C40-, C28-, and C-32-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 Ic:
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
R 32 is —H, ═O, —OR 3 , —N 3 , or —O—C(═Z 1 )—R 32a ;
R 28 is —H, (C 1 -C 6 )alkyl, or —C(═Z 1 )—R 28a ;
R 40 is —H or —C(═Z 1 )—R 40a ;
wherein when R 28 and R 40 are H, then R 32 is not ═O;
each Z 1 is independently O or S;
R 28a , R 32a , and R 40a are independently -A 1 -L 1 -A 2 -B; -A 1 -A 2 -B; -L 2 -A 1 -L 1 -A 2 -L 3 -B; —O—(C 1 -C 6 )alkyl; or —O—(C 6 -C 10 )aryl; wherein the aryl of —O—(C 6 -C 10 )aryl is unsubstituted or substituted with 1-5 substituents selected from —NO 2 and halogen;
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(═Z 1 )— 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 , L 3 , or L 1 ; and wherein the heteroarylene, heterocyclylene, and arylene are each independently optionally substituted with alkyl, hydroxy alkyl, 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 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 or tautomer thereof, wherein R 32 is ═O.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 32 is —OR 3 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is represented by the structure of Formula (I-40b):
wherein R 40 is —C(═Z 1 )—R 40a .
5 - 15 . (canceled)
16 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is represented by the structure of Formula (I-28b):
wherein R 28 is —C(═Z 1 )—R 28a .
17 - 27 . (canceled)
28 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein the compound is represented by the structure of Formula (I-32b):
wherein R 32 is —O—C(═Z 1 )—R 32a .
29 - 39 . (canceled)
40 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 1 is
41 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 1 is
42 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 1 is
43 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 1 is
44 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 1 is
45 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 1 is
46 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 2 is
47 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein L 3 is
48 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is absent.
49 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
50 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
51 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
52 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
53 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
54 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
55 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
56 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 1 is
57 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is absent.
58 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
59 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
60 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
61 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
62 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
63 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
64 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
65 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein A 2 is
66 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein B is
67 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein B is
68 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein B 1 is
69 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein B 1 is
70 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 4 is 5-12 membered heteroaryl, 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, or —C(O)NR 3 -heteroaryl.
71 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutically acceptable salt or tautomer thereof, wherein compound has the following formula:
72 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or isomer thereof.
73 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or isomer thereof.
74 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or isomer thereof.
75 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
76 . A method of treating a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
77 . A method of preventing a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
78 . A method of reducing the risk of a disease or disorder mediated by mTOR comprising administering to the subject suffering from or susceptible to developing a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
79 - 81 . (canceled)
82 . A method of treating cancer comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
83 . (canceled)
84 . A method of treating an immune-mediated disease comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
85 . (canceled)
86 . A method of treating an age related condition comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
87 - 95 . (canceled)