Benzopyran and benzoxepin PI3K inhibitor compounds and methods of use

A method of treating breast cancer, prostate cancer or pharynx cancer in a mammal comprised of administering to said mammal a pharmaceutical formulation comprised of:

• (i) a pharmaceutically acceptable carrier, glidant, diluent, or excipient;
• and
• (ii) a compound of Formula I:
• or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
• Z1 is CR1;
• Z2 is CR2;
• Z3 is CR3;
• Z4 is CR4;
• where X1 is S and X2 is CR7;
• R1, R2, R3, R4, and R7 are independently selected from H, F, Cl, Br, I, —CN, —CF3, —CH2OR10, —CH2R10, —(C1-C12 alkylene)NR10R11, —(C1-C12 alkylene)NR12C(═O)R10, —(C1-C12 alkylene)C(═O)OR10, —(C1-C12 alkylene)OR10, —CO2R10, —C(═O)N(R10)OR11, —NO2, —NR10R11, —OR10, —S(O)2R10, —C(═O)NR10R11, —C(═O)NR10 (C1-C12 alkylene)NR10R11, —C(═O)NR10(C1-C12 alkylene)NR10C(═O)OR11, —C(═O)NR10 (C1-C12 alkylene)NR10C(═O)R11, —C(═O)NR10(C1-C12 alkylene)R10, —C(═NR10)NR10R11, —NR12C(═O)R10, —NR12C(═O)OR11, —NR12C(═O)NR10R11, —NR12C(═O) (C1-C12 alkylene)NR10R11, —NR12(C1-C12 alkylene)NR10R11, —NR12(C1-C12 alkylene)OR10, —NR12(C1-C12 alkylene)C(═O)NR10R11, —C≡CR10, —CH═CHR10, C2-C20 heterocyclyl, C1-C20 heteroaryl, and phenyl, where heterocyclyl, heteroaryl, phenyl and alkylene are optionally substituted with one or more groups selected from F, Cl, Br, I, —CH2OH, —(CH2)2OH, —CH2CO2H, —CN, —CH2NH2, —(CH2)2N(CH3)2, —CH3, —C(═O)CH3, —C(═O)NHCH3, —CO2H, —CH2CO2CH3, —NH2, —OCH3, —S(O)2CH3, 4-methylpiperazin-1-yl, and 4-morpholinyl;
• A is selected from —C(═O)NR5R6, C2-C20 heterocyclyl and C1-C20 heteroaryl wherein C2-C20 heterocyclyl and C1-C20 heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2CO2H, —CH(CH3)CH2OCH3, —CN, C1-C12 alkyl, —(C1-C12 alkylene)NR10R11, —(C1-C12 alkylene)OR10, —CH3, —C(═O)CH3, —C(═O)NHCH3, —C(═O)N(CH3)2, —CO2H, —CO2CH3, —CH2CO2CH3, —NH2, —NHC(═O)CH3, —OCH3, —S(O)2CH3, 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, triazolylmethyl, benzyl, and phenyl, where alkyl, alkylene, benzyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CF3, —CH2OH, —CH2CO2H, —CN, —CH2NH2, —CH3, —C(═O)CH3, —C(═O)NHCH3, —CO2H, —CH2CO2CH3, —NH2, —OH, —OCH3, —S(O)2CH3, 1-methylpiperid-4-yl, (4-methylpiperazin-1-yl)carboxamide, —CH2(1H-1,2,4-triazol-5-yl), 4-methylpiperazin-1-yl, and 4-morpholinyl;
• R5 is selected from H, C1-C12 alkyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CO2H, —CONH2, —CONHCH3, —NH2, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, and —S(O)2CH3;
• R6 is selected from C1-C12 alkyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C1-C20 heteroaryl, and C6-C20 aryl, each optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —C(═O)NR10R11, —NH2, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, —S(O)2CH3, —C(═O)NR10(C1-C12 alkylene)NR10R11, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, —C≡CR13, —CH═CHR13, and —C(═O)NR10R11;
• or R5 and R6 together with the nitrogen atom to which they are attached form morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl or S-dioxothiomorpholin-4-yl, each optionally substituted with one or more groups 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, and —S(O)2CH3;
• R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-C2-C20 heterocyclyl, C1-C12 alkylene-C6-C20 aryl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl, where C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 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, 2-oxopyrrolidin-1-yl, —S(O)2NH2, and —S(O)2CH3;
• or R10 and R11 together with the nitrogen atom to which they are attached form a C2-C20 heterocyclyl ring or C1-C20 heteroaryl each optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —CONH2, —CONHCH3, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, oxo, —OCH3, —OCH2CH3, —S(O)2NH2, and —S(O)2CH3;
• and
• R13 is selected from H, F, Cl, Br, I, —CH3, —CH2CH3, —CN, —CF3, —CH2N(CH3)2, —CH2OH, —CO2H, —CONH2, —CON(CH3)2, —NO2, and —S(O)2CH3.