Pyrazolopyrimidine PI3K inhibitor compounds and methods of use

摘要

Compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.;

主权项

1. A compound selected from Formula I: and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R1 is H; R2 is methyl or ethyl; R3 is 1H-indazol-4-yl; R4 is selected from —NR10R13, —NR12C(═O)R10, —NR10C1-C12 alkyl)NR10R13, —NR10(C1-C12 alkyl)OR10, —NR10(C1-C12 alkyl)C(═O)NR10R13, —NR10(C1-C12 alkylene)-(C3-C12 carbocyclyl), —NR10(C1-C12 alkylene)-(C2-C20 heterocyclyl), —NR10(C1-C12 alkylene)-(C6-C20 aryl), —NR10(C1-C12 alkylene)-(C1-C20 heteroaryl), —OR10, —O(C1-C12 alkylene)-(C3-C12 carbocyclyl), —O(C1-C12 alkylene)-(C2-C20 heterocyclyl), —O(C1-C12 alkylene)-(C6-C20 aryl), —O(C1-C12 alkylene)-(C1-C20 heteroaryl), —(C1-C12 alkylene)NR10R13, —(C1-C12 alkylene)-(C3-C12 carbocyclyl), —(C1-C12 alkylene)-(C2-C20 heterocyclyl), —(C1-C12 alkylene)-(C6-C20 aryl), —(C1-C12 alkylene)-(C1-C20 heteroaryl), —(C2-C8 alkynylene)NR10R13, —(C2-C8 alkynylene)-(C3-C12 carbocyclyl), —(C2-C8 alkynylene)-(C2-C20 heterocyclyl), —(C2-C8 alkynylene)-(C6-C20 aryl), —(C2-C8 alkynylene)-(C1-C20 heteroaryl), —(C1-C12 alkylene)-(C6-C20 arylene)-(C2-C20 heterocyclyl), —(C6-C20 aryl)-(C1-C12 alkylene)-(C2-C20 heterocyclyl), —C(═O)NR10R11, C1-C12 alkyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl, where alkyl, alkylene, alkynyl, alkynylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2OH, —CN, —CF3, —CO2H, —COCH3, —CONH2, —CONHCH3, —CON(CH3)2, —NO2, —NH2, —NHCH3, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —S(O)2N(CH3)2, —SCH3, —CH2OCH3, and —S(O)2CH3; or wherein R4 is 4-(2-pyridyl)piperazin-1-yl; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —CONH2, —CONHCH3, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, —SCH3, —S(O)CH3, —CH2OCH3, —CH3, and —S(O)2CH3; or R10 and R11 together with the nitrogen atom to which they are attached form a C2-C20 heterocyclyl ring; and R13 is selected from C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —CONH2, —CONHCH3, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, —SCH3, —S(O)CH3, —OCH2CH2—N(CH3)2, and —S(O)2CH3; or R10 and R13 together with the nitrogen atom to which they are attached form a C2-C20 heterocyclyl ring.