WO2014203132A1 - Composés de benzopyran substitués, leurs compositions et utilisations - Google Patents

Composés de benzopyran substitués, leurs compositions et utilisations Download PDF

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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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David C. Myles
Peter J. Kushner
Cyrus L. Harmon
Leslie Hodges GALLAGHER
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Olema Pharmaceuticals Inc
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Olema Pharmaceuticals Inc
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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.

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Abstract

L'invention concerne des composés de benzopyran ayant une activité anti-estrogénique sous les formules I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII et XVIII. Ces composés sont utiles dans le traitement ou la prévention de divers états qui sont modulés par le récepteur des œstrogènes chez des mammifères tels que des êtres humains.
PCT/IB2014/062183 2013-06-19 2014-06-12 Composés de benzopyran substitués, leurs compositions et utilisations Ceased WO2014203132A1 (fr)

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