Benzamides and nicotinamides as Syk modulators

1. A compound of having the formula (I):

or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof,

wherein:

Q 1 is CX 1 ; Q 2 is CX 1 or N;

each X 1 is independently selected from the group consisting of: hydrogen, C 1-8 alkyl, halogen, cyano, and aminocarbonyl;

X 2 is H or halogen;

D 1 is selected from the group consisting of:

(a) aryl;

(b) heteroaryl; and

(c) heterocyclyl;

each R 1 is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkylthio, aminocarbonyl, C 1-8 alkoxycarbonylC 1-8 alkylene, C 1-8 alkoxycarbonylC 1-8 alkoxy, C 1-8 alkoxycarbonylamino, oxo, halo, cyano, haloC 1-8 alkyl, haloC 1-8 alkoxy, aminosulfonyl, heteroarylsulfinyl; amino, hydroxyl, C 1-8 arylalkylene, phenyl, aminoC 1-8 alkyl, aminoC 3-8 cycloalkyl, heterocyclyl, heteroaryl, heterocyclylC 1-8 alkylene and hydroxyC 1-8 alkylene;

D 2 is selected from the group consisting of:

R 3a is selected from the group consisting of: H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, hydroxyl, oxo, amino, thio, halo, carboxy, aminocarbonyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 alkylamino, diC 1-8 alkylamino, cyano, C 1-8 alkylthio, C 1-8 alkylsulfonyl, aminocarbonyl, C 1-8 alkoxycarbonylamino, C 1-8 alkylC 3-8 cycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylamino, C 3-8 cycloalkylthio, heteroaryl, heteroarylalkoxy, aryl, arylalkoxy, heterocyclyl and heterocyclyloxy; wherein the aryl is optionally substituted by hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, halo, haloC 1-8 alkyl, C 1-8 alkylsulfonyl or heteroaryl;

R 3b is selected from the group consisting of: H and C 1-8 alkyl; or may be combined with R 3a to form a 3 to 8 membered carbocyclic or heterocyclic ring;

R 3c is selected from the group consisting of: H, C 1-8 alkyl and C 3-8 cycloalkyl; or taken together with R 3d and the atoms to which they are attached to form a heterocyclyl ring;

R 3d is selected from the group consisting of: H, C 1-8 alkyl and C 3-8 cycloalkyl;

L 2 is selected from the group consisting of a bond and C 1-8 alkylene;

R 4a is independently selected from the group consisting of: C 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 haloalkyl, amino, C 1-8 alkylamino, C 1-8 alkoxycarbonylaminoC 1-8 alkylene, C 3-8 cycloalkyl, heteroaryl, C 1-8 alkylC 3-8 cycloalkyl, C 1-8 alkylthioC 1-8 alkyl, C 1-8 alkylsulfonylC 1-8 alkylene, aminocarbonyl, C 1-8 alkoxyC 1-8 alkyl, C 1-8 alkoxyC 1-8 alkoxy, haloC 1-8 alkyl, aryl and heterocyclyl; wherein the aryl is optionally substituted by hydroxyl, C 1-8 alkoxy, halo or haloC 1-8 alkyl; or taken together with R 4b and the atoms to which they are attached to form a C 3-8 cycloalkyl or heterocycloalkyl ring;

R 4b is selected from the group consisting of C 1-8 alkyl, C 1-8 alkylamino, amino, aminoC 1-8 alkyl, carboxy, C 1-8 alkylaminoC 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, hydroxyC 1-8 alkyl; carboxyC 1-8 alkyl, C 3-8 cycloalkylC 1-8 alkyl, aryloxyC 1-8 alkyl, arylC 1-8 alkyl, heteroarylC 1-8 alkyl, and hydroxyC 1-8 alkoxy; or may be combined with R 4a or R 4c and the atoms to which they are attached to form a C 3-8 cycloalkyl or heterocyclyl ring;

R 4c is H or alkyl or may be combined with R 4b and the atoms to which they are attached to form a C 3-8 cycloalkyl or heterocyclyl ring;

(c) C 3-8 cycloalkyl; optionally substituted with from 1 to 3 substituents, R 6a , independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, aminocarbonyl-, hydroxy, oxo, halogen, C 1-8 alkoxy and C 1-8 alkylsulfonyl;

(d) heterocycloalkyl; optionally substituted with from 1 to 3 substituents, R 6a , independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, aminocarbonyl-, hydroxy, oxo, halogen, C 1-8 alkoxy and C 1-8 alkylsulfonyl; and

(e) arylalkylene; optionally substituted with from 1 to 3 substituents, R 6a , independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, aminocarbonyl-, hydroxy, oxo, halogen, C 1-8 alkoxy and C 1-8 alkylsulfonyl;

each R 2 is independently selected from the group consisting of H and C 1-8 alkyl;

the subscript n is 0, 1, 2, 3 or 4; and

the wavy line indicates the point of attachment to the rest of the molecule.

2. The compound of claim 1 having formula (Ia):

or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.

3. The compound of claim 1 having formula (Ib) or (Ic):

or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.

4. The compound of claim 1 having formula (Ie):

or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof.

5. The compound of claim 1 wherein the compound has the formula (If):

wherein each Y 1 and Y 2 is each independently selected from the group consisting of: O, CR 2 , NH, NCOCH 3 and S.

6. The compound of claim 1 wherein the compound has the formula (Ig):

Wherein each R 9a and R 8b is independently H or F.

