Tricyclic PI3K inhibitor compounds and methods of use

摘要

Tricyclic PI3k inhibitor compounds of Formula I with anti-cancer activity, anti-inflammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are described. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.;;Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.

主权项

1. A method of treating cancer characterized by over expression of PI3 kinase in a patient, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula I: and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein: the dashed lines indicate an optional double bond, and at least one dashed line is a double bond; X1 is S, O, N, NRa, CR1, C(R1)2, or —C(R1)2O—; X2 is C, CR2 or N; X3 is C, CR3 or N; A is a 5, 6, or 7-membered carbocyclyl or heterocyclyl ring fused to X2 and X3, optionally substituted with one or more R5 groups; Ra is selected from H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C1-C12 alkylene)-C(═O)—(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C6-C20 aryl), and —(C1-C12 alkylene)-(C1-C20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —C(CH3)3, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH2OCH3, —CN, —CH2F, —CHF2, —CF3, —CO2H, —COCH3, —COC(CH3)3, —CO2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; R1, R2, and R3 are independently selected from H, F, Cl, Br, I, —CH3, —CH2CH3, —C(CH3)3, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH2OCH3, —CN, —CF3, —CO2H, —COCH3, —COC(CH3)3, —CO2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; R4 is selected from C6-C20 aryl, C2-C20 heterocyclyl and C1-C20 heteroaryl, each of which are optionally substituted with one or more R6 groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH(CH3)2, —CH2CN, —CN, —CF3, —CH2OH, —CO2H, —CONH2, —CONH(CH3), —CON(CH3)2, —NO2, —NH2, —NHCH3, —NHCOCH3, —OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —SH, —NHC(═O)NHCH3, —NHC(═O)NHCH2CH3, —NHC(═O)NHCH(CH3)2, —NHS(O)2CH3, —N(CH3)C(═O)OC(CH3)3, —S(O)2CH3, benzyl, benzyloxy, morpholinyl, morpholinomethyl, and 4-methylpiperazin-1-yl; and R5 is independently selected from C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C1-C12 alkylene) -C(═O)—(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C6-C20 aryl), and —(C1-C12 alkylene)-(C1-C20 heteroaryl); or two geminal R5 groups form a 3, 4, 5, or 6-membered carbocyclyl or heterocyclyl ring, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3—CH2CH3, —C(CH3)3, —CH2OH, —CH2CH2OH, —C(CH3)2OH, —CH2OCH3, —CN, —CH2F, —CHF2, —CF3, —CO2H, —COCH3, —COC(CH3)3, —CO2CH3, —CONH2, —CONHCH3, —CON(CH3)2, —C(CH3)2CONH2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —N(CH3)C(CH3)2CONH2, —N(CH3)CH2CH2S(O)2CH3, ═O, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —S(O)2CH3, cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; mor is selected from: wherein mor is optionally substituted with one or more R7 groups independently selected from F, Cl, Br, I, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C(CH3)3, —CH2OCH3, —CHF2, —CN, —CF3, —CH2OH, —CH2OCH3, —CH2CH2OH, —CH2C(CH3)2OH, —CH(CH3)OH, —CH(CH2CH3)OH, —CH2CH(OH)CH3, —C(CH3)2OH, —C(CH3)2OCH3, —CH(CH3)F, —C(CH3)F2, —CH(CH2CH3)F, —C(CH2CH3)2F, —CO2H, —CONH2, —CON(CH2CH3)2, —COCH3, —CON(CH3)2, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —NHCH(CH3)2, —NHCH2CH2OH, —NHCH2CH2OCH3, NHCOCH3, —NHCOCH2CH3, —NHCOCH2OH, —NHS(O)2CH3, —N(CH3)S(O)2CH3, ═O, —OH, —OCH3, —OCH2CH3, —OCH(CH3)2, —SH, —NHC(═O)NHCH3, —NHC(═O)NHCH2CH3, —S(O)CH3, —S(O)CH2CH3, —S(O)2CH3, —S(O)2NH2, —S(O)2NHCH3, —S(O)2N(CH3)2, and —CH2S(O)2CH3; and wherein the cancer is characterized by over expression of PI3 kinase and is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, renal, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia.