US20210069154A1

US20210069154A1 - Treatment of Breast Cancer

Info

Publication number: US20210069154A1
Application number: US16/749,133
Authority: US
Inventors: Andrew A. Protter; Jennifer Richer; Dawn Cochrane
Original assignee: Medivation Prostate Therapeutics LLC; University of Colorado
Current assignee: Medivation Prostate Therapeutics LLC; University of Colorado
Priority date: 2011-07-29
Filing date: 2020-01-22
Publication date: 2021-03-11
Also published as: HK1198867A1; EA201400178A1; WO2013066440A9; SI2739153T1; CN103997894B; US10111861B2; EP2739153B1; JP6158180B2; HK1201413A1; CY1121038T1; PL2739153T3; BR112014002200A2; ES2696074T3; EA028452B1; JP2017141269A; PT2739153T; US9517229B2; WO2013066440A1; EP2739153A1; US20170087132A1

Abstract

The disclosure describes compounds useful for treating breast cancers.

Description

This application claims the benefit of and incorporates by reference Ser. No. 61/513,361 filed on Jul. 29, 2011.
This invention was made with government support under grant number W81XWM-8-1-0311 awarded by Army Medical Research Material and Command. The government has certain rights in the invention.
All documents cited in this disclosure are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The technical field is treatment of breast cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Graph demonstrating that RD162′ blocks DHT-mediated growth in MCF7 cells. Error bars represent standard error of the mean for 6 wells at each time point. See Example 1.

FIG. 2. Graph demonstrating that RD162′ blocks DHT-mediated growth in BCK4 cells.

FIGS. 3A-B. FIG. 3A, graph demonstrating that RD162′ blocks estradiol (E2)-mediated growth in MCF7 cells. Error bars represent standard error of the mean for 6 wells at each time point. See Example 3. FIG. 3B, Western blot demonstrating expression of estrogen receptor alpha treated for 48 hours under various conditions and a tubulin (a loading control).

FIG. 4. Graph demonstrating that RD162′ blocks E2-mediated upregulation of SDF-1, a gene involved in E2-driven proliferation, progesterone receptor, and androgen receptor.

FIGS. 5A-D. Graphs demonstrating that RD162′ inhibits DHT-mediated tumor growth in vivo as described in Example 5. FIG. 5A, caliper measurements of tumor size over time. FIG. 5B, whole body in vivo luminescent (IVIS) imaging over time.

FIG. 5C, caliper measurements of individual tumor size at the end of the study. FIG. 5D, IVIS measurements of individual tumor size at the end of the study.

FIGS. 6A-C. FIG. 6A, Western blot of four luminal (ER+, PR+) and four triple negative (ER−,PR−, Her2−) breast cancer cell lines for androgen receptor, estrogen receptor and tubulin (as a loading control). FIG. 6B, graph demonstrating that RD162′ inhibits cell growth in triple negative breast cancer cell line BT20 and actually decreases cell viability. FIG. 6C, graph demonstrating that RD162′ inhibits cell growth in triple negative breast cancer cell line MDA468 and actually decreases cell viability.

FIGS. 7A-E. FIG. 7A, Graph showing results of an MTS in vitro proliferation assay using MDA-MB-453 cells (AR+, ER−, HER2+, PR−), indicating that 10 μM RD162′ inhibits proliferation induced by 10 nM DHT. FIG. 7B, Graph showing results of a luciferase assay with MDA-kb2 cells, demonstrating that RD162′ inhibits proliferation induced by DHT in a dose dependent manner. FIG. 7C, Graph showing the ratio of nuclear to total AR in MDA-kb2 cells treated as described in Example 7.

FIG. 7D and FIG. 7E, Graphs demonstrating that RD162′ inhibits tumor growth induced by DHT.

FIG. 8. Graph demonstrating that RD162′ inhibits the growth of triple negative breast cancer cells.

FIG. 9. Graph demonstrating that RD162′ with HERCEPTIN® inhibits the growth of Her2+ breast cancer cells

FIG. 10A. Graph showing weekly measurement of tumor volume.

FIG. 10B. Graph showing weight of tumors at the end of the experiment described in Example 10.

FIG. 10C. Representative tumor sections stained for cleaved caspase 3.

FIG. 10D. Images of nuclear AR staining.

FIG. 11A. Graph showing mean total flux of all mice in each of the treatment groups.

FIG. 11B. Graph showing the total luminescent flux is shown for all individual mice at the day of matching (Day −3) and at the final imaging day (Day 11).

FIG. 11C. Images of luminescent signal in the two treatment groups at the day of matching (day −2) and the final day of imaging (day 11).

FIG. 11D. Representative images of BrdU staining (left, 400× magnification) and quantification (right).

DETAILED DESCRIPTION

This disclosure describes the use of one or more compounds that fall within the scope of one or more of structural formulae I, II, III, IV, V, or VI for treating breast cancer. Compounds useful for treating breast cancer include those compounds of formula I, II, III, IV, V, or VI that inhibit proliferation of breast cancer cells and/or lead to the death of breast cancer cells.

1. Definitions for Formulae I and II

The following definitions apply to Formulae (I) and (II).
The term “alkyl” denotes branched or unbranched hydrocarbon chains, in some embodiments having about 1 to about 8 carbons, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, 2-methylpentyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl pentyl, octyl, 2,2,4-trimethylpentyl and the like. “Substituted alkyl” includes an alkyl group optionally substituted with one or more functional groups which can be attached to such chains, such as, hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form alkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.
Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or more double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, in some embodiments 3 to 10 carbons, forming the ring and which can be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl. “Substituted cycloalkyl” includes a cycloalkyl group optionally substituted with 1 or more substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/or any of the substituents included in the definition of “substituted alkyl;” for example:
and the like.
Unless otherwise indicated, the term “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, in some embodiments 2 to 12 carbons, and in some embodiments 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like. “Substituted alkenyl” includes an alkenyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.”
Unless otherwise indicated, the term “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, in some embodiments 2 to 12 carbons and in some embodiments 2 to 8 carbons in the normal chain, which include one or more triple bonds in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like. “Substituted alkynyl” includes an alkynyl group optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.”
The terms “arylalkyl”, “arylalkenyl” and “arylalkynyl” as used alone or as part of another group refer to alkyl, alkenyl and alkynyl groups as described above having an aryl substituent. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like. “Substituted arylalkyl” includes arylalkyl groups wherein the aryl portion is optionally substituted with one or more substituents, such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.”
The term “halogen” or “halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.
The terms “halogenated alkyl”, “halogenated alkenyl” and “alkynyl” as used herein alone or as part of another group refers to “alkyl”, “alkenyl” and “alkynyl” which are substituted by one or more atoms selected from fluorine, chlorine, bromine, fluorine, and iodine.
Unless otherwise indicated, the term “aryl” or “Ar” as employed herein alone or as part of another group refers to monocyclic and polycyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and can optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings).
“Substituted aryl” includes an aryl group optionally substituted with one or more functional groups, such as halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl and/or any of the alkyl substituents set out herein.
Unless otherwise indicated, the term “heterocyclic” or “heterocycle”, as used herein, represents an unsubstituted or substituted stable 5- to 10-membered monocyclic ring system which can be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized. The heterocyclic ring can be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. The term “heterocyclic aromatic” as used here in alone or as part of another group refers to a 5- or 7-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocycloalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. “Substituted heteroaryl” includes a heteroaryl group optionally substituted with 1 to 4 substituents. such as the substituents included above in the definition of “substituted alkyl” and “substituted cycloalkyl.” Examples of heteroaryl groups include the following:
and the like.

2. Definitions for Formula III, IV, and V

The following definitions apply to Formulae (III), (IV), and (V).
“Alkyl” refers to and includes saturated linear, branched, or cyclic hydrocarbon structures and combinations thereof. Particular alkyl groups are those having 1 to 12 carbon atoms (a “C₁-C₁₂alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C₁-C₈alkyl”). When an alkyl group having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl and cyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. In some embodiments cycloalkyl has from 3 to 12 annular carbon atoms (a “C₃-C₁₂cycloalkyl”). In some embodiments cycloalkyl has from 3 to 7 annular carbon atoms (a “C₃-C₇cycloalkyl”). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl and the like.
“Alkenyl” refers to an unsaturated linear, branched, or cyclic hydrocarbon group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and in some embodiments having from 2 to 10 carbon atoms and more in some embodiments 2 to 8 carbon atoms. Examples of alkenyl groups include but are not limited to —CH₂—CH═CH—CH₃and —CH₂—CH₂-cyclohexenyl, where the ethyl group of the later example can be attached to the cyclohexenyl moiety at any available position on the ring.
“Alkynyl” refers to an unsaturated linear, branched, or cyclic hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and in some embodiments having from 2 to 10 carbon atoms and more in some embodiments 3 to 8 carbon atoms.
“Substituted alkyl” refers to an alkyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted alkenyl” refers to an alkenyl group having from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted alkynyl” refers to an alkynyl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Aryl,” “arene” or “Ar” refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments the aryl group contains from 6 to 14 annular carbon atoms.
“Heteroaryl,” “heteroarene” or “HetAr” refers to an unsaturated aromatic carbocyclic group having from 2 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl).
“Substituted aryl” or “substituted arene” refers to an aryl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Substituted heteroaryl” or “substituted heteroarene” refers to a heteroaryl group having from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.
“Aralkyl” refers to a residue in which an aryl moiety is attached to an alkyl residue and wherein the aralkyl group may be attached to the parent structure at either the aryl or the alkyl residue. In some embodiments an aralkyl is connected to the parent structure via the alkyl moiety.
“Aralkenyl” refers to a residue in which an aryl moiety is attached to an alkenyl residue and wherein the aralkenyl group may be attached to the parent structure at either the aryl or the alkenyl residue. In some embodiments an aralkenyl is connected to the parent structure via the alkenyl moiety.
“Aralkynyl” refers to a residue in which an aryl moiety is attached to an alkynyl residue and wherein the aralkynyl group may be attached to the parent structure at either the aryl or the alkynyl residue. In some embodiments an aralkynyl is connected to the parent structure via the alkynyl moiety.
“Heteroaralkyl” refers to a residue in which a heteroaryl moiety is attached to an alkyl residue and wherein the heroaralkyl group may be attached to the parent structure at either the heroaryl or the alkyl residue. In some embodiments a heteroaralkyl is connected to the parent structure via the alkyl moiety.
“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having a single ring or multiple condensed rings, and having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof.
“Substituted heterocyclic” or “substituted heterocyclyl” refers to a heterocycle group which is substituted with from 1 to 3 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. In some embodiments a substituted heterocycle is a heterocycle substituted with an additional ring, wherein the additional ring may be aromatic or non-aromatic.
“Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. In some embodiments halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. Similarly, a “haloalkenyl” or “haloalkynyl” indicates an alkenyl or alkynyl moiety respectively in which at least one H is replaced with a halo group. An alkyl group in which each H is replaced with a halo group is referred to as a “perhaloalkyl.” In some embodiments a perhaloalkyl group is trifluoromethyl (—CF₃).
A “substituted” group similarly refers to a group which is substituted with from 1 to 5 substituents including, but not limited to, substituents such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, substituted or unsubstituted carbamoyl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

3. Diarylhydantoin Compounds

In some embodiments the compound of formula I, II, III, IV, V, or VI is a diarylhydantoin compound. Useful diarylhydantoin compounds and their syntheses are disclosed, for example, in U.S. Pat. No. 7,709,517.
In some embodiments the compound is a compound of Formula I:
wherein X is selected from the group consisting of trifluoromethyl and iodo, wherein W is selected from the group consisting of O and NR5, wherein R5 is selected from the group consisting of H, methyl, and
wherein D is S or O and E is N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or D is S or O and E-G together are C1-C4 lower alkyl,
wherein R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group,
wherein R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl,
wherein R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl, and
wherein R3 is not methylaminomethyl or dimethylaminomethyl.
In some embodiments R5 is
In some embodiments the compound is a compound of Formula I-A:
wherein R3 is selected from the group consisting of hydroxy, methylcarbamoyl, methylcarbamoylpropyl, methylcarbamoyl ethyl, methylcarbamoylmethyl, methylsulfonecarbamoylpropyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, carbamoylmethyl, carbamoylethyl, carb oxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoylpropyl, carboxypropyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, methoxycarbonyl, 3-cyano-4-trifluoromethylphenylcarbamoyl, hydroxyethylcarbamoylethyl, and hydroxyethoxycarbonylethyl, and
wherein R10 and R11 are both H or, respectively, F and H, or H and F. In some embodiments R10 and R11 can both be H or, respectively, F and f, R3 can be methylcarbamoyl.
In some embodiments R1 and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms, and R3 is selected from the group consisting of carbamoyl, alkylcarbamoyl, carbamoylalkyl, and alkylcarbamoylalkyl, and R4 is H or F or R4 is 3-fluoro.
In some embodiments R1 and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms, R3 is selected from the group consisting of cyano, hydroxy, methylcarbamoyl, methylcarbamoyl-substituted alkyl, methylsulfonecarbamoyl-substituted alkyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, methoxycarbonyl, acetamido, methanesulfonamido, carbamoyl-substituted alkyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoyl-substituted alkyl, carboxy-substituted alkyl, 4-(1,1-dimethylethoxy)carbonyl)-1-piperazinyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyethoxycarbonyl-substituted alkyl, and 3-cyano-4-trifluoromethylphenylcarbamoyl, and R4 is F.
In some embodiments the compound is a compound of Formula I-B:
wherein R3 is selected from the group consisting of methylcarbonyl, methoxycarbonyl, acetamido, and methanesulfonamido, and R4 is selected from the group consisting of F and H.
In some embodiments the compound is a compound of Formula I-C:
wherein R4 is selected from the group consisting of F and H.
In some embodiments R1 and R2, together with the carbon to which they are linked, are
In some embodiments the compound is a compound of Formula I-D:
wherein R5 is CN or NO2 or SO2R11, wherein R6 is CF3, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, wherein A is sulfur (S) or oxygen (O), wherein B is O or S or NR8, wherein R8 is selected from the group consisting of H, methyl, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO2R11, NR11R12, (CO)OR11, (CO)NR11R12, (CO)R11, (CS)R11, (CS)NR11R12, (CS)OR11,
wherein D is S or O and E id N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or D is S or O and E-G together are C1-C4 lower alkyl, wherein R1 and R2 are independently alkyl, haloalkyl, hydrogen, aryl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocylic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, or R1 and R2 are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl,
wherein X is carbon or nitrogen and can be at any position in the ring, and wherein R3, R4, and R7 are independently selected from the group consisting of hydrogen, halogen, methyl, methoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methylcarbamoyl-substituted alkyl, dimethylcarbamoyl-substituted alkyl, methoxy carbonyl, acetamido, methanesulfonamino, carbamoyl-substituted alkyl, methanesulfonyl, 4-methanesulfonyl-lpiperazinyl, piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyl-substituted alkyl, hydroxyl-substituted alkenyl, carbamoyl-substituted alkenyl, methoxycarbonyl-substituted alkyl, cyano-substituted alkyl,
aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkenyl, halogenated alkynyl, SO2R11, NR11R12, NR12(CO)OR11, NH(CO)NR11R12, NR12 (CO)R11, O(CO)R11, O(CO)OR11, O(CS)R11, NR12(CS)R11, NH(CS) NR11R12, NR12(CS)OR11, aryl alkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, haloalkyl, methylsulfonecarbamoyl-substituted alkyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, methoxycarbonyl, acetamido, methanesulfonamido, carbamoyl-substituted alkyl, carboxymethyl, methoxycarbonylmethyl, methane sulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoyl-substituted alkyl, carboxy-substituted alkyl, 4-(1,1-dimethylethoxy)carbonyl)-1-piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyethoxycarbonyl-substituted alkyl, 3-cyano-4-trifluoromethylphenylcarbamoyl,
wherein R11 and R12 are independently hydrogen, aryl, aralkyl, substituted aralkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, aryl alkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or R11 and R12 can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, or substituted cycloalkyl.
In some embodiments the compound is a compound selected from:
In some embodiments, the compound is RD162′ (enzalutamide):
In some embodiments the compound is a compound disclosed in U.S. Pat. No. 7,709,517. In some embodiments the compound is a compound listed in Tier 1, Tier 2, Tier 3, and/or Tier 4 of U.S. Pat. No. 7,709,517, reproduced below:


TIER 1 COMPOUNDS

	RD7

	RD8

	RD10

	RD35

	RD36

	RD37

	RD57

	RD58

	RD90

	RD91

	RD92

	RD93

	RD94

	RD95

	RD96

	RD97

	RD100

	RD102

	RD119

	RD120

	RD130

	RD131

	RD145

	RD152

	RD153

	RD163

	RD162

	RD162

	RD162*

	RD168

	RD169

	RD170

TIER

2 COMPOUNDS

	RD6

	RD13

	RD48

	RD49

	RD51

	RD53

	RD54

	RD59

	RD60

	RD66

	RD68

	RD71

	RD87

	RD103

	RD110

	RD111

	RD114

	RD116

	RD133

	RD134

	RD138

	RD161

TIER

3 COMPOUNDS

	RD3

	RD4

	RD5

	RD69

	RD127

	RD128

	RD129

	RD135

	RD137

	RD129

	RD135

	RD137

TIER

4 COMPOUNDS

	RD2

	RD9

	RD21

	RD22

	RD23

	RD24

	RD25

	RD26

	RD27

	RD30

	RD31

	RD39

	RD40

	RD44

	RD59

	RD60

	RD67

	RD82

	RD83

	RD117

	RD118

	RD148

	RD149

	RD150

	RD151

In some embodiments the compound is a compound selected from:


	RD1

	RD19

(comparative)

	RD52

	RD79

	RD80

	RD81

	RD89

	RD104

	RD105

	RD106

	RD115

	RD132

	RD136

	RD139

	RD140

	RD141

	RD142

	RD146

	RD147

	RD154

Other useful diarylhydantoin compounds and their syntheses are disclosed, for example, in U.S. 2009/0111864.
In some embodiments the compound is a compound of Formula I-E:
wherein R₁and R₂together include eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group. R₃is hydrogen, cyano, formyl,
R₄is hydrogen, F, Cl, Br, or I. R₁₁and R₁₂can be the same or different and are hydrogen or methyl. R13 is hydrogen or —NR₁₄R₁₅. R₁₄and R₁₅can be the same or different and are hydrogen or methyl.
In some embodiments R₁and R₂can be independently methyl or, together with the carbon to which they are linked, cyclobutyl or cyclopentyl. In some embodiments R₁₁and R₁₂can be both hydrogen or both methyl. In some embodiments R13 can be —NH(CH₃) or —N(CH₃)₂. In some embodiments, when R₄, R₁and R₁₂are each hydrogen and when R₁and R₂together with the carbon to which they are linked are cyclobutyl, then R₃can be other than cyano and
with R13 hydrogen, —NH₂, —NH(CH₃), or —N(CH₃)₂.
Representative compounds of Formula (I)-E include:

4. Hydantoin Compounds

In some embodiments the compound is a hydantoin compound. Useful hydantoin compounds and their syntheses are disclosed, for example, in US 2011/0003839.
In some embodiments a hydantoin compound is a compound of Formula I
In Formula II, Het represents a heterocyclic unit of 5 or 6 atoms. A and B are independently selected from oxygen, sulfur, and NR₉, with R₉being selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO₂R₁₁, NR₁₁R₁₂, NR₁₂(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, or NR₁₂(CS)OR₁₁. R and R₁₂are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic or non-aromatic. R₁is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substitutedcycloalkyl, S₂R, NR₁₁R₁₂, NR₁₂(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, or NR₁₂(CS)OR₁₁. R₂and R₃are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or, together with the carbon to which they are linked, form a cycle which can be cycloalkyl, substituted cycloalkyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic.
R₂and R₃can be connected to form a cycle which can be heterocyclic aromatic or non aromatic, substituted heterocyclic aromatic or non aromatic. Ru and R₁can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, or substituted cycloalkyl.
For example, the compound can be
In some embodiments heterocyclic units are selected from compounds represented by the structures
and the like. However, the hydantoins are not intended to be limited to compounds having these structures.
R₄, R₅, R₆, and R₇are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO₂, OR₁₁, SR₁₁, NR₁₁R₁₂, NH(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, NR₁(CS)OR₁₁. In some embodiments R4 is CN or NO₂. R₅is trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl and halogen. R₆and R7 are hydrogen, alkyl or halogen. R4, R₅, R₆, and R7 can be independently connected to form a cycle which can be aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl. X is selected from sulfur (S), oxygen (O), NR₈wherein N is nitrogen and is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, (CO)R₁₁, (CO)OR₁₁, (CS)R₁₁, (CS)OR₁₁.
R₁is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO₂R₁₁, NR₁₁R₁₂, NR₁₂(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₁(CS)R₁₁, NH(CS)NR₁₁R₁₂, NR₁₂(CS)OR₁₁. In some embodiments R₁is aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl.
R₂and R₃are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl. R₂and R₃can be connected to form a cycle which can be heterocyclic aromatic or non aromatic, substituted heterocyclic aromatic or non aromatic, cycloalkyl, substituted cycloalkyl. R₁and R₂can be connected to form a cycle which can be heterocyclic aromatic or non aromatic, substituted heterocyclic aromatic or non aromatic.
A and B are independently selected from oxygen (O), sulfur (S) and N—R₉. R₉is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO₂R₁₁, NR₁₁R₁₂, NR₁₂(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, NR₁₂(CS)OR₁₁.
R₁₁and R₁₂, are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic. R₁₁and R₁₂can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, substituted cycloalkyl.
In some embodiments R₁is alkyl, substituted alkyl, alkenyl, or substituted alkenyl. In some embodiments R₁is selected from the group consisting of aryl and substituted aryl. In some embodiments R₁is aryl substituted by at least one fluorine atom. In some embodiments R₁is a 5- to 8-membered heterocyclic aromatic or non aromatic ring. In some embodiments R₂and R₃are independently methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, or bromomethyl.
In some embodiments A and B are independently oxygen or sulfur.
In some embodiments Het comprises a heterocyclic unit of 6 atoms in which 1 or 2 heteroatoms independently are selected from nitrogen, oxygen, and sulfur. In some embodiments Het comprises a 0 or 1 double-bonded substituent on the heterocyclic unit selected from the group consisting of oxygen and sulfur. In some embodiments Het comprises from 3 to 4 single-bonded substituents on the heterocyclic unit selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO₂, OR₁₁, SR₁₁, NR₁₁R₁₂, NH(CO)OR₁₁, NH(CO)NR₁₁R₁₁, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₁, and NR₁₂(CS)OR₁₁. In some embodiments a single-bonded substituent can be connected to another single-bonded substituent to form a cycle which is aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl.
In some embodiments Het is
and R₄, R₅, R₆and R₇are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO₂, OR₁₁, SR₁₁, NR₁₁R₁₂, NH(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, NR₁₂(CS)OR₁₁, wherein any of R₄, R₅, R₆and R₇can be connected to any of R₄, R₅, R₆and R₇to form a cycle which can be aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl.
In some embodiments R₆and R₇are independently selected from the group consisting of hydrogen, alkyl, and or halogen. In some embodiments R₄is selected from the group consisting of CN and NO₂, wherein R₅is selected from the group consisting of trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, and halogen; in some of these embodiments R₆and R₇are independently selected from the group consisting of hydrogen, alkyl, and or halogen.
In some embodiments R₄is CN or NO₂. In some embodiments R₅is trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, or halogen. In some embodiments R₆, and R₇are independently hydrogen, alkyl, and or halogen.
In some embodiments R₄is CN or NO₂and R₅is trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, or halogen.
In some embodiments R₄is CN or NO₂and R₆, and R₇are independently hydrogen, alkyl, and or halogen.
In some embodiments R₄is CN or NO₂, R₅is trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, or halogen, and R₆, and R₇are independently hydrogen, alkyl, and or halogen.
In some embodiments R₅is trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, or halogen and R₆, and R₇are independently hydrogen, alkyl, and or halogen.
In some embodiments R₅is trifluoromethyl or iodide and R₆and R₇are independently hydrogen or halogen.
In some embodiments Het is one of
In some embodiments Het comprises a heterocyclic unit of 5 atoms, wherein the heterocyclic unit comprises 1 or 2 heteroatoms independently selected from the group consisting of sulfur, oxygen, nitrogen, and NR8, wherein R₈is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, (CO)R₁₁, (CO)OR₁₁, (CS)R₁₁, (CS)OR₁₁, wherein Het comprises from 2 to 3 single-bonded substituents on the heterocyclic unit selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO₂, OR₁₁, SR₁₁, NR₁₁R₁₂, NH(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, NR₁₂(CS)OR₁₁, wherein a single-bonded substituent can be connected to another single-bonded substituent to form a cycle which is aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl.
In some embodiments Het is selected from the group consisting of 5-membered rings of the compounds
and R₄, R₅, and R₆, are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, CN, NO₂, OR₁₁, SR₁₁, NR₁₁R₁₂, NH(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, NR₁₂(CS)OR₁₁, wherein any of R₄, R₅, and R₆can be connected to any of R₄, R₅, and R₆to form a cycle which can be aromatic, substituted aromatic, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, wherein X is selected from sulfur, oxygen, and NR₈, and wherein R₈is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogen, (CO)R₁₁, (CO)OR₁₁, (CS)R₁₁, and (CS)OR₁₁.
In some embodiments R₄is selected from the group consisting of CN and NO₂, wherein R₅is selected from the group consisting of trifluoromethyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, and halogen, and wherein R₆is selected from the group consisting of hydrogen, alkyl, and halogen.

