Bipyridylaminopyridines as Syk inhibitors

1. A compound having formula Ia

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl or C 1-4 alkoxy;

R 2 is H or halogen;

R 3 is H, halogen, NR b R c , C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 1-4 hydroxyalkyl;

Y is selected from the group consisting of a bond, —NH—, and —C(R 5 )(R 6 )—;

R 5 is H, OH, C 1-4 alkoxy or halogen;

R 6 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 1-4 hydroxyalkyl;

Z is (a) an optionally benzofused C 3-6 cycloalkyl optionally substituted with 1-5 groups independently selected from C 1-4 alkyl, OR a , CO 2 R a , and CONR b R c ;

R a is selected from the group consisting of:

(i) H;

(ii) C 1-8 alkyl;

(iii) a group of the formula -M-R CH , wherein

M is a bond or —(CH 2 ) 1-2 -;

R CH is aryl or carbocycle optionally substituted with 1-3 groups independently selected from halo, C 1-4 alkyl, or C 1-4 alkoxy;

(iv) a group of the formula —(CH 2 ) 1-2 —R e or —(CH 2 ) 2 —O—(CH 2 ) 2 —R e wherein

R e is CO 2 R e1 , C(O)N(R e2 ) 2 , or —O(CO)R e1 ;

R e1 is C 1-4 alkyl; and

R e2 is H or C 1-4 alkyl;

(v) a group of the formula —(CH 2 ) 2 —R f ,

R f is OH, —OC 1-4 alkyl, NH 2 , —N(H)(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;

(vi) a group of the formula

wherein

R g is H or C 1-4 alkyl; and

R h is C 1-4 alkyl, C 3-6 cycloalkyl, or phenyl; and,

(vii) a group of the formula

wherein R g and R h are as set forth above;

R b and R c are each independently selected from H and C 1-4 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R a is H or C 1-4 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is a bond and Z is (a)

each optionally further substituted with 1 to 2 methyl groups.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is —NH— or —C(R 5 )(R 6 )— and Z is cyclohexyl substituted with a group selected from CO 2 R a and CONR b R c , and optionally further substituted with 1 or 2 methyl groups.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Y is —C(R 5 )(R 6 )— and R 5 is OH.

6. The compound of claim 1 having the formula Ic:

or a pharmaceutically acceptable salt thereof; wherein

Y is a bond or —NH—;

Cy is cyclohexyl substituted with CO 2 R a , and optionally further substituted with 1 to 2 methyl groups;

R 4 is H; and

R 1 , R 2 , R 3 , R a , R b , and R c are as defined in claim 1 .

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R a is H or C 1-4 alkyl.

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein Y is —NH—, and Cy is cyclohexyl substituted with CO 2 R a , and optionally further substituted with 1 to 2 methyl groups.

9. The compound of claim 1 having the formula Id:

or a pharmaceutically acceptable salt thereof; wherein R a is selected from the group consisting of:

(i) H;

(ii) C 1-8 alkyl;

(iii) a group of the formula -M-R CH , wherein

M is a bond or —(CH 2 ) 1-2 -;

R CH is aryl or carbocycle optionally substituted with 1-3 groups independently selected from halo, C 1-4 alkyl, or C 1-4 alkoxy;

(iv) a group of the formula —(CH 2 ) 1-2 —R e or —(CH 2 ) 2 —O—(CH 2 ) 2 —R e wherein

R e is CO 2 R e1 , C(O)N(R e2 ) 2 , or —O(CO)R e1 ;

R e1 is C 1-4 alkyl; and

R e2 is H or C 1-4 alkyl;

(v) a group of the formula —(CH 2 ) 2 R f ,

R f is OH, —OC 1-4 alkyl, NH 2 , —N(H)(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;

(vi) a group of the formula

wherein

R g is H or C 1-4 alkyl; and

R h is C 1-4 alkyl, C 3-6 cycloalkyl, or phenyl; and

(vii) a group of the formula

wherein R g and R h are as set forth above.

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

trans-4-(1-hydroxy-1-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-yl)ethyl)cyclohexanecarboxylic acid;

trans-4-[(4-cyclopropyl-6-{[4-(difluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid;

(1,2-cis)-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]-2-methylcyclohexanecarboxylic acid;

trans-4-[(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid;

trans-4-[1-hydroxy-1-{4-methyl-6-[(4-methylpyridin-2-yl)amino]-2,3′-bipyridin-6′-yl}ethyl]cyclohexanecarboxylic acid;

trans-4-[1-hydroxy-1-{6-[(4-methoxypyridin-2-yl)amino]-4-methyl-2,3′-bipyridin-6′-yl}ethyl]cyclohexanecarboxylic acid;

trans-4-[{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methyl-2,3′-bipyridin-6′-yl}-1-hydroxyethyl)cyclohexanecarboxylic acid

trans-4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)methyl]cyclohexanecarboxylic acid

trans-4-((6-(4-(difluoromethyl)pyridin-2-ylamino)-4-methyl-2,3′-bipyridin-6′-yl)-1-fluoroethyl)cyclohexanecarboxylic acid;

trans-4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)ethyl]cyclohexanecarboxylic acid;

(trans-4-[{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methyl-2,3′-bipyridin-6′-yl}-1-hydroxyethyl]cyclohexanecarboxylic acid;

trans-4-[[6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-(2-hydroxypropan-2-yl)-2,3′-bipyridin-6′-yl]-1-hydroxyethyl}cyclohexanecarboxylic acid

trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-methoxyethyl]cyclohexanecarboxylic acid;

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

5-hydroxy-5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid;

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

trans-4-[cyclopropyl(hydroxy)(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)methyl]cyclohexanecarboxylic acid;

methyl trans-4-[(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-hydroxyethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

benzyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

propyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

propan-2-yl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

butyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

butan-2-yl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-methylpropyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

pentyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2,2-dimethylpropyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

hexyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

heptyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

octyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

cyclohexyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

cyclohexylmethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-methoxyethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-(2-ethoxyethoxy)ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-methoxy-2-oxoethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-(dimethylamino)-2-oxoethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-(dimethylamino)ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

[(ethoxycarbonyl)oxy]methyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

{[(propan-2-yloxy)carbonyl]oxy}methyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

1-[(ethoxycarbonyl)oxy]ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

1-{[(propan-2-yloxy)carbonyl]oxy}ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

1-{[(cyclohexyloxy)carbonyl]oxy}ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

(acetyloxy)methyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

[(2,2-dimethylpropanoyl)oxy]methyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

1-(acetyloxy)ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

1[(2-methylpropanoyl)oxy]ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

2-(acetyloxy)ethyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate;

methyl trans-4-[1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylate; and

1-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6-yl)-1-[trans-4-(hydroxymethyl)cyclohexyl]ethanol;

or a pharmaceutically acceptable salt thereof.

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

12. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R a is H or C 1-4 alkyl.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is trans-4-[(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methyl-2,3′-bipyridin-6′-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid.