Substituted pyridine spleen tyrosine kinase (SYK) inhibitors

1. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R 1 is selected from the group consisting of C 1 -C 3 fluoroalkyl;

R 2 is H;

R 3 is H;

R 4 is selected from the group consisting of C 1 -C 3 alkyl and —N(H)C(O)R 4b ;

R 4b is C 1 -C 3 alkyl;

C y is

t is 1;

R cy is a group of the formula

 wherein

Y 1 is a bond;

D 1 is a 4- to 8-membered mono- or bicyclic heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of N and S;

each R 10 is independently selected from the group consisting of C 1 -C 3 alkyl, hydroxyl, —CO 2 H, —CH 2 CO 2 R g , —C(O)N(H)—(CH 2 CO 2 H), or wherein when two R 10 moieties are geminally substituted on a common ring carbon atom of D 1 , the two geminally substituted R 10 moieties together with the carbon atom on which they are attached form —C(O)—;

R g is H or C 1 -C 3 alkyl; and

q is 1.

2. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R 1 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, and cyclopropyl;

R 2 is H or halo;

R 3 is H;

R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, and halo;

C y is a 6-membered heteroaryl selected from the group consisting of:

t is 1;

R cy is a group of the formula

 wherein

Y 2 is a bond or —N(H)—;

s is 0, 1 or 2;

R i is H, methyl, hydroxyl, or —CO 2 H;

R j is H or methyl;

D 2 is selected from the group consisting of:

(i) cyclohexyl;

(ii) a 5- to 6-membered heterocyclyl containing one to two N atoms;

(iii) a 5-membered heteroaryl containing two to three N atoms; and

(iv) phenyl;

each R 10 is independently selected from the group consisting of C 1 -C 3 alkyl, hydroxyl, —CO 2 R g , —C(O)NH 2 , —C(O)CH 2 CN, and —C(O)CH 2 OH;

R g is H or C 1 -C 3 alkyl; and

q is 0, 1, 2, 3, or 4.

3. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof

wherein

R 1 is selected from the group consisting of C 1 -C 3 fluoroalkyl and cyclopropyl;

R 2 is H or halo;

R 3 is H;

R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, and —N(H)C(O)R 4b ;

R 4b is C 1 -C 3 alkyl;

C y is a 6-membered heteroaryl selected from the group consisting of:

t is 1;

R cy is a group of the formula

 wherein

Y 3 is a bond,

R e is H, C 1 -C 3 alkyl, or —(CH 2 ) n3 CN;

wherein n3 is 2 or 3;

each R a is independently selected from the group consisting of H, C 1 -C 6 alkyl, hydroxy(C 1 -C 3 )alkyl, —(CH 2 ) n4 —O—(C 1 -C 3 )alkyl, —(CH 2 ) n4 C(O)NH 2 , —(CH 2 ) n4 S—(C 1 -C 3 )alkyl, and —(CH 2 ) n4 S(O) 2 —(C 1 -C 3 )alkyl;

wherein each n4 is independently 1, 2, or 3;

each R b is independently selected from the group consisting of H, hydroxyl, C 1 -C 6 alkyl, fluoro, C 1 -C 3 fluoroalkyl, hydroxy(C 1 -C 3 )alkyl, —(CH 2 ) n4 —O—(C 1 -C 3 )alkyl,

—(CH 2 ) n4 C(O)NH 2 , —(CH 2 ) n4 S—(C 1 -C 3 )alkyl, and —(CH 2 ) n4 S(O) 2 —(C 1 -C 3 )alkyl;

each R c and R d is independently selected from the group consisting of H or C 1 -C 3 alkyl;

R f is —CO 2 R g , hydroxyl, or —C(O)N(R h ) 2 ;

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

wherein each R h is independently H, C 1 -C 3 alkyl, or —CH 2 CO 2 H;

n1 is 0, 1 or 2; and

n2 is 0 or 1.