5. Substituted Di-Arylhydantoin and Di-Arylthiohydantoin Compounds

In some embodiments the compound is a substituted di-arylhydantoin or substituted di-arylthiohydantoin compound. Useful compounds and their syntheses are disclosed, for example, in WO 2010/118354.
In some embodiments the compound is a compound of Formula III:
wherein:
W¹is CN, NO₂or SO₂R⁴;
W²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl
or halogen;
Z¹is S or O
Z²is S, O or NR⁴;
Y¹and Y²are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y¹and Y²are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R¹is —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^dor —C(O)NR, where:

- R^ais a C₂-C₁₂alkyl and R^bis H or a C₁-C₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring;
- R is a C₁-C₁₂alkyl and R^eis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring;
- R^eis a C₂-C₁₂alkyl and R^fis H or a C₁-C₂alkyl, or
- R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl, or
- R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring;

R²is hydrogen, halogen, nitro, alkyl and substituted alkyl; and
R⁴is independently H, alkyl, or aryl.
In some embodiments W¹is CN. In some embodiments W²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. In some embodiments W²is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with a halogen. W²in some embodiments is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl. W²in some embodiments is a substituted alkyl. In some embodiments W²is substituted alkyl where the alkyl is substituted with a halogen. In some embodiments W²is a haloalkyl or perhaloalkyl. In some embodiments W²is a perhaloalkyl. The perhaloalkyl in some embodiments is a C₁-C₈perhaloalkyl, such as trihalomethyl. In some embodiments W²is trifluoromethyl. In some embodiments W¹is CN and W²is perhaloalkyl. In some embodiments W¹is CN and W²is CF₃.
In some embodiments Y¹and Y²are both a C₁-C₈alkyl. In some embodiments Y and Y²are the same C₁-C₈alkyl, such as when both Y¹and Y²are methyl, ethyl, propyl or butyl. In some embodiments Y¹and Y²are both methyl or are taken together with the carbon to which they are attached to form a C₄-C₅cycloalkyl. In some embodiments Y¹and Y²are both methyl. In some embodiments at least one of Y¹and Y²is alkyl where the alkyl is a cycloalkyl. In some embodiments at least one of Y¹and Y²is substituted alkyl where the substituted alkyl is a substituted cycloalkyl. In some embodiments one or both of Y¹and Y²are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with a halogen. In some embodiments at least one of Y¹and Y²is a haloalkyl, haloalkenyl or haloalkynyl. In some embodiments both Y¹and Y²are a haloalkyl, haloalkenyl or haloalkynyl. In some embodiments Y¹and Y²are taken together with the carbon to which they are attached to form a C₄-C₅cycloalkyl. In some embodiments Y¹and Y²are taken together to form a cyclobutyl moiety. In some embodiments Y¹and Y²are both methyl, W¹is CN. In some embodiments Y¹and Y²are both methyl and W²is a perhaloalkyl such as CF₃. In some embodiments Y¹and Y²are both methyl, W¹is CN and W²is a perhaloalkyl such as CF₃.
In some embodiments Z¹and Z²are independently S or O. In some embodiments Z¹is S and Z²is O. In some embodiments Z¹and Z²are independently S or O and Y and Y²are both a C₁-C₈alkyl. In some embodiments Z is S, Z²is O and Y¹and Y²are the same C₁-C₈alkyl. In some embodiments Z¹and Z²are independently S or O and Y and Y²are both methyl or are taken together with the carbon to which they are attached to form a C₄-C₅cycloalkyl. In some embodiments Z¹is S, Z²is O and the compound is further defined by one or more of the following structural features: (i) Y and Y²are both a C₁-C₈alkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl. In some embodiments Z¹is S, Z²is O, Y¹and Y²are the same C₁-C₈alkyl, W¹is CN and W²is CF₃.
In some embodiments T is C. In some embodiments T is N. In some embodiments a compound of formula (III) may be further defined by T being C. In some embodiments a compound of formula (III) may be further defined by T being N. For example, in some embodiments the compound may be further defined by T being C or by T being N.
In some embodiments R¹is —C₁-C₈alkyl-NR^aR^bwhere R^ais a C₂-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the —C₁-C₈alkyl moiety of —C₁-C₈alkyl-NR^aR^bis a —(CH₂)_nmoiety where n is an integer from 1 to 8. In some embodiments n is less than 4. In some embodiments n is 1. In some embodiments R^ais a C₂-C₁₂alkyl and R^bis H. For example, R^ain some embodiments is ethyl, propyl, butyl or pentyl and R^bis H. In some embodiments R^ais a C₂-C₈alkyl and R^bis H. In some embodiments R^ais a C₃-C₆alkyl and R^bis H. In some embodiments R^ais a C₂-C₁₂alkyl and R^bis a C₁-C₁₂alkyl. In some embodiments R^ais a C₃-C₁₂cycloalkyl and R^bis a C₁-C₁₂alkyl (e.g., methyl). In some embodiments R^aand R^bare independently a C₂-C₈alkyl. In some embodiments R^aand R^bare the same C₂-C₁₂alkyl, e.g., when both R^aand R^bare ethyl. In some embodiments R^aand R^bare independently a C₃-C₆alkyl. In some embodiments R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^aand R^bare taken together to form a heterocyclic ring, the ring is a C₄-C₇heterocyclic ring. The heterocyclic ring formed by R^a, R^band the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^aand R^bare taken together with the N to which they are attached. In some embodiments R^aand R are taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
Where applicable, for any detailed herein wherein R1 is —C₁-C₈alkyl-NR^aR^b, the C₁-C₈alkyl moiety of —C₁-C₈alkyl-NR^aR^bis a —(CH₂)_nmoiety where n is 1. Thus, R¹in some embodiments is —CH₂NR^aR^bwhere R^aand R^bmay be as defined herein. In some embodiments R¹is
In some of these embodiments, the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z¹is S; (iv) Z²is O; (v) Y¹and Y²are both methyl and (vi) T is C.
In some embodiments R¹is —O—C₁-C₈alkyl-NR^cR^dwhere R^cis a C₁-C₁₂alkyl and R^dis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the —C₁-C₈alkyl moiety of —O—C₁-C₈alkyl-NR^cR^dis a —(CH₂)_nmoiety where n is an integer from 1 to 8. In some embodiments n is less than 4. In some embodiments n is 2. In some embodiments R^cis a C₁-C₁₂alkyl and R^dis H. For example, R^cin some embodiments is methyl, ethyl, propyl, butyl or pentyl and R^dis H. In some embodiments R^cis a C₁-C₈alkyl and R^dis H. In some embodiments R^cis a C₁-C₄alkyl and R^dis H.
In some embodiments R^cand R^dare independently a C₁-C₁₂alkyl. In some of these embodiments R^cand R^dare the same C₁-C₁₂alkyl, e.g., when both R^cand R^dare methyl. In some embodiments R^cand R^dare independently a C₁-C₈alkyl. In some embodiments R^cand R^dare independently a C₁-C₄alkyl. In some embodiments R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^cand R^dare taken together to form a heterocyclic ring, the ring is a C₄-C₇heterocyclic ring. The heterocyclic ring formed by R^c, R^dand the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^cand R^dare taken together with the N to which they are attached. In some embodiments R^cand R^dare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R¹is —O—C₁-C₈alkyl-NR^cR^d, the C₁-C₈alkyl moiety of —O—C₁-C₈alkyl-NR^cR^dis a —(CH₂)_nmoiety where n is 2. Thus, R¹in some embodiments is —OCH₂CH₂NR^cR^dwhere R^cand R^dmay be as defined herein. In some embodiments R¹is:
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z¹is S; (iv) Z²is O; (v) Y¹and Y²are both methyl; (vi) R²is H, and (vii) T is C.
In some embodiments R¹is —C(O)NR^eR^fwhere R^eand R^fare as defined in provisions (i) or (ii) or (iii): (i) R^eis a C₂-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl; (ii) R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl; or (iii) R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments R is —C(O)NR^eR^fand R^eis a C₂-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl. In some embodiments R¹is —C(O)NR^eR^fand R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl. In some embodiments R¹is —C(O)NR^eR^fand R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments R^eis a C₂-C₁₂alkyl and R^fis H. For example, R^ein some embodiments is ethyl, propyl, butyl, pentyl or hexyl and R^fis H. In some embodiments R^eis a C₃-C₁₂cycloalkyl (e.g., cyclopentyl) and R^fis H. In some embodiments R^eis a C₃-C₁₂branched alkyl (e.g., tert-butyl) and R^fis H. In some embodiments R^eis a C₂-C₈alkyl and R^fis H. In some embodiments R^eis a C₃-C₆alkyl and R^fis H. In some embodiments R^eis a C₂-C₁₂alkyl and R^fis a C₁-C₁₂alkyl (e.g., where R^eis ethyl and R^fis methyl). In some embodiments R^eand R^fare independently a C₁-C₁₂alkyl (e.g., where both R^eand R^fare methyl). In some embodiments R^eand R^fare independently a C₂-C₁₂alkyl. In some embodiments R^eand R^fare the same C₂-C₁₂alkyl, e.g., when both R^eand R^fare ethyl. In some embodiments R^eand R^fare independently a C₂-C₅alkyl. In some embodiments R^eand R^fare independently a C₃-C₆alkyl. In some embodiments at least one of R^eand R^fis a C₃-C₆cycloalkyl. In some embodiments R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^eand R^fare taken together to form a heterocyclic ring, the ring is a C₄-C₇heterocyclic ring. The heterocyclic ring formed by R^e, R^fand the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^eand R^fare taken together with the N to which they are attached. In some embodiments R^eand R^fare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring.
In some embodiments R¹is:
In some of these embodiments, the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is S; (iv) Z²is O; (v) Y¹and Y²are both methyl and (vi) T is C.
In some embodiments R²is halo (e.g., F). In some embodiments R²is H. In some embodiments R²is halo when R is —C₁-C₈alkyl-NR^aR^bor —C(O)NR^eR^f. In some embodiments R²is H when R is —O—C₁-C₈alkyl-NR^cR^d
In some embodiments the compound is a compound of Formula III-A:
where Z¹, Z², Y¹, Y², T, R and R²are as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-B:
where W¹, W², T, R¹and R²are as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-C:
where T, R¹and R²are as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-D:
where R¹and R²are as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-E:
where R¹is as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-F:
where n is an integer from 1 to 8 and W¹, W², Z¹, Z², Y², Y¹, R^aand R^bare as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-G:
where n is an integer from 1 to 8 and W¹, W², Z¹, Z², Y¹, R^cand R^dare as defined in formula (III) or any embodiment thereof.
In some embodiments the compound is a compound of Formula III-H:
where W¹, W², Z¹, Z², Y², Y¹, R^eand R^fare as defined in formula (III) or any embodiment thereof.
Examples of compounds according to Formula III are depicted in Table 1. The compounds depicted may be present as salts even if salts are not depicted and it is understood that the this disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. It is thus understood that pharmaceutically acceptable salts of compounds are intended.

TABLE 1

Representative Compounds of Formula III.

Structure	Compound No.

	1

	2

	3

	4

	5

	6

	7

	8

6. Substituted Phenylcarbamoyl Alkylamino Arene and N,N′-Bis-Arylurea Compounds

In some embodiments the compound is a substituted phenylcarbamoyl alkylamino arene or an N,N′-bis-arylurea compound. Other useful compounds and their syntheses are disclosed in WO 2011/044327. In some embodiments a compound is a compound of Formula IV:
wherein:
W¹is CN, NO₂or SO₂R⁴;
W²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;

Z is S, O or NR⁵;

Y¹and Y²are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Yi and Y²are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R¹is —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^dor —C(O)NR^eR^f,
where:
R^ais a C₁-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring;
R^cis a C₁-C₁₂alkyl and R^dis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring;
R^eis a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl, or R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring;
R²is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R⁴is H, alkyl, substituted alkyl, aryl or substituted aryl; and
R⁵is H, alkyl, substituted alkyl, aryl or substituted aryl.
In some embodiments the salt is a pharmaceutically acceptable salt.
In some embodiments the compound is of the formula (IV) where W¹is CN. In some embodiments W²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. In some embodiments W²is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens. W²in some embodiments is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl. W²in some embodiments is a substituted alkyl. In some embodiments W²is substituted alkyl where the alkyl is substituted with one or more halogens. In some embodiments W²is a haloalkyl or perhaloalkyl. In some embodiments W²is a perhaloalkyl. The perhaloalkyl in some embodiments is a C₁-C₈perhaloalkyl, such as trihalomethyl. In some embodiments W²is trifluoromethyl. In a particular, W¹is CN and W²is perhaloalkyl. In another particular, W¹is CN and W²is CF₃.
In some embodiments Y¹and Y²are both a C₁-C₈alkyl. In some embodiments Y and Y²are the same C₁-C₈alkyl, such as when both Y¹and Y²are methyl, ethyl, propyl or butyl. In some embodiments Y¹and Y²are both methyl or are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In some embodiments Y¹and Y²are both methyl. In some embodiments one of Y or Y²is hydrogen and the other of Y or Y²is C₁-C₈alkyl. In some embodiments one of Y or Y²is hydrogen and the other of Y or Y²is methyl, ethyl, propyl or butyl. In some embodiments at least one of Y¹and Y²is alkyl where the alkyl is a cycloalkyl. In some embodiments at least one of Y¹and Y²is substituted alkyl where the substituted alkyl is a substituted cycloalkyl. In some embodiments one or both of Y¹and Y²are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens. In some embodiments at least one of Y and Y²is a haloalkyl, haloalkenyl or haloalkynyl. In some embodiments both Y¹and Y²are a haloalkyl, haloalkenyl or haloalkynyl. In some embodiments Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In some embodiments Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl or cyclopentyl moiety. In some embodiments Y¹and Y²are both methyl and W¹is CN. In some embodiments Y and Y²are both methyl and W²is a perhaloalkyl such as CF₃. In some embodiments Y and Y²are both methyl, W¹is CN and W²is a perhaloalkyl such as CF₃. In some embodiments Y is isopropyl, Y²is H, W¹is CN and W²is a perhaloalkyl such as CF₃. In a particular, Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, W¹is CN. In another particular of formula (IV), Y and Y²are taken together with the carbon to which they are attached to form a cyclopropyl and W²is a perhaloalkyl such as CF₃. In some embodiments Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, W¹is CN and W²is a perhaloalkyl such as CF₃.
In some embodiments Z is substituted N (e.g., NR⁵), S or O. In some embodiments Z is O. In a particular, Z is S or O and Y¹and Y²are both a C₁-C₈alkyl. In some embodiments Z is O and Y¹and Y²are the same C₁-C₈alkyl. In some embodiments Z is S or O and Y¹and Y²are both methyl or are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In some embodiments Z is O and the compound is further defined by one or more of the following structural features: (i) Y¹and Y²are both a C₁-C₈alkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl. In some embodiments Z is O, Y¹and Y²are the same C₁-C₈alkyl, W¹is CN and W²is CF₃. In one particular such embodiment Z is O, Y¹and Y²are each methyl, W¹is CN and W²is CF₃. In some embodiments the compounds of formula (IV) are provided where Z is O and the compound is further defined by one or more of the following structural features: (i) Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl. In some embodiments Z is O, Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl, W¹is CN and W²is CF₃. In one particular embodiment Z is O, Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, W¹is CN and W²is CF₃.
In some embodiments T is C. In some embodiments T is N. It is understood that where applicable, a compound may be further defined by T being C. It is understood that where applicable, a compound may be further defined by T being N. For example, the embodiments described herein may in some cases be further defined by T being C or by T being N.
Compounds of formula (IV) are provided where R¹is —C₁-C₈alkyl-NR^aR^bwhere R^ais a C₁-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the —C₁-C₈alkyl moiety of —C₁-C₈alkyl-NR^aR^bis a —(CH₂)_nmoiety where n is an integer from 1 to 8. In some embodiments n is less than 4. In some embodiments n is 1. In some embodiments R^ais a C₁-C₁₂alkyl and R^bis H. For example, R^ain some embodiments is methyl, ethyl, propyl, butyl or pentyl and R^bis H. In some embodiments R^ais a C₁-C₈alkyl and R^bis H. In some embodiments R^ais a C₃-C₆alkyl and R^bis H. Compounds of formula (IV) are also provided where R^ais a C₁-C₁₂alkyl and R^bis a C₁-C₁₂alkyl. In some embodiments R^ais a C₃-C₁₂cycloalkyl and R^bis a C₁-C₁₂alkyl (e.g., methyl). In some embodiments R^aand R^bare independently a C₁-C₈alkyl. In some embodiments R^aand R^bare the same C₁-C₁₂alkyl, e.g., when both R^aand R^bare ethyl. In some embodiments R^aand R^bare independently a C₃-C₆alkyl. In still some embodiments R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^aand R^bare taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R^a, R^band the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^aand R^bare taken together with the N to which they are attached. In a particular, R^aand R^bare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R is —C₁-C₈alkyl-NR^aR^b, in some embodiments the C₁-C₈alkyl moiety of —C₁-C₈alkyl-NR^aR^bis a —(CH₂)_nmoiety where n is 1. Thus, R¹in some embodiments is —CH₂NR^aR^bwhere R^aand R^bmay be as defined herein. In some embodiments R¹is:
In some of these embodiments, the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y²are both methyl and (v) T is C. In some embodiments the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y²are both methyl, (v) R²is halogen (e.g., F) and (vi) T is C.
Compounds of formula (IV) are provided where R¹is —O—C₁-C₈alkyl-NR^cR^dwhere R^cis a C₁-C₁₂alkyl and R^dis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the —C₁-C₈alkyl moiety of —O—C₁-C₈alkyl-NR^cR^dis a —(CH₂)_nmoiety where n is an integer from 1 to 8. In some embodiments n is less than 4. In some embodiments n is 2. In some embodiments R^cis a C₁-C₁₂alkyl and R^dis H. For example, R^cin some embodiments is methyl, ethyl, propyl, butyl or pentyl and R^dis H. In some embodiments R^cis a C₁-C₈alkyl and R^dis H. In some embodiments R^cis a C₁-C₄alkyl and R^dis H. Compounds of formula (IV) are also provided where R^cand R^dare independently a C₁-C₁₂alkyl. In some embodiments R^cand R^dare the same C₁-C₁₂alkyl, e.g., when both R^cand R^dare methyl. In some embodiments R^cand R^dare independently a C₁-C₈alkyl. In some embodiments R^cand R^dare independently a C₁-C₄alkyl. In still some embodiments R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^cand R^dare taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R^c, R^dand the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^cand R^dare taken together with the N to which they are attached. In a particular, R^cand R^dare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R¹is —O—C₁-C₈alkyl-NR^cR^d, in some embodiments the C₁-C₈alkyl moiety of —O—C₁-C₈alkyl-NR^cR^dis a —(CH₂)_nmoiety where n is 2. Thus, R in some embodiments is —OCH₂CH₂NR^cR^dwhere R^cand R^dmay be as defined herein.
In some embodiments R¹is:
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y²are both methyl; (v) R²is H, and (vi) T is C.
In some embodiments R¹is —C(O)NR^eR^fwhere R^eand R^fare as defined in provisions (i) or (ii) or (iii) or (iv): (i) R^eand R^fare independently H or a C₁-C₁₂alkyl; (ii) R^eis a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl; (iii) R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl; or (iv) R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments R¹is —C(O)NR^eR^fand R^eand R^fare independently H or a C₁-C₁₂alkyl. In some embodiments R¹is —C(O)NR^eR^fand R^eis a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl. In some embodiments R¹is —C(O)NR^eR^fand R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl. In some embodiments R is —C(O)NR^eR^fand R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments R^eis a C₁-C₁₂alkyl and R^fis H. For example, R^ein some embodiments is methyl, ethyl, propyl, butyl, pentyl or hexyl and R^fis H. In some embodiments R^eis a C₃-C₁₂cycloalkyl (e.g., cyclopentyl) and R^fis H. In some embodiments R^eis a C₃-C₁₂branched alkyl (e.g., tert-butyl) and R^fis H. In some embodiments R^eis a C₁-C₈alkyl and R^fis H (e.g., where R^eis methyl and R^fis H). In some embodiments R^eis a C₃-C₆alkyl and R^fis H (e.g., where R^eis propyl or butyl and R^fis H). In some embodiments R^eis a C₁-C₁₂alkyl and R^fis a C₁-C₁₂alkyl (e.g., where R^eis ethyl and R^fis methyl). In some embodiments R^eand R^fare independently a C₁-C₁₂alkyl (e.g., where both R^eand R^fare methyl). In some embodiments R^eand R^fare independently a C₁-C₁₂alkyl. In some embodiments R^eand R^fare the same C₁-C₁₂alkyl, e.g., when both R^eand R^fare ethyl. In some embodiments R^eand R^fare independently a C₁-C₁₂alkyl. In some embodiments R^eand R^fare independently a C₃-C₆alkyl. In some embodiments at least one of R^eand R^fis a C₃-C₆cycloalkyl. In still some embodiments R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^eand R^fare taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R^e, R^fand the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^eand R^fare taken together with the N to which they are attached. In a particular, R^eand R^fare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. In some embodiments R is:
In some embodiments the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y²are both methyl and (vi) T is C. In some embodiments R is as defined above and the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is O; (iv) Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl and (vi) T is C.
In any embodiment detailed herein, R in some embodiments is halo (e.g., F). In some embodiments R²is H. In some embodiments R²is halo when R¹is —C₁-C₈alkyl-NR^aR^bor —C(O)NR^eR^f. In some embodiments R²is H when R¹is —O—C₁-C₈alkyl-NR^cR^d.
In some embodiments the compound is a compound of Formula IV-A:
where Z, Y¹, Y², T, R¹and R²are as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-B:
where W¹, W², T, R¹and R²are as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-C:
where T, R¹and R²are as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-D:
where R¹and R²are as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-E:
where R¹is as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-F:
where n is an integer from 1 to 8 and R^cand R^dare as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-G.
where n is an integer from 1 to 8 and R^cand R^dare as defined in formula (IV) or any embodiment thereof.
In some embodiments the compound is a compound of Formula IV-H:
where n is an integer from 1 to 8 and R^cand R^dare as defined in formula (IV) or any embodiment thereof
In some embodiments the compound is a compound of Formula IV-J:
where n is 0 to 3, and R^eand R^fare as defined in formula (IV) or any embodiment thereof.
Examples of compounds according to Formula (IV) are depicted in Table 2. The compounds depicted may be present as salts even if salts are not depicted and it is understood that this disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. It is thus understood that pharmaceutically acceptable salts of compounds are intended.

TABLE 2

Representative Compounds of Formula IV.

Structure	Compound No.

	1

	2

	3

	4

	5

	6

	7

	8

	9

	10

In some embodiments the compound is a compound of Formula V:
wherein:
W¹is CN, NO₂or SO₂R⁴;
W²is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, O or NR⁵;
Y¹and Y²are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y and Y²are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
Y³is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkylhydroxymethyl, substituted alkoxymethyl,
thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl;
heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;
T is carbon or nitrogen and can be at any position in the ring;
R¹is hydrogen, —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^d, —C(O)NR^eR^for —NR^gR^h,

- where:
  - R^ais a C₁-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring;
  - R^cis a C₁-C₁₂alkyl and R^dis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring;
  - R^eis H or a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl, or R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring;
  - R^gis H or a C₁-C₁₂alkyl and R^his H or a C₁-C₁₂alkyl, or R^gand R^hare taken together with the N to which they are attached to form a heterocyclic ring;

R²is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R⁴is H, alkyl, substituted alkyl, aryl or substituted aryl;
R⁵is H, alkyl, substituted alkyl, aryl or substituted aryl.
In some embodiments the compound is of the formula (V) where T is nitrogen when R⁴and R⁵are both hydrogen.
In some embodiments the compound is of the formula (V) where W¹is CN. In some embodiments W²is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl. In some embodiments W²is substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens. W²in some embodiments is a haloalkyl, haloalkenyl, haloalkynyl or perhaloalkyl. W²in some embodiments is a substituted alkyl. In some embodiments W²is substituted alkyl where the alkyl is substituted with one or more halogens. In some embodiments W²is a haloalkyl or perhaloalkyl. In some embodiments W²is a perhaloalkyl. The perhaloalkyl in some embodiments is a C₁-C₈perhaloalkyl, such as trihalomethyl. In some embodiments W²is trifluoromethyl. In a particular, W¹is CN and W²is perhaloalkyl. In another particular, W¹is CN and W²is CF₃. In some embodiments W²is hydrogen. In a particular, W¹is CN and W²is hydrogen.
In some embodiments Y¹and Y²are both a C₁-C₈alkyl. In some embodiments Y and Y²are the same C₁-C₈alkyl, such as when both Y¹and Y²are methyl, ethyl, propyl or butyl. In some embodiments Y¹and Y²are both methyl or are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In some embodiments the compounds of formula (V) are provided where Y¹and Y²are both methyl. In some embodiments the compounds of formula (V) are provided where one of Y or Y²is hydrogen and the other of Y or Y²is C₁-C₈alkyl. In some embodiments one of Y or Y²is hydrogen and the other of Y or Y²is methyl, ethyl, propyl or butyl. In some embodiments the compounds of formula (V) are provided where at least one of Y¹and Y²is alkyl where the alkyl is a cycloalkyl. In some embodiments the compounds of formula (V) are provided where at least one of Y¹and Y²is substituted alkyl where the substituted alkyl is a substituted cycloalkyl. In some embodiments the compounds of formula (V) are provided where one or both of Y¹and Y²are substituted alkyl, substituted alkenyl or substituted alkynyl where the alkyl, alkenyl or alkynyl is substituted with one or more halogens. In some embodiments at least one of Y¹and Y²is a haloalkyl, haloalkenyl or haloalkynyl. In another such embodiment both Y¹and Y²are a haloalkyl, haloalkenyl or haloalkynyl. In some embodiments the compounds of formula (V) are provided where Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl. In some embodiments Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl or cyclopentyl moiety. In a particular, Y¹and Y²are both methyl, W¹is CN. In another particular, Y¹and Y²are both methyl and W²is a perhaloalkyl such as CF₃. In some embodiments Y¹and Y²are both methyl, W¹is CN and W²is a perhaloalkyl such as CF₃. In some embodiments Y is isopropyl, Y²is H, W¹is CN and W²is a perhaloalkyl such as CF₃. In a particular, Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, W¹is CN. In another particular of formula (V), Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl and W²is a perhaloalkyl such as CF₃. In some embodiments Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, W¹is CN and W²is a perhaloalkyl such as CF₃.
In a, Y³is carboxyl, carbonyl or derivative thereof, such as carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, carbamyl, N-alkyl carbamyl, N,N-dialkyl carbamyl, N-substituted alkyl carbamyl, N,N-bis-substituted alkyl carbamyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkylhydroxymethyl or substituted alkoxymethyl. In a, Y³is thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl.
In a particular, Y³is thiocarboxyl or carboxyl. In a particular, Y³is carboxyl.
In a particular, Y is aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl. In a particular, Y³is aminocarbonyl.
In another particular, Y³is formyl, alkyl carbonyl or alkoxy carbonyl. In a particular, Y³is alkoxycarbonyl.
In a, Y³is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl,
In some embodiments the compounds of formula (V) are provided where Z is substituted N (e.g., NR⁵), S or O. In some embodiments Z is O. In some embodiments Z is S. In a particular, Z is S or O and Y¹and Y²are both a C₁-C₈alkyl. In some embodiments Z is S or O and Y¹and Y²are the same C₁-C₈alkyl. In some embodiments Z is S or O and Y¹and Y²are both methyl or are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl.
In some embodiments the compounds of formula (V) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y¹and Y²are both a C₁-C₈alkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl. In some embodiments Z is S, Y¹and Y²are the same C₁-C₈alkyl, W¹is CN and W²is CF₃. In one particular such embodiment Z is S, Y¹and Y²are each methyl, W¹is CN and W²is CF₃. In one particular such embodiment Z is S, Y¹and Y²are each methyl, Y³is carboxyl, W¹is CN and W²is CF₃. In some embodiments the compounds of formula (V) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl, (iv) Y³is carboxyl. In some embodiments Z is S, Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl, W¹is CN and W²is CF₃. In one particular embodiment Z is O, Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, Y³is carboxyl, W¹is CN and W²is CF₃.
In some embodiments the compounds of formula (V) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y¹and Y²are both a C₁-C₈alkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl; (iv) Y³is selected from the group consisting of thiocarboxyl, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxycarbonyl. In one particular such embodiment Y³is alkoxycarbonyl or aminocarbonyl. In one particular such embodiment Z is S, Y¹and Y²are each methyl, Y³is alkoxycarbonyl or aminocarbonyl, W¹is CN and W²is CF₃. In some embodiments the compounds of formula (V) are provided where Z is S and the compound is further defined by one or more of the following structural features: (i) Y and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl; (ii) W¹is CN; (iii) W²is perhaloalkyl, (iv) Y³is alkoxycarbonyl or aminocarbonyl. In some embodiments Z is S, Y¹and Y²are taken together with the carbon to which they are attached to form a C₃-C₅cycloalkyl, W¹is CN and W²is CF₃. In one particular embodiment Z is O, Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl, Y³is alkoxycarbonyl or aminocarbonyl, W¹is CN and W²is CF₃.
In some embodiments T is C. In some embodiments T is N. It is understood that where applicable, any embodiment may in some embodiments be further defined by T being C. It is understood that where applicable, any embodiment may in some embodiments be further defined by T being N. For example, the embodiments described herein may in some embodiments be further defined by T being C. Additionally, it is understood that the embodiments described herein may in some embodiments be further defined by T being N.
Compounds of formula (V) are provided where R¹is —C₁-C₈alkyl-NR^aR^bwhere R^ais a C₁-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the —C₁-C₈alkyl moiety of —C₁-C₈alkyl-NR^aR^bis a —(CH₂)_nmoiety where n is an integer from 1 to 8. In some embodiments n is less than 4. In some embodiments n is 1. In some embodiments R^ais a C₁-C₁₂alkyl and R^bis H. For example, R^ain some embodiments is methyl, ethyl, propyl, butyl or pentyl and R^bis H. In some embodiments R^ais a C₁-C₈alkyl and R^bis H. In some embodiments R^ais a C₃-C₆alkyl and R^bis H. Compounds of formula (V) are also provided where R^ais a C₁-C₁₂alkyl and R^bis a C₁-C₁₂alkyl. In some embodiments R^ais a C₃-C₁₂cycloalkyl and R^bis a C₁-C₁₂alkyl (e.g., methyl). In some embodiments R^aand R^bare independently a C₁-C₈alkyl. In some embodiments R^aand R^bare the same C₁-C₁₂alkyl, e.g., when both R^aand R^bare ethyl. In some embodiments R^aand R^bare independently a C₃-C₆alkyl. In still some embodiments R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^aand R^bare taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R^a, R^band the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^aand R^bare taken together with the N to which they are attached. In a particular, R^aand R^bare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R¹is —C₁-C₈alkyl-NR^aR^b, in some embodiments the C₁-C₈alkyl moiety of —C₁-C₈alkyl-NR^aR^bis a —(CH₂)_nmoiety where n is 1. Thus, R in some embodiments is —CH₂NR^aR^bwhere R^aand R^bmay be as defined herein. In some embodiments R is:
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is S; (iv) Y¹and Y²are both methyl and (v) T is C. In some embodiments R is as defined above and the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is S; (iv) Y¹and Y²are both methyl, (v) R²is halogen (e.g., F) and (vi) T is C.
In some embodiments R¹is —O—C₁-C₈alkyl-NR^cR^dwhere R^cis a C₁-C₁₂alkyl and R^dis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the —C₁-C₈alkyl moiety of —O—C₁-C₈alkyl-NR^cR^dis a —(CH₂)_nmoiety where n is an integer from 1 to 8. In some embodiments n is less than 4. In some embodiments n is 2. In some embodiments R^cis a C₁-C₁₂alkyl and R^dis H. For example, R^cin some embodiments is methyl, ethyl, propyl, butyl or pentyl and R^dis H. In some embodiments R^cis a C₁-C₈alkyl and R^dis H. In some embodiments R^cis a C₁-C₄alkyl and R^dis H. Compounds of formula (V) are also provided where R^cand R^dare independently a C₁-C₁₂alkyl. In some embodiments R^cand R^dare the same C₁-C₁₂alkyl, e.g., when both R^cand R^dare methyl. In some embodiments R^cand R^dare independently a C₁-C₈alkyl. In some embodiments R and R^dare independently a C₁-C₄alkyl. In still some embodiments R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^cand R^dare taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R^c, R^dand the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^cand R^dare taken together with the N to which they are attached. In a particular, R^cand R^dare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. Where applicable, for any detailed herein wherein R¹is —O—C₁-C₈alkyl-NR^cR^d, in some embodiments the C₁-C₈alkyl moiety of —O—C₁-C₈alkyl-NR^cR^dis a —(CH₂)_nmoiety where n is 2. Thus, R¹in some embodiments is —OCH₂CH₂NR^cR^dwhere R^cand R^dmay be as defined herein. In some embodiments R is:
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W is CN; (ii) W²is perhaloalkyl (e.g., CF₃); (iii) Z is S; (iv) Y¹and Y²are both methyl; (v) R²is H, and (vi) T is C.
In some embodiments R¹is —C(O)NR^eR^fwhere R^eand R^fare as defined in provisions (i) or (ii) or (iii) or (iv): (i) R^eand R^fare independently H or a C₁-C₁₂alkyl; (ii) R^eis a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl; (iii) R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl; or (iv) R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments the compound is of the formula (V) where R¹is —C(O)NR^eR^fand R^eand R^fare independently H or a C₁-C₁₂alkyl. In some embodiments the compound is of the formula (V) where R¹is —C(O)NR^eR^fand R^eis a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl. In some embodiments the compound is of the formula (V) where R¹is —C(O)NR^eR^fand R is a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl. In some embodiments the compound is of the formula (V) where R¹is —C(O)NR^eR^fand R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments R^eis a C₁-C₁₂alkyl and R^fis H. For example, R^ein some embodiments is methyl, ethyl, propyl, butyl, pentyl or hexyl and R^fis H. In another particular embodiment R^eis a C₃-C₁₂cycloalkyl (e.g., cyclopentyl) and R^fis H. In some embodiments R^eis a C₃-C₁₂branched alkyl (e.g., tert-butyl) and R^fis H. In some embodiments R^eis a C₁-C₈alkyl and R^fis H (e.g., where R^eis methyl and R^fis H). In some embodiments R^eis a C₃-C₆alkyl and R^fis H (e.g., where R^eis propyl or butyl and R^fis H). In another particular embodiment R^eis a C₁-C₁₂alkyl and R^fis a C₁-C₁₂alkyl (e.g., where R^eis ethyl and R^fis methyl). Compounds of formula (V) are also provided where R^eand R^fare independently a C₁-C₁₂alkyl (e.g., where both R^eand R^fare methyl). In some embodiments the compounds of formula (V) are provided where R^eand R^fare independently a C₁-C₁₂alkyl. In some embodiments R^eand R^fare the same C₁-C₁₂alkyl, e.g., when both R^eand R^fare ethyl. In some embodiments R^eand R^fare independently a C₁-C₈alkyl. In some embodiments R^eand R^fare independently a C₃-C₆alkyl. In some embodiments at least one of R^eand R^fis a C₃-C₆cycloalkyl. In still some embodiments R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring. In some embodiments when R^eand R^fare taken together to form a heterocyclic ring, the ring is a 4- to 7-membered heterocyclic ring. The heterocyclic ring formed by R^e, R^fand the N to which they are attached in some embodiments contains only C and N as annular atoms. In some embodiments the heterocycle contains as annular atoms only C and the N provided when R^eand R^fare taken together with the N to which they are attached. In a particular, R^eand R^fare taken together with the N to which they are attached to form a pyrrolidinyl or piperidinyl ring. In some embodiments R¹is:
In some of these embodiments the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃) or hydrogen; (iii) Z is S; (iv) Y¹and Y²are both methyl and (vi) T is C. In some embodiments R is as defined above and the compound is further defined by any one or more of the following structural features: (i) W¹is CN; (ii) W²is perhaloalkyl (e.g., CF₃) or hydrogen; (iii) Z is S; (iv) Y¹and Y²are taken together with the carbon to which they are attached to form a cyclopropyl and (vi) T is C.
In any embodiment detailed herein, R²in some embodiments is halo (e.g., F). In some embodiments R²is H. In some embodiments R²is halo when R¹is —C₁-C₈alkyl-NR^aR^bor —C(O)NR^eR^f. In some embodiments R²is H when R¹is —O—C₁-C₈alkyl-NR^cR^d.
In any embodiment detailed herein, Y³is thiocarboxyl, carboxyl, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxy carbonyl. In a particular, Y³is carboxyl. In another particular, Y³is alkoxycarbonyl. In another particular, Y³is aminocarbonyl.
In some embodiments the compound is a compound of Formula V-A:
where Y, Y², Y³, T, R¹and R²are as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-B:
where W¹, W², Y³, T, R¹and R²are as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-C:
where Y³, T, R¹and R²are as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-D:
where Y³, R¹and R²are as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-E:
where Y³and R¹is as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-F:
where n is an integer from 1 to 8 and Y³, R^aand R^bare as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-G:
where n is an integer from 1 to 8 and Y³, R^cand R^dare as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-H:
where Y³, R^eand R^fare as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-J:
where n is 0 to 3, and Y³, R^eand R^fare as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-K:
where Y, Y², Y³, R¹and R²are as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-L:
where n is 0 to 3, and Y, Y², Y³, R^eand R^fare as defined in formula (V) or any embodiment thereof.
In some embodiments the compound is a compound of Formula V-M:
where Y¹, Y²and Y³are as defined in formula (V) or any embodiment thereof.
In a variation of any one of formula (V-A), (V-B), (V-C), (V-D), (V-E), (V-F), (V-G), (V-H), (V-J), (V-K), (V-L) to (V-M) detailed herein, in particular embodiments Y³is thiocarboxyl, carboxyl, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, formyl, alkyl carbonyl or alkoxy carbonyl. In a particular variation of any one of formula (V-A), (V-B), (V-C), (V-D), (V-E), (V-F), (V-G), (V-H), (V-J), (V-K), (V-L) to (V-M) detailed herein, Y³is carboxyl. In another particular variation of any one of formula (V-A), (V-B), (V-C), (V-D), (V-E), (V-F), (V-G), (V-H), (V-J), (V-K), (V-L) to (V-M) detailed herein, Y³is alkoxy carbonyl. In another particular variation of any one of formula (V-A), (V-B), (V-C), (V-D), (V-E), (V-F), (V-G), (V-H), (V-J), (V-K), (V-L) to (V-M) detailed herein, Y³is aminocarbonyl.
Examples of compounds according to Formula (V) are depicted in Table 3. The compounds depicted may be present as salts even if salts are not depicted and it is understood that this disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. It is thus understood that pharmaceutically acceptable salts of compounds are intended.

TABLE 3

Representative Compounds of Formula V.

Structure	Compound No.

	11

	12

	13

	14

	15

	16

	17

	18

	19

	20

	21

	22

	23

	24

	25

	26

	27

7. Metabolites

In some embodiments the compound is a metabolite of a diarylthiohydantoin compound, for example as disclosed in WO 2010/099238.
In some embodiments the compound is a compound of Formula VI:
wherein:
X is S or O, and
when X is S, then R¹is OH or NH₂; and
when X is O then R¹is OH, N₂or NHMe,
or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments a compound of Formula VI is:

8. Salts

Salts of compounds described above can be used in the disclosed methods. If a compound has, for example, at least one basic center, it can form an acid addition salt. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. Compounds having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. Corresponding internal salts can furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds or their pharmaceutically acceptable salts, are also included. In some embodiments salts of compounds which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate. In some embodiments salts of compounds which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
In some embodiments the salts are pharmaceutically acceptable (e.g., non-toxic, physiologically acceptable) salts. Pharmaceutically acceptable salts retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, 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, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
Therapeutic Methods
In addition to the breast cancer indications discussed below and the therapeutic indications disclosed in U.S. Pat. No. 7,709,517; US 2011/0003839; WO 2010/118354; WO 2011/044327; and WO 2010/099238, compounds of Formulae (I), (II), (III), (IV), (V), and (VI) can be used to treat androgen receptor related diseases or conditions such as benign prostate hyperplasia, hair loss, and acne. These and related compounds may also be useful as modulators of other nuclear receptors, such as glucocorticoid receptor, estrogen receptor, and peroxisome proliferator-activated receptor, and as therapeutic agents for diseases in which nuclear receptors play a role, such as breast cancer, ovarian cancer, diabetes, cardiac diseases, and metabolism related diseases.
“Treating” or “treatment” as used herein is an approach for obtaining a beneficial or desired result, including, but not limited to, relief from a symptom, lessening of a symptom, and preventing a worsening of a symptom associated with the disease being treated. Treatment also includes, but is not limited to, any one or more of enhancing survival time, enhancing progression-free survival time, and reducing tumor size.
1. Breast Cancers
Compounds can be used to treat various forms of breast cancer, whether or not the breast cancers express androgen receptors or estrogen receptors. Breast cancers that can be treated include, but are not limited to, basal-like breast cancer, BRCA1-related breast cancer, medullary breast cancer, metaplastic breast cancer, special histologic type of breast cancer, triple negative breast cancer, and breast cancer resistant to endocrine therapy.
In some embodiment, patients to be treated are post-menopausal. In other embodiments patients to be treated are pre-menopausal. In other embodiments patients to be treated are peri-menopausal. In some embodiments patients to be treated are men.
In some embodiments breast cancers are ER+(i.e., 1% or more of the cells tested express ER detectable by immunocytochemistry). In some embodiments, breast cancers contain cells that demonstrate estradiol-mediated growth. In some embodiments patients to be treated have no detectable circulating levels of estradiol. In some embodiments patients to be treated have circulating levels of estradiol greater than 10 pmol/L. In some embodiments patients to be treated have circulating levels of estradiol less than 10 pmol/L. In some embodiments estradiol levels are measured by a double-antibody procedure as described in Cummings et al., JAMA 287, 216-20, 2002.
i. Triple Negative Breast Cancer
In some of embodiments the breast cancer is a triple negative breast cancer including, but not limited to, subtypes of triple negative breast cancer such as of basal-like type 1 (BLi), basal-like type 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR) subtypes. “Triple negative breast cancer” as used herein is characterized by lack of estrogen receptor (ER), progesterone receptor (PR), and lack of overexpression or amplification of Her2neu. A tumor is negative for expression of ER or PR if fewer than 1% of the cells tested are positive for ER or PR, as measured by immunohistochemistry, and if the Her2 gene is not expressed (for example, amplification is not detected by FISH). Triple negative breast cancer is clinically characterized as more aggressive and less responsive to standard treatment and is associated with poorer overall patient prognosis. It is diagnosed more frequently in younger women and in women with BRCA1 mutations.
In some embodiments a triple negative breast cancer is AR+; i.e., it contains cells that express detectable androgen receptors as detected by immunohistochemistry, ligand binding, or other methods known in the art. In other embodiments a triple negative breast cancer is AR−.
ii. ER+ Breast Cancer Resistant to Endocrine Therapy
Approximately 75% of breast cancers express the estrogen receptor (ER) and are candidates for endocrine therapy. The selective ER modulator tamoxifen is the most commonly prescribed endocrine therapy; however, approximately 30 percent of tumors that retain estrogen (ER) do not respond to estrogen/ER directed therapies such as tamoxifen or aromatase inhibitors (AI) and nearly all patients with metastatic disease develop resistance. In such patients, a compound can provide a therapeutic intervention.
In some embodiments the breast cancer is ER+, i.e., it contains detectable levels of estrogen receptor, measured as described above, but is resistant to endocrine therapy. “Endocrine therapy” as used herein includes administration of one or more aromatase inhibitors (e.g., anastrozole, exemestane, letrozole) and/or administration of one or more estrogen receptor modulators (e.g., tamoxifen, raloxifen, fulvestrant). “Resistant to endocrine therapy” as used herein means that the tumors (primary or metastases) do not respond to one or more of the above treatments by shrinking, but rather remains the same size or increases in size, or that recur in response to such treatment at any time in the patient's livespan.
In some embodiments the breast cancer is ER+/AR+. In some embodiments the breast cancer is ER+/AR−. In some embodiments the breast cancer contains cells that are progesterone receptor positive (PR+) as detected by immunohistochemistry or ligand binding assays or any other method of detection. In some embodiments the breast cancer contains no detectable cells with progesterone receptors; e.g., the breast cancer is progesterone receptor negative (PR−). In some embodiments a breast cancer contains cells that are Her2 positive (Her2+) as detected by observable Her2 gene amplification after in situ hybridization. In some embodiments a breast cancer contains no detectable cells with amplification or expression or overexpression of Her2; e.g., the breast cancer is Her2 negative (Her2−). The progesterone receptors and Her2 can be present on the same or different populations of cells, which may be the same or different as the populations of cells expressing ER and/or AR.
In some embodiments abreast cancer is identified as AR+, ER+, and Her2+. In some embodiments a breast cancer is identified as AR+, ER+, and PR+. In some embodiments a breast cancer is identified as AR+, ER+, Her2+, and PR+. In some embodiments a breast cancer is identified as AR−, ER+, and Her2+. In some embodiments a breast cancer is identified as AR−, ER+, and PR+. In some embodiments a breast cancer is identified as AR−, ER+, Her2+, and PR+. In some embodiments, a breast cancer is identified as AR+, ER−, HER2+, PR−.
2. Pharmaceutical Compositions
Compounds can be formulated in any type of pharmaceutical composition known in the art, including, but not limited to, tablets, troches, pills, capsules, syrups, elixirs, injectable solutions, and the like.
A pharmaceutical composition typically includes a pharmaceutically or pharmacologically acceptable excipient or carrier. As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. In some embodiments pharmaceutically acceptable carriers or excipients have met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose d (dc=“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
Tablets, troches, pills, capsules, and the like can also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials can be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules can be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir can contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, a diarylhydantoin compound can be incorporated into sustained-release preparations and devices. For example, a compound can be incorporated into time release capsules, time release tablets, and time release pills.
Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising a compound which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form typically is sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating a compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Other solid carriers include nontoxic polymeric nanoparticles or microparticles. Useful liquid carriers include water, alcohols or glycols or water/alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver a compound to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
In some embodiments the pharmaceutical composition is a unit dosage form. As used herein, “unit dosage form” is a physically discrete unit containing a predetermined quantity of active.
3. Dosages
As used herein, the term “effective amount” intends such amount of a compound which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
Useful dosages of compounds can be determined by comparing their in vitro activity and/or in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949. For example, the concentration of a compound in a liquid composition, such as a lotion, can be from about 0.1-25% by weight, or from about 0.5-10% by weight. The concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1-5% by weight, or about 0.5-2.5% by weight.
The amount of a compound required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
Effective dosages and routes of administration of compounds are conventional. The exact amount (effective dose) of the agent will vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like. A therapeutically effective dose can be determined empirically, by conventional procedures known to those of skill in the art. See, e.g., The Pharmacological Basis of Therapeutics, Goodman and Gilman, eds., Macmillan Publishing Co., New York. For example, an effective dose can be estimated initially either in cell culture assays or in suitable animal models. The animal model can also be used to determine the appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. A therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents.
The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years.
In general, however, a suitable dose will be in the range of from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about 100 mg/kg of body weight per day, such as above about 0.1 mg per kilogram, or in a range of from about 1 to about 10 mg per kilogram body weight of the recipient per day. For example, a suitable dose can be about 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day.
A compound is conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, or about 100 mg of active ingredient per unit dosage form.
A compound can be administered to achieve peak plasma concentrations of, for example, from about 0.5 to about 75 M, about 1 to 50 M, about 2 to about 30 M, or about 5 to about 25 M. Exemplary desirable plasma concentrations include at least or no more than 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100 or 200 M. For example, plasma levels can be from about 1 to 100 micromolar or from about 10 to about 25 micromolar. This can be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of a diarylhydantoin or hydantoin compound, optionally in saline, or orally administered as a bolus containing about 1-100 mg of a diarylhydantoin or hydantoin compound. Desirable blood levels can be maintained by continuous infusion to provide about 0.00005-5 mg per kg body weight per hour, for example at least or no more than 0.00005, 0.0005, 0.005, 0.05, 0.5, or 5 mg/kg/hr. Alternatively, such levels can be obtained by intermittent infusions containing about 0.0002-20 mg per kg body weight, for example, at least or no more than 0.0002, 0.002, 0.02, 0.2, 2, 20, or 50 mg of a compound per kg of body weight.
A compound can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself can be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
4. Methods of Administration
A compound can be administered using pharmaceutical compositions comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier or diluent, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperitoneally, or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue.
A compound can be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier; or by inhalation or insufflation. It can be enclosed in hard or soft shell gelatin capsule, can be compressed into a tablet, or can be incorporated directly with the food of a patient's diet. For oral therapeutic administration, a compound can be combined with one or more excipients and used in the form of an ingestible tablet, a buccal tablet, troche, capsule, elixir, suspension, syrup, wafer, and the like. A compound can be combined with a fine inert powdered carrier and inhaled by the subject or insufflated. In some embodiments such compositions and preparations contain at least 0.1% diarylhydantoin or hydantoin compound. The percentage of the compositions and preparations can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of a given unit dosage form. The amount of diarylhydantoin or hydantoin compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
A compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of a compound can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
5. Combination Therapies
In some embodiments combinations of one or more compounds are used. A “combination” compounds includes one or more compounds administered substantially simultaneously, whether or not in the same pharmaceutical composition, or sequentially. compounds can, but need not be, chemically similar (e.g., two diarylhydantoin compounds; a diarylhydantoin compound and a diarylthiohydantoin, etc.).
In some embodiments one or more compounds is combined other therapies, such as internal or external radiation, surgery, and chemotherapies, including:

- 1. anthracyclines, such as doxorubicin (e.g., ADRIAMYCIN®, DOXIL®), including liposomal doxorubicin, epirubicin (e.g., ELLENCE®), and daunorubicin (e.g., CERUBIDINE®, DAUNOXOME®);
- 2. taxanes, such as docetaxel (e.g., TAXOTERE®), paclitaxel (e.g., TAXOL®, ABRAXANE®), and protein-bound paclitaxel (e.g., ABRAXANE®);
- 3. estrogen receptormodulators, such as tamoxifen (e.g., NOLVADEX®, SOLTAMOX®, ISTUBAL®, VALODEX®);
- 4. cyclophosphamide (e.g., CYTOXAN®);
- 5. capecitabine (e.g., XELODA®)
- 6. 5-fluorouracil or 5 FU (e.g., ADRUCIL®);
- 7. vinorelbine (e.g., NAVELBINE®);
- 8. gemcitabine (e.g., GEMZAR®);
- 9. trastuzumab (e.g., HERCEPTIN®);
- 10. carboplatin (e.g., PARAPLATIN®);
- 11. eribulin (e.g., HALAVEN®);
- 12. ixabepilone (e.g., IXEMPRA®);
- 13. methotrexate (e.g., AMETHOPTERIN®, MEXATE®, FOLEX®);
- 14. mutamycin (e.g., MITOMYCINk);
- 15. mitoxantrone (e.g., NOVANTRONE®);
- 16. thiotepa (e.g., THIOPLEX®);
- 17. vincristine (e.g., ONCOVIN®, VINCASAR PES®, VINCREX®);
- 18. aromatase inhibitors such as anastrozole (e.g., ARIMIDEX), exemestane (AROMASIN), and letrozole (FEMARA);
- 19. raloxifene (e.g., EVISTA®);
- 20. toremifene (e.g., FARESTON®);
- 21. fulvestrant (e.g., FASLODEX®);
- 22. lapatinib (e.g., TYKERB®); and
- 23. metformin.

One or more compounds also can be used in conjunction with combinations of chemical therapies, such as:

- 1. doxorubicin and docetaxel (e.g., “AT,” ADRIAMYCIN® and TAXOTERE®);
- 2. doxorubicin and cyclophosphamide, with or without paclitaxel or docetaxel (e.g. “AC±T,” ADRIAMYCIN® and CYTOXAN®, with or without TAXOL® or TAXOTERE®);
- 3. cyclophosphamide, methotrexate, and fluorouracil (e.g., “CMF,” CYTOXAN®, methotrexate, and fluorouracil);
- 4. cyclophosphamide, epirubicin, and fluorouracil (e.g., “CEF,” CYTOXAN®, ELLENCE®, and fluorouracil);
- 5. fluorouracil, doxorubicin, and cyclophosphamide (e.g., “FAC,” fluorouracil, ADRIAMYCIN®, and CYTOXAN® or “CAF,” CYTOXAN®, ADRIAMYCIN®, and fluorouracil);
- 6. docetaxel, doxorubicin, and cyclopho9sphamide (e.g., “TAC,” TAXOTERE®, ADRIAMYCIN®, and CYTOXAN®); and
- 7. gemcitabine, epirubicin, and paclitaxel (e.g., “GET,” GEMZAR®, ELLENCE®, and TAXOL®).

Other therapeutic agents which can be combined with compounds disclosed herein include:

- 1. PI3K/mTOR inhibitors, such as everolimus (e.g., AFINITOR®); temsirolimus (e.g., TORISEL®); rapamycin (sirolimus; e.g., RAPAMMUNE®); and radaforolimus;
- 2. EGFR inhibitors, such as trastuzumab; trastuzumab entansine (TDM1); pertuzumab (e.g., PERJECTA™); gefinitib (e.g., RESSA®), neratinib (HK1-272); afatinib; erlotinib (e.g., TARCERA®);
- 3. angiogenesis inhibitors, such as bevacizumab (e.g., AVASTIN®); ramucirumab; sunitinib (e.g., SUTENT®); pazopanib (e.g., VOTRIENT®); sorafenib (e.g., NEXAVAR®); vandetanib (e.g., CAPRELSA®); and cediranib (e.g., RECENTIN®);
- 4. cytotoxics, such as vinflunine (e.g., JAVLOR®); trabectedin (e.g., YONDELIS®); and NKTR-102 (PEG-IRINOTECAN®);
- 5. vaccines, such as NeuVax™ (E75 peptide derived from HER2 combined with the immune adjuvant granulocyte macrophage colony stimulating factor (GM-CSF);
- 6. Bcr-Abl kinase inhibitors, such as imatinib (e.g., GLEEVEC®); and dasatinib (e.g., SPRYCEL®);
- 7. bone targeting agents, such as denosumab (e.g., PROLIA®, XGEVA®); and zoledronic acid (e.g., ZOMETA®, RECLAST®);
- 8. GnRH analogs, such as goserelin (e.g., Zoladex®); leuprolide (e.g., LUPRON®); degarelix (e.g., FIRMAGON®); nafarelin (e.g., SYNAREL®);
- 9. anthracyclines, such as idarubicin (e.g., IDAMYCIN®); inparib; gefinitib (e.g., IRESSA®); cetuximab (e.g., ERBITUX®); irinotecan (ERBITUX®); megestrol acetate (e.g., MEGACE®);
- 10. PARP inhibitors, such as olaparib; veliparib; MK4827;
- 11. Akt inhibitors, such as hexadecylphosphocholine (e.g., MILTEFOSINE®); and
- 12. Her3 inhibitors, such as U3-1287.

Nothing in this specification should be considered as limiting the scope of this disclosure. All examples presented are representative and non-limiting. The above-described embodiments can be modified or varied, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the embodiments disclosed herein can be practiced otherwise than as specifically described.

Example 1

RD162′ Blocks DHT-Mediated Proliferation in MCF7 Cells
MCF7 cells are commonly used luminal breast cancer cells that express high levels of ER and some AR. MCF7 cells were plated in phenol red-free medium containing charcoal stripped serum. The next day, cells were treated with vehicle alone (ethanol, EtOH), 10 nM dihydrotestosterone (DHT), 10 μM RD162′ (RD162′), or a combination of DHT+RD162′. An in vitro proliferation assay using the tetrazolium salt MTT was performed at various time points. The values were normalized to an untreated plate read 24 hours after plating to account for differences in cell density. The results are shown in FIG. 1. These experiments demonstrated that RD162′ blocks DHT-mediated growth of MCF7 cells.

Example 2

RD162′ Blocks DHT-Mediated Growth in BCK4 Cells
BCK4 cells are breast cancer cells that express more AR than ER and respond better to androgens than to estrogens. Proliferation of BCK4 cells was assayed as described above in the presence of DHT and in the presence of RD162′ and DHT. The results are shown in FIG. 2. These experiments demonstrated that RD162′ blocks DHT-mediated growth of BCK4 cells.

Example 3

RD162′ Blocks Estradiol-Mediated Growth in MCF7 Cells
MCF7 cells were plated in phenol red-free medium containing charcoal stripped serum. The next day, cells were treated with vehicle alone (EtOH), 10 nM estradiol (E2), 10 μM RD162′, or a combination of E2 and RD162′. An MTT assay was performed at various time points. The values were normalized to an untreated plate read 24 hours after plating to account for differences in cell density. The results are shown in FIG. 3. This experiment demonstrates that RD162′ blocks estradiol-mediated growth of MCF7 cells.

Example 4

RD162′ Blocks E2-Mediated Upregulation of SDF-1 and Progesterone Receptor Gene Expression
Expression of SDF-1, a gene involved in estrogen mediated proliferation, and the progesterone receptor gene (a known estrogen regulated gene and marker of ERα activity, were assayed in the presence or absence of estradiol (E2). RD162′ blocks E2-mediated upregulation of these E2/ER regulated genes, indicating that RD162′ modulates ERα activity, as shown in FIG. 4.

Example 5

In Vivo Studies Demonstrating that RD162′ Inhibits DHT-Mediated Growth in MCF7 Cells Grown in the Mammary Glands of Nod-Scid Mice.
MCF7 cells (1×10⁶cells) engineered to express luciferase were mixed with 100 of matrigel and injected into the mammary fat pad of 6-8 week old ovariectomized nod/scid mice. Two tumors were implanted per mouse, one on each side. The mice had a DHT pellet implanted subcutaneously at the time of injection of tumor cells. Tumor burden was measured by either caliper or whole body in vivo luminescent (IVIS) imaging. At day 22, mice were matched based on tumor burden measured by IVIS imaging and separated into two groups. One group received a control chow and the other received chow containing 50 mg/kg RD162′. The results are shown in FIGS. 5A-D. FIGS. 5A-B depict tumor growth over time. FIGS. 5C-D show individual tumor size at the end of the study.

Example 6

RD162′ Blocks Proliferation of Triple Negative Breast Cancer Cells
A Western blot of four luminal (ER+, PR+) and four triple negative (ER−,PR−, Her2−) breast cancer cell lines for androgen receptor, estrogen receptor and tubulin (as a loading control) was prepared (FIG. 6A). Three of the triple negative cell lines have robust AR expression.
MDA468 and BT20 cells were plated in phenol red-free medium containing charcoal stripped serum. The next day, cells were treated with vehicle alone (EtOH), 10 nM dihydrotestosterone (DHT), 10 μM RD162′, or a combination of DHT and RD162′. An MTT assay was performed at various time points. The values were normalized to an untreated plate read 24 hours after plating to account for differences in cell density. The results are shown in FIGS. 6B-C. This experiment demonstrates that RD162′ blocks growth of triple negative breast cancer cells.

Example 7

RD162′ Inhibits DHT-Induced Proliferation in Apocrine Breast Cancer Cells (AR+, ER−, HER2+, PR−) and Inhibits the In Vivo Growth of these Cells in a Xenograft Model in Mammary Glands of NOD SCID Mice.
The effect of RD162′ on DHT-induced proliferation of apocrine breast cancer cells was assessed in MDA-MB-453 cells, which are AR+, ER−, HER2+, and PR−, using a colorimetric in vitro proliferation assay using the tetrazolium salt MTS (“MTS assay”) and a luciferase assay. The results of the MTS assay are shown in FIG. 7A. These results indicate that 10 μM RD162′ inhibits proliferation induced by 10 nM DHT.
A luciferase assay carried out with MDA-kb2 cells, which were derived from MDA-MB-453 cells but contain an androgen-dependent luciferase reporter, demonstrated that RD162′ inhibits proliferation induced by DHT in a dose dependent manner. The results are shown in FIG. 7B. Error bars reflect the SEM of independent experiments and * indicates P<0.05, ** indicates P<0.01, *** indicates P<0.001 (ANOVA with Bonferroni's multiple comparison test correction).
Immunocytochemical assays were carried out in MDA-kb2 cells using an antibody to AR. Cells were treated for 3 hours with vehicle (Vh), 1 nM DHT, 10 μM RD162′, or 10 μM RD162′ and DHT. The graph shown in FIG. 7C displays the ratio of nuclear to total AR for all cells measured. The results demonstrate that RD162′ inhibits nuclear translocation of AR induced by DHT.
In vivo growth of apocrine breast cancer cells was investigated in a xenograft model in mammary glands of NOD SCID mice. MDA-MB-453 cells (6×10⁶) were injected into the 4^thinguinal mammary fat pad of NOD-SCID-IL2Rgc−/− female mice. A 60-day release DHT pellet was implanted subcutaneously into 3 groups of mice at the time of cell injection. Tumor size was measured using calipers and once the tumors reached 100 mm³, the mice began receiving 10 mg/kg/d RD162′, 25 mg/kg/d RD162′ or vehicle by oral gavage.
The results are shown in FIG. 7D and FIG. 7E. The results demonstrate that RD162′ at either dose inhibited tumor growth induced by DHT (FIG. 7D). Tumors were weighed at necropsy and both doses of RD162′ significantly inhibited DHT induced tumor growth (FIG. 7E). Error bars reflect the SEM and * indicates P<0.05, *** indicates P<0.001 (Mann Whitney).

Example 8

RD162′ Inhibits the Growth of Triple Negative Breast Cancer Cells
Hs578T, a TNBC cell line, was plated in phenol red free DMEM/F12 containing 5% DCC for 2 days before treated with vehicle control, RD162′ (10 μM), DHT (10 nM), and RD162′+DHT for 9 days. Viable cells were assayed by MTS assay. The results are shown in FIG. 8. Averages of the triplicate data points are shown with standard deviation. *** p<0.001 (two-tail t-test). Note that DHT treatment does not increase the growth of Hs578T cells.

Example 9

RD162′ Together with Herceptin Inhibits the Growth of Her2+ Breast Cancer Cells
SKBR3, a Her2+ breast cancer cell line, was grown in DMEM+1% FBS in the presence of vehicle control, 10 μM RD162′, 20 μg/ml of Herceptin, and RD162′+Herceptin respectively for 8 days before analyzed for viable cells with MTS assay. The results are shown in FIG. 9. Averages of the triplicate data points are shown with standard deviation. *p<0.05 and ***p<0.001 (two-tail t-test).

Example 10

RD162′ Inhibits Androgen Stimulated Growth of MDA-MB-453 Tumors
MDA-MB-453 cells were injected orthotopically in the mammary gland of female NOD-SCID-IL2Rgc−/− mice. Three groups had a DHT pellet implanted SQ and one group had no pellet (Vehicle). Once the tumors reached 100 mm³, the mice were given either RD162′ (10 mg/kg) or vehicle (Vehicle and DHT groups) by daily oral gavage. When the tumors reached 400 mm³, another group was given a higher dose of RD162′ (25 mg/kg) by oral gavage. The results are shown in FIGS. 10A-D.
Tumor volume was measured weekly by caliper. Error bars represent SEM. * indicates P<0.05, ** indicates P<0.01 for DHT vs DHT+RD162′ (10 mg/kg), Wilcoxon rank sum (FIG. 10A). There were no significant differences at any time point for DHT vs DHT+RD162′ (25 mg/kg). Tumors were excised and weighed at the end of the experiment (FIG. 10B). Tumor sections stained for cleaved caspase 3 were quantified and representative images shown below (200× magnification). For tumor weights and cleaved caspase 3 staining, * indicates P<0.05, ** indicates P<0.01, *** indicates P<0.001, ANOVA with Bonferroni's multiple comparison test correction (FIG. 10C). Nuclear AR staining was quantified and representative images (400× magnification) are shown below. * indicates P<0.05, *** indicates P<0.001, Kruskal-Wallis with Dunn's multiple comparison test correction (FIG. 10D).

Example 11

RD162′ is as Effective as Tamoxifen at Inhibiting Estrogen Stimulated Tumor Growth.
MCF7-TGL cells stably expressing luciferase were implanted orthotopically in the mammary gland of ovariectomized female nude mice. All mice had an E2 pellet implanted SQ and were either given control chow (E2), control chow plus a tamoxifen pellet implanted SQ (E2+tam) or chow containing 50 mg/kg RD162′ (E2+RD162′). The beginning of treatment is indicated by an arrow. Tumor burden was measured by whole body luminescence. The results are shown in FIGS. 11A-D. Mean total flux of all mice in each of the treatment groups is shown. Mice were matched on day −3 and treatment began on day 0. * indicates P<0.05, ANOVA with Bonferroni's multiple comparison test correction (FIG. 11A). The total luminescent flux is shown for all individual mice at the day of matching (Day −3) and at the final imaging day (Day 11). * indicates P<0.05, ANOVA with Bonferroni's multiple comparison test correction (FIG. 11B). Images of luminescent signal in the two treatment groups at the day of matching (day −2) and the final day of imaging (day 11) is shown (FIG. 11C). Mice were injected with BrdU two hours prior to sacrifice. Immunohistochemistry for BrdU was performed on tumor sections and quantified using image J. Representative images of BrdU staining (left, 400× magnification) and quantification (right) shown are shown. ** indicates P<0.01 for E2 vs E2+Tamoxifen, *** indicates P<0.001 for E2 vs E2+RD162′, ANOVA with Bonferroni's multiple comparison test correction (FIG. 11D).

Claims

1. A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (I):

wherein:

X is selected from the group consisting of trifluoromethyl and iodo;

W is selected from the group consisting of O and NR5, wherein R⁵is selected from the group consisting of H, methyl, and

wherein D is S or O and E is N or O and G is alkyl, aryl,

substituted alkyl or substituted aryl; or D is S or O and E-G together are C1-C4 lower alkyl;

R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group;

R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl, with the proviso that R3 is not methylaminomethyl or dimethylaminomethyl; and

R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl.

2. The method of claim 1, wherein the compound is selected from the group consisting of:

3. The method of claim 1, wherein the compound is enzalutamide:

4. A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (II):

wherein:

Het represents a heterocyclic unit of 5 or 6 atoms;

A and B are independently selected from oxygen, sulfur, and N—R₉;

R₁is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO₂R₁₁, NR₁₁R₁₂, NR₁₂(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, or NR₁₂(CS)OR₁₁;

R₂and R₃are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or, together with the carbon to which they are linked, form a cycle which can be cycloalkyl, substituted cycloalkyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic; or R₂and R₃can be connected to form a cycle which can be heterocyclic aromatic or non aromatic, substituted heterocyclic aromatic or non aromatic;

R₉is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO₂R₁₁, NR₁₁R₁₂, NR₁₂(CO)OR₁₁, NH(CO)NR₁₁R₁₂, NR₁₂(CO)R₁₁, O(CO)R₁₁, O(CO)OR₁₁, O(CS)R₁₁, NR₁₂(CS)R₁₁, NH(CS)NR₁₁R₁₂, or NR₁₂(CS)OR₁₁; and

R₁₁and R₁₂are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic or non-aromatic; or R₁₁and R₁₂can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, or substituted cycloalkyl.

5. The method of claim 3 wherein the compound is selected from the group consisting of:

6. A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (III)

wherein:

W¹is CN, NO₂or SO₂R⁴;

W²is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;

Z¹is S or O

Z²is S, O or NR⁴;

Y¹and Y²are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y¹and Y²are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;

T is carbon or nitrogen and can be at any position in the ring;

R¹is —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^dor —C(O)NR^eR^f, where:

R^ais a C₂-C₁₂alkyl and R^bis H or a C₁-C₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring;

R^cis a C₁-C₁₂alkyl and R^eis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring;

R^eis a C₂-C₁₂alkyl and R^fis H or a C₁-C₂alkyl, or

R^eis a C₁-C₁₂alkyl and R^fis C₁-C₂alkyl, or

R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring;

R²is hydrogen, halogen, nitro, alkyl and substituted alkyl; and

R⁴is independently H, alkyl, or aryl.

7. A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (IV):

wherein:

W¹is CN, NO₂or SO₂R⁴;

Z is S, O or NR⁵;

Y¹and Y²are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y¹and Y²are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;

T is carbon or nitrogen and can be at any position in the ring;

R¹is —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^dor —C(O)NR^eR^f,

R^ais a C₁-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring;

R^cis a C₁-C₁₂alkyl and R^dis H or a C₁-C₁₂alkyl or R^cand R^dare taken together with the N to which they are attached to form a heterocyclic ring;

R^eis a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl, or R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring;

R²is hydrogen, halogen, nitro, alkyl or substituted alkyl;

R⁴is H, alkyl, substituted alkyl, aryl or substituted aryl; and

R⁵is H, alkyl, substituted alkyl, aryl or substituted aryl.

8. A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (V):

wherein:

W¹is CN, NO₂or SO₂R⁴;

W²is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;

Z is S, O or NR⁵;

Y³is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkylhydroxymethyl, substituted alkoxymethyl, thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl; heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;

T is carbon or nitrogen and can be at any position in the ring;

R¹is hydrogen, —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^d, —C(O)NR^eR^for —NR^gR^h,

R^eis H or a C₁-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl, or R^eand R^fare taken together with the N to which they are attached to form a heterocyclic ring;

R^gis H or a C₁-C₁₂alkyl and R^his H or a C₁-C₁₂alkyl, or R^gand R^hare taken together with the N to which they are attached to form a heterocyclic ring;

R²is hydrogen, halogen, nitro, alkyl or substituted alkyl;

R⁴is H, alkyl, substituted alkyl, aryl or substituted aryl; and

R⁵is H, alkyl, substituted alkyl, aryl or substituted aryl.

9. A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (VI): and

wherein:

X is S or O, and

when X is S, then R¹is OH or NH₂; and

when X is O then R¹is OH, NH₂or NHMe.

10. The method of any of claims 1-9, wherein the triple negative breast cancer is a subtype selected from the group consisting of basal-like type 1 (BL1), basal-like type 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR) subtypes.

11. The method of any of claims 1-10, wherein cells of the triple negative breast cancer comprise a BRCA1 mutation.

12. A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (I):

wherein:

X is selected from the group consisting of trifluoromethyl and iodo;

W is selected from the group consisting of O and NR5, wherein R5 is selected from the group consisting of H, methyl, and

wherein D is S or O and E is N or O and G is alkyl, aryl,

13. The method of claim 12, wherein the compound is selected from the group consisting of:

14. The method of claim 12, wherein the compound is enzalutamide:

15. A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (II):

wherein:

Het represents a heterocyclic unit of 5 or 6 atoms;

A and B are independently selected from oxygen, sulfur, and N—R₉;

16. The method of claim 15 wherein the compound is selected from the group consisting of:

17. A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (II):

wherein:

W¹is CN, NO₂or SO₂R⁴;

Z¹is S or O

Z²is S, O or NR⁴;

T is carbon or nitrogen and can be at any position in the ring;

R is —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^dor —C(O)NR^eR^f, where:

R^eis a C₂-C₁₂alkyl and R^fis H or a C₁-C₁₂alkyl, or

R^eis a C₁-C₁₂alkyl and R^fis C₁-C₁₂alkyl, or

R²is hydrogen, halogen, nitro, alkyl and substituted alkyl; and

R⁴is independently H, alkyl, or aryl.

18. A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (IV):

wherein:

W¹is CN, NO₂or SO₂R⁴;

Z is S, O or NR⁵;

T is carbon or nitrogen and can be at any position in the ring;

R²is hydrogen, halogen, nitro, alkyl or substituted alkyl;

R⁴is H, alkyl, substituted alkyl, aryl or substituted aryl; and

R⁵is H, alkyl, substituted alkyl, aryl or substituted aryl.

19. A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (V):

wherein:

W¹is CN, NO₂or SO₂R⁴;

Z is S, O or NR⁵;

T is carbon or nitrogen and can be at any position in the ring;

R¹is hydrogen, —C₁-C₈alkyl-NR^aR^b, —O—C₁-C₈alkyl-NR^cR^d, —C(O)NR^eR^for —NR^gR^h, R^ais a C₁-C₁₂alkyl and R^bis H or a C₁-C₁₂alkyl or R^aand R^bare taken together with the N to which they are attached to form a heterocyclic ring;

R²is hydrogen, halogen, nitro, alkyl or substituted alkyl;

R⁴is H, alkyl, substituted alkyl, aryl or substituted aryl; and

R⁵is H, alkyl, substituted alkyl, aryl or substituted aryl.

20. A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (VI):

wherein:

X is S or O, and

when X is S, then R¹is OH or NH₂; and

when X is O then R¹is OH, NH or NHMe

21. The method of any of claims 12-20, wherein the patient is post-menopausal.

22. The method of any of claims 12-21, wherein the endocrine therapy is administration of an aromatase inhibitor.

23. The method of any of claims 12-21, wherein the endocrine therapy is administration of an estrogen receptor modulator.

24. The method of any of claims 1-23 wherein the breast cancer comprises cells that do not express detectable androgen receptor.

25. The method of any of claims 1-23 wherein the breast cancer comprises cells that express an androgen receptor.

26. The method of any of claims 1-25 further comprising administering to the patient a second therapeutic treatment.