US 11,685,749 B2
C26-linked rapamycin analogs as mTOR inhibitors
Christopher Michael Semko, Redwood City, CA (US); Gang Wang, Redwood City, CA (US); G. Leslie Burnett, Redwood City, CA (US); James Bradley Aggen, Redwood City, CA (US); Gert Kiss, Redwood City, CA (US); James Joseph Cregg, Redwood City, CA (US); Micah James Evans Gliedt, Redwood City, CA (US); Jennifer Pitzen, Redwood City, CA (US); Julie Chu-Li Lee, Redwood City, CA (US); Walter Won, Redwood City, CA (US); Arun P. Thottumkara, Redwood City, CA (US); and Adrian Liam Gill, Redwood City, CA (US)
Assigned to REVOLUTION MEDICINES, INC., Redwood City, CA (US)
Filed by Revolution Medicines, Inc., Redwood City, CA (US)
Filed on Oct. 30, 2020, as Appl. No. 17/86,169.
Application 17/086,169 is a continuation of application No. PCT/US2019/029738, filed on Apr. 29, 2019.
Claims priority of provisional application 62/836,040, filed on Apr. 18, 2019.
Claims priority of provisional application 62/752,881, filed on Oct. 30, 2018.
Claims priority of provisional application 62/665,426, filed on May 1, 2018.
Prior Publication US 2022/0340596 A1, Oct. 27, 2022
Int. Cl. C07D 519/00 (2006.01)
CPC C07D 519/00 (2013.01) 8 Claims
 
1. A compound of Formula Ia:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, wherein:
R32 is H, ═O, —OR3, or —N3;
A3 is —[C(R3)2]n—, (C6-C10)arylene, cycloalkylene, heteroarylene, or heterocyclylene;
R26 is -A1-L1-A2-B; -A1-A2-B; or -L2-A1-L1-A2-L3-B;
A1 and A2 are independently absent or are independently selected from

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wherein the bond on the left side of A1, as drawn, is bound to —C(═O)— 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

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L2 and L3 are independently absent or are independently selected from

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each B is independently selected from

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each B1 is independently selected from

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wherein the

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bond on the left side of B1, as drawn, is bound to A2 or L1; and wherein the heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, 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 each independently 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.