7. A compound of claim 6 wherein D 1 is selected from the group consisting of:

and

R 1 is alkyl, alkoxy or halo.

8. The compound of claim 6 wherein the compound has the formula (Ih):

wherein each Y 1 and Y 2 is each independently selected from the group consisting of: O, CR 2 , NH, NCOCH 3 and S.

9. The compound of claim 6 wherein the compound has the formula (Ii):

10. The compound of claim 6 wherein the compound has the formulae (Ija-la):

11. The compound of claim 6 wherein the wherein the compound has the formula (Im):

12. The compound of claim 6 wherein the a compound, wherein the compound has the formulae (In-p):

13. The compound of claim 6 wherein the a compound, wherein the compound has the formula (Iq):

14. The compound of claim 6 wherein a compound, wherein the compound has the formulae (Ir):

15. The compound of claim 6 wherein a compound, wherein the compound has the formulae (Is):

16. The compound of claim 6 wherein a compound, wherein the compound has the formulae (It):

17. The compound of claim 6 wherein R 1 is selected from the group methyl or fluoro.

18. The compound of claim 1 wherein a compound having the formula (Im):

19. The compound of claim 18 wherein the compound has the formula (In):

20. The compound of claim 18 wherein the compound has a formula selected from the group consisting of:

21. The compound of claim 20 wherein R 3a is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl.

22. The compound of claim 20 wherein R 3a is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, benzyl, benzyloxymethyl, hydroxymethyl, methoxymethyl, cyclohexylmethyl, phenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, ethyl, 4-fluorophenylmethyl, 3-fluorophenylmethyl, 4-pyridinylmethyl, 3-pyridinylmethyl, 4-hydroxyphenylmethyl, 4-methoxyphenylmethyl.

23. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.

24. A method for inhibiting Syk kinase or a signal transduction pathway mediated at least in part by Syk kinase activity comprising the step of contacting a cell with a compound of claim 1 .

25. A kit comprising a composition of claim 23 , packaging and instructions for use.

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

4-((1R,2S)-2-aminocyclohexylamino)-2-(m-tolylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(1-methyl-1H-indol-4-ylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(4-fluorophenylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(3,5-dimethylphenylamino)benzamide;

2-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-4-((1R,2S)-2-aminocyclohexylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(3-phenylisoxazol-5-ylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(1-methyl-1H-pyrazol-4-ylamino)benzamide;

(R)-4-(1-amino-4-methyl-1-oxopentan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-methyl-1-oxobutan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-4-methyl-1-oxopentan-2-ylamino)-2-(5-methylisoxazol-3-ylamino)benzamide;

(R)-4-(1-amino-4-methyl-1-oxopentan-2-ylamino)-2-(3-methylisoxazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-phenylpropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(benzyloxy)-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-hydroxy-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-cyclohexyl-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(2-amino-2-oxo-1-phenylethylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-4-methyl-1-oxopentan-2-ylamino)-2-fluoro-6-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-4-methyl-1-oxopentan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(2-amino-1-cyclohexyl-2-oxoethylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-4-methyl-1-oxopentan-2-ylamino)-3-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-phenylpropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-cyclopropyl-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxobutan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(4-fluorophenyl)-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(2-amino-3-methoxypropylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(S)-4-(2-aminobutylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(S)-4-(2-aminopropylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(S)-4-(2-amino-4-methylpentylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxobutan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxobutan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-cyclopropyl-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(4-methoxyphenyl)-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(3-fluorophenyl)-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(pyridin-4-yl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(pyridin-3-yl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-methoxy-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

6-(cis-2-aminocyclohexylamino)-4-(3-toluidino)nicotinamide;

6-(cyclopentylamino)-4-(4-morpholinophenylamino)nicotinamide;

4-(4-carbamoylphenylamino)-6-(cyclopentylamino)nicotinamide;

4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-phenylisoxazol-5-ylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-2-(3-methylisoxazol-5-ylamino)benzamide;

4-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(3-methylisoxazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(2-fluorophenyl)-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-6-((1R,2S)-2-aminocyclohexylamino)nicotinamide;

6-((1R,2S)-2-aminocyclohexylamino)-4-(3-methylisothiazol-5-ylamino)nicotinamide;

(R)-4-(2-amino-1-cyclopropyl-2-oxoethylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

2-(3-methylisothiazol-5-ylamino)-4-(2-oxoazepan-3-ylamino)benzamide;

(R)-4-(1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(pyridin-2-yl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

4-(1-amino-4,4,4-trifluoro-1-oxobutan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(thiophen-2-yl)propan-2-ylamino)-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(4-(pyridin-4-yl)phenyl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(3-(4-(1H-imidazol-1-yl)phenyl)-1-amino-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(4-(2-oxopyridin-1(2H)-yl)phenyl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-(4-(methylsulfonyl)phenyl)-1-oxopropan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-1-oxo-3-(4-(pyridin-3-yl)phenyl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide;

(R)-4-(1-amino-3-cyclopropyl-1-oxopropan-2-ylamino)-5-fluoro-2-(3-phenylisoxazol-5-ylamino)benzamide;

6-((1R,2S)-2-aminocyclohexylamino)-4-(pyrazolo[1,5-a]pyridin-3-ylamino)nicotinamide; and,

6-((1R,2S)-2-aminocyclohexylamino)-4-(thieno[2,3-b]pyridin-3-ylamino)nicotinamide, and pharmaceutically acceptable salts thereof.