METHODS OF TREATMENT OF CELL PROLIFERATIVE AND/OR OPHTHALMIC DISEASES, DISORDERS AND CONDITIONS USING INHIBITORS OF PROTEIN TYROSINE KINASE ACTIVITY

摘要

This invention relates to methods for treating cell proliferative diseases and conditions and ophthalmic diseases, disorders and conditions using compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to the methods of treatment which utilize compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling.

主权项

1. A method of inhibiting angiogenesis and/or treating a disease responsive to inhibition of kinase activity and/or treating a cell proliferative disease and/or treating an ophthalmic disease, condition or disorder in patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I): including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein, D is M is Z is O; Ar is phenyl substituted with a halogen; and G is wherein R38 is selected from the group consisting of C2-C6alkynyl-heterocyclyl, R37O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, R37O—C(O)—C0-C6alkyl-heterocyclyl-CH2—, R37—O—C(O)—C1-C6alkyl-heterocyclyl-C(O)—, (R9)(R10)N—C1-C6alkyl-C(O)-heterocyclyl-CH2—, (R9)(R10)N—C(O)—C1-C6alkyl-heterocyclyl-CH2—, (R9)(R10)N—C1-C6alkyl-C(O)—O—C1-C6alkyl-heterocyclyl-CH2—, NC—C1-C6alkyl-heterocyclyl-CH2—, F3C—C1-C6alkyl-heterocyclyl-CH2—, C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)-(5 to 10-membered heterocyclyl)-C1-C6alkyl-, (optionally substituted 8- to 10-membered fused heterocyclyl)-C1-C6alkyl-, F-heterocyclyl-C1-C6alkyl-, heteroaryl-C1-C6alkyl-heterocyclyl-C1-C6alkyl-, R37—C1-C6alkyl-O—C1-C6alkyl-heterocyclyl-C1-C6alkyl-, R37O—C(O)—C1-C6alkyl-O-heterocyclyl-C1-C6alkyl-, R37O—C(O)—C1-C6alkyl-heterocyclyl-C1-C6alkyl-, (R6)2N-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, C1-C6alkylC(O)—O—C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, heteroaryl-C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-S(O)2—N(R6)-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-O—C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-heterocyclyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl)-C1-C6alkyl-, C1-C6alkyl-heterocyclyl-C(O)—C1-C6alkyl-, heterocyclyl-C(O)—C1-C6alkyl-, (C1-C6alkyl)2N-heterocyclyl-C(O)—C1-C6alkyl-, (Boc)(H)N-heterocyclyl-C(O)—C1-C6alkyl-, C1-C6alkyl-O—C(O)-heterocyclyl-C(O)—C1-C6alkyl-, Boc-heterocyclyl-C(O)—C1-C6alkyl-, Ac—O—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-, R37O—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-, (Boc)(H)N—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-, NH2—C1-C6alkyl-C(O)-heterocyclyl-C(O)—C1-C6alkyl-, (C1-C6alkyl)(H)N—C(O)-heterocyclyl-C(O)—C1-C6alkyl-, NH2-heterocyclyl-C(O)—C1-C6alkyl-, R37O—C1-C6alkyl-O—C1-C6alkyl-heterocyclyl-C(O)—, C1-C6alkyl-O—C(O)—N(R6)-heterocyclyl-C(O)—, (R6)(R6)N-heterocyclyl-C(O)—, (R6)(R6)N-heterocyclyl-C1-C6alkyl-, heterocyclyl-O—C1-C6alkyl-, C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl-C(O)—, (R6)(R6)N—C(O)-heterocyclyl-O—C1-C6alkyl-, C2-C6alkenyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-C(O)-heterocyclyl-O—C1-C6alkyl-, R37O—C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-, R37O—(CH2)j—[(CH2)iO]x—C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-, halo