Imidazopyrizine 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 (1-hydroxycyclobutyl)phenyl, (1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl, (2,2,2-trifluoro-1-hydroxyethyl)phenyl, (2-hydroxy-2-methylpropoxy)-3-methoxyphenyl, (2-hydroxyethyl)(methyl)amino)-3-methoxyphenyl, (2-methoxyethyl)(methyl)amino)-3-methoxyphenyl, (1-hydroxyethyl)phenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl, 4-ethoxy-3-methoxyphenyl, 4-hydroxymethyl-3-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-(dimethylamino)propoxy-3-methoxyphenyl, 4-hydroxypropoxy-3-methoxyphenyl, 4-(2-hydroxy-1,1-dimethylethyl)phenyl, 4-(1-hydroxy-1-methylethyl)phenyl, 4-methoxy-3-(pyrrolidin-1-yl)phenyl, 3-methoxy-4-(pyrrolidin-1-yl)phenyl, 3-methoxy-4-(propan-2-yloxy)phenyl, 3-methoxy-4-(morpholin-4-yl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(3-hydroxypyrrolidinyl)phenyl, 4-(4-hydroxypiperidinyl)-3-methoxyphenyl, 4-(3-hydroxyazetidinyl)-3-methoxyphenyl, 4-(3-hydroxypyrrolidinyl)-3-methoxyphenyl, 4-(2-methoxypropan-2-yl)phenyl, 4-(4-ethylpiperazin-1-yl)-3-methoxyphenyl, 4-(4-ethylpiperazin-1-yl)phenyl, 4-(3-hydroxy-3-methylpiperidinyl)phenyl, 3-hydroxymethylphenyl, and 4-(morpholin-4-yl)phenyl, or

R 1 is

 wherein A is chosen from aryl, cycloalkyl and heterocycloalkyl groups, each of which groups having from 5 to 7 ring atoms including the atoms shared with the 6 membered aromatic ring and each of which groups being 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 ;

wherein, for each occurrence,

R a is independently chosen from optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R b is independently chosen from H, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R c is independently 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 substitutent 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 2 is chosen from 1,3-benzoxazol-5-yl, 2-aminoquinazolin-6-yl, 2-hydroxyethyl-2H-indazol-6-yl, 1-hydroxyethyl-2H-indazol-6-yl, 1H-indazol-7-yl, 3-(diethylamino)methyl-1H-indazol-6-yl, 1,2-dihydroquinoxalin-2-on-6-yl, 1,2-dihydroquinolin-2-on-6-yl, 2-methyl-1,3-benzothiazol-5-yl, 3-(1,3-thiazol-4-ylmethylidene)-2,3-dihydro-1H-indol-2-on-6-yl, 1-methyl-1H-indazol-6-yl, (N,N-dimethylaminocarbonyl)indol-6-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 3-ethyl-1H-indazol-6-yl, 1H-indol-2-yl, 1H-indol-3-yl, 4-fluoro-1H-indazol-6-yl, 1H-1,2,3-benzotriazol-6-yl, 1H-1,3-benzodiazol-6-yl, 1H-indol-6-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-methyl-1H-1,3-benzodiazol-5-yl, 1-methyl-1H-1,3-benzodiazol-6-yl, 1-methyl-1H-benzo[d]imidazol-5-yl, 2-methyl-1H-benzo[d]imidazol-5-yl, 3-amino-1H-indazol-5-yl, 3-amino-1H-indazol-6-yl, 3-carbamoyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 5-fluoro-1H-indazol-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 3-amino-1H-indazol-5-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-5-yl, 2,3-dimethyl-2H-indazol-5-yl, 3-amino-1H-indazol-5-yl, quinolin-6-yl, 2-aminoquinolin-6-yl, 3-aminoquinolin-6-yl, 2-aminoquinazolin-6-yl, 1H-1,2,3-benzotriazol-6-yl, 1H-imidazo[4,5-b]pyridin-6-yl, 1,3-benzoxazol-6-yl, 1H-indol-5-yl, 2-amino-1H-1,3-benzodiazol-6-yl, 2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-on-6-yl, 1H,2H,3H-pyrido[3,2-b][1,4]oxazin-3-on-6-yl, 4-benzoxazin-3-on-6-yl, 2-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-on-6-yl, 2-hydroxyquinolin-6-yl, and quinoxalin-2-ol-7-yl;

R 3 is chosen from hydrogen, lower alkyl, and halo;

R 4 is chosen from hydrogen and lower alkyl; and

R 5 is hydrogen.

2. The method according to claim 1 , wherein R 3 is chosen from hydrogen, methyl, ethyl, and chloro.

3. The method according to claim 2 , wherein R 3 is hydrogen.

4. The method according to claim 1 , wherein R 4 is chosen from hydrogen and methyl.

5. The method according to claim 4 , wherein R 4 is hydrogen.

6. The method according to claim 1 , wherein R 1 is chosen from (1-hydroxyethyl)phenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl, 4-ethoxy-3-methoxyphenyl, 4-hydroxymethyl-3-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-(dimethylamino)propoxy-3-methoxyphenyl, 4-hydroxypropoxy-3-methoxyphenyl, 4-(2-hydroxy-1,1-dimethylethyl)phenyl, 4-(1-hydroxy-1-methylethyl)phenyl, 4-methoxy-3-(pyrrolidin-1-yl)phenyl, 3-methoxy-4-(pyrrolidin-1-yl)phenyl, 3-methoxy-4-(propan-2-yloxy)phenyl, 3-methoxy-4-(morpholin-4-yl)phenyl, 4-(pyrrolidin-1-yl)phenyl, 4-(3-hydroxypyrrolidinyl)phenyl, 4-(4-hydroxypiperidinyl)-3-methoxyphenyl, 4-(3-hydroxyazetidinyl)-3-methoxyphenyl, 4-(3-hydroxypyrrolidinyl)-3-methoxyphenyl, 4-(2-methoxypropan-2-yl)phenyl, 4-(4-ethylpiperazin-1-yl)-3-methoxyphenyl, 4-(4-ethylpiperazin-1-yl)phenyl, 4-(3-hydroxy-3-methylpiperidinyl)phenyl, 3-(hydroxymethyl)phenyl, and 4-(morpholin-4-yl)phenyl.

7. The method according to claim 6 , wherein R 3 and R 4 are both hydrogen.

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

9. The method according to claim 1 , wherein R 3 and R 4 are both hydrogen.

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

11. The method according to claim 1 , wherein the at least one chemical entity is:

or pharmaceutically acceptable salts thereof.

12. A method for inhibiting spleen tyrosine kinase activity in a human in need thereof, comprising administering to the human an effective amount of the compound having the structure:

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12 , wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof is administered to the human intravenously, intramuscularly, and parenterally, or orally.