Picolinamide inhibitors of kinases

1. A compound of formula (I):

wherein

A is phenyl, naphthyl, indenyl, C 3-8 cycloalkyl, 5-7 membered heterocycloalkyl, 5-7 membered heterocycloalkenyl, or 5-7 membered heteroaryl;

B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyrazolinyl;

Z is bond, C 1-6 alkylene, C 2-6 alkenylene, —O—, or —(NR 4 )—;

R 1 , at each occurrence, is independently selected from the group consisting of halo, CN, NO 2 , C 1-6 -alkyl, C 1-6 -haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, OR 5 , SR 5 , C(O)R 5 , C(O)NR 6 R 7 , C(O)OR 5 , OC(O)R 5 , OC(O)NR 6 R 7 , NR 6 R 7 , NR 6 C(O)R 5 , S(O)R 5 , S(O)NR 6 R 7 , S(O) 2 R 5 , NR 6 S(O) 2 R 5 , and S(O) 2 NR 6 R 7 ; wherein the C 3-8 cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R a , C(O)NR b R c , C(O)OR a , OC(O)R a , OC(O)NR b R c , NR b R c , NR b C(O)R a , S(O)R a , S(O)NR b R c , S(O) 2 R a , NR b S(O) 2 R a , and S(O) 2 NR b R c ;

R 2 , at each occurrence, is independently selected from the group consisting of halo, CN, OH, C 1-4 alkyl, C 1-4 -haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 -thioalkoxy, amino, C 1-4 alkylamino, and C 1-4 dialkylamino;

R 3 is selected from the group consisting of aryl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, aryl-C 1-6 -alkyl-, C 3-8 cycloalkyl-C 1-6 -alkyl-, heteroaryl-C 1-6 -alkyl-, heterocycloalkyl-C 1-6 -alkyl-, OR 8 , C(O)R 8 , C(O)NR 9 R 10 , C(O)OR 8 , OC(O)R 8 , OC(O)NR 9 R 10 , NR 9 R 10 , NR 9 C(O)R 8 , S(O)R 8 , S(O)NR 9 R 10 , S(O) 2 R 8 , NR 9 S(O) 2 R 8 , and S(O) 2 NR 9 R 10 , wherein the C 3-8 cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, alone or part of another moiety, are optionally substituted with one, two, or three R 11 ;

R 4 is H or C 1-6 -alkyl;

R 5 , R 6 , and R 7 , at each occurrence, are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl, wherein the aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl moiety is optionally substituted with halo, CN, OH, C 1-4 alkyl, C 1-4 -haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C(O)OH, C(O)C 1-4 alkyl, C(O)NH 2 , C(O)NH(C 1-4 alkyl), or C(O)N(C 1-4 alkyl) 2 ;

R 8 , R 9 , and R 10 , at each occurrence, are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, heteroaryl-C 1-6 -alkyl-, heterocycloalkyl-C 1-6 -alkyl-, R 12 R 13 N—C 1-6 -alkyl-, aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl, wherein the aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl, alone or as part of another moeity, is optionally substituted with halo, CN, OH, C 1-4 alkyl, C 1-4 -haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C(O)OH, C(O)C 1-4 alkyl, C(O)NH 2 , C(O)NH(C 1-4 alkyl), or C(O)N(C 1-4 alkyl) 2 ;

R 11 is selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, amino-C 1-4 -alkyl-, C 1-4 alkylamino-C 1-4 alkyl-, C 1-4 dialkylamino-C 1-4 alkyl-, hydroxy-C 1-4 -alkyl-, C 1-4 alkyl-C 1-4 alkoxy, aryl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, aryl-(C 1-2 alkyl)-, C 3-8 cycloalkyl-(C 1-2 alkyl)-, heteroaryl-(C 1-2 alkyl)-, heterocycloalkyl-(C 1-2 alkyl)-, CN, NO 2 , OR d , SR d , C(O)R d , C(O)NR e R f , C(O)OR d , OC(O)R d , OC(O)NR e R f , NR e R f , NR e C(O)R d , S(O)R d , S(O)NR e R f , S(O) 2 R d , NR e S(O) 2 R d , and S(O) 2 NR e R f , wherein the aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl, alone or as part of another moiety, are optionally substituted with one, two or three substituents independently selected from halo and C 1-4 alkyl;

R 12 and R 13 , at each occurrence, are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl;

R a is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl;

R b and R c are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl;

R d is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl;

R e and R f are independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl;

m is 0, 1, 2, or 3; and

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 of formula (I) wherein Z is —CH 2 —, —CH 2 CH 2-5 —CH(CH 3 )—, or —C(CH 3 ) 2 —.

3. The compound of claim 1 of formula (I) wherein Z is —C(═CH 2 )— or —CH═CH—.

4. The compound of claim 1 of formula (I) wherein Z is a bond.

5. The compound of claim 1 of formula (I) wherein A is phenyl.

6. The compound of claim 5 of formula (I) wherein

n is 0, 1, or 2; and

R 1 is halo, OR 5 , C 1-6 alkyl, C 1-6 haloalkyl, or CN.

