Piperidine or piperazine linked imidazole and triazole derivatives and methods of use

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

n is 1;

W is —N═ or —CH═;

X is —N(R 3 )—;

R 1 is selected from —(C 1 -C 6 alkylene)-aryl, —(C 1 -C 6 alkylene)-(5 or 6-membered heteroaryl), —(C 1 -C 6 alkylene)-O-aryl, —(C 1 -C 6 alkylene)-O-(5 or 6-membered heteroaryl) and C 3 -C 6 cycloalkyl, wherein any aryl, heteroaryl or C 3 -C 6 cycloalkyl group can be optionally substituted with up to four R 9 groups, which can be the same or different, and wherein said C 3 -C 6 cycloalkyl group can be fused to a benzene ring and said fused benzene ring can be optionally substituted with up to four R 9 groups, which can be the same or different;

one occurrence of R 2 is H and the other occurrence of R 2 is C 1 -C 6 alkyl;

R 3 is selected from Y, —O—Y, —C(O)—Y, —(C 1 -C 6 alkylene)-Y, —(C 1 -C 6 alkylene)-C(O)—Y, —(C 1 -C 6 alkylene)-C(O)—O—Y and —(C 1 -C 6 alkylene)-O—Y, wherein each Y is independently selected from:

(1) C 1 -C 4 alkyl,

(2) C 1 -C 4 haloalkyl,

(3) C 1 -C 4 hydroxyalkyl,

(4) C 3 -C 6 cyclohaloalkyl,

(5) C 3 -C 6 cycloalkyl,

(6) phenyl, wherein said phenyl group can be optionally substituted with up to four R 7 groups,

(7) 5 or 6-membered heteroaryl, wherein said 5 or 6-membered heteroaryl group can be optionally substituted with up to four R 7 groups, and

(8) 5 or 6-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can optionally form a spirocycle with a C 3 -C 6 cycloalkyl group or another 5 or 6-membered monocyclic heterocycloalkyl group, and wherein said 5 or 6-membered monocyclic heterocycloalkyl group and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to four R 7 groups, which can be the same or different, and wherein a ring carbon atom of a 5 or 6-membered monocyclic heterocycloalkyl group may be functionalized as a carbonyl group;

R 5 is selected from H, C 1 -C 6 alkyl, phenyl, —C(O)N(R 8 ) 2 and —C(O)—Z, wherein Z is selected from piperidinyl, piperazinyl and morhoplinyl and wherein said Z is optionally substituted with 1 to 3 halo groups, and phenyl is optionally substituted with —N(R 8 ) 2 ,

R 6 is H;

each occurrence of R 7 and each occurrence of R 9 are is independently selected from C 1 -C 6 alkyl, phenyl, benzyl, 5 or 6-membered heteroaryl, —CH 2 -(5 or 6-membered heteroaryl), 5 or 6-membered heterocycloalkyl, —CH 2 -(5 or 6-membered heterocycloalkyl), C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, halo, —CN, —N(R 8 ) 2 , —(C 1 -C 6 alkylene)-N(R 8 ) 2 , —OR 8 , —C(O)OR 8 , —SR 8 , —S(O) 2 R 8 , —C(O)N(R 8 ) 2 , —(C 1 -C 6 alkylene)-C(O)OR 8 , —(C 1 -C 6 alkylene)-SR 8 , —(C 1 -C 6 alkylene)-S(O) 2 R 8 and (C 1 -C 6 alkylene)-C(O)N(R 8 ) 2 , wherein said phenyl, 5 or 6-membered heteroaryl and 5 or 6-membered heterocycloalkyl groups can be optionally substituted with one to three groups selected from C 1 -C 6 alkyl, halo, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, halo, —CN, —N(R 8 ) 2 and —OR 8 ; and

each occurrence of R 8 is independently H, C 1 -C 6 alkyl or benzyl optionally substituted with one or two methoxy groups.

2. The compound of claim 1 , having the formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R 9 is present and is F or —CN.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is thiazolyl substituted with —(C 1 -C 6 alkylene)-S(O) 2 R 8 , R 5 is H, and R 6 is H.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, R 5 is —C(O)—Z, wherein Z is selected from piperidinyl, piperazinyl and morhoplinyl and wherein said Z is optionally substituted with 1 to 3 halo groups, and R 6 is H.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —C(O)—Y, Y is selected from (1) cyclobutyl, (2) phenyl, (3) pyridinyl, and (4) tetrahydro-2H-pyran-4-yl; R 5 is selected from H, C 1 -C 4 alkyl and phenyl; and R 6 is H.

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 3 is selected from C 1 -C 6 hydroxyalkyl, —(C 1 -C 6 alkylene)-C(O)—Y, —(C 1 -C 6 alkylene)-C(O)—O—Y and —(C 1 -C 6 alkylene)-O—Y;

Y is C 1 -C 4 alkyl;

R 5 is H; and

R 6 is H.

7. A compound selected from the following:

(R)-2-(4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

(R)-4-(1-(5-((4-(benzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

4-(1-(5-((4-(benzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)cyclopropyl)benzonitrile;

2-(4-((1-(2-isopropoxyethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

2-(4-((1-(3-methylbutan-2-yl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

(R)-4-(1-(5-((4-(7-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

(R)-4-(1-(5-((4-(7-methylbenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

(R)-4-(1-(5-((4-(6-fluorobenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

(R)-4-(1-(5-((4-(6,7-difluorobenzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

2-(4-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

2-(4-((1-(2-(pyridin-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

2-(4-((1-(1-(4-(methylsulfonyl)phenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

6,7-difluoro-2-(4-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

2-(4-((1-(3,3,3-trifluoro-2-methylpropyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

2-(4-((1-(4-fluorophenethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole;

(R)-4-(1-(5-((4-(6-methoxybenzo[d]thiazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

(R)-4-(1-(5-((4-(1H-benzo[d]imidazol-2-yl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

(R)-5-(ethylsulfonyl)-2-(4-((1-(1-(4-fluorophenyl)propan-2-yl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)thiazole;

(R)-5-(2-(ethylsulfonyl)ethyl)-2-(4-((1-(1-(4-fluorophenyl)propan-2-yl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)thiazole;

(R)-2-(4-((1-(1-(4-chlorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)-5-(2-(ethylsulfonyl)ethyl)thiazole;

(R)-2-(4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)-5-(2-(ethylsulfonyl)ethyl)thiazole;

N-(tert-butyl)-4-((1-((R)-1-(4-cyanophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-phenylpiperazine-2-carboxamide;

4-((1R)-1-(5-((4-phenyl-3-(piperidine-1-carbonyl)piperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

4-((1R)-1-(5-((3-(morpholine-4-carbonyl)-4-phenylpiperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

4-((1R)-1-(5-((3-(4,4-difluoropiperidine-1-carbonyl)-4-phenylpiperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

((S)-4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-phenylpiperazin-2-yl)(piperidin-1-yl)methanone;

(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(5-methylisoxazol-3-yl)methanone;

(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(phenyl)methanone;

1-(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)ethanone;

(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;

(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2-phenylpiperazin-1-yl)(pyridin-2-yl)methanone;

(4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-2,6-dimethylpiperazin-1-yl)(1-methylcyclopropyl)methanone;

(2-(tert-butyl)-4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(phenyl)methanone;

(2,6-dimethyl-4-((1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(1-methylcyclopropyl)methanone;

(2-(4-(dimethylamino)phenyl)-4-((1-((R)-1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(1-methylcyclopropyl)methanone;

4-((1R)-1-(5-((4-(3,3-difluorocyclobutanecarbonyl)-3,5-dimethylpiperazin-1-yl)methyl)-1H-imidazol-1-yl)ethyl)benzonitrile;

(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)(phenyl)methanone;

1-(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)ethanone;

(R)-1-benzyl-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;

(R)-1-(2-((1H-1,2,4-triazol-1-yl)methyl)benzyl)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;

(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-(imidazo[1,2-a]pyridin-2-ylmethyl)piperazin-2-one;

(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)piperazin-2-one;

(R)-1-((2-((2,4-dimethoxybenzyl)amino)thiazol-5-yl)methyl)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;

(R)-1-((2-(dimethylamino)thiazol-5-yl)methyl)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-2-one;

(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((2-(methylamino)thiazol-5-yl)methyl)piperazin-2-one;

(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((2-morpholinothiazol-5-yl)methyl)piperazin-2-one;

(R)-4-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-1-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)methyl)piperazin-2-one;

ethyl 2-(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)acetate;

2-(4-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)piperazin-1-yl)ethanol; and

1-((1-(1-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-1H-imidazol-5-yl)methyl)-4-(2-methoxyethyl)piperazine;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , and a pharmaceutically acceptable carrier.