C40-, C28-, and C-32-Linked Rapamycin Analogs as mTOR Inhibitors

A compound of Formula Ic:

• or a pharmaceutically acceptable salt or tautomer thereof, wherein:
• R32 is —H, ═O, —OR3, —N3, or —O—C(═Z1)—R32a;
• R28 is —H, (C1-C6)alkyl, or —C(═Z1)—R28a;
• R40 is —H or —C(═Z1)—R40a;
• wherein when R28 and R40 are H, then R32 is not ═O;
• each Z1 is independently O or S;
• R28a, R32a, and R40a are independently -A1-L1-A2-B;
• -A1-A2-B;
• -L2-A1-L1-A2-L3-B;
• —O—(C1-C6)alkyl;
• or —O—(C6-C10)aryl;
• wherein the aryl of —O—(C6-C10)aryl is unsubstituted or substituted with 1-5 substituents selected from —NO2 and halogen;
• A1 and A2 are independently absent or are independently selected from
• wherein the bond on the left side of A1, as drawn, is bound to —C(═Z1)— or L2;
• and wherein the bond on the right side of the A2 moiety, as drawn, is bound to B or L3;
• each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
• each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
• each X1 is independently a heteroarylene or heterocyclylene ring;
• each W is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
• each W1 is independently a heteroarylene or heterocyclylene ring;
• each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
• each G1 and G2 are independently heteroarylene or heterocyclylene ring;
• each L1 is independently selected from
• L2 and L3 are independently absent or are independently selected from
• each B is independently selected from
• each B1 is independently selected from
• wherein the bond on the left side of B1, as drawn, is bound to A2, L3, or L1;
• and wherein the heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxy alkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
• each R3 is independently H or (C1-C6)alkyl;
• each R4 is independently H, (C1-C6)alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C6-C10)aryl, wherein the heteroaryl, heterocyclyl, and aryl are optionally substituted with —N(R3)2, —OR3, halogen, (C1-C6)alkyl, —(C1-C6)alkylene-heteroaryl, —(C1-C6)alkylene-CN, —C(O)NR3-heteroaryl, or —C(O)NR3-heterocyclyl;
• each R5 is independently H, (C1-C6)alkyl, —C(O)OR3, or —N(R3)2, wherein the alkyl of (C1-C6)alkyl is optionally substituted with —N(R3)2 or —OR3;
• each R6 is independently H, (C1-C6)alkyl, —C(O)OR3, or —N(R3)2, wherein the alkyl of (C1-C6)alkyl is optionally substituted with —N(R3)2 or —OR3;
• each R7 is independently H, (C1-C6)alkyl, —C(O)OR3, or —N(R3)2, wherein the alkyl of (C1-C6)alkyl is optionally substituted with —N(R3)2 or —OR3;
• each R8 is independently H, (C1-C6)alkyl, —C(O)OR3, or —N(R3)2, wherein the alkyl of (C1-C6)alkyl is optionally substituted with —N(R3)2 or —OR3;
• each Y is independently C(R3)2 or a bond;
• each n is independently an integer from one to 12;
• each o is independently an integer from zero to 30;
• each p is independently an integer from zero to 12;
• each q is independently an integer from zero to 30;
• and
• each r is independently an integer from one to 6.