Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of:

(a) C 1 -C 6 alkyl;

(b) C 1 -C 3 alkoxy;

(c) C 1 -C 3 fluoroalkyl;

(d) —(CH 2 ) r CO 2 R b ,

(e) —O(CH 2 ) s N(R c ) 2 ,

(f) hydroxyl;

(g) halo;

(h) H;

(i) —C(O)—C 1 -C 6 alkyl; and

(j) C 3 -C 6 cycloalkyl;

R 2 is selected from the group consisting of H and halo;

R 3 is selected from the group consisting of

(a) H;

(b) C 1 -C 3 alkyl;

(c) —N(R c ) 2 ;

(d) —N(H)C(O)—C 1 -C 4 alkyl;

(e) —CH 2 —O—C 1 -C 3 alkyl;

R 4 is selected from the group consisting of H or halo;

R 5 is selected from the group consisting of

(a) —C(O)OR A ; and

(b) —C(O)N(R c ) 2 ;

each R 6 is a moiety independently selected from the group consisting of fluoro and C 1 -C 3 alkyl;

ring C y is a saturated, mono- or bicyclic carbocyclic ring system consisting of 4 to 12 carbon atoms;

R b is H or C 1 -C 3 alkyl;

each R c is independently H, C 1 -C 3 alkyl, or —C(O)—O—C 1 -C 6 alkyl;

R d is H or —C(O)—O—C 1 -C 6 alkyl;

the subscript r is 0, 1, or 2;

the subscript s is 1, 2, 3, or 4;

the subscript t is 0, 1, 2, 3, 4, or 5;

R A is H or C 1 -C 3 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of —CF 3 , —CH 3 , —C(CH 3 ) 3 , —OCH 3 , —OC(H)(CH 3 ) 2 , —OCH 2 CH 2 CH 2 NH 2 , —OCH 2 CH 2 CH 2 N(H)C(O)OC(CH 3 ) 3 , H, —CO 2 H, —CO 2 CH 3 , —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —OH, F, Cl, —O—C(O)C(CH 3 ) 3 , and

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, or Cl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is H, —CH 3 , —CH 2 OCH 3 , —NH 2 , or —N(H)—C(O)CH 3 .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof,

wherein the moiety

and the subscripts m and n are independently 0, 1, 2, or 3, with the proviso that m and n are not both 0.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof,

wherein the moiety

is selected from the group consisting of

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof,

wherein the moiety

is selected from the group consisting of:

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the Formula (IA)

wherein R 1 is —CH 3 , —CF 3 , or

R 2 is H or F;

R 3 is H or —CH 3 ;

R A is H or C 1 -C 3 alkyl;

R 6 is —CH 3 ; and

the subscript t is 0, 1, or 2.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R A is H.

11. The compound of claim 1 selected from the group consisting of:

4-(5-(6-(4-cyclopropylpyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

methyl 4-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate;

4-hydroxy-2,2-dimethyl-4-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-[5-(4-amino-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

methyl 4-{5-[4-(acetylamino)-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate;

methyl 4-[5-(4-amino-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate;

cis-4-(5-{6-[(4-{3-[(tert-butoxycarbonyl)amino]propoxy}pyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxycyclohexanecarboxylic acid;

cis-4-[5-(6-{[4-(carboxymethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylic acid;

2-({6-[2-(cis-4-carboxy-1-hydroxycyclohexyl)-1,3-thiazol-5-yl]-4-methylpyridin-2-yl}amino)pyridine-4-carboxylic acid;

ethyl cis-4-hydroxy-4-[5-(6-{[4-(2-methoxy-2-oxoethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylate;

methyl 2-[(6-{2-[cis-4-(ethoxycarbonyl)-1-hydroxycyclohexyl]-1,3-thiazol-5-yl}-4-methylpyridin-2-yl)amino]pyridine-4-carboxylate;

cis-4-[5-(6-{[4-(3-aminopropoxy)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-4-hydroxycyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-(5-{6-[(4-tert-butylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-(5-{6-[(4-chloropyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-(5-{6-[(5-fluoropyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-(5-{6-[(5-chloro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-(5-{6-[(4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)cyclohexanecarboxylic acid;

4-(5-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-4-(5-{6-[(4-methoxypyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-2,2-dimethylcyclohexanecarboxylic acid;

4-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-(5-{6-[(4-tert-butylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid;

4-hydroxy-2,2-dimethyl-4-(5-{4-methyl-6-[(4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiazol-2-yl)cyclohexanecarboxylic acid;

cis-2-hydroxy-2-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)spiro[3.5]nonane-carboxylic acid;

trans-2-hydroxy-2-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]spiro[3.5]nonane-7-carboxylic acid;

trans-3-hydroxy-3-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]bicyclo[3.2.1]octane-8-carboxylic acid;

cis-3-hydroxy-3-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]bicyclo[3.2.1]octane-8-carboxylic acid;

cis-4-hydroxy-4-[5-(4-methyl-6-{[4-(1-methylethoxy)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

cis-4-hydroxy-4-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid;

4-hydroxy-4-{5-[4-(methoxymethyl)-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylic acid;

methyl 4-hydroxy-4-{5-[4-(methoxymethyl)-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate;

4-(5-(6-((5-fluoro-4-methylpyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylic acid; and

4-hydroxy-4-(5-(6-((4-hydroxypyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-2-methylcyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R A is H.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(5-(6-((4-cyclopropylpyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid.