IP Library › Granted Patent US 10,287,295

Granted Patent B2

US 10,287,295 · App. 15/860,379 · Granted May 14, 2019

TGF-β inhibitors

Inventors: Todd Kinsella (Redwood City, CA); Marina Gelman (San Francisco, CA); Hui Hong (Foster City, CA); Ihab S. Darwish (San Carlos, CA); Rajinder Singh (Belmont, CA); Jiaxin Yu (San Carlos, CA); Robert M. Borzilleri (Carversville, PA); Upender Velaparthi (Cheshire, CT); Peiying Liu (Madison, CT); Chetan Padmakar Darne (Orange, CT); Hasibur Rahaman (Bangalore, IN); Jayakumar Sankara Warrier (Bangalore, IN)

Assignees: Rigel Pharmaceuticals, Inc.; Bristol-Meyers Squibb Company

C07D487/04 C07D401/04 C07D403/04 C07D417/04 C07D471/04

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Quick Facts

Patent No.: US 10,287,295
App. No.: 15/860,379
Granted: May 14, 2019
Kind: B2

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Abstract

Disclosed are imidazole and thiazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein X, A, Z, R 1 and R′ are as described herein. In certain embodiments, a compound disclosed herein inhibits TGF-β, and can be used to treat disease by blocking TGF-β signaling.

Claims (697)

1. A method of TGF-β superfamily of growth factors, the method comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula (I ∘ ),

or a pharmaceutically acceptable salt thereof,

wherein

X is —S— or —N(R′)—;

R′ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, —(C 0 -C 12 alkyl)-cycloalkyl or —(C 0 -C 6 alkyl)-heterocycloalkyl, each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —OR S0 , C 1 -C 6 alkyl-OR S0 , —C(O)OR S0 , —C(O)R S0 , —C(O)NR S0 2 , —R S0 or cyano;

wherein each R S0 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, —OR S1 , —NR S1 2 , —SR S1 or —N(R S1 )C(O)R S1 , each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

wherein each R S1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

A′ is phenyl optionally substituted with one to five R 2 groups, wherein

each R 2 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —NO 2 , —N(R S2 )C(O)R S2 , —OR S2 , —C(O)NR S2 2 , —N(R S2 )S(O) 2 R S2 , —S(O) 2 R S2 , —(C 0 -C 6 alkyl)-aryl or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —OR S2 , —SR S2 , —NR S2 2 , —C(O)OR S2 , —C(O)NR S2 2 , —C(O)R S2 , —S(O)R S2 , —S(O) 2 R S2 , —S(O)OR S2 , —S(O) 2 OR S2 , —S(O)NR S2 2 , —S(O) 2 NR S2 2 , —OC(O)R S2 , —OC(O)OR S2 , —OC(O)NR S2 2 , —N(R S2 )C(O)R S2 , —N(R S2 )C(O)OR S2 , —N(R S2 )C(O)NR S2 2 , —N(R S2 )S(O)R S2 , —N(R S2 )S(O) 2 R S2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

wherein each R S2 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

Z is

a fused bicyclic ring of the formula,

wherein

ring A is aryl or 5- or 6-membered heteroaryl,

ring B is 5- or 6-membered heteroaryl,

wherein

Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-heterocycloalkyl, —OR S3 , —SR S3 , —NR S3 2 , —C(O)R S3 , —C(O)OR S3 , —C(O)NR S3 2 , —C(NR S3 )NR S3 OR S3 , —S(O) 2 NR S3 2 , —S(O) 2 R S3 , —OC(O)R S3 , —N(R S3 )C(O)R S3 , —OC(O)OR S3 , —OC(O)NR S3 2 , —N(R S3 )C(O)OR S3 , —N(R S3 )C(O)NR S3 2 , —N(R S3 )S(O) 2 R S3 , —OP(O)(OR S3 ) 2 or —CH 2 —OP(O)(OR S3 ), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —R Z2 groups;

wherein each R S3 is independently hydrogen, —NR S3 2 , —OR S3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, —C(O)NR S4 2 or cyano; and

each —R Z2 is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR S4 , —SR S4 , —NR S4 2 , —C(O)R S4 , —C(O)OR S4 , —C(O)NR S4 2 , —S(O) 2 NR S4 2 , —S(O) 2 R S4 , —OC(O)R S4 , —N(R S4 )C(O)R S4 , —OC(O)OR S4 , —OC(O)NR S4 2 , —N(R S4 )C(O)OR S4 , —N(R S4 )C(O)NR S4 2 , —N(R S4 )S(O) 2 R S4 , —OP(O)(OR S4 ) 2 or —CH 2 —OP(O)(OR S4 ); and

wherein each R S4 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with one or two C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

provided that

(a) when ring A is aryl, ring B is not triazolyl or imidazolidin-2-onyl; and

(b) Z is not

2. The method of claim 1 wherein the compound has the structure of formula (I), (I)

or a pharmaceutically acceptable salt thereof,

wherein

X is —S— or —N(R′)—;

R′ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy or, each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, —OR S1 , —NR S1 2 or, —SR S1 , each optionally substituted with 1 to 3 moieties that are each independently C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

A′ is phenyl optionally substituted with one to five R 2 groups, wherein

each R 2 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —NO 2 or —CN, wherein each alkyl, haloalkyl and alkoxy are optionally substituted with 1, 2, 3, or 4 groups that are each independently halogen, cyano, nitro, —OR S2 , —SR S2 , —NR S2 2 , —C(O)OR S2 , —C(O)NR S2 2 , —C(O)R S2 , —S(O)R S2 , —S(O) 2 R S2 , —S(O)OR S2 , —S(O) 2 OR S2 , —S(O)NR S2 2 , —S(O) 2 NR S2 2 , —OC(O)R S2 , —OC(O)OR S2 , —OC(O)NR S2 2 , —N(R S2 )C(O)R S2 , —N(R S2 )C(O)OR S2 , —N(R S2 )C(O)NR S2 2 , —N(R S2 )S(O)R S2 , —N(R S2 )S(O) 2 R S2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

Z is

a fused bicyclic ring of the formula,

wherein

ring A is aryl or 5- or 6-membered heteroaryl,

ring B is 5- or 6-membered heteroaryl,

wherein

Z is optionally substituted by one or two —R Z groups that are each independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —C 1 -C 6 alkoxy, —OR S3 , —SR S3 , —NR S3 2 , —C(O)R S3 , —C(O)OR S3 , —C(O)NR S3 2 , —S(O) 2 NR S3 2 , —S(O) 2 R S3 , —OC(O)R S3 , —N(R S3 )C(O)R S3 , —OC(O)OR S3 , —OC(O)NR S3 2 , —N(R S3 )C(O)OR S3 , —N(R S3 )C(O)NR S3 2 , —N(R S3 )S(O) 2 R S3 , —OP(O)(OR S3 ) 2 , or —CH 2 —OP(O)(OR S3 ), wherein each alkyl, haloalkyl and alkoxy is optionally substituted by one or two —R Z2 groups;

wherein each R S3 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano; and

provided that

(a) when ring A is aryl, ring B is not triazolyl or imidazolidin-2-onyl; and

(b) Z is not

3. The method of claim 1 , wherein

Z is

(a) a fused bicyclic ring of the formula,

wherein

(1) ring A is -aryl, and

ring B is a 6-membered heteroaryl; or

(2) ring A is 6-membered heteroaryl, and

ring B is a 5-membered heteroaryl; or

(b)

wherein

z is CH, O, S or N;

y is CH, CH 2 , or N; and

x is CH, O, S, or N(R a );

provided that when z is N and x is N(R a ), y is not N;

wherein R a is hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C(O)OR, —C(O)NR 2 , —C(O)R, —S(O)R, —S(O) 2 R, —S(O)OR, —S(O) 2 OR, or —S(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —OC(O)OR, or —OC(O)NR 2 ;

wherein each R is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —(C 0 -C 6 alkyl)-aryl, —(C 0 -C 6 alkyl)-heteroaryl, —(C 0 -C 6 alkyl)-cycloalkyl, or —(C 0 -C 6 alkyl)-heterocycloalkyl, wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, and haloalkyl are optionally substituted with C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl or cyano;

wherein Z is optionally substituted by one or two —R Z groups.

4. The method of claim 1 wherein the compound is,

5-(4-Phenyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-Phenyl-1H-imidazol-5-yl)-1H-indazole,

5-(4-(4-Fluoro-3-methylphenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

5-(4-(4-Chlorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(4-Fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

5-(4-(4-Fluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluorophenyl)-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(4-Fluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(4-Fluorophenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

5-(4-(m-Tolyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(m-Tolyl)-1H-imidazol-5-yl)-1H-indazole,

1-Methyl-6-(4-(m-tolyl)-1H-imidazol-5-yl)-1H-benzo[d]imidazole,

6-(4-(m-Tolyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(m-Tolyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(m-Tolyl)-1H-imidazol-5-yl)quinoxaline,

6-(4-(4-Fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)quinoxaline,

5-(4-(3-Chlorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(3-Chlorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3-Chlorophenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

5-(4-(3-Fluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Fluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Fluorophenyl)-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(3-Fluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

5-(4-(3,4-Difluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(3,4-Difluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3,4-Difluorophenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(3,4-Difluorophenyl)-1H-imidazol-5-yl)quinoline,

6-(4-(4-Fluoro-3-methylphenyl)-1-methyl-1H-imidazol-5-yl)quinoline,

6-(4-(4-Fluorophenyl)-1H-imidazol-5-yl)quinoline,

6-(4-(3-Chlorophenyl)-1H-imidazol-5-yl)quinoline,

6-(4-(3-Fluorophenyl)-1H-imidazol-5-yl)quinolone,

5-(1-Methyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-indazole,

6-(1-Methyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-indazole,

1-Methyl-6-(1-methyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-benzo[d]imidazole,

6-(1-Methyl-4-(m-tolyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(1-Methyl-4-(m-tolyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(1-Methyl-4-(m-tolyl)-1H-imidazol-5-yl)quinoline,

6-(1-Methyl-4-(m-tolyl)-1H-imidazol-5-yl)quinoxaline,

5-(4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(4-Fluorophenyl)-1-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

5-(4-(4-Fluoro-3-methylphenyl)-1,2-dimethyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-1,2-dimethyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-1,2-dimethyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(4-Fluoro-3-methylphenyl)-1,2-dimethyl-1H-imidazol-5-yl)benzo[d]thiazole,

5-(1,2-Dimethyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-indazole,

6-(1,2-Dimethyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-indazole,

6-(1,2-Dimethyl-4-(m-tolyl)-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(1,2-Dimethyl-4-(m-tolyl)-1H-imidazol-5-yl)benzo[d]thiazole,

5-(4-(3-Chlorophenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(3-Chlorophenyl)-1-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

5-(4-(3,4-Difluorophenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-1-methyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(3,4-Difluorophenyl)-1-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3,4-Difluorophenyl)-1-methyl-1H-imidazol-5-yl)quinoxaline,

5-(4-(4-Methoxyphenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Methoxyphenyl)-1-methyl-1H-imidazol-5-yl)-1H-indazole,

5-(4-(4-Fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(4-Fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(4-Fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)quinoline,

6-(4-(4-Fluoro-3-methylphenyl)-2-methyl-1H-imidazol-5-yl)quinoxaline,

5-(4-(4-Fluorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(4-Fluorophenyl)-2-methyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(4-Fluorophenyl)-2-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(4-Fluorophenyl)-2-methyl-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(4-Fluorophenyl)-2-methyl-1H-imidazol-5-yl)quinoxaline,

5-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)-1-methyl-1H-benzo[d]imidazole,

6-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)quinoline,

6-(4-(3,4-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)quinoxaline,

5-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)quinoline,

6-(2-Methyl-4-(3,4,5-trifluorophenyl)-1H-imidazol-5-yl)quinoxaline,

5-(2-Methyl-4-(2,4,5-trifluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Methyl-4-(2,4,5-trifluorophenyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Methyl-4-(2,4,5-trifluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Methyl-4-(2,4,5-trifluorophenyl)-1H-imidazol-5-yl)quinoline,

5-(4-(3-Chlorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-2-methyl-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(4-(3-Chlorophenyl)-2-methyl-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(3-Chlorophenyl)-2-methyl-1H-imidazol-5-yl)quinoline,

5-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)quinoline,

6-(2-Ethyl-4-(4-fluoro-3-methylphenyl)-1H-imidazol-5-yl)quinoxaline,

5-(2-Ethyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(m-tolyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(m-tolyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Ethyl-4-(m-tolyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Ethyl-4-(m-tolyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(2-Ethyl-4-(m-tolyl)-1H-imidazol-5-yl)quinoxaline,

5-(2-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

5-(4-(3-Chlorophenyl)-2-ethyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chlorophenyl)-2-ethyl-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(4-(3-Chlorophenyl)-2-ethyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3-Chlorophenyl)-2-ethyl-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(3-Chlorophenyl)-2-ethyl-1H-imidazol-5-yl)quinoline,

6-(4-(3-Chlorophenyl)-2-ethyl-1H-imidazol-5-yl)quinoxaline,

5-(4-(3,4-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,4-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(4-(3,4-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3,4-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(4-(3,4-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)quinoxaline,

6-(2-Ethyl-4-(3-fluorophenyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Ethyl-4-(3-fluorophenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Ethyl-4-(3-fluorophenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

5-(4-(3-Chloro-5-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3-Chloro-5-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3-Chloro-5-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)quinoxaline,

5-(2-Ethyl-4-(3-fluoro-5-methylphenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(3-fluoro-5-methylphenyl)-1H-imidazol-5-yl)-1H-indazole,

6-(2-Ethyl-4-(3-fluoro-5-methylphenyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Ethyl-4-(3-fluoro-5-methylphenyl)-1H-imidazol-5-yl)benzo[d]thiazole,

6-(2-Ethyl-4-(3-fluoro-5-methylphenyl)-1H-imidazol-5-yl)imidazo[1,2-a]pyridine,

6-(2-Ethyl-4-(3-fluoro-5-methylphenyl)-1H-imidazol-5-yl)quinoxaline,

5-(4-(3,5-Difluorophenyl)-2-methyl-1H-imidazol-5-yl)-1H-indazole,

6-(4-(3,5-Difluorophenyl)-2-ethyl-1H-imidazol-5-yl)benzo[d]thiazole,

6-(4-(3-Chlorophenyl)-2-(trifluoromethyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(4-(4-Fluorophenyl)-2-(trifluoromethyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

6-(2-Isopropyl-4-(m-tolyl)-1H-imidazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine,

5-(1H-indazol-6-yl)-4-(m-tolyl)thiazole,

5-(1H-indazol-5-yl)-4-(m-tolyl)thiazole,

4-(4-fluoro-3-methylphenyl)-5-(imidazo[1,2-a]pyridin-6-yl)thiazol-2-amine,

4-(4-fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)thiazole,

5-(1H-indazol-5-yl)-4-(4-methoxyphenyl)thiazol-2-amine,

4-(4-fluoro-3-methylphenyl)-5-(quinoxalin-6-yl)thiazol-2-amine,

4-(4-fluoro-3-methylphenyl)-5-(1H-indazol-6-yl)thiazole,

4-(4-fluoro-3-methylphenyl)-5-(1H-indazol-5-yl)thiazol-2-amine,

6-(4-(m-tolyl)thiazol-5-yl)benzo[d]thiazole,

5-(benzo[d]thiazol-6-yl)-4-(4-fluoro-3-methylphenyl)thiazol-2-amine,

5-(imidazo[1,2-a]pyridin-6-yl)-4-(4-methoxyphenyl)thiazol-2-amine,

4-(3-chlorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)thiazol-2-amine,

6-(4-(4-fluoro-3-methylphenyl)thiazol-5-yl)benzo[d]thiazole,

6-(4-(3-chlorophenyl)thiazol-5-yl)benzo[d]thiazole,

4-(4-fluoro-3-methylphenyl)-5-(imidazo[1,2-a]pyridin-6-yl)thiazole,

4-(3-chlorophenyl)-5-(1H-indazol-5-yl)thiazol-2-amine,

4-(3-chlorophenyl)-5-(quinoxalin-6-yl)thiazol-2-amine,

4-(4-fluorophenyl)-5-(quinoxalin-6-yl)thiazol-2-amine,

5-(imidazo[1,2-a]pyridin-6-yl)-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine,

4-(3-chlorophenyl)-5-(1H-indazol-6-yl)thiazol-2-amine,

5-(1H-indazol-6-yl)-4-(4-methoxyphenyl)thiazol-2-amine,

4-(4-fluoro-3-methylphenyl)-5-(1H-indazol-6-yl)thiazol-2-amine,

5-(1H-indazol-5-yl)-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine,

5-(benzo[d]thiazol-6-yl)-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine,

5-(1H-indazol-5-yl)-4-(3-methoxyphenyl)thiazol-2-amine,

5-(benzo[d]thiazol-6-yl)-4-(3-fluorophenyl)thiazol-2-amine,

4-(3-fluorophenyl)-5-(1H-indazol-5-yl)thiazol-2-amine,

5-(quinoxalin-6-yl)-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine,

6-(4-(4-fluorophenyl)thiazol-5-yl)benzo[d]thiazole,

4-(4-methoxyphenyl)-5-(quinoxalin-6-yl)thiazol-2-amine,

4-(3-fluorophenyl)-5-(quinoxalin-6-yl)thiazol-2-amine,

5-(imidazo[1,2-a]pyridin-6-yl)-4-(3-methoxyphenyl)thiazol-2-amine,

5-(1H-indazol-6-yl)-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine,

5-(benzo[d]thiazol-6-yl)-4-(3-methoxyphenyl)thiazol-2-amine,

4-(3-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)thiazol-2-amine, or

4-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)-N-methylthiazol-2-amine,

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 wherein the compound has the structure of formula (II),

or a pharmaceutically acceptable salt thereof,

wherein

R′ is hydrogen or C 1 -C 6 alkyl;

R 1 is hydrogen or C 1 -C 6 alkyl;

each R 2 is independently hydrogen, halogen or —C 1 -C 6 alkyl;

Z is

(a) a fused bicyclic ring of the formula,

wherein

ring A is 6-membered heteroaryl, and

ring B is a 5-membered heteroaryl; or

(b)

wherein

z is CH, O, S or N;

y is CH, CH 2 , or N; and

x is CH, O, S, or N(R a );

provided that when z is N and x is N(R a ), y is not N;

wherein R a is hydrogen or —C 1 -C 6 alkyl.

6. The method of claim 5 , wherein

Z is

7. The method of claim 6 , wherein the compound is