C26-linked rapamycin analogs as mTOR inhibitors
The present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
1. A compound of Formula Ia:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, wherein:
R 32 is H, ═O, —OR 3 , or —N 3 ;
A 3 is —[C(R 3 ) 2 ]n—, (C 6 -C 10 )arylene, cycloalkylene, heteroarylene, or heterocyclylene;
R 26 is -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; or -L 2 -A 1 -L 1 -A 2 -L 3 -B;
A 1 and A 2 are independently absent or are independently selected from
wherein the bond on the left side of A 1 , as drawn, is bound to —C(═O)— or L 2 ; and wherein the bond on the right side of the A 2 moiety, as drawn, is bound to B or L 3 ;
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 X 1 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 W 1 is independently a heteroarylene or heterocyclylene ring;
each G is independently absent or a ring selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene;
each G 1 and G 2 are independently heteroarylene or heterocyclylene ring;
each L 1 is independently selected from
L 2 and L 3 are independently absent or are independently selected from
each B is independently selected from
each B 1 is independently selected from
wherein the
bond on the left side of B 1 , as drawn, is bound to A 2 or L 1 ; and wherein the heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl;
each R 3 is independently H or (C 1 -C 6 )alkyl;
each R 4 is independently H, (C 1 -C 6 )alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, (C 6 -C 10 )aryl, wherein the heteroaryl, heterocyclyl, and aryl are each independently optionally substituted with —N(R 3 ) 2 , —OR 3 , halogen, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-heteroaryl, -(C 1 -C 6 )alkylene-CN, —C(O)NR 3 -heteroaryl, or —C(O)NR 3 -heterocyclyl;
each R 5 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
each R 6 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
each R 7 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
each R 8 is independently H, (C 1 -C 6 )alkyl, —C(O)OR 3 , or —N(R 3 ) 2 , wherein the alkyl of (C 1 -C 6 )alkyl is optionally substituted with —N(R 3 ) 2 or —OR 3 ;
each Y is independently C(R 3 ) 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.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, wherein R 32 is ═O or —OR 3 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, wherein A 3 is —[C(R 3 ) 2 ]—or —(C 6 -C 10 )arylene—.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, wherein R 26 is
-A 1 -L 1 -A 2 -B, wherein A 1 and A 2 are absent;
-A 1 -L 1 -A 2 -B, wherein A 2 is absent;
-A 1 -L 1 -A 2 -B, wherein A 1 is absent;
-A 1 -L 1 -A 2 -B;
-A 1 -A 2 -B; or
-L 2 -A 1 -L 1 -A 2 -L 3 -B.
5. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.
6. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.
7. The compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.
8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.