7. The compound of claim 5 of formula (I) wherein

n is 1,

R 1 is C(O)NR 6 R 7 , C(O)OR 5 , NR 6 C(O)R 5 , NR 6 S(O) 2 R 5 , or S(O) 2 NR 6 R 7 .

8. The compound of claim 1 of formula (I) wherein A is a 5-7 membered heteroaryl selected from the group consisting of include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazoyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

9. The compound of claim 1 of formula (I) wherein B is phenyl.

10. The compound of claim 1 of formula (I) wherein R 3 is heterocycloalkyl.

11. The compound of claim 1 of formula (I) wherein B is

12. The compound of claim 10 of formula (I) wherein

m is 0 or 1;

R 2 is halo, C 1-4 alkyl, or C 1-4 alkoxy;

R 3 is

and

R 11 is C 1-4 alkyl, C 1-4 haloalkyl, amino-C 1-4 -alkyl-, C 1-4 alkylamino-C 1-4 alkyl-, C 1-4 dialkylamino-C 1-4 alkyl-, and hydroxy-C 1-4 -alkyl-, C 1-4 alkyl-C 1-4 alkoxy, aryl, C 3-8 cycloalkyl, heteroaryl, heterocycloalkyl, aryl-(C 1-2 alkyl)-, C 3-8 cycloalkyl-(C 1-2 alkyl)—, heteroaryl-(C 1-2 alkyl)-, or heterocycloalkyl-(C 1-2 alkyl)-, wherein the aryl, C 3-8 cycloalkyl, heteroaryl, and heterocycloalkyl, alone or as part of another moiety, are optionally substituted with 1, 2, or 3 substituents independently selected from halo and C 1-4 alkyl.

13. The compound of claim 1 of formula (I) or a salt or a solvate thereof selected from the group consisting of

5-(2,6-dichlorobenzyl)-3-{[2-methoxy-4-(piperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-[1-(2,6-dichlorophenyl)ethyl]-3-{[2-methoxy-4-(piperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-benzyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-benzyl-3-{[3-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(cyclohexylmethyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-phenylpyridine-2-carboxamide;

5-benzyl-3-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-benzyl-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-benzyl-3-{[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(1-phenylvinyl)pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(1-phenylethyl)pyridine-2-carboxamide;

5-(4-fluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-fluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-fluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2,6-difluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(4-methoxybenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(2-naphthylmethyl)pyridine-2-carboxamide;

5-(3,5-difluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3,4-difluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2,4-difluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2,5-difluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-methoxybenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chlorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-chlorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(4-chlorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-methylbenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-methylbenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-methoxybenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(4-methylbenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2,6-dichlorobenzyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(biphenyl-2-ylmethyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-[3-(trifluoromethyl)benzyl]pyridine-2-carboxamide;

5-[1-(3-fluorophenyl)ethyl]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-[2-(3-fluorophenyl)propan-2-yl]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-[1-(3-fluorophenyl)ethyl]pyridine-2-carboxamide;

5-[1-(3-fluorophenyl)ethyl]-3-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2,6-dichlorobenzyl)-3-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2,6-dichlorobenzyl)-3-{[4-(piperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-5-fluorobenzyl)-3-{[3-chloro-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-5-fluorobenzyl)-3-{[2-methoxy-4-(piperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-{[2-methoxy-4-(piperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-[(2-methoxy-4-{4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl}phenyl)amino]pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-[(4-{4-[2-(diethylamino)ethyl]piperazin-1-yl}-2-methoxyphenyl)amino]pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-({4-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]-2-methoxyphenyl}amino)pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-6-fluorobenzyl)-3-{[4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl]amino}pyridine-2-carboxamide;

5-(2-chloro-3,6-difluorobenzyl)-3-{[2-methoxy-4-(piperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-methylphenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(2-fluorophenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-fluorophenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-chlorophenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-carbamoylphenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-{3-[(methylsulfonyl)amino]phenyl}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-{2-[(methylsulfonyl)amino]phenyl}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-[(E)-2-phenylvinyl]pyridine-2-carboxamide;

3-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-{3-[(methylsulfonyl)amino]phenyl}pyridine-2-carboxamide;

5-(2-chlorophenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-cyanophenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3,3′-bipyridine-6-carboxamide;

5-(2-cyanophenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-[3-(dimethylcarbamoyl)phenyl]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(1H-pyrazol-4-yl)pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-{[(2,2,2-trifluoroethyl)sulfonyl]amino}phenyl)pyridine-2-carboxamide;

5-{3-[(cyclopropylsulfonyl)amino]phenyl}-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

5-(3-{[(5-methyl-1,2-oxazol-4-yl)sulfonyl]amino}phenyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-{3-[(2-thienylsulfonyl)amino]phenyl}pyridine-2-carboxamide;

3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-{[(1-methyl-1H-pyrazol-3-yl)sulfonyl]amino}phenyl)pyridine-2-carboxamide;

5-anilino-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide; and

5-{[2-(dimethylsulfamoyl)phenyl]amino}-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyridine-2-carboxamide.

14. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 1 and pharmaceutically acceptable excipient.

15. A method of inhibiting ALK in a mammal comprising administering thereto a therapeutically acceptable amount of a compound or pharmaceutically acceptable salt of claim 1 .