrolidine (1 equiv) is dissolved in dichloromethane (0.1-3.0 M). To this solution is added triethyl amine (1.2 equiv). The solution is cooled in an ice bath. To the cooled solution is added acetyl chloride (1.05 equiv) or acetic anhydride (1.05 equiv). The solution is allowed to warm to room temperature and stirred for up to 3 h. The reaction is quenched by addition of sodium bicarbonate solution (0.1 M- saturated). Some gas may be seen to evolve. After stirring for up to 1 h, the phases are separated and the upper phase is washed with dichloromethane. The combined dichloromethane phases are dried over anhydrous sodium sulfate or similar drying agent, filtered, concentrated in vacuo and carried on in the following procedure.
[00132] The product of the preceding operation is dissolved in THF and cooled to -78°C. To the solution is added slowly a solution of LDA (1.1 equiv) in THF. After stirring the chilled solution for lh, a solution of 4-bromomethyl benzaldehyde dimethyl acetal (1.05 equiv) in THF is slowly added. Upon completion of the addition, the dry ice bath is removed and the solution allowed to warm to room temperature over several hours. Sodium bicarbonate solution (0.1 M- saturated)is the added. After stirring for up to 1 h, diethyl ether is added with stirring and the phases are separated. The organic phase is washed with brine. The aqueous phase is washed with diethyl ether. The combined organic phases are dried over anhydrous sodium sulfate or similar drying agent, filtered, concentrated in vacuo and carried on in the following procedure. Optionally, the products are purified via silica gel chromatography. Reduction of the amide is achieved with borane DMS complex in THF under standard conditions.
[00133] The product of the preceding operation is carried forward into a sequence similar to steps 3, 4, 7, and 8 above to afford the desired product Formula VIII.
Separation of the Diastereomers of Formula VIII
[00134] Separation of the diastereomers of Formula VIII, (2S)-3-(4-hydroxyphenyl)-4- methyl-2-(4-{3-[(3R)-3-methylpyrrolidin-l-yl]propyl}phenyl)-2H-chromen-7-ol and (2R)-3-(4- hydroxyphenyl)-4-methyl-2-(4-{3-[(3R)-3-methylpyrrolidin-l-yl]propyl}phenyl)-2H-chromen-7- ol, is achieved according to step 8 above.
Synthesis of 4-[4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H- chromen-3-yl]phenol (Formula II)
[00135] The synthesis of Formula II and its diastereomers 4-[(2S)-4-methyl-2-(4-{2-[(3R)-
3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H-chromen-3-yl]phenol and 4-[(2R)-4-methyl-2-(4-{2- [(3R)-3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H-chromen-3-yl]phenol is carried out in a way substantially similar to the method used for the synthesis of OP-1038, OP-1074, and OP-1075 (Scheme 1) wherein phenol is used in place of resorcinol.
Synthesis of 6-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (Formula III)
[00136] The synthesis of Formula III and its diastereomers (2S)-6-fluoro-3-(4- hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy}phenyl)-2H-chromen- 7-ol and (2R)-6-fluoro-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol is carried out in a way substantially similar to the method used for the synthesis of OP-1038, OP-1074, and OP-1075 (Scheme 1) wherein 4- fluororesourcinol is used in place of resorcinol.
[00137] Alternatively, the key intermediate ketone for the synthesis of Formula III can be prepared as described below.
Figure imgf000042_0001
Figure imgf000042_0002
[00138] Treatment of 2,4-dimethoxybenzoicacid is dissolved in acetonitrile. The solution is treated with an electrophilic fluorinating reagent (1.05 equiv). After aqueous workup, this affords 2,4-dimethoxy-5-fluorobenzoic acid. This material is carried on in the subsequent reaction but may be purified by several methods including silica gel chromatography.
[00139] A solution of 2,4-dimethoxy-5-fluorobenzoic acid and triethyl amine (excess) in dicloromethane is cooled in an ice bath. To this solution is added drop wise a solution of oxalyl chloride in dichloromethane. The solution is stirred for 1-4 h at bath temperature. To this solution is then added N-methoxymethyl amine HC1. The desired amide is then isolated by aqueous workup. This material is carried on in the subsequent reaction but may be purified by several methods including silica gel chromatography.
[00140] The amide from the previous step is dissolved in THF and cooled in a dry ice acetone bath. To this solution is added 4-methoxybenzylmagnesium chloride (1-1.5 equiv) in THF (0.25 M). The reaction is stirred at bath temperature for 1-8 h. The reaction is quenched with methanol followed by an aqueous work up. To afford the desired ketone. This material is carried on in the subsequent reaction but may be purified by several methods including silica gel chromatography.
[00141] Global demethylation is achieved with borotribromide in dichloromethane at 0 degrees C. After aqueous work up, this material is carried on in the subsequent reaction but may be purified by several methods including silica gel chromatography.