-C1-C6alkyl-heterocyclyl-C1-C6alkyl-, halo-C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-, R37O—C(O)—C1-C6alkyl-N(R6)-heterocyclyl-C1-C6alkyl-, R37—O—C(O)—C1-C6alkyl-N(R6)—C(O)—N(R6)-heterocyclyl-C1-C6alkyl-, (C1-C6alkyl)(H)N—C(O)-heterocyclyl-N[C1-C6alkyl-C(O)—OH]—C1-C6alkyl-, C1-C6alkyl-O—C(O)-heterocyclyl-C1-C6alkyl-, HO—C(O)-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-heterocyclyl-C(O)-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-, (R6)(R6)N—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-, (C1-C6alkyl)(C1-C6alkyl)N-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-C(O)-[(C1-C6alkyl)(C1-C6alkyl)heterocyclyl]-C1-C6alkyl-, C2-C6alkenyl-C(O)-[(C1-C6alkyl)(C1-C6alkyl)heterocyclyl]-C1-C6alkyl-, R37—O—C1-C6alkyl-[(C1-C6alkyl)(C1-C6alkyl)heterocyclyl]-C1-C6alkyl-, R37O—C(O)—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, R37O—C(O)—C1-C6alkyl-heterocyclyl-C1-C6alkyl-, spiro-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-C(O)-spiro-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-heterocyclyl-C1-C6alkyl-, C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, heterocyclyl-C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, (R6)(R6)N—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, heterocyclyl-C(O)-heterocyclyl-C1-C6alkyl-, (R6)(R6)N—C2-C6alkenyl-C(O)-heterocyclyl-C1-C6alkyl-, heterocyclyl-C2-C8alkenyl-C(O)-heterocyclyl-C1-C6alkyl-, (R6)(R6)N—C1-C6alkyl-N(R6)—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl-, heterocyclyl-C(O)—, (R6)(R6)N—C(O)-heterocyclyl-C1-C6alkyl-, R37O—C(O)—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-, C2-C6alkenyl-C(O)—O—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-, (R6)(R6)N—C(O)-heterocyclyl-C(O)—, R37O—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-, R37O—C1-C6alkyl-heterocyclyl-C1-C6alkyl-(heterocyclyl)-, R37O—C(O)—C1-C6alkyl-heterocyclyl-C(O)—, R37O—C1-C6alkyl-heterocyclyl-C(O)—, R37O—C1-C6alkyl-C(O)-heterocyclyl-C(O)—, C1-C6alkyl-O—C(O)—N(R6)—C1-C6alkyl-C(O)—O—C1-C6alkyl-C(O)-heterocyclyl-C1-C6alkyl- R37O—(CH2)n[(CH2)iO]x—C1-C6alkyl-N(R6)—C(O)-heterocyclyl-C1-C6alkyl-, HO-heterocyclyl-C1-C6alkyl-, R37O-cycloalkyl-C(O)-heterocyclyl-C1-C6alkyl- and R37O—(CH2)n[(CH2)iO]x—C1-C6alkyl-C(O)—N(R6)-heterocyclyl-C1-C6alkyl-; each R6 is independently H or C1-C6alkyl; R37 is selected from the group consisting of H, C1-C6alkyl and C3-C10cycloalkyl; j is an integer ranging from 0 to 4; i is 2 or 3; x is an integer ranging from 0 to 6; n is an integer ranging from 0 to 4; R9 is selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n3(C6-C10 aryl), —(CH2)n3(C5-C10 heteroaryl), —(CH2)n3(5-10 membered heterocyclyl), —(CH2)n3O(CH2)i3OR37 and —(CH2)n3OR37, wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R9 groups are optionally substituted; R10 is selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n4(C6-C10 aryl), —(CH2)n4(C5-C10 heteroaryl), —(CH2)n4(5-10 membered heterocyclyl), —(CH2)n4O(CH2)i4OR37 and —(CH2)n4OR37, wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R10 groups are optionally substituted; n3 is an integer ranging from 0 to 6; i3 is an integer ranging from 2 to 6 n4 is an integer ranging from 0 to 6; and i4 is an integer ranging from 2 to 6.