Heteroaryl carboxamide derivatives

1. A compound of formula (I):

or a tautomer or pharmaceutically acceptable salt thereof, wherein:

is piperidin-1-yl substituted by m R 4 groups wherein m is 0,1,2,3, or 4;

X—Y is selected from the group consisting of:

C(NR 6 R 7 )═N,

CR 8 ═N,

C(O)—NR 9 , and

CR 8 ═N(O),

R 1 is selected from the group consisting of: (1) C 1-6 alkyl, (2) C 3-7 cycloalkyl, (3) C 2-6 alkenyl, (4) C 2-6 alkynyl, (5) optionally substituted C 3-7 cycloalkyl, (6) optionally substituted C 3-7 cycloalkyl C 1-6 alkyl, (7) C 1-6 alkoxy, (8) halo C 1-6 alkoxy, (9) halo C 1-6 alkyl, (10) C 3-7 cycloalkoxy, (11) heteroalkyl, (12) heteroalkoxy, (13) halogen, (14) optionally substituted phenyl which does not have nitro as a substituent, (15) optionally substituted heteroaryl, and (16) optionally substituted heterocyclyl;

R 2 is hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkyl, cyano or halogen;

R 3 is phenyl substituted by one, two or three substituents independently selected from the group consisting of C 1-8 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halogen and cyano;

each R 4 is independently selected from the group consisting of: (1) hydrogen, (2) C 1-6 alkyl, (3) hydroxy C 1-6 alkyl or halo C 1-6 alkyl, (4) heteroalkyl, (5) C 2-6 alkenyl, (6) C 2-6 alkynyl, (7) hydroxy C 3-6 alkenyl, (8) hydroxy C 3-6 alkynyl, (9) C 1-6 alkoxy C 3-6 alkenyl, (10) C 1-6 alkoxy C 3-6 alkynyl, (11) hydroxy, (12) C 1-6 alkoxy, (13) halo C 1-6 alkoxy, (14) heteroalkoxy, (15) halogen, (16) cyano, (17) optionally substituted phenyl, (18) optionally substituted C 3-7 cycloalkyl, (19) optionally substituted C 3-7 cycloalkyl C 1-6 alkyl, (20) optionally substituted heteroaryl, (21) optionally substituted heterocyclyl, (22) optionally substituted phenyl-C 1-6 alkyl, (23) optionally substituted heteroaryl-C 1-6 alkyl, (24) optionally substituted heterocyclyl-C 1-6 alkyl, (25) nitro, (26) carboxy, (27) formyl, (28) acyl, (29) C 1-6 alkoxycarbonyl, (30) carbamoyl, (31) mono- or di-C 1-6 alkyl substituted aminocarbonyl, (32) C 1-6 alkylthio, (33) C 1-6 alkylsulfinyl, (34) C 1-6 alkylsulfonyl, and (35) amino optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, heteroalkyl, optionally substituted C 3-7 cycloalkyl and optionally substituted heterocyclyl;

R 6 is selected from the group consisting of:

hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkyl, optionally substituted phenyl-C 1-6 alkyl, optionally substituted heteroaryl-C 1-6 alkyl, and optionally substituted heterocyclyl-C 1-6 alkyl;

R 7 is selected from the group consisting of:

hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkanoyl, and heteroalkyl;

R 8 is selected from the group consisting of: (1) hydrogen, (2) hydroxy, (3) mercapto, (4) C 1-6 alkyl, (5) C 3-7 cycloalkyl, (6) C 2-6 alkenyl, (7) C 2-6 alkynyl, (8) optionally substituted C 3-7 cycloalkyl, (9) optionally substituted C 3-7 cycloalkyl C 1-6 alkyl, (10) C 1-6 alkoxy, (11) C 1-6 alkylthio, (12) halo C 1-6 alkoxy, (13) halo C 1-6 alkyl, (14) C 3-7 cycloalkoxy, (15) heteroalkyl, (16) heteroalkoxy, (17) halogen, (18) cyano, (19) optionally substituted phenyl, (20) optionally substituted heteroaryl, (21) optionally substituted heterocyclyl, (22) optionally substituted phenyloxy, (23) optionally substituted heteroaryloxy; (24) optionally substituted phenylthio, (25) optionally substituted heteroarylthio; (26) optionally substituted phenyl-C 1-6 alkoxy, (27) optionally substituted heteroaryl-C 1-6 alkoxy, (28) C 1-6 alkoxy-carbonyl, (29) carboxy, and (30) —CONR 13 R 14 ;

R 9 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, halo C 1-6 alkyl, heteroalkyl, optionally substituted heteroaryl, optionally substituted phenyl-C 1-6 alkyl, or optionally substituted heteroaryl-C 1-6 alkyl;

R 13 is hydrogen, C 1-6 alkyl, heteroalkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

R 14 is hydrogen, C 1-6 alkyl or heteroalkyl; or alternatively, R 13 and R 14 taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring.

2. A compound of claim 1 , wherein X—Y is C(NR 6 R 7 )═N, CR 8 ═N or C(O)—NR 9 .

3. A compound of claim 1 , wherein X—Y is C(NH 2 )═N, CH═N, C(CI)═N, C(O)—NH, C(pyridinyl)═N, C(triazolyl)═N, C(NH((CH 2 ) 2 OH))═N, C(NH 2 -pyrimidinyl)═N, C(CH 2 OH)═N, C(pyrazinyl)═N, C(C(O)NH(pyridinyl))═N, or C(O) —N(CH 3 ).

4. A compound of claim 1 , wherein X—Y is C(NH 2 )═N, C(NH 2 -pyrimidinyl)═N, C(pyrazinyl)═N, C(triazolyl)═N or C)—NH

5. A compound of claim 1 , wherein m is 1.

6. A compound of claim 1 , wherein R 4 is optionally substituted heterocyclyl or heteroalkyl.

7. A compound of claim 1 , wherein R 4 is hydroxy C 1-6 alkyl, optionally substituted pyrrolidin-1-yl, or optionally substituted piperidin-1-yl.

8. A compound of claim 1 , wherein R 4 is piperidin-1-yl or pyrrolidin-1-yl, wherein said piperidin-1-yl or pyrrolidin-1-yl is optionally substituted by hydroxyl C 1-6 alkyl or hydroxy.

9. A compound of claim 1 , wherein R 4 is pyrrolidin-1-yl, 2-hydroxymethyl-pyrrolidin-1-yl or 4-hydroxy-piperidin-1-yl.

10. A compound of claim 1 , wherein:

is 4-pyrrolidin-1-yl-piperidin-1-yl, 4-(2-hydroxymethyl-pyrrolidin-1-yl)- piperidin-1-yl, or 4-hydroxy-[1,4′]bipiperidinyl-1′-yl.

11. A compound of claim 1 , wherein R 1 is C 1-6 alkyl, halogen, or optionally substituted phenyl, and R 2 is hydrogen or halogen.

12. A compound of claim 1 , wherein R 1 is C 1-6 alkyl and R 2 is hydrogen.

13. A compound of claim 1 , wherein R 1 is methyl and R 2 is hydrogen.

14. A compound of claim 1 , wherein R 3 is optionally substituted by one or two substituents independently selected from the group consisting of trifluoromethyl and trifluoromethoxy.

15. A compound of claim 1 , wherein R 3 is 3-trifluoromethyl phenyl.

16. A compound of claim 1 , wherein R 13 is hydrogen, C 1-6 alkyl, heteroalkyl, pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl and R 14 is hydrogen.

17. A compound of claim 1 , wherein R 13 is hydrogen, methyl, hydroxyethyl, 1-carboxylic acid-t-butyl ester-piperidin-4-yl, pyridin-3yl, 1-carboxylic acid-t-butyl ester-piperazin-4-yl, piperidin-4-yl or piperazin-4-yl and R 14 is hydrogen.

18. A compound of claim 1 , selected from the group consisting of:

[3-Methyl-5-(3-trifluoromethyl-phenyl) -pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[6-Chloro-3-methyl-5-(3-trifluoromethyl-phenyl) -pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-l) -methanone,

[4((S)-2-Hydroxymethyl-pyrrolidin-1-yl) -piperidin-1-yl]-[3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl ]-A-methanone,

[6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl) -pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

5-Methyl-6-(4-yrrolidin-1-yl-piperidine-1-carbonyl) -3-(3-trifluoromethyl-phenyl) -1 H-pyridin-2-one,

[6-Amino-3-methyl-5-(3-trifluoromethyl-phenyl) -pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone,

[5-Methyl-3-(3-trifluoromethyl-phenyl) -[2,3′]bipyridinyl-6-yl) -(4-pyrrolidin-1-yl-piperidin-1-y1)-methanone,

[3-Chloro-6-hydroxy-5-(3-trifluoromethyl-phenyl) -pyridin-2-yl]-(4-pyrrolidin-1 -yl-piperidin-1-yl)-methanone, 5-Chloro-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl) -3-(3-trifluoromethyl-phenyl) -1 H-pyridin-2-one, and

[3-Methyl-6-[1,2,4]triazol-1-yl-5-(3-trifluoromethyl-phenyl) -pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone.

19. A process for manufacturing a compound of formula (I):

comprising a step of reacting a compound of formula (II):

with a compound of formula (III):

wherein

m, R 1 , R 2 , R 3 , R 4 , X—Y are as defined in claim 1 .

20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

21. A compound of claim 1 , selected from the group consisting of:

[6-(2-Hydroxy-ethylamino) -3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[5-(2-Fluoro-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[3-Methyl-6-(1H-[1,2,3]triazol-4-yl)-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[5-(2-Methoxy-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[6-(2-Amino-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[6-Hydroxymethyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

[3-Methyl-6-pyrazin-2-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,

5-Methyl-6-(4-pyrrolidin-1 -yl-piperidine-1 -carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid pyridin-3-ylamide, and

1 ,5-Dimethyl-6-(4-pyrrolidin-1 -yl-piperidine-1 -carbonyl)-3-(3-trifluoromethyl-phenyl)-1 H-pyridin-2-one.