| 主权项 |
1. A method for the treatment of a PI3K-mediated cancer, comprising administration to a mammal in need thereof, a therapeutically effective dose of a composition in an amount effective to inhibit PI3K enzyme activity, comprising a compound of Formula IA:or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof;or a pharmaceutically acceptable salt, or prodrug thereof;wherein:
R1 and R2 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1b, —C(O)NR1bR1c, —C(NRa)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR16R1c; wherein each R1a, R1b, R1c, and Rid is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1b and R1c together with the N atom to which they are attached form heterocyclyl; R3 and R4 are each independently hydrogen or C1-6 alkyl; or R3 and R4 are linked together to form a bond, C1-6 alkylene, C1-6heteroalkylene, C2-6alkenylene, or C2-6 heteroalkenylene; R5 is independently C1-6 alkyl C2-6alkenyl, each optionally substituted with one or more substituents, each of which is independently selected from the group consisting of heterocyclyl and —NRfRg, or R5 is —NR5mR5n, where R5m and R5n are each independently hydrogen, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; R6 is independently hydrogen or C1-6 alkyl; Q is C1-6 alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; T1 is independently a bond, C1-6 alkylene, —O—, or —NR8—; T2 is independently a bond, C1-6 alkylene, or —NR8—; wherein each R8 is independently hydrogen, C1-6 alkyl, C2-6alkenyl, or C2-6alkynyl; and with the proviso that at least one of the two atoms that are directly attached to the —SO2— group is nitrogen; X, Y, and Z are each independently a nitrogen atom or CR9, with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R9 is hydrogen or C1-6 alkyl; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene in R1, R2, R3, R4, R6, R8, R9, R1a, R1b, R1c, R1d R5m, R5n, Q, T1, and T2, is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q1; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OS(O)Ra—OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q1; wherein each Q1 is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(NRe)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(═NRe)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRfRg, —NReC(═NRh)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl. |