4. A compound of the Formula (IB) or a pharmaceutically acceptable salt thereof,

wherein

R 1 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, and C 3 -C 6 cycloalkyl;

R 4 is selected from the group consisting of H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl;

one of X 1 and X 2 is N and the other is C;

R i is H or hydroxyl;

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

s is 0, 1, 2, or 3;

R 10 is C 1 -C 3 alkyl or hydroxyl;

q1 is 0, 1, 2, or 3;

u is 1 or 2; and

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

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof,

wherein

R 1 is selected from the group consisting of methyl, —CF 3 , and cyclopropyl;

R 4 is selected from the group consisting of H, methyl, and —CF 3 ; and

R i is H or hydroxyl;

R j is H or methyl;

s is 0 or 1; and

R 10 is methyl or hydroxyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof,

wherein the group

 is a group of the formula

and

q1 is 0, 1, or 2.

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

8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

trans-4-[1-hydroxy-1-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)ethyl]cyclohexanecarboxylic acid;

trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyridin-2-yl]-1-hydroxyethyl}cyclohexanecarboxylic acid;

trans-4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethyl}cyclohexanecarboxylic acid;

trans-4-[1-hydroxy-1-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridin-2-yl)ethyl]cyclohexanecarboxylic acid;

2-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]alanine;

trans-4-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid;

cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]cyclohexanecarboxylic acid;

trans-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]cyclohexanecarboxylic acid;

1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}cyclobutanecarboxylic acid;

3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-proline;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]serine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-homoserine;

4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}piperidine-4-carboxylic acid;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azetidine-2-carboxylic acid;

O-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]serine;

1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}cyclopentanecarboxylic acid;

1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}cyclopropanecarboxylic acid;

2-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-proline;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-alanine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]glycine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-D-alanine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-D-valine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-threonine;

N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-D-asparagine;

N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-asparagine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-methionine;

2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}butanoic acid;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-leucine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-histidine;

4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidin-4-ol;

3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]cyclohexanecarboxylic acid;

(2 S)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azetidine-2-carboxylic acid;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azetidine-2-carboxylic acid;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperidine-2-carboxylic acid;

2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid;

trans-4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridin-2-yl)amino]cyclohexanecarboxylic acid;

trans-4-[(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)amino]cyclohexanecarboxylic acid;

4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethyl}benzoic acid;

3-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-valine;

cis-4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}cyclohexanecarboxylic acid;

trans-4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}cyclohexanecarboxylic acid;

2-methyl-N-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]alanine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-beta-alanine;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-phenylalanine;

3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}-3-oxopropanoic acid;

1-{5-[3-(acetylamino)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyridin-2-yl}azetidine-2-carboxylic acid;

N-{5-[3-(acetylamino)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyridin-2-yl}-2-methylalanine;

2-methyl-2-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propane-1,3-diol;

2-methyl-2-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propan-1-ol;

2-{[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propan-1-ol;

5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azepan-2-one;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-D-histidine;

4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}pyrrolidin-2-one;

3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}pyrrolidin-2-one;

4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperidine-1-carboxamide;

4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]piperazin-2-one;

N-(3-[6-(3-oxopiperazin-1-yl)pyridin-3-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide;

N,N-dimethyl-N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]glycinamide;

3-(4-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)propanoic acid;

trans-4-[(5-{3-[(5-chloro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)amino]cyclohexanecarboxylic acid;

N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-alanine;

trans-4-[(5-{3-[(5-fluoro-4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)amino]cyclohexanecarboxylic acid;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperidine-3-carboxylic acid;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-D-leucine;

4-(methylsulfonyl)-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}butanoic acid;

N-(2-cyanoethyl)-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]glycine;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl-L-prolylglycine;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-proline;

2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid;

2,2-difluoro-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid;

3-hydroxy-2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid;

3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]pyrrolidine-1-carboxamide;

{1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperidin-2-yl}acetic acid;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]azetidine-3-carboxylic acid;

3-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-L-proline;

1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperidine-4-carboxylic acid;

3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-1,3-thiazolidine-4-carboxylic acid;

N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]glycylglycine;

{4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]piperazin-1-yl}acetic acid;

N-[5-(3-{[5-bromo-4-(trifluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyridin-2-yl]-2-methylalanine;

3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyridin-3-yl)propanoic acid; and

4-({[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}methyl)cyclohexanecarboxylic acid.

9. 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.

10. A method of treating rheumatoid arthritis comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

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

12. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R g is H.

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

14. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R g is H.

15. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R g is H.

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.