[00142] Treatment of this material with DFIP under catalysis with PPTS affords the desired ketone. This material is carried on in the subsequent reaction but may be purified by several methods including silica gel chromatography. This material is used in according to step 3 through 8 (Scheme 1) above.
Synthesis of 3-(3-fluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (Formula IV)
[00143] The synthesis of Formula IV and its diastereomers (2S)-3-(3-fluoro-4- hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy}phenyl)-2H-chromen- 7-ol and (2R)-3-(3-fluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol is carried out in a way substantially similar to the method used for the synthesis of OP-1038 and its diastereomers OP-1074 and OP-1075 (Scheme 1) wherein 3-fluoro-4-hydroxyphenyl acetic acid is used in place of 4-hydroxyphenyl acetic acid.
Synthesis of 3-(2,3-difluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (Formula V)
[00144] The synthesis of Formula V and its diastereomers (2S)-3-(2,3-difluoro-4- hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy}phenyl)-2H-chromen- 7-ol and (2R)-3-(2,3-difluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol is carried out in a way substantially similar to the method used for the synthesis of OP-1038 and its diastereomers OP-1074 and OP-1075 (Scheme 1) wherein 2,3-difluoro-4-hydroxyphenyl acetic acid is used in place of 4-hydroxyphenyl acetic acid.
Synthesis of 3-(3,5-difluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (Formula VI)
[00145] The synthesis of Formula VI and its diastereomers (2S)-3-(3,5-difluoro-4- hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy}phenyl)-2H-chromen- 7-ol and (2R)-3-(3,5-difluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol is carried out in a way substantially similar to the method used for the synthesis of OP-1038 and its diastereomers OP-1074 and OP-1075 (Scheme 1) wherein 3,5-difluoro-4-hydroxyphenyl acetic acid is used in place of 4-hydroxyphenyl acetic acid.
[00146] The synthesis of 3,5-difluoro-4-hydroxyphenyl acetic acid is described below.
Figure imgf000044_0001
[00147] A solution of 4-hydroxyphenyl acetic acid is dissolved in acetonitrile. This solution is treated with N,N'-difluoro-2,2'-bipyridinium bistetrafluoroborate according to Adachi, et al. (J. Fluor. Chem., 120 (2003) 173-183).
Synthesis of 3-(2-fluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol (Formula VII)
[00148] The synthesis of Formula VII and its diastereomers (2S)-3-(2-fluoro-4- hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3 -methyl pyrrolidin-1 -yl]ethoxy}phenyl)-2H-chromen- 7-ol and (2R)-3-(2-fluoro-4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l- yl]ethoxy}phenyl)-2H-chromen-7-ol is carried out in a way substantially similar to the method used for the synthesis of OP-1038 and its diastereomers OP-1074 and OP-1075 (Scheme 1) wherein 2-fluoro-4-hydroxyphenyl acetic acid is used in place of 4-hydroxyphenyl acetic acid.
Synthesis of Formula IX
[00149] The synthesis of Formula IX and its diastereomers is carried out in a way substantially similar to the method used for the synthesis of OP-1038 and its diastereomers OP- 1074 and OP-1075 (Scheme 1) wherein 2,6-difluoro-4-hydroxyphenyl acetic acid is used in place of 4-hydroxyphenyl acetic acid.
ASSAYS
[00150] Compounds provided herein can be evaluated using various in vitro and in vivo assays; examples of which are described below.
[00151] The following biological examples are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting the scope thereof. Demonstration of the Activity of the Compounds of the Present Invention Using
Sensitive In vitro Estrogenicity Assays
[00152] Method for performing the alkaline phosphatase (AP) assay. ECC-1 cells
(American Type Culture Collection, Manassus, VA) are maintained in RPMI medium plus 10% fetal bovine serum at 37°C. At the beginning of the assay trypsinized cells are resuspended in RPMI medium plus 5% charcoal dextran stripped serum (CDSS, (Hyclone, Logan, UT)) and plated at a density of 25-50k cells per well into a 96-well plate for at least 6 hours. Compounds are diluted in serum-free medium and added 1 : 1 to plated cells in replicate wells (2.5% CDSS final). Plates are incubated for 3 days at 37°C and subsequently frozen at -80°C to lyse cells after removing the medium. Thawed plates are incubated with a chromogenic substrate of AP, p- nitrophenyl phosphate (Invitrogen, Grand Island, NY), for 40 minutes at 40°C. Absorbance is read at 405nm using a plate spectrophotometer. This assay is shown to correlate with the in vivo studies comparing uterine wet weight in ovariectomized rats following treatment with a number of anti-estrogens.
[00153] Compounds of invention are tested for their inhibitory activity of estrogen according to the assay methods described in Hodges-Gallagher, L., Valentine, C.V., El Bader, S. and Kushner, P.J. (2007) "Histone Deacetylase Inhibitors Enhance the Efficacy of Hormonal Therapy Agents on Breast Cancer Cells and Blocks Anti-estrogen-Driven Uterine Cell
Proliferation" Breast Cancer Res Treat, Nov; 105(3):297-309. Specifically, an estrogen- responsive reporter gene (ERE-tkl09-Luc) is transiently transfected into MCF-7 cells and treated with anti-estrogens in triplicate in the presence of 100 pM 17P-estradiol (E2) for 18-22 hours. Luciferase activity is normalized to activity of E2 alone and IC50's were calculated using the least squares fit method.
[00154] Proliferation in MCF-7 is measured using a fluorescent DNA binding dye 6-8 days after treatment in triplicate with anti-estrogens in the presence of 100 pM E2.
[00155] ERa expression is detected in MCF-7 cell lysates treated with 100 nM anti- estrogens in serum-free medium for 22-24 hours and immunoblotted with an antibody specific to ERa.
Mammary Tumor Xenograft Study
[00156] The purpose of a tumor xenograft study is to examine the ability of compounds of the present invention, to slow or shrink a tamoxifen resistant tumor (MCF-7 HER2/neu Clone 18) xenograft growing on ovariectomized athymic nude mice under stimulation from exogenous estrogen. Clone 18 cells grown in culture are implanted along with 0.18 mg estradiol/ 90 day release pellets (Innovative Research, Sarasota Florida) into mice to initiate the experiment. When the tumors have reached 250 cubic millimeters the mice are divided into groups of mice and dosing initiated. The groups are:
[00157] 1) No hormonal treatment- this group receives daily gavage with vehicle.
[00158] 2) Tamoxifen citrate lOOmg/kg daily by oral gavage in vehicle.
[00159] 3) A positive control such as fulvestrant lOOmg/kg delivered daily by
subcutaneous injection.
[00160] 4) Compounds of the present invention dosed at, for instance, lOOmg/kg twice daily by oral gavage in vehicle with the exception of two weekends in which dosing was once daily.
Single Dose Oral Pharmacokinetics Study in Female Rats
[00161] The oral bioavailabilty in rats of compounds of the present invention are determined in the following study. 3 rats (female Sprague Dawley, non-fasted) are dosed by oral gavage (5 mg/kg body weight) in 0.5% CMC in water with a comparison to intravenous dosing (3 mg/kg body weight). Plasma is collected at the following hourly time points from rats in both groups (0, 0.08, 1.0, 2.0, 4.0, 8.0, 16.0, 24.0, 48.0 and 96.0 hours post dosing). Plasma concentrations of compounds of the present invention are determined by HPLC.
DEFINITIONS
[00162] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 33 :2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Unless otherwise stated, the invention encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[00163] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example "Ci_6 alkyl" is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci-6, Ci_5, Ci_3, Ci_2, C2-6, C2-5, C2-4, C2-3, C3_6, C3_5, C3_4, C4_6, C4_5, and Cs_6 alkyl.
[00164] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
[00165] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group which in one embodiment has from 1 to 20 carbon atoms ("Ci-20 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("Ci_i2 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("Ci_i0 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci-8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci_6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("Ci_5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("Ci_4 alkyl"). In some
embodiments, an alkyl group has 1 to 3 carbon atoms ("Ci_3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("Ci_2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2_6 alkyl"). Examples of Ci_6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6).
Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted Ci-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci_i0 alkyl.
[00166] "Alkylene" refers to a substituted or unsubstituted alkyl group, as defined above, wherein two hydrogens are removed to provide a divalent radical. Exemplary divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like. [00167] "Alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group which in one embodiment has from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-20 alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2_10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2_8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2_7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2_6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2_5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2_3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2_ alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2_10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl.
[00168] "Alkenylene" refers a substituted or unsubstituted alkenyl group, as defined above, wherein two hydrogens are removed to provide a divalent radical. Exemplary divalent alkenylene groups include, but are not limited to, ethenyl ene (-CH=CH-), propenylenes {e.g., - CH=CHCH2- and -C(CH3)=CH- and -CH=C(CH3)-) and the like.
[00169] "Alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group which in one embodiment has from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C2_2o alkynyl"). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2_i0 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2_9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2_8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2_7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2_5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2_3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1- butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2_4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like.
Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2_10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-io alkynyl.
[00170] "Alkynyl ene" refers a substituted or unsubstituted alkynyl group, as defined above, wherein two hydrogens are removed to provide a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, ethynylene, propynylene, and the like.
[00171] Naturally occurring or non-naturally occurring "amino acids" can be used in the preparation of compounds of the invention as described herein. For example, natural amino acids include valine, leucine, isoleucine, methionine, phenylalanine, asparagine, glutamic acid, glutamine, histidine, lysine, arginine, aspartic acid, glycine, alanine, serine, threonine, tyrosine, tryptophan, cysteine, proline, 4-hydroxyproline, g-carboxyglutamic acid, selenocysteine, desmosine, 6-N-methyllysine, e-N,N,N-trimethyllysine, 3-methylhistidine, O-phosphoserine, 5- hydroxylysine, e-N-acetyllysine, s-N-methylarginine, N-acetyl serine, g-aminobutyric acid, citrulline, ornithine, azaserine, homocysteine, b-cyanoalanine and S-adenosylmethionine. Non- limiting examples of non-naturally occurring amino acids include phenyl glycine, meta-tyrosine, para-amino phenylalanine, 3-(3-pyridyl)-L-alanine, 4-(trifluoromethyl)-D-phenylalanine, and the like. In one embodiment, an L-amino acid is used.
[00172] '"Aryl" refers to a radical of a monocyclic or polycyclic {e.g., bicyclic or tricyclic)
4n+2 aromatic ring system {e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6_i4 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C14 aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-i4 aryl. In certain embodiments, the aryl group is substituted C6-i4 aryl.
[00173] In certain embodiments, an aryl group substituted with one or more of groups selected from halo, Ci-C8 alkyl, Ci-C8 haloalkyl, cyano, hydroxy, Ci-C8 alkoxy, and amino.
[00174] Exam les of representative substituted aryls include the following:
Figure imgf000050_0001
In these Formula one of R and R may be hydrogen and at least one of R and R is each independently selected from Ci-C8 alkyl, Ci-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, R58COR59, R58SOR59 R58S02R59, COOalkyl, COOaryl, CO R58R59, CO R58OR59, R58R59,
S02 R58R59, S-alkyl, SOalkyl, S02alkyl, Saryl, SOaryl, S02aryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60 and R61 are independently hydrogen, Ci-C8 alkyl, C1-C4 haloalkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocyclyl, C6-Ci0 aryl, substituted C6-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
[00175] "Fused aryl" refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
[00176] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. [00177] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
[00178] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
[00179] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrol yl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, tnazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl,
benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[00180] Exam les of representative heteroaryls include the following:
Figure imgf000052_0001
wherein each Y is selected from carbonyl, N, R , O, and S; and R is independently hydrogen, Ci-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, and 5-10 membered heteroaryl. [00181] Examples of representative aryl having hetero atoms containing substitution include the followin :
Figure imgf000053_0001
wherein each W is selected from C(R )2, R , O, and S; and each Y is selected from carbonyl, NR66, O and S; and R66 is independently hydrogen, Ci-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, and 5-10 membered heteroaryl.
[00182] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
[00183] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C3_10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3_8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5_i0 carbocyclyl"). Exemplary C3_6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3_8 carbocyclyl groups include, without limitation, the aforementioned C3_6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3_i0 carbocyclyl groups include, without limitation, the aforementioned C3_8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3_i0 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3_i0 carbocyclyl.
[00184] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3_10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3_8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5_i0 cycloalkyl"). Examples of C5_6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3_6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3_8 cycloalkyl groups include the aforementioned C3_6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3_10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3_i0 cycloalkyl.
[00185] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
[00186] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
[00187] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thioranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[00188] Particular examples of heterocyclyl groups are shown in the following illustrative examples:
Figure imgf000056_0001
wherein each W is selected from CR , C(R )2, NR , O, and S; and each Y is selected from R67, O, and S; and R67 is independently hydrogen, Ci-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, 5-10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more substituents selected from the group consisting of the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(0)-alkyl ,-S(0)-aryl, -S(0)2-alkyl, and -S(0)2- aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
[00189] "Hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g, heteroaryl, cycloalkenyl, e.g,.cycloheteroalkenyl, and the like having from 1 to 5, and
particularly from 1 to 3 heteroatoms.
[00190] "Acyl" refers to a radical -C(0)R20, where R20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. "Alkanoyl" is an acyl group wherein R is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=0)CH3), cyclohexylcarbonyl,
cyclohexylmethylcarbonyl, benzoyl (-C(=0)Ph), benzylcarbonyl (-C(=0)CH2Ph),— C(0)-Ci-C8 alkyl, -C(O)-(CH2)t(C6-Ci0 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(0)-(CH2)t(C3- Cio cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21 is Ci-C8 alkyl, substituted with halo or hydroxy; or C3-Cio cycloalkyl, 4-10 membered heterocyclyl, C6-Ci0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroaryl alkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00191] "Acylamino" refers to a radical - R22C(0)R23, where each instance of R22 and R23 is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary "acylamino" groups are - R24C(0)-Ci-C8 alkyl, - R24C(O)-(CH2)t(C6-Ci0 aryl), - R24C(O)-(CH2)t(5-10 membered heteroaryl), - R24C(O)-(CH2)t(C3-Ci0 cycloalkyl), and - R24C(O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R24 independently represents H or Ci-C8 alkyl. In certain embodiments,
R25 is H, Ci-C8 alkyl, substituted with halo or hydroxy;
C3-Cio cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and
R26 is H, Ci-C8 alkyl, substituted with halo or hydroxy;
C3-Cio cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided at least one of R25 and R26 is other than H.
[00192] "Acyloxy" refers to a radical -OC(0)R27, where R27 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl,
cyclohexylmethylcarbonyl, benzoyl and benzyl carbonyl. In certain embodiments,
R28 is Ci-C8 alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted Ci- C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00193] "Alkoxy" refers to the group -OR29 where R29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[00194] In certain embodiments, R29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-Cio aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0)2- and aryl- S(0)2-. Exemplary 'substituted alkoxy' groups include, but are not limited to, -0-(CH2)t(C6-Cio aryl), -O-(CH2)t(5-10 membered heteroaryl), -O-(CH2)t(C3-Ci0 cycloalkyl), and -O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2 Me2.
[00195] "Amino" refers to the radical - H2.
[00196] "Substituted amino" refers to an amino group of the formula -N(R38)2 wherein R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38 is not a hydrogen. In certain embodiments, each R is independently selected from: hydrogen, Ci-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-Cio aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-Ci0 cycloalkyl; or Ci-C8 alkyl, substituted with halo or hydroxy; C3-C8 alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-Cio aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-Ci0 cycloalkyl), or -(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R38 groups are joined to form an alkylene group.
[00197] Exemplary ' substituted amino' groups are - R39-Ci-C8 alkyl, - R39-(CH2)t(C6-
C10 aryl), - R39-(CH2)t(5-10 membered heteroaryl), - R39-(CH2)t(C3-Ci0 cycloalkyl), and - R39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39 independently represents H or Ci-C8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term 'substituted amino' includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.
[00198] "Azido" refers to the radical -N3.
[00199] "Carbamoyl" or "amido" refers to the radical -C(0) H2.
[00200] "Substituted carbamoyl" or "substituted amido" refers to the radical -C(0)N(R62)2 wherein each R62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R62 is not a hydrogen. In certain embodiments, R62 is selected from H, Ci-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocyclyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or Ci-C8 alkyl substituted with halo or hydroxy; or C3-Cio cycloalkyl, 4-10 membered heterocyclyl, C6-Cio aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H.
[00201] Exemplary 'substituted carbamoyl' groups include, but are not limited to, -C(O) R64-Ci-C8 alkyl, -C(O) R64-(CH2)t(C6-Ci0 aryl), -C(O)N64-(CH2)t(5-10 membered heteroaryl), -C(0) R64-(CH2)t(C3-Cio cycloalkyl), and -C(O) R64-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, each R64 independently represents H or Ci-C8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[00202] 'Carboxy' refers to the radical -C(0)OH.
[00203] "Cyano" refers to the radical -CN.
[00204] "Halo" or "halogen" refers to fluoro (F), chloro (CI), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. In further embodiments, the halo group is iodo.
[00205] "Hydroxy" refers to the radical -OH.
[00206] "Nitro" refers to the radical -N02.
[00207] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropyl ethyl, cyclobutyl ethyl, cyclopentylethyl, cyclohexyl ethyl, cycloheptyl ethyl, and cyclooctylethyl, and the like.
[00208] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
[00209] "Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
[00210] "Fused cycloalkenyl" refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring. [00211] "Ethenyl" refers to substituted or unsubstituted -(C=C)-.
[00212] "Ethylene" refers to substituted or unsubstituted -(C-C)-.
[00213] "Ethynyl" refers to -(C≡C)-.
[00214] "Nitrogen-containing heterocyclyl" group means a 4- to 7- membered non- aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piped dine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine.
Particular examples include azetidine, piperidone and piperazone.
[00215] "Thioketo" refers to the group =S.
[00216] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN,
-N02, -N3, -S02H, -S03H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X- - N(ORcc)Rbb, -SH, -SRaa, -SSRcc, -C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -C02Raa, - OC(=0)Raa, -OC02Raa, -C(=0)N(Rbb)2, -OC(=0)N(Rbb)2, -NRbbC(=0)Raa, - NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, - OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, - C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa, -S020Raa, -OS02Raa, - S(=0)Raa, -OS(=0)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, - SC(=S)SRaa, -SC(=0)SRaa, -OC(=0)SRaa, -SC(=0)ORaa, -SC(=0)Raa, -P(=0)2Raa, - OP(=0)2Raa, -P(=0)(Raa)2, -OP(=0)(Raa)2, -OP(=0)(ORcc)2, -P(=0)2N(Rbb)2, - OP(=0)2N(Rbb)2, -P(=0)(NRbb)2, -OP(=0)(NRbb)2, -NRbbP(=0)(ORcc)2, - NRbbP(=0)(NRbb)2, -P(Rcc)2, -P(Rcc)3, -OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, - BRaa(ORcc), Cl-10 alkyl, Cl-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORcc;
each instance of Raa is, independently, selected from Cl-10 alkyl, Cl-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -ORaa, - N(Rcc)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -S02Raa, -C(= Rcc)ORaa, - C(= Rcc)N(Rcc)2, -S02N(Rcc)2, -S02Rcc, -S020Rcc, -SORaa, -C(=S)N(Rcc)2, - C(=0)SRcc, -C(=S)SRcc, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)( Rcc)2, Cl- 10 alkyl, Cl-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, Cl-10 alkyl, Cl- 10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered
heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X- -N(ORee)Rff, -SH, - SRee, -SSRee, -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, - OC(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, - OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, - NRffC(=NRff)N(Rff)2 ,-NRffS02Ree, -S02N(Rff)2, -S02Ree, -S020Ree, -OS02Ree, - S(=0)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, - P(=0)2Ree, -P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Cl-6 alkyl, Cl-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S;
each instance of Ree is, independently, selected from Cl-6 alkyl, Cl-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, Cl-6 alkyl, Cl-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -N02, -N3, -S02H, - S03H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(Cl-6 alkyl)2, -N(Cl-6 alkyl)3+X- - H(Cl-6 alkyl)2+X- - H2(Cl-6 alkyl) +X-, - H3+X-, -N(OCl-6 alkyl)(Cl-6 alkyl), - N(OH)(Cl-6 alkyl), -NH(OH), -SH, -SCl-6 alkyl, -SS(Cl-6 alkyl), -C(=0)(Cl-6 alkyl), - C02H, -C02(Cl-6 alkyl), -OC(=0)(Cl-6 alkyl), -OC02(Cl-6 alkyl), -C(=0) H2, - C(=0)N(Cl-6 alkyl)2, -OC(=0)NH(Cl-6 alkyl), - HC(=0)( Cl-6 alkyl), -N(Cl-6 alkyl)C(=0)( Cl-6 alkyl), - HC02(Cl-6 alkyl), - HC(=0)N(Cl-6 alkyl)2, - HC(=0) H(Cl-6 alkyl), - HC(=0) H2, -C(= H)0(Cl-6 alkyl) ,-OC(= H)(Cl-6 alkyl), -OC(= H)OCl-6 alkyl, -C(= H)N(Cl-6 alkyl)2, -C(= H) H(Cl-6 alkyl), -C(= H) H2, -OC(= H)N(Cl-6 alkyl)2, -OC( H) H(Cl-6 alkyl), -OC( H) H2, -NHC( H)N(Cl-6 alkyl)2, - HC(=NH) H2, - HS02(Cl-6 alkyl), -S02N(Cl-6 alkyl)2, -S02 H(Cl-6 alkyl), -S02 H2 -S02C1-6 alkyl, -S020C1-6 alkyl, -OS02C1-6 alkyl, -SOCl-6 alkyl, -Si(Cl-6 alkyl)3, -OSi(Cl-6 alkyl)3 -C(=S)N(Cl-6 alkyl)2, C(=S) H(Cl-6 alkyl), C(=S) H2, - C(=0)S(Cl-6 alkyl), -C(=S)SCl-6 alkyl, -SC(=S)SCl-6 alkyl, -P(=0)2(Cl-6 alkyl), - P(=0)(Cl-6 alkyl)2, -OP(=0)(Cl-6 alkyl)2, -OP(=0)(OCl-6 alkyl)2, Cl-6 alkyl, Cl-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S; wherein X- is a counterion.
[00217] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
[00218] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F", CI", Br", Γ), N03 ", C104 ", OH", H2P04 ", HS04 ", sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,
benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-l-sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).
[00219] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -S02Raa, -C(=NR )Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, - S02N(Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)2N(Rcc)2, -P(=0)(NRcc)2, d_10 alkyl, d_10 perhaloalkyl, C2_10 alkenyl, C2_ io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, R , Rcc and Rdd are as defined above.
