Inhibitors of protein kinases

1. A method for the treatment of pain, the method comprising administering to a subject in need of such treatment an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, polymorph, tautomer and stereoisomer thereof wherein:

R a is H or methyl;

R 1 is selected from the group consisting of:

carbocyclic or —C 1-6 alkyl-carbocyclic, wherein the carbocyclic group is cyclohexyl or cyclopentyl;

heterocyclic or —C 1-6 alkyl-heterocyclic group, wherein the heterocyclic group is piperidine, piperazine, morpholine or pyrrolidine;

aryl or alkyl-aryl;

heteroaryl or —C 1-6 alkyl-heteroaryl, wherein the heteroaryl group is pyridine, thiazole or thiophene;

wherein any of the aforesaid carbocyclic, heterocyclic, aryl or heteroaryl groups may optionally be substituted by one or more groups independently selected from:

halo, OH, NH 2 and, for carbocyclic and heterocyclic groups, ═O; or

C 1-4 alkyl, —O(C 1-4 alkyl), —NH(C 1-4 alkyl), —NHC(O)(C 1-4 alkyl), —S(C 1-4 alkyl), —SO(C 1-4 alkyl), —SO 2 (C 1-4 alkyl) or —SO 2 NH(C 1-4 alkyl) any of which may be further substituted with halo or OH; or

R 3 , —C 1-4 alkyl-R 3 , OR 3 , NHR 3 , —NHC 1-4 alkyl-R 3 , —OC 1-4 alkyl-R 3 , SR 3 , SOR 3 or SO 2 R 3 ;

wherein R 3 is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be substituted with one or more halo, C 1-4 alkyl, —O(C 1-4 alkyl), NH 2 , —NH(C 1-4 alkyl), —C(O)(C 1-4 alkyl), —NHC(O)(C 1-4 alkyl) groups, any of which alkyl groups may be substituted with halo or OH;

each R 2 is independently halo, OH, NH 2 ; or

C 1-4 alkyl, —O(C 1-4 alkyl), —NH(C 1-4 alkyl), —C(O)(C 1-4 alkyl), any of which may be further substituted with halo or OH; or

R 4 , —C 1-4 alkyl-R 4 , OR 4 , NHR 4 , alkyl-R 4 , —OC 1-4 alkyl-R 4 , SR 4 , SOR 4 or SO 2 R 4 ;

wherein R 4 is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be further substituted with one or more halo, OH, C 14 alkyl, —O(C 1-4 alkyl), NH 2 , —NH(C 1-4 alkyl), —C(O)(C 1-4 alkyl), —NHC(O)(C 1-4 alkyl) groups, any of which alkyl groups may be substituted with halo or OH; and

x is 0-4.

2. The method of claim 1 , wherein in Formula (I) R a is H.

3. The method of claim 1 wherein in Formula (I) x is 2.

4. The method of claim 1 wherein in Formula (I) R 2 is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.

5. The method of claim 4 , wherein in Formula (I) there are two R 2 groups, one of which is halo and the other of which is methoxy or halomethoxy.

6. The method of claim 1 wherein in Formula (I) R 1 is C 5 or C 6 carbocyclic, C 5 or C 6 heterocyclic, —C 1-3 alkyl-phenyl, —C 1-3 alkyl(C 5 or C 6 heteroaryl), —C 1-3 alkyl(C 5 or C 6 carbocyclic), —C 1-3 alkyl(C 5 or C 6 heterocyclic), phenyl or C 5 or C 6 heteroaryl, wherein any of the aforesaid cyclic groups may optionally be substituted as described in claim 1 .

7. The method of claim 1 wherein in Formula (I) R 1 is cyclohexyl, cyclopentyl, —C 1-3 alkyl(cyclohexyl), —C 1-3 alkyl(cyclopentyl); or R 1 is piperidine, piperazine, morpholine and pyrrolidine, —C 1-3 alkyl(piperidine), —C 1-3 alkyl(piperazine), —C 1-3 alkyl(morpholine), —C 1-3 alkyl(pyrrolidine); or R 1 is phenyl or —C 1-3 alkyl-phenyl; or R 1 is pyridine, thiazole, thiophene, —C 1-3 alkyl(pyridine), —C 1-3 alkyl(thiazole) or —C 1-3 alkyl(thiophene), wherein any of the aforesaid cyclic groups may optionally be substituted as described in claim 1 .

8. The method of claim 1 wherein in Formula (I) R 1 is a —C 1-3 alkyl(carbocyclic), —C 1-3 alkyl(heterocyclic), —C 1-3 alkyl(aryl) or —C 1-3 alkyl(heteroaryl) group, and the —C 1-3 alkyl linker is:

—CH 2 —;

—CH(CH 3 )—;

—CH 2 CH(CH 3 )—;

—CH(CH 3 )CH 2 —; or

—CH 2 CH 2 —.

9. The method of claim 1 , wherein in Formula (I) R 1 is unsubstituted or is substituted, with one or more groups chosen from:

halo, OH, NH 2 and, for carbocyclic and heterocyclic groups, ═O; or

C 1-4 alkyl, —O(C 1-4 alkyl), —NH(C 1-4 alkyl), —NHC(O)(C 1-4 alkyl), any of which may be further substituted with halo or OH; or

R 3 , —C 1-4 alkyl-R 3 , OR 3 , NHR 3 , —NHC 1-4 alkyl-R 3 , —OC 1-4 alkyl-R 3 ;

wherein R 3 is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be substituted with one or more halo, OH, NH 2 or C 1-4 alkyl or —O(C 1-4 alkyl) groups, either of which alkyl groups may be substituted with halo.

10. The method of claim 9 , wherein in Formula (I) R 1 is unsubstituted or is substituted with one or more groups chosen from NH 2 , methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, ═O (for carbocyclic and heterocyclic groups), NHC(O)Me, R 3 , NHR 3 , and NHCH 2 R 3 ;

wherein R 3 is an aryl, heteroaryl, carbocyclic or heterocyclic group any of which may be substituted with one or more halo, OH, NH 2 or C 1-4 alkyl or —O(C 1-4 alkyl) groups, either of which alkyl groups may be substituted with halo.

11. The method of claim 9 , wherein in Formula (I) R 3 is piperidine, 4-methylpiperidine, piperazine, 4-methylpiperazine, thienyl, thien-2-yl, thiazolyl, thiazol-2-yl, pyridinyl, pyridin-2-yl, pyridine-3-yl, pyridine-4-yl, and phenyl.

12. The method of claim 1 wherein the compound is selected from the group consisting of:

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)cyclohexanecarboxamide;

2-Cyclohexyl-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)acetamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)piperidine-4-carboxamide;

4-Amino-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclohexane-carboxamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-5-oxopyrrolidine-3-carboxamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-methoxyphenyl)-acetamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-phenylacetamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(pyridin-4-yl)acetamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(thiophen-2-yl)acetamide;

(2S)-N-(4-(5-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-phenylpropanamide;

(2S)-N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-methoxyphenyl)-propanamide;

isomers of N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(pyridin-3-yl)propanamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(6-methoxypyridin-3 -yl)acetamide;

isomers of N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(pyridin-4-yl)propanamide;

isomers of (2R)-N-(4-(5-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(thiophen-2-yl)propanamide;

2-(2-Chloropyridin-4-yl)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)acetamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-(4-methylpiperazin-1-yl)phenyl)acetamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-3-(pyridin-4-yl)butanamide;

N-(4-(4-Fluoro-2-methoxyphenyppyridin-2-yl)-2-((pyridin-4-yl)methyl)-propanamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-3 -(pyridin-3 -yl)butanamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-((pyridin-3-yl)methyl)-propanamide;

trans-3 -Acetamido-N-(4-(4-fluoro-2-methoxyphenyl)-pyridin-2-yl)cyclohexanecarboxamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-(4-methylpiperazin-l-yl)phenyl)propanamide;

2-(4-(4-Methylpiperazin- 1 -yObenzyl)-N-(4-(4-fluoro-2-methoxyphenyl)-pyridin-2-yl)propanamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-3 -(4-(4-methylpiperazin-l-yl)phenyl)butanamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-4-(pyridin-2-ylamino)-cis-cyclohexanecarboxamide;

N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(2-(4-methylpiperazin-l-yl)pyridin-4-yl)acetamide;

cis-N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-4-(pyridin-4-ylamino)-cyclohexanecarboxamide;

(1R,3S)-3-Acetamido-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclo-pentanecarboxamide;

cis-N-(4-(4-Fluoro-2-methoxyphenyppyridin-2-yl)-4-(thiazol-2-ylamino)-cyclohexanecarboxamide;

cis-N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-4-(phenylamino)-cyclohexanecarboxamide;

(1R,3S)-3-(Benzylamino)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclopentanecarboxamide;

cis-4-(Benzylamino)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclo-hexanecarboxamide;

(1R,3S)-N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-3-(phenylamino)-cyclopentanecarboxamide;

(1R,3S)-3-Acetamido-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclohexanecarboxamide;

(1S,3R)-3-Acetamido-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclopentanecarboxamide; or a

pharmaceutically acceptable salt, polymorph, tautomer and stereoisomer thereof.

13. The method of claim 1 wherein the compound is cis-3-acetamido-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)cyclo-hexanecarboxamide.