Imidazopyrazine Syk inhibitors

1. A method for inhibiting spleen tyrosine kinase activity in a human in need thereof, comprising administering to the human an effective amount of at least one chemical entity chosen from compounds of Formula (I):

and pharmaceutically acceptable salts thereof, wherein:

R 1 is chosen from (2-methyl-2-hydroxypropoxy)pyridin-6-yl, (2-methoxyethoxy)pyridinyl, 2-(dimethylamino)ethoxy-3-pyridinyl, hydroxyethoxy-5-pyridinyl, (3-methyl-3-hydroxyazetidin-1-yl)pyridin-3-yl, (3-methyl-3-hydroxyazetidin-1-yl)pyridin-2-yl, (3-hydroxyazetidin-1-yl)pyridin-2-yl, (hydroxy(dimethylethyl))-5-pyridinyl, (4-methyl-4-hydroxypiperidin-1-yl)pyridin-2-yl, (3-methyl-3-hydroxypiperidin-1-yl)pyridin-2-yl, 5-morpholinopyridin-2-yl, 6-morpholinopyridin-3-yl, ((2-methoxyethyl)(methyl)amino)pyridin-5-yl, ((2-hydroxyethyl)(methyl)amino)pyridin-5-yl, 2-methoxy-4-pyridinyl, 2-hydroxy-5-pyridinyl, (2-hydroxyethyl)-1H-pyrazol-4-yl, (2-hydroxypropyl)-1H-pyrazol-4-yl, (2-methoxyethyl)-1H-pyrazol-4-yl, 1-ethylpyrazol-4-yl, 1-isopropylpyrazol-4-yl, 3-cyclopropyl-1H-pyrazol-5-yl, and 1-ethyl-5-methylpyrazol-3-yl, or

R 1 is

wherein A is a heteroaryl group having from 5 to 7 ring atoms including the atoms shared with the 6 membered aromatic ring, optionally substituted with one or more substituents 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 a lower-alkyl group, —NR b R c , halo, cyano, 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 , where

R a is chosen from C 1 -C 6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is optionally substituted;

R b is chosen from hydrogen, C 1 -C 6 alkyl, aryl, and heteroaryl, each of which is optionally substituted; and

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

R b and R c , and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

where each optionally substituted group of R a , R b , and R c is unsubstituted or independently substituted with one or more substituents independently selected from C 1 -C 4 alkyl, 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, —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 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 2 is chosen from 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, 2,3-dihydro-1H-indol-6-yl, benzothiazolyl, 2-aminoquinazolin-6-yl, 3,3-dimethylindolin-2-one, 2,3-dihydro-1H-indol-2-on-6-yl, 4-fluoro-1H-indazol-6-yl, 5-fluoro-1H-indazol-6-yl, and 3-amino-1H-indazol-6-yl;

R 3 is hydrogen;

R 4 is hydrogen; and

R 5 is hydrogen.

2. The method according to claim 1 , wherein R 1 is

3. The method according to claim 2 , wherein A is a pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, or imidazolyl group, each of which is optionally substituted with one or more substituents 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 a lower-alkyl group, —NR b R c , halo, cyano, 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 , where

R a is chosen from C 1 -C 6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is optionally substituted;

R b is chosen from hydrogen, C 1 -C 6 alkyl, aryl, and heteroaryl, each of which is optionally substituted; and

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

R b and R c , and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and

where each optionally substituted group of R a , R b , and R c is unsubstituted or independently substituted with one or more substituents independently selected from C 1 -C 4 alkyl, 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, —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 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).

4. The method according to claim 3 , wherein the imidazolyl group is substituted with C 1 -C 6 alkyl.

5. The method according to claim 1 , wherein R 1 is chosen from 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-6-yl, 1H-indazol-5-yl, 1-methyl-1H-benzo[d]imidazol-6-yl, benzoxazol-6-yl, benzoxazol-5-yl, imidazo[1,2-a]pyridin-6-yl, 1H-indol-6-yl, 1H-indol-5-yl, benzothiazol-6-yl, and benzothiazol-5-yl.

