Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

• US 20050192253A1
• Filed: 10/25/2004
• Published: 09/01/2005
• Est. Priority Date: 09/19/2000
• Status: Active Grant

• Current Assignee: Aberra Fura, Dacia A. Pickering, Hai-Yun Xiao, Jacques Y. Roberge, James Aaron Balog, James R. Corte, Mark E. Salvati, Raj N. Misra, Ramesh N. Patel, Richard A. Rampulla, Ronald L. Hanson, Soren Giese, Steven H. Spergel, Toomas Mitt, Wenying Li
• Original Assignee: Aberra Fura, Dacia A. Pickering, Hai-Yun Xiao, Jacques Y. Roberge, James Aaron Balog, James R. Corte, Mark E. Salvati, Raj N. Misra, Ramesh N. Patel, Richard A. Rampulla, Ronald L. Hanson, Soren Giese, Steven H. Spergel, Toomas Mitt, Wenying Li
• Inventors: Salvati, Mark E., Corte, James R., Balog, James Aaron, Roberge, Jacques Y., Xiao, Hai-Yun, Li, Wenying, Pickering, Dacia A., Rampulla, Richard A., Spergel, Steven H., Patel, Ramesh N., Mitt, Toomas, Fura, Aberra, Hanson, Ronald L., Misra, Raj N., Giese, Soren
• Granted Patent: US 7,141,578 B2
• Time in Patent Office: Days
• US Class Current: 514/80
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07D 401/08 linked by a carbon chain containing alicyclic rings
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 487/18 Bridged systems
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 491/18 Bridged systems
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 495/08 Bridged systems
• CPC Class Codes: C07D 495/18 Bridged systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C40B 40/00 Libraries per se, e.g. arrays, mixtures

Abstract

Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.

Claims

1-26. -26. (canceled)

27. A compound of the following formula:

28. The compound of claim 27 wherein:

G is a monocyclic aryl group which is optionally substituted at one or more positions;

Z₁ and Z₂ are independently O or S;

A₁ and A₂ are CR⁷, wherein each R⁷ group of each of A₁ and A₂ is other than hydrogen;

Y′

is —

O—

(CR⁷R^7′

)_n where n=0 or 1;

W′

is —

CR⁷R^7′

—

CR⁷R^7′

—

wherein every R⁷ and R^7′

group of W′

is not simultaneously hydrogen;

Q₁ and Q₂ are independently H, alkyl or substituted alkyl; and

L is a bond or (CR⁷R^7′

)_n where n=1-2;

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

29. The compound of claim 28 wherein:

R¹ and R^1′

are each independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, heterocyclo or substituted heterocyclo, and aryl or substituted aryl;

R⁴ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkylalkyl or substituted cycloalkylalkyl, arylalkyl or substituted arylalkyl, —

C(═

O) R¹, —

C(═

O)OR¹, —

C(═

O)NHR¹, —

SO₂R¹ or —

SO₂NR¹R^1′

;

R⁵ is alkyl or substituted alkyl, —

C(═

O) R¹, —

SO₂R¹, or —

SO₂NR¹R^1′

; and

R⁷ and R^7′

are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, halo, cyano, OR⁴, —

NHR⁴, —

NR⁵R⁵, —

C(═

O)R¹, —

OC(═

O)R¹, —

C(═

O)OR¹, —

C(═

O)NR¹R^1′

, —

SO₂R¹, or —

SO₂NR¹R^1′

;

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

30. The compound of claim 27, wherein

G is phenyl substituted at two or three positions;

Z₁ and Z₂ are O;

W′

is —

CR⁷R^7′

—

CR⁷R^7′

—

, wherein every R⁷ and R⁷ group of W′

is not simultaneously hydrogen;

Q₁ and Q₂ are both hydrogen; and

L is a bond;

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

31. The compound of claim 30, wherein

R¹ and R^1′

are each independently selected from H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, heterocyclo or substituted heterocyclo, and aryl or substituted aryl;

R⁴ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkylalkyl or substituted cycloalkylalkyl, arylalkyl or substituted arylalkyl, —

C(═

O) R¹, —

C(═

O)OR¹, —

C(═

O)NHR¹, —

SO₂R¹ or —

SO₂NR¹R^1′

;

R⁵ is alkyl or substituted alkyl, —

C(═

O) R¹, —

SO₂R¹, or —

SO₂NR¹R¹; and

R⁷ and R^7′

are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, halo, cyano, OR⁴, —

NHR⁴, —

NR⁵R⁵, —

C(═

O)R¹, —

OC(═

O)R¹, —

C(═

O)OR¹, —

C(═

O)NR¹R^1′

, —

SO₂R¹, or —

SO₂NR¹R^1′

;

