Imidazopyrazine Syk inhibitors

摘要

Certain imidazopyrazines of Formula (I):;
or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof are provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.

主权项

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: R1 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 R1 iswherein 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 —Ra, —ORb, —O(C1-C2 alkyl)O—, —SRb, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, —NRbRc, halo, cyano, nitro, —CORb, —CO2Rb, —CONRbRc, —OCORb, —OCO2Ra, —OCONRbRc, —NRcCORb, —NRcCO2Ra, —NRcCONRbRc, —SORa, —SO2Ra, —SO2NRbRc, and —NRcSO2Ra, where
Ra is chosen from C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, each of which is optionally substituted; Rb is chosen from hydrogen, C1-C6 alkyl, aryl, and heteroaryl, each of which is optionally substituted; and Rc is chosen from hydrogen and optionally substituted C1-C4 alkyl; or Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group of Ra, Rb, and Rc is unsubstituted or independently substituted with one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkyl-OH, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 haloalkyl, —OC(O)C1-C4 alkyl, —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, —SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl); R2 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; R3 is hydrogen; R4 is hydrogen; and R5 is hydrogen.