Substituted imidazo[1,2-a]pyrazines as Syk inhibitors

1. At least one chemical entity of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is pyridinyl;

R 2 is a 5- to 6-membered aromatic carbocyclic ring fused to (i) a 5- to 7-membered heterocycloalkyl ring or to (ii) a 5- to 7-membered heteroaryl ring;

wherein R 1 and R 2 are each independently and optionally substituted with one or more substituent groups independently chosen from —R a , —OR b , —O(C 1 -C 2 alkyl)O—, —SR b , guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with C 1 -C 6 alkyl, —NR b R c , halo, cyano, oxo (as a substituent for heterocycloalkyl), nitro, —COR b , —CO 2 R b , —CONR b R c , —OCOR b , —OCO 2 R a , —OCONR b R c , —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —SOR a , —SO 2 R a , —SO 2 NR b R c , and —NR c SO 2 R a ;

wherein R a is chosen from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, heterocycloalkyl, and heteroaryl;

wherein R b is chosen from hydrogen, C 1 -C 6 alkyl, aryl, and heteroaryl; and

wherein R c is chosen from hydrogen and C 1 -C 4 alkyl; or

wherein R b and R c , and the nitrogen to which they are attached, form a heterocycloalkyl group;

wherein R a , R b , and R c are each independently and optionally substituted with one or more substituent groups independently chosen from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl-, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH(C 1 -C 4 alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), —CO 2 H, —C(O)OC 1 -C 4 alkyl, —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CONH 2 , —NHC(O)(C 1 -C 4 alkyl), —NHC(O)(phenyl), —N(C 1 -C 4 alkyl)C(O)(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)C(O)(phenyl), —C(O)C 1 -C 4 alkyl, —C(O)C 1 -C 4 phenyl, —C(O)C 1 -C 4 haloalkyl, —OC(O)C 1 -C 4 alkyl, —SO 2 (C 1 -C 4 alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 4 haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 4 alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 4 haloalkyl);

R 3 is hydrogen;

R 4 is hydrogen; and

R 5 is hydrogen.

2. At least one chemical entity of claim 1 , wherein R 1 is optionally substituted with one or more groups independently chosen from

—OH,

—NR b R c , wherein R b is chosen from hydrogen or C 1 -C 6 alkyl optionally substituted with one or two groups independently chosen from —OH and —OC 1 -C 4 alkyl, and

R c is independently chosen from hydrogen and C 1 -C 4 alkyl optionally substituted with one or two groups independently chosen from —OH and —OC 1 -C 4 alkyl,

heterocycloalkyl optionally substituted with one or two groups independently chosen from —OH, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —OC 1 -C 4 alkyl,

C 1 -C 6 alkyl optionally substituted with one or two groups independently chosen from —OH, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —OC 1 -C 4 alkyl, and

—OC 1 -C 6 alkyl optionally substituted with one or two groups independently chosen from —OH, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —C 1 -C 4 alkyl-O—C 1 -C 4 alkyl, —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), and —OC 1 -C 4 alkyl.

3. At least one chemical entity of claim 1 , wherein R 1 is optionally substituted with one or more groups independently chosen from:

—OH,

—OC 1 -C 6 alkyl optionally substituted with one or two groups independently chosen from —OH, —OC 1 -C 4 alkyl, NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), and —NH(C 1 -C 4 alkyl,

heterocycloalkyl optionally substituted with one or two groups independently chosen from —OH, —OC 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, and C 1 -C 4 alkyl,

C 1 -C 6 alkyl optionally substituted with —OH, and

—NR b R c , wherein R b is chosen from H or C 1 -C 6 alkyl optionally substituted with one or two groups independently chosen from —OH and —OC 1 -C 4 alkyl, and R c is independently chosen from hydrogen and C 1 -C 4 alkyl optionally substituted with one or two groups independently chosen from —OH and —OC 1 -C 4 alkyl.

4. At least one chemical entity of claim 1 , wherein R 1 is optionally substituted with one or more groups chosen from —OH and —OC 1 -C 6 alkyl optionally substituted with one or two groups independently chosen from —OH, —OC 1 -C 4 alkyl, and —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl).

5. At least one chemical entity of claim 1 , wherein R 1 is 6-morpholinopyridin-3-yl, ((2-methoxyethyl)(methyl)amino)pyridin-3-yl, ((2-hydroxyethyl)(methyl)amino)pyridin-3-yl, or 2-methoxypyridin-4-yl.

6. At least one chemical entity of claim 1 , wherein R 2 is dihydroindolinyl optionally substituted with one or more groups independently chosen from oxo and C 1 -C 6 alkyl, or dihydrobenzoxazinyl optionally substituted with oxo.

7. At least one chemical entity of claim 1 , wherein R 2 is 2,3-dimethyl-2H-indazol-6-yl, 1H-indazol-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl, 3,4-dihydro-2H-1,4-benzoxazin-3-on-6-yl, 1,3-benzoxazol-6-yl, 3-aminoquinolin-6-yl, or 2,3-dihydro-1H-indolin-6-yl.

8. At least one chemical entity of claim 1 , wherein R 2 is 1H-indazol-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl, 3,4-dihydro-2H-1,4-benzoxazin-3-on-6-yl, 1,3-benzoxazol-6-yl, 3-aminoquinolin-6-yl, or 2,3-dihydro-1H-indolin-6-yl.

9. A pharmaceutical composition comprising at least one chemical entity of claim 1 , together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.

10. At least one chemical entity selected from:

or a pharmaceutically acceptable salt thereof.