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

32. The compound of claim 27 wherein

G is

wherein R′

and R″

are selected from hydrogen, trifluoromethyl, methyl, halogen, nitro, cyano, and alkyl;

Z₁ and Z₂ are O;

W′

is —

CH₂—

CHR⁷—

;

Q₁ and Q₂ are both hydrogen;

A₁ and A₂ are selected from C(alkyl) and C(substituted alkyl);

R¹ and R^1′

are selected from alkyl, substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, heterocyclo or substituted heterocyclo, and aryl or substituted aryl;

R⁷ is selected from alkyl or substituted alkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, halo, cyano, OR⁴, —

NHR⁴, —

NR⁵R⁵, —

C(═

O)R¹, —

OC(═

O)R¹, —

C(═

O)OR¹, —

C(═

O)NR¹R^1′

, —

SO₂R¹, and —

SO₂NR¹R^1′

;

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

33. The compound of claim 27 wherein

W′

is —

CH₂—

CHR⁷—

; and

R⁷ is selected from alkyl or substituted alkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, halo, cyano, OR⁴, —

NHR⁴, —

NR⁵R⁵, —

C(═

O)R¹, —

OC(═

O)R¹, —

C(═

O)OR¹, —

C(═

O)NR¹R^1′

, —

SO₂R¹, and —

SO₂NR¹R^1′

;

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

34. The compound of claim 27 wherein A₁ and A₂ are both —

C(CH₃).

35. The compound of claim 27 wherein the compound is:

42. A pharmaceutical composition capable of treating a nuclear hormone receptor-associated condition, comprising at least one compound of claim 27, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof;

and a pharmaceutically acceptable carrier.

44. The pharmaceutical composition of claim 42 further comprising another anti-cancer agent.

45. The pharmaceutical composition of claim 44 wherein the at least one compound is (3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-alkylsulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile or a pharmaceutically acceptable salt, solvate or prodrug thereof.

51. A method for preparation of a compound of the following formula XVI, or salt thereof:

52. A method for preparation of a compound of the following formula XVIII, or salt thereof:

36. A compound having the formula,

37. A compound selected from the group consisting of:

(i) (3aα

,4β

,5β

,7β

,7aα

)-4-[Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-1-isoquinolinecarbonitrile (748D);

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile (471 Di);

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile (471Dii);

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[7-[2-[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (744);

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[7-[2-(3-Fluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (745);

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[7-[2-(4-Fluorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[7-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl] -8-quinolinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (737);

[3aS-(3aα

,4β

,7β

,7aα

)]-5-[4-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (577);

[3aS-(3aα

,4β

,7β

,7aα

)]-5-[Octahydro-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (579);

[3aS-(3aα

,4β

,7β

,7aα

)]-5-[4-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (581);

[3aS-(3aα

,4β

,7β

,7aα

)]-5-[Octahydro-4-methyl-7-[2-(5-methyl-2H-1,2,3-benzotriazol-2-yl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl] -8-quinolinecarbonitrile (589);

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]ethyl]-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (689);

[3aR-(3aα

,4β

,7β

,7aα

)]-5-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-8-quinolinecarbonitrile (487);

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile (489Gi);

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile (489Gii);

(3aα

,4β

,7β

,7aα

)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-1,2-benzenedicarbonitrile (313);

(3aα

,4β

,7β

,7aα

)-2-Methoxy-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile (328);

(3aα

,4β

,7β

,7aα

)-5-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-8-quinolinecarbonitrile (345);

(3aα

,4β

,7β

,7aα

)-2-(Methylthio)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)benzonitrile (224);

(3aα

,4β

,7β

,7aα

)-2-(6-Benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (368);

(3aα

,4β

,7β

,7aα

)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2,1,3-benzoxadiazole-4-carbonitrile (423);

(3aα

,4β

,7β

,7aα

)-2-(2,1,3-Benzoxadiazol-5-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (480B);

[3aS-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5β

,6α

,7β

,7aα

)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3methyl-2-pyridinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-2-(2,1,3-Benzoxadiazol-5-yl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3,4-dimethyl-2-pyridinecarbonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3,4-dimethyl-2-pyridinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-2-(6-Benzothiazolyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1 H-isoindole-1,3(2H)-dione;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-2-(7-Chloro-2,1,3-benzoxadiazol-4-yl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

(3aα

,4β

,5α

,6β

,7β

,7aα

)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-6-cyano-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic acid, methyl ester;

(3aα

,4β

,7β

,7aα

)-4-(Octahydro-4,7,8-trimethyl-1,3-dioxo-4,7-imino-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5β

,6α

,7β

,7aα

)]-4-(Octahydro-5,6-dichloro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5β

,6α

,7β

,7aα

)]-4-(Octahydro-5,6-dichloro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,7β

,7aα

)-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[difluoromethyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[phenylmethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[propyloxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[cyclopropylmethyloxy]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[methoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2,3-dichlorobenzonitrile;

[3aR-(3aα

,4β

,4aα

,5aα

,6β

,7aα

)]-4-(Octahydro-4a-hydroxy-4,6-dimethyl-1,3-dioxo-4,6-epoxycycloprop[f]isoindol-2(1H)-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N,N-dimethyl-1H-isoindole-5-carboxamide;

[3aR-(3aα

,4β

,5β

,6β

,7β

,7aα

)]-4-(Octahydro-5-chloro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5β

,6β

,7β

,7aα

)]-4-(Octahydro-5-chloro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[5-chloro-2-pyridinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[[phenylamino]carbonyl];

amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[(1-methylethyloxy)carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[5-fluoro-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[ethyloxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic acid, 4-pyridinylmethyl ester;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[4-pyridinylmethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)2-(trifluoromethyl)benzonitrile;

3aα

,4β

,5β

,7β

,7aα

)-4-(Octahydro-5-[[[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]oxy]methyl]-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic acid, methyl ester;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-cyclopropylmethoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[((phenylmethyl)amino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-cyclopropyloxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-2-(4-Chloro-3-iodophenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

[3aS-(3aα

,4β

,5β

,6α

,7β

,7aα

)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,7β

,7aα

)]-4-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-2-(4-Chloro-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-2-(4-Chloro-3-(trifluoromethyl)pyridinyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl 1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-5-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,7β

,7aα

)]-5-(Octahydro-4,7-dimethyl-1,3,5-trioxo-4,7-epoxy-2H-isoindol-2-yl)-3-(trifluoromethyl)-2-pyridinecarbonitrile;

[3aS-(3aα

,4β

,5β

,7β

,7aα

)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-2-(4-Chloro-2-methyl-3-(trifluoromethyl)phenyl)hexahydro-5-hydroxy-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione;

(3aα

,4β

,6β

,7β

,7aα

)-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic acid, methyl ester;

[3aS-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-ethylsulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[(4-fluorophenylamino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[(1-methylethylamino)carbonyl]oxy]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[(1-methylethoxy)carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile;

[3aR-(3aα

,4β

,5α

,7α

,7aα

)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-N-methyl-N-phenyl-1H-isoindole-5-carboxamide;

[3aR-(3aα

,4β

,5β

,7β

,7aα

)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-chloro-3-methylbenzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[ethoxycarbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aS-(3aα

,4β

,5α

,6β

,7β

,7aα

)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic acid, methyl ester;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-[[[6-(trifluoromethyl)-4-pyrimidinyl]oxy]methyl]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-methoxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carbonitrile;

[3aR-(3aα

,4β

,5β

,6α

,7β

,7aα

)]-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-methyl-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[[(cyclopropylmethyl)amino]carbonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[(dimethylamino)sulfonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-benzenesulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,6β

,7β

,7aα

)]-4-(Octahydro-6-fluoro-5,5-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

[3aR-(3aα

,4β

,5α

,6β

,7β

,7aα

)]-2-(4-Cyano-3-(trifluoromethyl)phenyl)-hexahydro-6-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-1H-isoindole-5-carboxylic acid, methyl ester; and

[3aR-(3aα

,4β

,5α

,7β

,7aα

)]-4-(Octahydro-5-[[(dimethylamino)sulfonyl]amino]-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile;

(ii) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

38. A compound having the formula,

39. A compound according to claim 38 having the formula,

40. A compound according to claim 38 having the formula,

41. A compound according to claim 38, wherein G is

43. A pharmaceutical composition capable of treating a nuclear hormone receptor-associated condition, comprising at least one compound of claim 38, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof;

and a pharmaceutically acceptable carrier.

46. A method of modulating the function of a nuclear hormone receptor which comprises administering to a mammalian species in need thereof an effective nuclear hormone receptor modulating amount of at least one compound of the following formula Ia:

47. The method of claim 46 wherein the at least one compound is (3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-alkylsulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

48. The method of claim 46 wherein the nuclear hormone receptor is androgen receptor.

49. A method for treating a condition or disorder comprising administering to a mammalian species in need thereof a therapeutically effective amount of at least one compound of the following formula:

50. The method of claim 49 wherein said condition or disorder is prostate cancer and the at least one compound is a (3aα

,4β

,5α

,7β

,7aα

)-4-(Octahydro-5-alkylsulfonamido-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-(trifluoromethyl)benzonitrile or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof

53. A compound having the formula,

54. A compound according to claim 53, wherein R⁷ is —

NHSO₂(CH₂CH₃).

55. A pharmaceutical composition comprising one or more compounds according to claim 53, in a pharmaceutically-acceptable carrier or diluent.