Tri-substituted aryl and heteroaryl derivatives as modulators of PI3-kinase and autophagy pathways

A method of interfering with, modulating, activating, increasing, or stimulating the process of autophagy in a cell, comprising contacting the cell with a compound of Formula (I):

• wherein
• R1 is —(CReRf)o-heterocycloalkyl;
• is 0, 1, or 2;
• Re and Rf are each independently H, halo, or C1-4alkyl,
• each heterocycloalkyl present in R1 is unsubstituted or substituted with one or two Rx substituents;
• wherein each Rx substituent is independently halo, C1-4alkyl, cycloalkyl, —C1-2-haloalkyl, —OH, —OC1-4alkyl, —O—C1-2-haloalkyl, cyano, —C(O)C1-4alkyl, —C(O)NRiRj, —SO2C1-4alkyl, —SO2NRkRl, —NRqRr, —C(O)-cycloalkyl, —C(O)-aryl (optionally substituted with methyl or halo), —CO2C1-4alkyl, —CO2aryl, —C(O)CH2-aryl (optionally substituted with methyl or halo), —CH2-aryl (optionally substituted with methyl or halo), or monocyclic heterocycloalkyl (optionally substituted with methyl, —C(O)C1-4alkyl, or —CO2C1-4alkyl);
• wherein Ri, Rj, Rk, and Rl are each independently H, C1-4alkyl, —C1-4alkyl-OH, or —C1-4alkyl-O—C1-4alkyl,
• wherein Rq and Rr are each independently H, C1-4alkyl, —C1-4alkyl-OH, —C1-4alkyl-O—C1-4alkyl, —C(O)C1-4alkyl, —CO2C1-4alkyl, or —SO2C1-4alkyl;
• L is —S(O)2—;
• X is O;
• one of Y1, Y2, and Y3 is N and the other two are each CH, or Y1, Y2, and Y3 are each CH;
• G2 is N;
• G3 is CR3;
• G4 is N;
• G5 is CR5;
• and
• G6 is CR6;
• wherein R3, R5, and R6 are each independently hydrogen, halogen, —OH, -alkyl, —O-alkyl, -haloalkyl, —O-haloalkyl, or —NRuRv;
• Ru is H or C1-4alkyl;
• Rv is H, C1-4alkyl, monocyclic cycloalkyl, —C(O)C1-4alkyl, or —C(O)NRwRy;
• wherein each alkyl present in Rv is unsubstituted or substituted with —OH, —NH2, —NH(C1-4alkyl), or —N(C1-4alkyl)2,
• Rw and Ry are each independently H or C1-4alkyl;
• and
• R7 and R8 are each independently hydrogen or C1-4alkyl,
• or R7 and R8 are taken together to form —CH2CH2—;
• or a pharmaceutically acceptable salt thereof.