6. The method according to claim 1 , wherein an effective amount of said at least one chemical entity is administered to the human intravenously, intramuscularly, parenterally, or orally.

7. The method according to claim 1 , wherein R 2 is chosen from 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, and 2,3-dihydro-1H-indol-2-on-6-yl.

8. A method for inhibiting spleen tyrosine kinase activity in a human in need thereof, comprising administering to the human an effective amount of a compound selected from the group consisting of:

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-methyl-1H-1,3-benzodiazol-6-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzoxazol-6-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzoxazol-5-amine;

5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-ol;

N-{imidazo[1,2-a]pyridin-6-yl}-6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indol-6-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indol-5-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-6-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine;

6-[8-(1H-1,3-benzodiazol-5-ylamino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H1,4-benzoxazin-3-one;

2-(4-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;

3-(4-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)propan-1-ol;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-(2-methoxyethyl)-1H-pyrazol-4-amine;

1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-4-amine;

N-[6-(1,3-benzoxazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;

N-[6-(1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-6-amine;

N-[6-(1-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol-5-amine;

N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-indazol 6-amine;

N-[6-(3-aminoquinolin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1,3-benzothiazol-5-amine;

6-{8-[(2-methoxypyridin-4-yl)amino]imidazo[1,2-a]pyrazin-6-yl}-3,4-dihydro-2H-1,4-benzoxazin-3-one;

N-[6-(2,3-dihydro-1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-methoxypyridin-4-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1-(propan-2-yl)-1H-pyrazol-4-amine;

1-methyl-N-[6-(1-methyl-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-1,3-benzodiazol-6-amine;

3-cyclopropyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-1H-pyrazol-5-amine;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

N-[6-(2,3-dimethyl-2H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

5-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-N-(2-methoxyethyl)-2-N methylpyridine-2,5-diamine;

2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol;

2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino 1H-pyrazol-1-yl)ethan-1-ol;

6-(8{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;

2-(4-{[6-(1,3-benzothiazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(2-methoxyethoxy)pyridin-3-amine;

6-(8{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)quinazolin-2-amine;

2-(4-{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}-1H-pyrazol-1-yl)ethan-1-ol;

6-[2-(dimethylamino)ethoxy]-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]pyridin-3-amine;

2-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]ethan-1-ol;

3,3-dimethyl-6-(8{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one;

1-(5{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylazetidin-3-ol;

2-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-2-methylpropan-1-ol;

1-[(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)oxy]-2-methylpropan-2-ol;

N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

N-[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

6-(8 {[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-2,3-dihydro-1H-indol-2-one;

N-[6-(1-methyl-1H-1,3-benzodiazol-5-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

2-[(5{[6-(3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)(methyl)amino]ethan-1-ol;

N-[6-(1-methyl-1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

1-(5{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;

N-[6-(1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

1-(5{[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol;

1-(5{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;

N-[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

6-(8{[6-(morpholin-4-yl)pyridin-3-yl]amino}imidazo[1,2-a]pyrazin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;

6-[8-({6-[(2-hydroxyethyl)(methyl)amino]pyridin-3-yl}amino)imidazo[1,2-a]pyrazin-6-yl]-3,4-dihydro-2H-1,4-benzoxazin-3-one;

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-amine;

N-[6-(4-fluoro-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-4-methylpiperidin-4-ol;

1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)azetidin-3-ol;

N-[6-(5-fluoro-1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-6-(morpholin-4-yl)pyridin-3-amine;

(3S)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol;

(3R)-1-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylpiperidin-3-ol;

1-(5-{[6-(1H-indol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)-3-methylazetidin-3-ol;

[(2R)-4-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2-yl]methanol;

[(2S)-4-(5-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]amino}pyridin-2-yl)morpholin-2-yl]methanol;

N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyrazin-8-yl]-2-(morpholin-4-yl)pyrimidin-5-amine;

1-ethyl-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)-1H-pyrazol-4-amine; and

2-{4-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyrazin-8-yl)amino]-1H-pyrazol-1-yl}ethan-1-ol,

or a pharmaceutically acceptable salt thereof.