[00220] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, - S02Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, - SORaa, -C(=S)N(RCC)2, -C(=0)SRcc, -C(=S)SRCC, Ci_i0 alkyl (e.g., aralkyl, heteroaralkyl), C2_i0 alkenyl, C2_i0 alkynyl, C3_i0 carbocyclyl, 3-14 membered heterocyclyl, C6_i aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, R , Rcc and Rdd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[00221] For example, nitrogen protecting groups such as amide groups (e.g., -C(=0)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenyl acetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, /?-phenylbenzamide, o- nitophenyl acetamide, o-nitrophenoxy acetamide, acetoacetamide, (Ν'- dithiobenzyloxyacylamino)acetamide, 3-( -hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, ø nitrobenzamide and o
(benzoyl oxymethyl)benzamide.
[00222] Nitrogen protecting groups such as carbamate groups (e.g., -C(=0)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-( 10, 10-dioxo-l 0, 10,10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methyl ethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l, l-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), l-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), /?-methoxybenzyl carbamate (Moz),/?-nitobenzyl carbamate, ^-bromobenzyl carbamate, ^-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-m ethyl sulfinylbenzyl carbamate (Msz), 9- anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, w-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), w-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o- nitrophenyl)methyl carbamate, t-amyl carbamate, ^-benzyl thiocarbamate, ?-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate,
cyclopropylmethyl carbamate, ^-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1 , l-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p '-methoxyphenylazo)benzyl carbamate, 1- methylcyclobutyl carbamate, 1 -methyl cyclohexyl carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1 -methyl- 1 -(3, 5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- \-{p- phenylazophenyl)ethyl carbamate, 1-methyl-l-phenylethyl carbamate, 1 -methyl- 1 -(4- pyridyl)ethyl carbamate, phenyl carbamate, ^-(phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
[00223] Nitrogen protecting groups such as sulfonamide groups {e.g., -S(=0)2Raa) include, but are not limited to, ^-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl- 4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5, 7,8-pentamethylchroman-6- sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
[00224] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-
(10)-acyl derivative, N '-^-toluenesulfonylaminoacyl derivative, N '-phenyl aminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4- nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenyl amine (PhF), N-2,7- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'- oxide, N-l, l-dimethylthiomethyleneamine, N-benzylideneamine, N-p—
methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2- pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Ν,Ν'- isopropylidenedi amine, N- ?-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, TV- copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,
diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).
[00225] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -Raa, -N(R )2, -C(=0)SRaa, -C(=0)Raa, -C02Raa, - C(=0)N(R )2, -C(= R )Raa, -C(= R )ORaa, -C(= R )N(R )2, -S(=0)Raa, -S02Raa, - Si(Raa)3, -P(RCC)2, -P(RCC)3, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)(ORcc)2, -P(=0)2N(R )2, and - P(=0)( R )2, wherein Raa, R , and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[00226] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
(phenyl dimethyl silyl)methoxym ethyl (SMOM), benzyl oxymethyl (BOM), ?- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl ( -AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-
(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4- methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, l-[(2-chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2- yl, 1-ethoxy ethyl, l-(2-chloroethoxy)ethyl, 1-methyl-l-methoxyethyl, 1-methyl-l- benzyloxy ethyl, l-methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, ?-chlorophenyl, ?-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), ?-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p— nitrobenzyl, ?-halobenzyl, 2,6-dichlorobenzyl, ?-cyanobenzyl, ?-phenylbenzyl, 2-picolyl, 4- picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, ?, ? -dinitrobenzhydryl, 5- dibenzosuberyl, tnphenylmethyl, a-naphthyldiphenylmethyl, /?-methoxyphenyldiphenylmethyl, di( -methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)m ethyl, 4-(4'- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-l- yl)bis(4',4"-dimethoxyphenyl)m ethyl, 1, l-bis(4-methoxyphenyl)-l '-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-l 0-oxo)anthryl, 1 ,3-benzodisulfuran-2-yl,
benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-^-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,/?-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl /?-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p- methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl ?-nitrobenzyl carbonate, alkyl ^-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(l, l,3,3-tetramethylbutyl)phenoxyacetate, 2,4— bis(l, 1— dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl Ν,Ν,Ν',Ν'- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
[00227] In certain embodiments, the substituent present on a sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -Raa, -N(R )2, -C(=0)SRaa, -C(=0)Raa, -C02Raa, -C(=0)N(R )2, - C(= R )Raa, -C(= R )ORaa, -C(= R )N(R )2, -S(=0)Raa, -S02Raa, -Si(Raa)3, -P(RCC)2, - P(RCC)3, -P(=0)2Raa, -P(=0)(Raa)2, -P(=0)(ORcc)2, -P(=0)2N(R )2, and -P(=0)( R )2, wherein Raa, R , and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
Other definitions
[00228] "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenyl propionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e.g., Berge, et al., J. Pharm. Sci. 66(1): 1-79 (Jan.'77).
[00229] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
"Pharmaceutically acceptable metabolically cleavable group" refers to a group which is cleaved in vivo to yield the parent molecule of the structural Formula indicated herein.
[00230] "Prodrugs" refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions a compound of the invention that are pharmaceutically active in vivo.
[00231] "Solvate" refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate"), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline or liquid form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[00232] A "subject" to which administration is contemplated includes, but is not limited to, humans {i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
[00233] As used herein the term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 95% by weight. In alternative embodiments, when specified, the term may refer to more than 96% by weight, more than 97% by weight, more than 98%) by weight, more than 98.5%> by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. The weights are based upon total weight of all enantiomers or stereoisomers of the compound.
[00234] As used herein and unless otherwise indicated, the term "enantiomerically pure R- compound" refers to at least 95% by weight R-compound and at most about 5% by weight S- compound. In alternative embodiments, when specified, the term can refer to at least about 99% by weight R-compound and at most about 1% by weight S-compound or at least about 99.9% by weight R-compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
[00235] As used herein and unless otherwise indicated, the term "enantiomerically pure S- compound" or "S-compound" refers to at least about 95% by weight S-compound and at most about 5% by weight R-compound. In alternative embodiments, when specified, the term can refer to at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.
[00236] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I, which has the chemical structure:
Figure imgf000072_0001
or a salt thereof.
3. A compound of Formula III, which has the chemical structure:
Figure imgf000072_0002
or a salt thereof.
4. A compound of Formula IV, which has the chemical structure:
Figure imgf000073_0001
or a salt thereof.
A compound of Formula V, which has the chemical structure:
Figure imgf000073_0002
or a salt thereof.
A compound of Formula VI, which has the chemical structure:
Figure imgf000073_0003
or a salt thereof.
A compound of Formula VII, which has the chemical structure:
Figure imgf000073_0004
or a salt thereof.
8. A compound of Formula VIII, which has the chemical structure:
Figure imgf000074_0001
or a salt thereof.
9. A compound of Formula IX, which has the chemical structure:
Figure imgf000074_0002
or a salt thereof.
10. The compound of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein the salt is pharmaceutically acceptable.
1 1. The compound of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, which is not in the form of a salt.
12. A compound of Formula X, XI, XII, XIII, XIV, XV, XVI, XVII or XVIII, which have the chemical structures:
Figure imgf000074_0003
Figure imgf000075_0001
wherein Ri and R2 are independently either: (i) R9 which is independently selected from H, halogen (CI, Br, I or F), natural or non- naturally occurring amino acid (bound through either the OC(O)- or C(0)0- (an ester) or the amino (through either -C(0)-N- or -N-C(O)- (an amide linkage)), R10, -OR10, or - SR10,
where R10 is -C(=0)RC1, -C(=0)0RC1, -C(=0)SRC1, -C(=0)N(RC1)2; or polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
-S(=0)2RC1, -S(=0)2ORcl, -S(=0)RC1, -S(=0)ORcl, -P(=0)2RC1, -P(=0)2ORcl, -P(=0)(ORcl)2, -P(=0)(RC1)2, or -P(RC1)(0RC1); or oxygen attached to an oxygen protecting group (to produce OH on administration), sulfur attached to a sulfur protecting group (to produce SH or a disulfide on administration), or nitrogen attached to a nitrogen protecting group (to produce - H- on administration);
and R can be independently selected from hydrogen, polyethylene glycol, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form an substituted or unsubstituted heterocyclic ring,
or its pharmaceutically acceptable salt.
13. The compounds of claim 12, wherein Ri and R2 are -OR9.
14. The compound of claim 13, wherein -OR9 is C(0)alkyl.
15. The compound of claim 13, wherein -OR9 is C(0)aryl.
16. The compound of claim 13, wherein -OR9 is OPO3H3.
17. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9 in a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 12, 13, 14, 15, or 16 in a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 17 wherein the carrier is suitable for oral
delivery.
20. The pharmaceutical composition of claim 18 wherein the carrier is suitable for oral delivery.
21. A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, optionally in a pharmaceutically acceptable carrier.
22. A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of claim 12, 13, 14, 15, or 16, optionally in a pharmaceutically acceptable carrier.
23. The method of claim 21, wherein the disorder is breast cancer.
24. The method of claim 22, wherein the disorder is breast cancer.
25. The method of claim 21, wherein the disorder is selected from the group consisting of ovarian, endometrial, or vaginal cancer, endometriosis or lung cancer.
26. The method of claim 22, wherein the disorder is selected from the group consisting of ovarian, endometrial, or vaginal cancer, endometriosis or lung cancer.
27. The compounds of claim 1 for use in medical therapy.
28. The compounds of claim 2 for use in medical therapy.
29. The method of claim 23, further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer.
30. The method of claim 24, further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer.
31. The method of claim 25, further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer.
32. The method of claim 26, further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer.
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