Triazolyl derivatives as Syk inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

is:

ring a is

ring b is

Y a1 is CH;

Y b1 is N;

Y b2 is CH;

R 1a is independently: H, halogen, or C 1 -C 3 -alkyl;

R 1 is

halogen;

Si(CH 3 ) 3 ; or

C 1 -C 6 -alkyl or C 2 -C 6 -alkenyl, optionally substituted with one to four substituents selected from the group consisting of: CN; OH; oxo; NH 2 ; halogen; CO 2 R c ; CONH 2 ; C 1 -C 3 -alkyl; C 1 -C 3 -haloalkyl; C 1 -C 3 -alkoxyl optionally substituted with OH or fluoro; aryl; Oaryl optionally substituted with halogen; or heterocyclyl;

Heterocyclyl is a 4-, 5-, 6-, or 7-membered monocyclic ring or 8-, 9-, 10-, 11-membered bicyclic ring, or 13- or 14-membered tricyclic ring; the monocyclic, bicyclic or tricyclic ring can be saturated, unsaturated or aromatic, containing 1, 2, 3 or 4 heteroatoms selected from O, N or S, the point of attachment of the heterocyclyl can be on the carbon or nitrogen and the heterocyclyl may optionally be substituted with one to four substituents selected from CN; OH; oxo; NH 2 ; halogen; CO(CH 2 ) m CH 3 , optionally substituted with one or two substituents selected from OH and CO 2 R c ; C 1 -C 3 -alkyl; C 2 -C 4 -alkenyl; C 1 -C 3 -haloalkyl; C 1 -C 3 -alkoxyl optionally substituted with OH; aryl optionally substituted with one or two substituents selected from C 1 -C 3 -alkoxyl, halogen, or Oaryl; CH 2 aryl; OCH 2 aryl; Oaryl optionally substituted with one or two substituents selected from halogen; (CR a R b ) n CO 2 R c ; (CR a R b ) n CONR d R e ; (CHR a ) n NHCONR d R e ; (CHR a ) p —C(O)-heterocyclyl; and furyl; or alternatively, 2 substituents which are geminally substituted on a common ring carbon atom of said heterocyclyl may together with the common ring carbon atom form a C 3 -C 6 spirocyclic ring;

Aryl is a phenyl or napthyl ring, the aryl may optionally be substituted with one to four substituents selected from halogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxyl, Oaryl, (CR a R b ) n CO 2 R c ; and (CR a R b ) n CONR d R e ;

R 2 is halogen, C 1 -C 3 -alkyl, or C 1 -C 3 -haloalkyl;

R 3 is halogen or C 1 -C 3 -fluoroalkyl;

R 4 is H, halogen, or C 1 -C 3 -alkyl;

R a and R b are independently: H, OH, CN, CO 2 R c , CONH 2 , NH 2 , cyclopropyl, C 1 -C 3 -haloalkyl, or C 1 -C 3 -alkyl optionally substituted with hydroxyl;

R c is: H; C 1-4 alkyl; -M-R CH ; —(CH 2 ) 1-2 —R f ; —(CH 2 ) 2 —O—(CH 2 ) 2 —R f ; —(CH 2 ) 2 —R g , —CHR h OCO 2 R i , —CHR i R h , or —(CHR h ) s OC(O)R i ;

R d and R e are independently: H, C 1 -C 3 -alkoxyl or C 1 -C 6 -alkyl, optionally substituted with one, two or three substituents CN; OH; oxo; NH 2 ; halogen; CO 2 R c ; CONH 2 ; C 1 -C 3 -alkoxyl, CO 2 R c ; aryl, carbocyclyl, or heterocyclyl; or cyclopropyl optionally substituted with phenyl;

R f is —OC(O)R f1 ;

R f1 is C 1-4 alkyl; and

R g is OH, C 1-4 alkoxyl, NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;

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

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

M is a bond or —(CH 2 ) 1-3 —;

R CH is (a) aryl or carbocycle optionally substituted with 1-3 groups independently selected from halo, C 1-4 alkyl, or C 1-4 alkoxy; or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of R CH is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C 1-3 alkyl;

m is 0, 1, or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1; and

s is 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the Formula Ia:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the Formula Ib:

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Formula Ia is:

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Formula Ia is:

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is Si(CH) 3 or C 1 -C 6 -alkyl, optionally substituted with one to four substituents selected from the group consisting of: CN, OH, oxo, NH 2 , halogen, CF 3 , C 1 -C 3 -alkyl, and C 1 -C 3 -alkoxyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 -alkyl, optionally substituted with one to four substituents selected from the group consisting of: CN, OH, oxo, NH 2 , halogen, CF 3 , CH 3 and OCH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

2-methyl-3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propane-1,2-diol;

(3R)-3-hydroxy-4-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]butanenitrile;

3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propane-1,2-diol;

1-fluoro-3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol;

3-hydroxy-4-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]pentanenitrile;

(2S)-3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propane-1,2-diol;

1-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]butane-2,3-diol;

(3R)-3-hydroxy-4-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]butanamide;

2-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanol;

2-methyl-1-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol;

(2R)-2-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

(R)-1-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2,3-dimethylbutane-2,3-diol;

(S)-1-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2,3-dimethylbutane-2,3-diol;

(R)-1-(4-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1H-1,2,3-triazol-1-yl)-2,3-dimethylbutane-2,3-diol;

(S)-1-(4-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-triazol-1-yl)-2,3-dimethylbutane-2,3-diol;

(R)-1-[4-(6-{[4-(1-fluoroethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2,3-dimethylbutane-2,3-diol;

(S)-1-[4-(6-{[4-(1-fluoroethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2,3-dimethylbutane-2,3-diol;

(R)-1-(4-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-triazol-1-yl)-2,3-dimethylbutane-2,3-diol;

(S)-1-(4-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-triazol-1-yl)-2,3-dimethylbutane-2,3-diol;

(R)-3-(4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)-2-methylpropane-1,2-diol;

(S)-3-(4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)-2-methylpropane-1,2-diol;

(3R)-4-(4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-hydroxy-3-methylbutanenitrile;

(3S)-4-(4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-hydroxy-3-methylbutanenitrile;

(4R)-4-((4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-2-one;

(4S)-4-((4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-2-one;

(2R,3R)-3-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-methylbutane-1,2-diol;

(2R,3S)-3-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-methylbutane-1,2-diol;

(2S,3R)-3-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-methylbutane-1,2-diol; and

(2S,3S)-3-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-methylbutane-1,2-diol.

10. 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.

11. A method for the treatment of asthma or COPD, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. A method for the treatment of NHL B cell lymphomas, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 or a pharmaceutically salt thereof, wherein the compound of the Formula I has the formula Ih

wherein

Y a1 is CH and Y b1 is N;

each R q is independently H, C 1-3 alkyl, or C 1-3 fluoroalkyl;

R r is H or C 1-3 alkyl;

R s is hydroxyl or CN;

R 2 is methyl;

R 3 is C 1-3 fluoroalkyl; and

R 4 is H or fluoro.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein

Y a1 is CH and Y b1 is N;

each R q is independently H or Me;

R r is H or Me;

R s is hydroxyl;

R 2 is methyl;

R 3 is C 1-3 fluoroalkyl; and

R 4 is H or fluoro.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(4-(6-((4-(difluoromethyl)pyridin-2-yl)amino)-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl)-2-methylpropane-1,2-diol.