Rapamycin analogs as MTOR inhibitors
阅读说明：本技术 作为mtor抑制剂的雷帕霉素类似物 (Rapamycin analogs as MTOR inhibitors ) 是由 C·桑科 J·皮特森 G·王 N·提布雷瓦尔 J·B·阿根 A·P·托图姆卡拉 G·L· 于 2018-05-01 设计创作，主要内容包括：本公开涉及通式(I)的雷帕霉素类似物。化合物是mTOR抑制剂,并且因此适用于治疗癌症、免疫介导的疾病和与年龄相关的病状。<Image he="508" wi="700" file="DDA0002306547900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present disclosure relates to rapamycin analogs of general formula (I). The compounds are mTOR inhibitors and are therefore useful in the treatment of cancer, prophylaxisEpidemic-mediated diseases and age-related pathologies.)
1. A compound represented by the formula I-X,
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
R16is selected from R1、R2、H、(C1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ N-R1、＝N-R2、＝O、-OR3And N-OR3；
R28Is selected from R1、R2、-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is selected from ═ N-R1、＝N-R2、H、＝O、-OR3、＝N-OR3、＝N-NHR3And N (R)3)2；
R40Is selected from R1、R2、-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein the compound comprises one R1Or a R2；
R1is-A-L1-B；
R2is-A-C ≡ CH, -A-N3-A-COOH or-A-NHR3(ii) a And is
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, hydroxy, -C (O) OR3、-C(O)N(R3)2、-N(R3)2And is-N (R)3)2A substituted alkyl group;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently H, (C)1-C6) Alkyl, -C (O) (C)1-C6) Alkyl, -C (O) NH-aryl or-C (S) NH-aryl, wherein the alkyl is unsubstituted or substituted by-COOH, (C)6-C10) Aryl or-OH substitution;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN, -C (O) NR3-heteroaryl or-C (O) NR3-heterocyclyl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 30; and is
Each r is independently 1,2, 3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is that
2. A compound represented by formula I-Xa,
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
R16is selected from R1、R2、H、(C1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ N-R1、＝N-R2、＝O、-OR3And N-OR3；
R28Is selected from R1、R2、-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is selected from ═ N-R1、＝N-R2、H、＝O、-OR3、＝N-OR3、＝N-NHR3And N (R)3)2；
R40Is selected from R1、R2、-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein the compound comprises one R1Or a R2；
R1is-A-L1-B；
R2is-A-C ≡ CH, -A-N3-A-COOH or-A-NHR3(ii) a And is
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, hydroxy, -C (O) OR3、-C(O)N(R3)2、-N(R3)2And is-N (R)3)2A substituted alkyl group;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently H, (C)1-C6) Alkyl, -C (O) (C)1-C6) Alkyl, -C (O) NH-aryl or-C (S) NH-aryl, wherein the alkyl is unsubstituted or substituted by-COOH, (C)6-C10) Aryl or-OH substitution;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN, -C (O) NR3-heteroaryl or-C (O) NR3-heterocyclyl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 30; and is
Each r is independently 1,2, 3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is that
3. A compound represented by the formula (I),
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
R16is selected from R1、R2、H、(C1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, andwherein said aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
R26is selected from ═ N-R1、＝N-R2、＝O、-OR3And N-OR3；
R28Is selected from R1、R2、-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is selected from ═ N-R1、＝N-R2、H、＝O、-OR3And N-OR3；
R40Is selected from R1、R2、-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、And
wherein the compound comprises one R1Or a R2；
R1is-A-L1-B；
R2is-A-C ≡ CH, -A-N3-A-COOH or-A-NHR3(ii) a And is
Wherein
A is absent or selected from
-(C(R3)2)n-、
-O(C(R3)2)n-、
-NR3(C(R3)2)n-、
-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、
-C(O)(C(R3)2)n-、
-C(O)NR3-、
-NR3C(O)(C(R3)2)n-、
-NR3C(O)O(C(R3)2)n-、
-OC(O)NR3(C(R3)2)n-、
-NHSO2NH(C(R3)2)n-、
-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2, 3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is that
4. The compound according to any one of claims 1 to 3, represented by formula (Ia-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R16Is R1Or R2。
5. The compound according to any one of claims 1 to 3, represented by formula (Ib-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R26Is ═ N-R1Or ═ N-R2。
6. The compound according to any one of claims 1 to 3, represented by formula (Ic-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R28Is R1Or R2。
7. The compound according to any one of claims 1 to 3, represented by formula (Id-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R32Is ═ N-R1Or R2。
8. The compound according to any one of claims 1 to 3, represented by formula (Ie-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R40Is R1Or R2。
9. The compound of any one of claims 1 to 8, wherein the compound comprises R1。
10. The compound of any one of claims 1 to 8, wherein the compound comprises R2。
11. The compound of claim 10, wherein the compound comprises R2is-A-C ≡ CH.
12. The compound of claim 10, wherein the compound comprises R2is-A-N3。
13. The compound of claim 10, wherein the compound comprises R2is-A-COOH.
14. The compound of claim 10, wherein the compound comprises R2is-A-NHR3。
15. The compound according to any one of claims 1 to 14, wherein a is-O (C (R)3)2)n-。
16. The compound according to any one of claims 1 to 14, wherein a is-O (C (R)3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-。
17. The compound according to any one of claims 1 to 14, wherein a is-O (C (R)3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-。
18. The compound according to any one of claims 1 to 14, wherein a is-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-, -heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-, -heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-or-O (C (R)3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-.
19. The compound according to any one of claims 1 to 14, wherein a is-O (C (R)3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-or-O (C (R)3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-。
20. A compound according to any one of claims 1 to 14, which isWherein A is-O (C (R)3)2)n-heteroarylene-NR3-(C6-C10) Arylene-, -O (C (R)3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-or-O (C (R)3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-。
21. The compound according to any one of claims 1 to 14, wherein a is-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-, -heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-, or-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-。
22. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
23. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
24. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
25. The compound according to any one of claims 1 to 9 and 15 to 21,wherein L is1Is that
26. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
27. The compound of any one of claims 7, 8, and 15-21, wherein L1Is that
28. The compound of any one of claims 7, 8, and 15-21, wherein L1Is that
29. The compound of any one of claims 7, 8, and 15-21, wherein L1Is that
30. The compound of any one of claims 7, 8, and 15-21, wherein L1Is that
31. The compound of any one of claims 7, 8, and 15-21, wherein L1Is that
32. The compound of any one of claims 7, 8, and 15-21, wherein L1Is that
33. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
34. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
35. The compound of any one of claims 1 to 9 and 15 to 21, wherein L1Is that
36. The compound according to any one of claims 1 to 9 and 15 to 35, wherein B is
37. The compound of any one of claims 1 to 9 and 15 to 35Wherein B is
38. The compound according to any one of claims 1 to 9 and 15 to 37, wherein B1Is that
39. The compound according to any one of claims 1 to 9 and 15 to 37, wherein B1Is that
40. The compound according to any one of claims 1-9 and 15-39, wherein R4Is a 5 to 12 membered heteroaryl group optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution.
41. The compound according to any one of claims 1-9 and 15-41, wherein R4Is optionally substituted by-NH2A substituted heteroaryl group.
42. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or isomer thereof.
43. A pharmaceutical composition comprising a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
44. A method of treating a disease or disorder mediated by mTOR, the method comprising administering to an individual suffering from or susceptible to a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.
45. A method of preventing a disease or disorder mediated by mTOR, the method comprising administering to an individual suffering from or susceptible to a disease or disorder mediated by mTOR a therapeutically effective amount of one or more compounds of any one of claims 1-42, or a pharmaceutically acceptable salt thereof.
46. A method of reducing the risk of an mTOR-mediated disease or condition, the method comprising administering to an individual suffering from or susceptible to an mTOR-mediated disease or condition a therapeutically effective amount of one or more compounds of any one of claims 1-42, or a pharmaceutically acceptable salt thereof.
47. The method of any one of claims 44 to 46, wherein the disease is cancer or an immune-mediated disease.
48. The method of claim 47, wherein the cancer is selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer, liver cancer, ovarian cancer, endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, a blood proliferative disorder, lymphoma, leukemia, endometrial cancer, cervical cancer, vulval cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal stromal tumors, and neuroendocrine tumors.
49. The method of claim 47, wherein the immune-mediated disease is selected from resistance resulting from transplantation of heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or pancreatic islet cells; graft versus host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
50. A method of treating cancer, the method comprising administering to a subject a therapeutically effective amount of one or more compounds of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.
51. The method of claim 50, wherein the cancer is selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer, liver cancer, ovarian cancer, endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, a blood proliferative disorder, lymphoma, leukemia, endometrial cancer, cervical cancer, vulval cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal stromal tumors, and neuroendocrine tumors.
52. A method of treating an immune-mediated disease, the method comprising administering to a subject a therapeutically effective amount of one or more compounds of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.
53. The method of claim 52, wherein the immune-mediated disease is selected from resistance resulting from transplantation of heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or pancreatic islet cells; graft versus host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
54. A method of treating an age-related condition, the method comprising administering to an individual a therapeutically effective amount of one or more compounds according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.
55. The method of claim 54, wherein the age-related condition is selected from sarcopenia, skin atrophy, muscle atrophy, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, shortened life expectancy, impaired renal function and age-related hearing loss, age-related behavioral dysfunction (e.g., weakness), cognitive decline, age-related dementia, memory impairment, tendon stiffness, cardiac dysfunction (such as cardiac hypertrophy and contractile and diastolic dysfunction), immunosenescence, cancer, obesity, and diabetes.
56. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention or reduction of risk of a disease or condition mediated by mTOR.
57. Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention or reduction of risk of a disease or condition mediated by mTOR.
58. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
59. Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
60. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in the treatment of an immune-mediated disease.
61. Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an immune-mediated disease.
62. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in the treatment of an age-related condition.
63. Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an age-related condition.
Technical Field
The present disclosure relates to mTOR inhibitors. In particular, the embodiments relate to compounds and compositions that inhibit mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
Background
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase related to a lipid kinase of the phosphoinositide 3 kinase (PI3K) family. mTOR exists in two complexes, mTORC1 and mTORC2, which are differentially regulated, have distinct substrate specificities, and have distinct sensitivities to rapamycin. mTORC1 integrates signals from growth factor receptors with cell nutrition status and controls the level of cap-dependent mRNA translation by modulating the activity of key translational components such as cap-binding proteins and oncogene eIF 4E.
mTOR signaling has been explained in more and more detail. The different pharmacologies of mTOR inhibitors are particularly informative. Rapamycin is the first reported mTOR inhibitor, which is now understood to be an incomplete inhibitor of mTORC 1. Rapamycin is a selective mTORC1 inhibitor that acts by binding to the FK506 rapamycin binding (FRB) domain of mTOR kinase via FK506 binding protein 12(FKBP 12). The FRB domain of mTOR is accessible in the mTORC1 complex, but less accessible in the mTORC2 complex. Interestingly, the potency of the inhibitory activity against mTORC1 downstream substrates, produced by rapamycin treatment, is known to vary between mTORC1 substrates. For example, rapamycin strongly inhibits phosphorylation of mTORC1 substrate S6K, and indirectly inhibits phosphorylation of downstream ribosomal protein S6, which controls ribosome biogenesis. Rapamycin, on the other hand, showed only partial inhibitory activity against phosphorylation of 4E-BP1, 4E-BP1 being the major regulator of eIF4E, and eIF4E controlling the initiation of CAP-dependent translation. As a result, more complete inhibitors of mTORC1 signaling are of interest.
A second class of "ATP-site" inhibitors of mTOR kinase is reported. Such mTOR inhibitors will be referred to as asTORi (ATP site TOR inhibitors). The molecule competes with ATP (the substrate for the kinase reaction) in the active site of the mTOR kinase (and is therefore also an mTOR active site inhibitor). As a result, these molecules inhibit downstream phosphorylation of a wide range of substrates.
Although mTOR inhibition may have the effect of blocking phosphorylation of 4E-BP1, these agents may also inhibit mTORC2, which results in blocking of Akt activation due to inhibition of phosphorylation of Akt S473.
Disclosed herein are inter alia mTORC1 inhibitors.
Disclosure of Invention
The present disclosure relates to compounds capable of inhibiting mTOR activity. The disclosure further provides processes for preparing the compounds of the disclosure, pharmaceutical formulations comprising such compounds, and methods of using such compounds and compositions in the management of mTOR-mediated diseases or disorders.
The present disclosure provides compounds of formula I-X:
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16is selected from R1、R2、H、(C1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ N-R1、＝N-R2、＝O、-OR3And N-OR3；
R28Is selected from R1、R2、-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is selected from ═ N-R1、＝N-R2、H、＝O、-OR3、＝N-OR3、＝N-NHR3And N (R)3)2；
R40Is selected from R1、R2、-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein the compound comprises one R1Or a R2；
R1is-A-L1-B；
R2is-A-C ≡ CH, -A-N3-A-COOH or-A-NHR3(ii) a And is
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein said arylene, heteroarylene and heterocyclylene are optionally substituted with each otherSubstituted with one or more substituents independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, hydroxy, -C (O) OR3、-C(O)N(R3)2、-N(R3)2And is-N (R)3)2A substituted alkyl group; l is1Is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently H, (C)1-C6) Alkyl, -C (O) (C)1-C6) Alkyl, -C (O) NH-aryl or-C (S) NH-aryl, wherein the alkyl is unsubstituted or substituted by-COOH, (C)6-C10) Aryl or-OH substitution;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN, -C (O) NR3-heteroaryl or-C (O) NR3-heterocyclyl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 30; and is
Each r is independently 1,2,3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is thatB is
The present disclosure provides compounds of formula I-Xa:
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16is selected from R1、R2、H、(C1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ N-R1、＝N-R2、＝O、-OR3And N-OR3；
R28Is selected from R1、R2、-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is selected from ═ N-R1、＝N-R2、H、＝O、-OR3、＝N-OR3、＝N-NHR3And N (R)3)2；
R40Is selected from R1、R2、-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein the compound comprises one R1Or a R2；
R1is-A-L1-B；
R2is-A-C ≡ CH, -A-N3-A-COOH or-A-NHR3(ii) a And is
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, hydroxy, -C (O) OR3、-C(O)N(R3)2、-N(R3)2And is-N (R)3)2A substituted alkyl group;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently H, (C)1-C6) Alkyl, -C (O) (C)1-C6) Alkyl, -C (O) NH-aryl or-C (S) NH-aryl, wherein the alkyl is unsubstituted or substituted by-COOH, (C)6-C10) Aryl or-OH substitution;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN, -C (O) NR3-heteroaryl or-C (O) NR3-heterocyclyl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 30; and is
Each r is independently 1,2,3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is that
The present disclosure provides compounds of formula I:
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16is selected from R1、R2、H、(C1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ N-R1、＝N-R2、＝O、-OR3And N-OR3；
R28Is selected from R1、R2、-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is selected from ═ N-R1、＝N-R2、H、＝O、-OR3And N-OR3；
R40Is selected from R1、R2、-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein the compound comprises one R1Or a R2；
R1is-A-L1-B；
R2is-A-C ≡ CH, -A-N3-A-COOH or-A-NHR3(ii) a And is
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2,3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is that
The present disclosure provides compounds of formula (Ia):
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16is R1Or R2；
R26Is selected from ═ O and-OR3And N-OR3；
R28Is selected from-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Selected from H, ═ O, -OR3And N-OR3；
R40Is selected from-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、And
wherein R is1is-A-L1-B；
R2Is A-C ≡ CH, -A-N3-A-COOH or-A-NHR3；
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Aaryl-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2,3 or 4.
The present disclosure provides compounds of formula (Ib):
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16selected from H, (C)1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is ═ N-R1Or ═ N-R2；
R28Is selected from-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Selected from H, ═ O, -OR3And N-OR3；
R40Is selected from-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein R is1is-A-L1-B；
R2Is A-C ≡ CH, -A-N3-A-COOH or-A-NHR3；
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2,3 or 4.
The present disclosure provides compounds of formula (Ic):
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16selected from H, (C)1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ O and-OR3And N-OR3；
R28Is R1Or R2；
R32Selected from H, ═ O, -OR3And N-OR3；
R40Is selected from-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein the compound comprises one R1Or a R2；
Wherein R is1is-A-L1-B；
R2Is A-C ≡ CH, -A-N3-A-COOH or-A-NHR3；
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution；
Each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2,3 or 4.
The present disclosure provides compounds of formula (Id):
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16selected from H, (C)1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ O and-OR3And N-OR3；
R28Is selected from-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Is ═ N-R1Or R2；
R40Is selected from-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
wherein R is1is-A-L1-B；
R2Is A-C ≡ CH, -A-N3-A-COOH or-A-NHR3；
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroarylA group, a 5-to 12-membered heterocyclic group, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution;
each Q is independently C (R)3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2,3 or 4.
The present disclosure provides compounds of formula (Ie):
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16selected from H, (C)1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, andwherein said aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy,Halogen and hydroxy;
R26is selected from ═ O and-OR3And N-OR3；
R28Is selected from-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2、-OS(O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Selected from H, ═ O, -OR3And N-OR3；
R40Is R1Or R2；
Wherein R is1is-A-L1-B；
R2Is A-C ≡ CH, -A-N3-A-COOH or-A-NHR3；
Wherein
A is absent or selected from- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-、-OC(O)NHSO2NH(C(R3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-a heteroarylene group-,
-OC(O)NH(C(R3)2)n-(C6-C10) Arylene-radicals,
-O-(C6-C10) Arylene-radicals,
-O-heteroarylene-,
-heteroarylene- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-,
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-radicals,
-heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、
-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-radicals,
-O(C(R3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-、
-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、
-heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-and
-O(C(R3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-containing a substituted or unsubstituted alkylene group,
wherein the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S; heterocyclylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S;
wherein the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, and hydroxy;
L1is selected from
wherein the bond with variable positions in the triazole is at the 4-or 5-position, and wherein the a ring is phenylene or 5-to 8-membered heteroarylene;
b is selected from
B1Is selected from
each R3Independently is H or (C)1-C6) An alkyl group;
each R4Independently H, (C)1-C6) Alkyl, halogen, 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl, (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution;
each Q is independentlyC(R3)2Or O;
each Y is independently C (R)3)2Or a bond;
each Z is independently H or absent;
each n is independently a number from one to 12;
each o is independently a number from zero to 12;
each p is independently a number from zero to 12;
each q is independently a number from zero to 10; and is
Each r is independently 1,2,3 or 4;
with the proviso that when R40Is R1Wherein R is1is-A-L1-B；L1Is that
The present disclosure provides a method of treating a disease or disorder mediated by mTOR, the method comprising administering to an individual suffering from or susceptible to a disease or disorder mediated by mTOR a therapeutically effective amount of one or more of the disclosed compounds. The present disclosure provides a method of preventing a disease or disorder mediated by mTOR, the method comprising administering to an individual suffering from or susceptible to a disease or disorder mediated by mTOR a therapeutically effective amount of one or more of the disclosed compounds. The present disclosure provides a method of reducing the risk of an mTOR-mediated disease or condition, the method comprising administering to an individual suffering from or susceptible to an mTOR-mediated disease or condition a therapeutically effective amount of one or more of the disclosed compounds.
Another aspect of the disclosure relates to pharmaceutical compositions comprising a compound of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie, or If) or a compound of formula I-X (including compounds of formula I-Xa) or a compound of formula Ia-X, Ib-X, Ic-X, Id-X or Ie-X, or pharmaceutically acceptable salts and tautomers of any of the foregoing, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent or surfactant. The pharmaceutical composition may be effective to treat, prevent or reduce the risk of: an mTOR-mediated disease or disorder, an mTOR-mediated disease in an individual in need thereof.
Another aspect of the disclosure relates to compounds of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie, or If) or compounds of formula I-X (including compounds of formula I-Xa) or compounds of formula Ia-X, Ib-X, Ic-X, Id-X or Ie-X, or pharmaceutically acceptable salts and tautomers of any of the foregoing, for use in treating, preventing, or reducing the risk of: an mTOR-mediated disease or disorder, an mTOR-mediated disease in an individual in need thereof.
Another aspect of the disclosure relates to the use of a compound of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie, or If) or a compound of formula I-X (including compounds of formula I-Xa) or a compound of formula Ia-X, Ib-X, Ic-X, Id-X or Ie-X, or a pharmaceutically acceptable salt or tautomer of any of the foregoing, for the manufacture of a medicament for treating, preventing, or reducing the risk of: an mTOR-mediated disease or disorder, an mTOR-mediated disease in an individual in need thereof.
The present disclosure also provides compounds useful for inhibiting mTOR.
Detailed Description
The present disclosure relates to mTOR inhibitors. In particular, the embodiments relate to compounds and compositions that inhibit mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
The details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms "a", "an", and "the" may include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are herein incorporated by reference in their entirety.
Term(s) for
The article "a/an" is used in this disclosure and can refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" may mean one element or more than one element.
The term "and/or" is used in this disclosure and may mean "and" or "unless otherwise specified.
Unless otherwise specified, the term "alkyl", by itself or as part of another substituent, may mean having the indicated number of carbon atoms (i.e., C)1-C10Meaning one to ten carbons) or a branched acyclic carbon chain (or carbon) or combination thereof, which may be fully saturated, mono-unsaturated, or polyunsaturated, and may include divalent and multivalent groups. Examples of saturated hydrocarbon groups may include (but are not limited to) groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl) methyl, for example the n-pentyl, n-hexyl, n-heptyl, homologs and isomers of n-octyl, and the like. Unsaturated alkyl is alkyl having one or more double or triple bonds. Examples of unsaturated alkyl groups may include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.
Unless otherwise specified, the term "alkylene" by itself or as part of another substituent may mean a divalent group derived from alkyl. Typically, the alkyl (or alkylene) groups will have from 1 to 24 carbon atoms, such as those groups having 10 or fewer carbon atoms.
The term "alkenyl" may mean an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched having from about 2 to about 6 carbon atoms in the chain. Some alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups (such as methyl, ethyl or propyl) are attached to the linear alkenyl chain. Exemplary alkenyl groups can include ethenyl, propenyl, n-butenyl, and isobutenyl. C2-C6Alkenyl is alkenyl containing between 2 and 6 carbon atoms.
Unless otherwise specified, the term "alkenylene" by itself or as part of another substituent may mean a divalent group derived from an alkene.
The term "alkynyl" may mean an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and which may be straight or branched chain having from about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched may mean that one or more lower alkyl groups (such as methyl, ethyl or propyl) are attached to a linear alkynyl chain. Exemplary alkynyl groups can include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. C2-C6Alkynyl is alkynyl containing between 2 and 6 carbon atoms.
Unless otherwise specified, the term "alkynylene" by itself or as part of another substituent may mean a divalent group derived from an alkyne.
The term "cycloalkyl" may mean a monocyclic or polycyclic saturated carbocyclic ring containing from 3 to 18 carbon atoms. Examples of cycloalkyl groups may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl (norbomanyl), norbornenyl, bicyclo [2.2.2 ] 2]Octyl or bicyclo [2.2.2]An octenyl group. C3-C8Cycloalkyl is cycloalkyl containing between 3 and 8 carbon atoms. Cycloalkyl groups may be fused (e.g., decalin) or bridged (e.g., norbornane).
"cycloalkylene" alone or as part of another substituent may mean a divalent radical derived from a cycloalkyl group.
The term "heterocyclyl" or "heterocycloalkyl" or "heterocycle" may refer to a mono-or polycyclic 3 to 24 membered ring containing carbon and heteroatoms selected from oxygen, phosphorus nitrogen or sulfur, and in which there are no delocalized pi electrons shared among the ring carbons or heteroatoms (aromaticity). Heterocyclyl rings may include, but are not limited to, oxetanyl, azetidinyl (azetadinyl), tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, bisoxazolinyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxazepinyl, diazepine, tropanyl, and atropine (homotropanyl). The heterocyclyl or heterocycloalkyl ring may also be fused or bridged, for example, it may be a bicyclic ring.
"heterocyclylene" or "heterocycloalkylene" alone or as part of another substituent may mean a divalent radical derived from "heterocyclyl" or "heterocycloalkyl" or "heterocycle".
Unless otherwise indicated, the term "aryl" may mean a polyunsaturated aromatic hydrocarbon substituent which may be a single ring, or multiple rings (preferably 1 to 3 rings) which are fused together (i.e., a fused ring aryl) or covalently linked. A fused ring aryl group can refer to multiple rings fused together, wherein at least one of the fused rings is an aryl ring.
"arylene" alone or as part of another substituent may mean a divalent group derived from an aryl group.
The term "heteroaryl" may refer to an aryl (or ring) containing at least one heteroatom (e.g., N, O or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (S) are optionally quaternized. Thus, the term "heteroaryl" may include fused ring heteroaryl (i.e., multiple rings fused together where at least one of the fused rings is a heteroaromatic ring). A 5, 6-fused ring heteroarylene may refer to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6, 6-fused ring heteroarylene may refer to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6, 5-fused ring heteroarylene may refer to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. The heteroaryl group may be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups may include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-oxazolyl, 2-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for each of the above-indicated aryl and heteroaryl ring systems are selected from the group of acceptable substituents described herein.
The term may also include multiple fused ring systems having at least one such aromatic ring, which are described further below. The term may also include multiple fused ring systems (e.g., ring systems comprising 2,3, or 4 rings), wherein a heteroaryl group as defined above may be fused to one or more rings selected from the group consisting of: heteroaryl (to form, for example, naphthyridinyl, such as 1, 8-naphthyridinyl), heterocycle (to form, for example, 1,2,3, 4-tetrahydronaphthyridinyl, such as 1,2,3, 4-tetrahydro-1, 8-naphthyridinyl), carbocycle (to form, for example, 5,6,7, 8-tetrahydroquinolyl), and aryl (to form, for example, indazolyl). When valency requirements allow, the rings of the multiple fused ring system can be connected to one another by fused, spiro and bridged bonds. It is understood that the individual rings of the multiple fused ring system may be connected in any order relative to one another. It is also understood that the point of attachment of the multiple fused ring system (as defined above for heteroaryl) may be anywhere in the multiple fused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic moiety of the multiple fused ring system, and at any suitable atom of the multiple fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen).
"heteroarylene" alone or as part of another substituent may mean a divalent radical derived from heteroaryl.
Non-limiting examples of aryl and heteroaryl groups may include pyridyl, pyrimidinyl, thiophenyl, thienyl, furyl, indolyl, benzoxazolyl, benzodioxolyl, thiodecahydronaphthyl, pyrrolopyridyl, indazolyl, quinolyl, quinoxalinyl, pyridopyrazinyl, quinazolinone, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanylthienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, oxadiazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, thiazolyl, oxazolyl, quinoxalinyl, benzisothiazolyl, oxadiazolyl, pyrrolyl, oxadiazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, thiadiazolyl, and the like, Pyrazolopyrimidinyl, pyrrolopyrimidyl, benzotriazolyl, benzoxazolyl or quinolinyl. The above examples may be substituted or unsubstituted, and the divalent radicals of each of the above heteroaryl examples are non-limiting examples of heteroarylenes. The heteroaryl moiety may include a ring heteroatom (e.g., O, N or S). The heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N or S). The heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N or S). The aryl moiety may have a single ring. The aryl moiety may have two optionally different rings. The aryl moiety may have three optionally different rings. The aryl moiety may have four optionally different rings. The heteroaryl moiety may have one ring. The heteroaryl moiety may have two optionally different rings. The heteroaryl moiety may have three optionally different rings. The heteroaryl moiety may have four optionally different rings. The heteroaryl moiety may have five optionally different rings.
The term "halo" or "halogen" by itself or as part of another substituent may mean, unless otherwise stated, a fluorine, chlorine, bromine or iodine atom. In addition, terms such as "haloalkyl" may include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)1-C4) Alkyl groups "may include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
As used herein, the term "hydroxy" means-OH.
As used herein, the term "hydroxyalkyl" may mean an alkyl moiety as defined herein substituted with one or more (e.g., one, two, or three) hydroxy groups. In some cases, the same carbon atom does not carry more than one hydroxyl group. Representative examples may include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.
As used herein, the term "oxo" means an oxygen double bonded to a carbon atom.
As used herein, a substituent may be a group selected from the following moieties:
(A) oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Before takingSubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
(B) alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said groups being substituted with at least one substituent selected from:
(i) oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said groups substituted with at least one substituent selected from the group consisting of:
(a) oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said groups substituted with at least one substituent selected from the group consisting of: oxo, halogen, -CF3、-CN、-OH、-NH2、-COOH、-CONH2、-NO2、-SH、-SO3H、-SO4H、-SO2NH2、-NHNH2、-ONH2、-NHC＝(O)NHNH2、-NHC＝(O)NH2、-NHSO2H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCF3、-OCHF2Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.
An "effective amount," when used in conjunction with a compound, is an amount effective to treat or prevent a disease in a subject as described herein.
As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and can mean a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting an agent from one organ or portion of the body of an individual to another organ or portion of the body of the individual.
The term "treating" with respect to an individual may refer to ameliorating at least one symptom of a disorder in the individual. Treatment may include curing, ameliorating, or at least partially alleviating the condition.
The term "preventing" with respect to an individual may refer to preventing a disease or disorder from afflicting the individual. Prevention may include prophylactic treatment. For example, prevention can include administering a compound disclosed herein to an individual before the individual suffers from a disease, and the administration will protect the individual from the disease.
Unless otherwise indicated, the term "disorder" is used in the present disclosure and may mean, and may be used interchangeably with, the term disease, condition, or affliction.
As used in this disclosure, the term "administering" may refer to the direct administration of a disclosed compound or a pharmaceutically acceptable salt or tautomer or composition of a disclosed compound to a subject, or the administration of a prodrug derivative or analog of a compound or pharmaceutically acceptable salt or tautomer of a compound or composition to a subject, which may form an equivalent amount of the active compound in the subject.
A "patient" or "individual" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate (e.g., monkey, chimpanzee, baboon, or rhesus monkey).
Compound (I)
The present disclosure provides compounds having the structure of formula (I),
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
In some embodiments, the compound of formula I is a compound of formula Ia, Ib, Ic, Id, Ie, or If, or a pharmaceutically acceptable salt or tautomer thereof.
The present disclosure provides compounds having the structure of formula (Ia),
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
The present disclosure provides compounds having the structure of formula (Ib),
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
The present disclosure provides compounds having the structure of formula (Ic),
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As aboveAs described herein.
The present disclosure provides compounds having the structure of formula (Id),
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
The present disclosure provides compounds having the structure of formula (Ie),
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
The present disclosure provides compounds having the structure of formula (If),
and pharmaceutically acceptable salts and tautomers thereof, wherein:
R16selected from H, (C)1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5-to 7-membered heteroaryl, and
R26is selected from ═ O and-OR3And N-OR3；
R28Is selected from-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2and-OS (O)2N(R3)2and-N (R)3)S(O)2OR3；
R32Selected from H, ═ O, -OR3And N-OR3(ii) a And is
R40Is selected from-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、And
with the proviso that the compound does not comprise a combination of: r16is-OCH3；R26Is ═ O; r28is-OH; r32Is ═ O; and R is40is-OH.
The present disclosure provides compounds having the structure of formula I-X:
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
In some embodiments, the compounds of formula I-X are structurally represented by formula I-Xa:
and pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40As described above.
In some embodiments, the compounds of formulas I, I-X and I-Xa are represented by the structures of formulas (Ia-X):
and pharmaceutically acceptable salts and tautomers thereof, wherein R16Is R1Or R2。
In some embodiments, the compounds of formulas I, I-X and I-Xa are structurally represented by formula (Ib-X):
and pharmaceutically acceptable salts and tautomers thereof, wherein R26Is ═ N-R1Or ═ N-R2。
In some embodiments, the compounds of formulas I, I-X and I-Xa are represented by the structures of formula (Ic-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R28Is R1Or R2。
In some embodiments, the compounds of formulas I, I-X and I-Xa are represented by the structures of formula (Id-X):
or a pharmaceutically acceptable salt or tautomer thereof, whereinR32Is ═ N-R1Or R2。
In some embodiments, the compounds of formulas I, I-X and I-Xa are represented by the structures of formula (Ie-X):
or a pharmaceutically acceptable salt or tautomer thereof, wherein R40Is R1Or R2。
In certain embodiments, the disclosure provides compounds of formula Ia, Ib, Ic, Id, Ie, or If, or formula I-X (including compounds of formula I-Xa), wherein stereochemistry is not established, as shown below.
And pharmaceutically acceptable salts and tautomers thereof, wherein R16、R26、R28、R32And R40。
In certain embodiments, R16Is R1. In certain embodiments, R16Is R2. In certain embodiments, R16Is H, (C)1-C6) Alkyl, -OR3、-SR3、＝O、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、(C6-C10) Aryl and 5 to 7 membered heteroaryl, or
In certain embodiments, R26Is ═ N-R1. In certain embodiments, R26Is ═N-R2. In certain embodiments, R26Is ═ O, -OR3OR ═ N-OR3。
In certain embodiments, R28Is R1. In certain embodiments, R28Is R2. In certain embodiments, R28is-OR3、-OC(O)O(C(R3)2)n、-OC(O)N(R3)2and-OS (O)2N(R3)2or-N (R)3)S(O)2OR3。
In certain embodiments, R32Is ═ N-R1. In certain embodiments, R32Is ═ N-R2. In certain embodiments, R32Is H, ═ O, -OR3OR ═ N-OR3. In certain embodiments, R32Is ═ N-NHR3And N (R)3)2。
In certain embodiments, R40Is R1. In certain embodiments, R40Is R2. In certain embodiments, R40is-OR3、-SR3、-N3、-N(R3)2、-NR3C(O)OR3、-NR3C(O)N(R3)2、-NR3S(O)2OR3、-NR3S(O)2N(R3)2、-NR3S(O)2R3、-OP(O)(OR3)2、-OP(O)(R3)2、-NR3C(O)R3、-S(O)R3、-S(O)2R3、-OS(O)2NHC(O)R3、
In certain embodiments, the compound comprises R1. In certain embodiments, the compound comprises R2。
In certain embodiments, R2is-A-C ≡ CH. In certain embodiments, R2is-A-N3. In certain embodiments, R2is-A-COOH. In certain embodiments, R2is-A-NHR3。
In certain embodiments, a is absent. In certain embodiments, A is- (C (R)3)2)n-、-O(C(R3)2)n-、-NR3(C(R3)2)n-、-O(C(R3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-、-C(O)(C(R3)2)n-、-C(O)NR3-、-NR3C(O)(C(R3)2)n-、-NR3C(O)O(C(R3)2)n-、-OC(O)NR3(C(R3)2)n-、-NHSO2NH(C(R3)2)n-or-OC (O) NHSO2NH(C(R3)2)n-. In certain embodiments, A is-O (C (R)3)2)n-. In certain embodiments, A is-O (C (R)3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-。
In certain embodiments, A is-O (C (R)3)2)n-(C6-C10) Arylene-, -O (C (R)3)2)n-heteroarylene-, or-OC (O) NH (C (R)3)2)n-(C6-C10) An arylene radical-. In certain embodiments, A is-O- (C)6-C10) arylene-or-O-heteroarylene-.
In certain embodiments, a is-heteroarylene- (C)6-C10) Arylene-, -O (C (R)3)2)n-(C6-C10) Arylene radical- (C)6-C10) Arylene-, -O (C (R)3)2)n-heteroarylene-, -O (C (R)3)2)n-(C6-C10) Arylene-heteroarylene- (C (R)3)2)n-、-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-O (C (R)3)2)n-、-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-NR3(C(R3)2)n-or-O (C (R)3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-。
In certain embodiments, a is-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-, -heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-, -heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-、-O(C(R3)2)n-heteroarylene-NR3-(C6-C10) Arylene-, -O (C (R)3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-、-O(C(R3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-、-O(C(R3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-or-O (C (R)3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-. In certain embodiments, A is-O (C (R)3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-、-O(C(R3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-or-O (C (R)3)2)n-(C6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-. In certain embodiments, A is-O (C (R)3)2)n-heteroarylene-NR3-(C6-C10) Arylene-, -O (C (R)3)2)n-heteroarylene-heterocyclylene- (C (R)3)2)n-or-O (C (R)3)2)n-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-. In certain embodiments, a is-heteroarylene- (C)6-C10) Arylene radical- (C)6-C10) Arylene-, -heteroarylene- (C)6-C10) arylene-heteroarylene-O (C (R)3)2)n-or-heteroarylene- (C)6-C10) Arylene-heteroarylene- (C (R)3)2)n2-O(C(R3)2)n-。
In certain embodiments, a is-heteroarylene- (C)6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-, -heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-C (O) (C (R)3)2)n-, -heteroarylene- (C)6-C10) arylene-heteroarylene-heterocyclylene-SO2(C(R3)2)n-or-O (C (R)3)2)n-heteroarylene-heterocyclylene-S (O)2NR3-(C6-C10) An arylene radical-.
In certain embodiments, in a, the heteroarylene is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S. In certain embodiments, in a, the heterocyclylene group is 5 to 12 membered and contains 1 to 4 heteroatoms selected from O, N and S. In certain embodiments, the heteroarylene group is 5-to 6-membered, comprising 1 to 4 heteroatoms that are N. In certain embodiments, the heterocyclylene group is 5-to 6-membered, containing 1 to 4 heteroatoms which are N.
In certain embodiments, in a, the arylene, heteroarylene, and heterocyclylene are optionally substituted with one or more substituents each independently selected from: alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen and hydroxy. In certain embodiments, the arylene, heteroarylene, and heterocyclylene groups are substituted with alkyl, hydroxyalkyl, or haloalkyl. In certain embodiments, the arylene, heteroarylene, and heterocyclylene groups are substituted with alkoxy groups. In certain embodiments, the arylene, heteroarylene, and heterocyclylene groups are substituted with halogen or hydroxy. In certain embodiments, the arylene, heteroarylene, and heterocyclylene are substituted with, -C (O) OR3、-C(O)N(R3)2、-N(R3)2And is-N (R)3)2Substituted alkyl substitution.
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is thatIn certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, L1Is that
In certain embodiments, the a ring is phenylene. In certain embodiments, the A ring is 1, 3-phenylene. In certain embodiments, the A ring is 1, 4-phenylene. In certain embodiments, the a ring is a 5-to 8-membered heteroarylene, such as a 5-membered heteroarylene, a 6-membered heteroarylene, a 7-membered heteroarylene, or an 8-membered heteroarylene.
In certain embodiments, B is
In certain embodiments, B is
In certain embodiments, B is
In certain embodiments, B1Is thatNR3-(C(R3)2)n-。
In certain embodiments, B1Is that
In certain embodiments, B1Is that
In certain embodiments, B1Is thatA heteroarylene group-. In certain embodiments, B1Is that
In certain embodiments, in B1Wherein heteroaryl, heterocyclyl and arylene are optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen or hydroxy.
In certain embodiments, R3Is H. In certain embodiments, R3Is (C)1-C6) Alkyl radical. In certain embodiments, R3Is optionally substituted by-COOH or (C)6-C10) Aryl substituted (C)1-C6) An alkyl group. In certain embodiments, R3Is substituted by-COOH (C)1-C6) An alkyl group. In certain embodiments, R3Is a quilt (C)6-C10) Aryl substituted (C)1-C6) An alkyl group. In certain embodiments, R3Is substituted by OH (C)1-C6) An alkyl group.
In certain embodiments, R3is-C (O) (C)1-C6) An alkyl group. In certain embodiments, R3is-C (O) NH-aryl. In certain embodiments, R3is-C (S) NH-aryl.
In certain embodiments, R4Is H. In certain embodiments, R4Is (C)1-C6) An alkyl group. In certain embodiments, R4Is a halogen. In certain embodiments, R4Is 5-to 12-membered heteroaryl, 5-to 12-membered heterocyclyl or (C)6-C10) Aryl, wherein the heteroaryl, heterocyclyl and aryl are optionally substituted with-N (R)3)2、-OR3Halogen, (C)1-C6) Alkyl, - (C)1-C6) Alkylene-heteroaryl, - (C)1-C6) alkylene-CN or-C (O) NR3-heteroaryl substitution. In certain embodiments, R4is-C (O) NR3-a heterocyclic group. In certain embodiments, R4Is optionally substituted by-N (R)3)2OR-OR3Substituted 5 to 12 membered heteroaryl.
In certain embodiments, Q is C (R)3)2. In certain embodiments, Q is O.
In certain embodiments, Y is C (R)3)2. In certain embodiments, Y is a bond.
In certain embodiments, Z is H. In certain embodiments, Z is absent.
In certain embodiments, n is 1,2,3,4, 5,6,7, or 8. In certain embodiments, n is 1,2,3, or 4. In certain embodiments, n is 5,6,7, or 8. In certain embodiments, n is 9,10, 11, or 12.
In certain embodiments, o is 0,1, 2,3,4, 5,6,7, or 8. In certain embodiments, o is 0,1, 2,3, or 4. In certain embodiments, o is 5,6,7, or 8. In certain embodiments, o is 9,10, 11, or 12. In certain embodiments, o is one to 2.
In certain embodiments, p is 0,1, 2,3,4, 5, or 6. In certain embodiments, p is 7,8, 9,10, 11, or 12. In certain embodiments, p is 0,1, 2, or 3. In certain embodiments, p is 4,5, or 6.
In certain embodiments, q is a number from zero to 10. In certain embodiments, q is 0,1, 2,3,4, or 5. In certain embodiments, q is 6,7,8, 9, or 10. In certain embodiments, q is one to 7. In certain embodiments, q is one to 8. In certain embodiments, q is one to 9. In certain embodiments, q is 3 to 8.
In certain embodiments, q is a number from zero to 30. In certain embodiments, q is a number from zero to 26,27, 28,29, or 30. In certain embodiments, q is a number from zero to 21,22,23,24, or 25. In certain embodiments, q is a number from zero to 16, 17, 18, 19, or 20. In certain embodiments, q is a number from zero to 11, 12,13,14, or 15.
In certain embodiments, r is 1,2,3, or 4. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4.
The present disclosure provides compounds of formula (I),
it has one, two, three or four of the following features:
a) a is-O (C (R)3)2)n-or-O (C (R)3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-；
b)L1Is that
c) B isAnd
d)B1is thatNR3-(C(R3)2)n-or
The present disclosure provides compounds of formula (I),
it has one, two, three or four of the following features:
a) a is-O (C (R)3)2)n-or-O (C (R)3)2)n-[O(C(R3)2)n]o-O(C(R3)2)p-；
b)L1Is that
c) B is
d)B1is that
The present disclosure provides compounds of formula (I),
it has one, two, three or four of the following features:
a) a is-O (C (R)3)2)n-(C6-C10) Arylene-heteroarylene-heterocyclylene- (C (R)3)2)n-；
b)L1Is that
c) B is
d)B1is that
The present disclosure provides compounds of formula (I),
it has one, two, three or four of the following features:
a) a is-O (C (R)3)2)n-；
b)L1Is that
c) q is zero;
d) b is
e)B1Is that
f)R4Is optionally substituted by-NH2Substituted heteroaryl; and
g)R26is ═ N-R1。
In certain embodiments, the present disclosure provides compounds, and pharmaceutically acceptable salts and tautomers thereof,
the compounds of the present disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein. Representative "pharmaceutically acceptable salts" may include, for example, water-soluble and water-insoluble salts such as acetate, astragaloside (4, 4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate (clavulanate), dihydrochloride, ethylenediaminetetraacetate, edisylate, etolate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, lactam phenylarsonate (glycinate), hexylresorcinate (hexyresoricinate), hydrabamine (hydrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, acetate, and acetate, Lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthoate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, 1-methylene-bis-2-hydroxy-3-naphthoate, salts of embonate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suronate, tannate, tartrate, theachlorate (teoclate), tosylate, triethiodide, and valerate.
"pharmaceutically acceptable salts" may also include both acid addition salts and base addition salts. "pharmaceutically acceptable acid addition salts" may refer to salts that retain the biological effectiveness and properties of the free base (which are not biologically or otherwise undesirable) and may be formed with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, and organic acids such as, but not limited to, the following: acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, maleic acid, cinnamic acid, succinic acid, tartaric acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like.
A "pharmaceutically acceptable base addition salt" may refer to a salt that retains the biological effectiveness and properties of the free acid (which are not biologically or otherwise undesirable). These salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. For example, inorganic salts may include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases may include (but are not limited to) the following salts: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dandol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine (benethamine), benzathine (benzathine), ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
Unless otherwise indicated, the structures depicted herein may also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen atoms are replaced by deuterium or tritium, or carbon atoms by13C or14C being substituted or nitrogen atoms being substituted15By replacement of N, or by oxygen atoms17O or18Compounds having the structure of the present invention other than O substitution are within the scope of the present disclosure. Such isotopically labeled compounds are useful as research or diagnostic tools.
Methods of synthesizing the disclosed compounds
The compounds of the present disclosure can be made by a variety of methods, including standard chemical methods. Suitable synthetic routes are depicted in the schemes given below.
Compounds of any of the formulae described herein can be prepared by methods known in the art of organic synthesis as set forth in the synthetic schemes and examples section below. In the schemes described below, it is well understood that, according to general principles or chemistry, protecting groups for sensitive or reactive groups are employed as necessary. The protecting Groups were manipulated according to standard methods of organic synthesis (t.w.greene and p.g.m.wuts, "Protective Groups in organic synthesis", third edition, Wiley, New York (New York) 1999). These groups are removed at a suitable stage of the compound synthesis using methods apparent to those skilled in the art. The selection of the method and reaction conditions and the order of their performance should be consistent with the preparation of compounds of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie or If) or compounds of formula I-X (including compounds of formula I-Xa), or the pharmaceutically acceptable salts and tautomers of any of the foregoing.
One of skill in the art will recognize whether a stereocenter is present in any of the compounds of the present disclosure. Thus, the present disclosure may include both possible stereoisomers (unless specified in the synthesis), and may include not only racemic compounds, but also individual enantiomers and/or diastereomers. When a compound in the form of a single enantiomer or diastereomer is desired, it may be obtained by stereospecific synthesis or by resolution of the final product or any suitable intermediate. The resolution of the final product, intermediate or starting material may be affected by any suitable method known in the art. See, e.g., E.L.Eliel, S.H.Wilen and L.N.Mander for "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).
Preparation of the Compounds
The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic methods.
The compounds of the present disclosure can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods may include, but are not limited to, the methods described below.
The term "tautomer" may refer to a group of compounds having the same number and type of atoms, but different bonds and in equilibrium with each other. "tautomers" are individual members of this group of compounds. A single tautomer is generally drawn, but it is understood that such a single structure may represent all possible tautomers that may exist. Examples may include enol-ketone tautomerism. When a ketone is drawn, it is understood that both the enol and ketone forms are part of this disclosure.
In addition to tautomers that may exist at all amide, carbonyl and oxime groups within compounds of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie or If) or compounds of formula I-X (including compounds of formula I-Xa) or compounds of formula Ia-X, Ib-X, Ic-X, Id-X or Ie-X, compounds in this family are readily interconverted between the two major isomeric forms, known as the pyran and oxepane isomers, by ring-opening species (FIG. 1 below). This interconversion can be facilitated by magnesium ions, mildly acidic conditions, or alkylamine salts, as described in the following references: i) hughes, p.f.; musser, j.; conklin, m.; russo, R.1992, Tetrahedron letters 33(33) (4739-32. ii) Zhu, T.2007, U.S. Pat. No. 7,241,771; huishh (Wyeth) iii) Hughes, P.F.1994. U.S. Pat. No. 5,344,833; american Home Products Corp. The following scheme shows the interconversion between the pyran and oxepane isomers in compounds of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie or If) or compounds of formula I-X (including compounds of formula I-Xa) or compounds of formula Ia-X, Ib-X, Ic-X, Id-X or Ie-X.
Since this interconversion takes place under mild conditions, the thermodynamic equilibrium position may vary between different members of the compounds of formula I (including compounds of formulae Ia, Ib, Ic, Id, Ie or If) or of the compounds of formulae I-X (including compounds of formulae I-Xa) or of the compounds of formulae Ia-X, Ib-X, Ic-X, Id-X or Ie-X, with two isomers being envisaged for the compounds of formula I (including compounds of formulae Ia, Ib, Ic, Id, Ie or If) or of the compounds of formulae I-X (including compounds of formulae I-Xa) or of the compounds of formulae Ia-X, Ib-X, Ic-X, Id-X or Ie-X. For brevity, all intermediates and pyran isomeric forms of compounds of formula I (including compounds of formula Ia, Ib, Ic, Id, Ie or If) or compounds of formula I-X (including compounds of formula I-Xa) or compounds of formula Ia-X, Ib-X, Ic-X, Id-X or Ie-X are shown.
Methods for the general Assembly of bifunctional rapamycin analogs (Rapalog)
With reference to the following scheme, rapamycin is of formula II,
wherein R is16is-OCH3；R26Is ═ O; r28is-OH; r32Is ═ O; and R is40is-OH. "rapamycin analog" may refer to an analog or derivative of rapamycin. For example, with reference to the following schemes, a rapamycin analog can be at any position, such as R16、R26、R28、R32Or R40Rapamycin substituted therein. The active site inhibitor (AS inhibitor) is an active site mTOR inhibitor. In certain embodiments, in formula I or formula I-X, the AS inhibitor is depicted by B.
Assembly of series 1 bifunctional rapamycin analogs
The method of assembly of the series 1 bifunctional rapamycin analogues is shown in scheme 1 below. For these types of bifunctional rapamycin analogues, the type a linker may comprise a variant of q ═ 0 to 30 or 0 to 10 (e.g. q ═ 1 to 7). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The alkyne moieties can be linked by a variety of linking fragments, including the variants found in table 1 in the examples section. Type 1 mTOR active siteThe point inhibitor may be linked to the linker through a primary or secondary amine, and may include the variants in table 2 in the examples section. This assembly sequence begins with the amino-terminal reaction of a type a linker with an active site inhibitor (such as those shown in table 2) to provide intermediate a 1. The intermediate is then coupled to an alkyne-containing rapamycin analogue (such as those from table 1) via a 3+2 cycloaddition to provide the series 1 bifunctional rapamycin analogues.
Scheme 1. general Assembly of series 1 bifunctional rapamycin analogs.
Assembly of series 2 bifunctional rapamycin analogs
The method of assembly of the series 2 bifunctional rapamycin analogues is shown in scheme 2 below. For these types of bifunctional rapamycin analogues, the type B linkers may include variants wherein q is 0 to 30 or 0 to 10, such as q is 1 to 8; o is 0 to 8, such as o is 0 to 2; and Q is CH2Or O (when O)>At 0 time). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The alkyne moieties can be linked by a variety of linking fragments, including the variants in table 1. The active site inhibitor may comprise a variant in table 2. This assembly sequence begins with the reaction of a type B linker with a cyclic anhydride to afford intermediate B1. The intermediate is then coupled to the amino terminus of an active site inhibitor (such as those in table 2) to provide intermediate B2. The intermediate is then coupled to an alkyne-containing rapamycin analogue (such as those from table 1) via a 3+2 cycloaddition to provide a series of 2 bifunctional rapamycin analogues.
Scheme 2. general Assembly of series 2 bifunctional rapamycin analogs.
The overall assembly of series 2 bifunctional rapamycin analogs can be used to prepare a combination of type B linkers, alkyne-containing rapamycin analogs in table 1, and type 1 active site inhibitors in table 2.
Assembly of series 3 bifunctional rapamycin analogs
The method of assembly of the series 3 bifunctional rapamycin analogues is shown in scheme 3 below. For these types of bifunctional rapamycin analogues, the type B linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 8). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The alkyne moieties can be linked by a variety of linking fragments, including the variants in table 1. This assembly sequence begins with the reaction of a type B linker with a carboxylic acid of an active site inhibitor (such as those in table 3 in the examples section) to provide intermediate C1 (scheme 3). The intermediate is then coupled to an alkyne-containing rapamycin analogue (such as those from table 1) via a 3+2 cycloaddition to provide a series of 3 bifunctional rapamycin analogues.
Scheme 3. general Assembly of series 3 bifunctional rapamycin analogs.
Assembly of series 4 bifunctional rapamycin analogs
The method of assembly of the series 4 bifunctional rapamycin analogues is shown in scheme 4 below. For these types of bifunctional rapamycin analogues, the C-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 9). The azide moiety may be at R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants in table 4 in the examples section. This assembly sequence begins with the reaction of a type C linker with an amine-reactive alkyne-containing pre linker (such as those in Table 5 in the examples section), followed by carboxylic acid deprotection to provide an intermediateVolume D1 (scheme 4). The intermediate is then coupled with a nucleophilic amine-containing active site inhibitor (such as those in table 2) to provide intermediate D2. The intermediate was then coupled to an azide-containing rapamycin analogue (such as those in table 4) via 3+2 cycloaddition to provide the series 4 bifunctional rapamycin analogues. Another scheme for preparing the series 4 bifunctional rapamycin analogs is shown in scheme 4A.
Scheme 4. general Assembly of series 4 bifunctional rapamycin analogs.
Scheme 4a. additional overall assembly of series 4 bifunctional rapamycin analogs.
Assembly of series 5 bifunctional rapamycin analogs
The method of assembly of the series 5 bifunctional rapamycin analogs is shown in scheme 5 below. For these types of bifunctional rapamycin analogues, the C-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 8). The azide moiety may be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants in table 4. This assembly sequence begins with reaction of a type C linker with an amine-reactive alkyne-containing pre-linker (such as those in table 5 in the examples section) followed by carboxylic acid deprotection to provide intermediate E1 (scheme 5). The intermediate is then coupled to a C-type linker using standard peptide formation conditions, followed by carboxylic acid deprotection to provide intermediate E2. The intermediate was then coupled to an amine-containing active site inhibitor (such as those in table 2) using standard peptide bond formation conditions to provide intermediate E3. The intermediate was then coupled to an azide-containing rapamycin analogue (such as those in table 4) via 3+2 cycloaddition to provide a series5 bifunctional rapamycin analogs.
Scheme 5. general Assembly of series 5 bifunctional rapamycin analogs.
Assembly of series 6 bifunctional rapamycin analogs
The method of assembly of the series 6 bifunctional rapamycin analogues is shown in scheme 6 below. For these types of bifunctional rapamycin analogues, the C-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 9). The azide moiety may be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants in table 4. This assembly sequence begins with reaction of type C linker with amine-reactive alkyne-containing pre-linker (such as those in table 5 in the examples section) followed by carboxylic acid deprotection to afford intermediate F1 (scheme 6). The intermediate was then coupled to an amine-containing linker (such as those found in table 6 in the examples section) using standard peptide bond formation conditions, followed by carboxylic acid deprotection to provide intermediate F2. The intermediate was then coupled to an amine-containing active site inhibitor (such as those in table 2) using standard peptide bond formation conditions to provide intermediate F3. Finally, the intermediate was coupled to the azide-containing rapamycin analogs (such as those in table 4) via 3+2 cycloaddition to provide the series 6 bifunctional rapamycin analogs.
Scheme 6. general Assembly of series 6 bifunctional rapamycin analogs.
Assembly of series 7 bifunctional rapamycin analogs
The method of assembly of the series 7 bifunctional rapamycin analogs is shown in scheme 7 below. For these types of bifunctional rapamycin analogs, AType D linkers may include variants of q-0 to 30 or 0 to 10 (e.g., q-1 to 8), and type D linkers may include variants of o-0 to 10 (e.g., o-1 to 8). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The alkyne moieties can be linked by a variety of linking fragments, including the variants in table 1. This assembly sequence begins with the reaction of a type D linker with a carboxylic acid of an active site inhibitor (such as those in table 3 in the examples section) followed by N-deprotection to afford intermediate G1 (scheme 7). The intermediate is then coupled to a type a linker to provide intermediate G2. Finally, the intermediate was coupled to an alkyne-containing rapamycin analogue (such as those in table 1) via a 3+2 cycloaddition to provide the series of 7 bifunctional rapamycin analogues.
Scheme 7. general Assembly of series 7 bifunctional rapamycin analogs.
Assembly of series 8 bifunctional rapamycin analogs
The method of assembly of the series 8 bifunctional rapamycin analogs is shown in scheme 8 below. For these types of bifunctional rapamycin analogues, the C-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 9). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The alkyne moieties can be linked by a variety of linking fragments, including the variants in table 1. This assembly sequence begins with the reaction of the type C linker with an azide-containing pro-linker (such as those in table 7 in the examples section) followed by carboxylic acid deprotection to afford intermediate H1 (scheme 8). The intermediate was then coupled to an amine-containing active site inhibitor (such as those in table 2) using standard peptide bond formation conditions to provide intermediate H2. Finally, the intermediate was coupled to an alkyne-containing rapamycin analogue (such as those in table 1) via a 3+2 cycloaddition to provide the series 8 bifunctional rapamycin analogues.
Scheme 8. general Assembly of series 8 bifunctional rapamycin analogs.
Assembly of series 9 bifunctional rapamycin analogs
The method of assembly of the series 9 bifunctional rapamycin analogs is shown in scheme 9 below. For these types of bifunctional rapamycin analogues, the type E linkers may include variants with q ═ 0 to 30 or 0 to 10 (e.g. q ═ 1 to 7). The azide moiety may be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants found in table 4 in the examples section. The type 1 mTOR active site inhibitor may be linked to the linker through a primary or secondary amine and may include the variants in table 2 in the examples section. This assembly sequence begins with the amino-terminal reaction of an E-type linker with an active site inhibitor (such as those in table 2) to provide intermediate I1. The intermediate was then coupled to an alkyne-containing rapamycin analogue (such as those from table 4) via 3+2 cycloaddition to provide the series 9 bifunctional rapamycin analogues.
Scheme 9. general Assembly of series 9 bifunctional rapamycin analogs.
Assembly of series 10 bifunctional rapamycin analogs
The method of assembly of the series 10 bifunctional rapamycin analogs is shown in scheme 10 below. For these types of bifunctional rapamycin analogues, the F-type linkers include variants with q ═ 0 to 30 or 0 to 10 (e.g., q ═ 1 to 8), and the G-type linkers include variants with o ═ 0 to 10 (e.g., o ═ 1 to 8). The azide moiety may be at R40、R16、R28、R32Or R26Attached in position (of formula I-X) to raparA mycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants in table 4. This assembly sequence begins with the amine reaction of type F linkers with active site inhibitors (such as those in table 2 in the examples section). The intermediate is then coupled to a G-type linker to provide intermediate J2. Finally, the intermediate was coupled to the azide-containing rapamycin analogs (such as those in table 4) via 3+2 cycloaddition to provide the series 10 bifunctional rapamycin analogs.
Scheme 10. general Assembly of series 10 bifunctional rapamycin analogs.
Assembly of series 11 bifunctional rapamycin analogs
The method of assembly of the series 11 bifunctional rapamycin analogs is shown in scheme 11 below. For these types of bifunctional rapamycin analogues, the type a linkers include variants with q ═ 0 to 30 or 0 to 10 (e.g., q ═ 1 to 8), and the type C linkers include variants with o ═ 0 to 10 (e.g., o ═ 1 to 8). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants in table 1. This assembly sequence begins with the amine reaction of type a linker with type C linker followed by carboxylic acid deprotection to provide intermediate K1. The intermediate is then coupled to an amine-containing active site inhibitor (such as those found in table 2) to provide intermediate K2. Finally, the intermediate was coupled to an alkyne-containing rapamycin analogue (such as those in table 1) via a 3+2 cycloaddition to provide the series 11 bifunctional rapamycin analogues.
Scheme 11. general Assembly of series 11 bifunctional rapamycin analogs.
Series 12 bifunctional rapamycinsAssembly of analogues
The method of assembly of the series 12 bifunctional rapamycin analogs is shown in scheme 12 below. For these types of bifunctional rapamycin analogues, the H-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 9). The alkyne moiety can be at R40、R16、R28、R32Or R26Attached at position (formula I-X) to a rapamycin analog. The alkyne moieties can be linked by a variety of linking fragments, including the variants in table 1. This assembly sequence begins with the reaction of a type H linker with a nucleophilic amine-containing active site inhibitor (such as those in table 2) followed by carboxylic acid deprotection to provide intermediate L1. The intermediate is then coupled with an azide-containing amine pre-linker (such as those in table 8), which may be composed of primary or secondary amines, to provide intermediate L2. Finally, the intermediate was coupled to an alkyne-containing rapamycin analogue (such as those in table 1) via a 3+2 cycloaddition to provide a series of 12 bifunctional rapamycin analogues.
Scheme 12. general Assembly of series 12 bifunctional rapamycin analogs.
Assembly of series 13 bifunctional rapamycin analogs
The method of assembly of the series 13 bifunctional rapamycin analogs is shown in scheme 13 below. For these types of bifunctional rapamycin analogues, the type I linker may comprise a variant of q ═ 0 to 30 or 0 to 10 (e.g. q ═ 1 to 9). The azide moiety may be at R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The azide moieties can be linked by a variety of linkage segments, including the variants in table 4. This assembly sequence begins with the reaction of a type I linker with an alkyne-containing pre-linker amine (such as those in table 9 in the examples section) which may be composed of primary or secondary amines, followed by N-deprotection to give intermediate M1. The intermediate is then coupled to the carboxylic acid-containing ligand using standard peptide bond formation conditionsA sexual site inhibitor (such as those in table 3) to provide intermediate M2. The intermediate was then coupled to an azide-containing rapamycin analogue (such as those in table 4) via 3+2 cycloaddition to provide the series 13 bifunctional rapamycin analogues.
Scheme 13. general Assembly of series 13 bifunctional rapamycin analogs.
Assembly of series 14 bifunctional rapamycin analogs
The method of assembly of the series 14 bifunctional rapamycin analogs is shown in scheme 14 below. For bifunctional rapamycin analogues of this type, the type I linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 9). The carboxylic acid moiety may be at R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The carboxylic acid moieties may be linked by a variety of linkage segments, including the variants in table 10. This assembly sequence begins with the reaction of a type I linker with a nucleophilic amine-containing active site inhibitor (such as those in table 2) followed by N-deprotection to provide intermediate N1. The intermediate is then coupled with a carboxylic acid-containing rapamycin analogue (such as those in table 10 in the examples section) to provide the series 14 bifunctional rapamycin analogues.
Scheme 14. general Assembly of series 14 bifunctional rapamycin analogs.
Assembly of series 15 bifunctional rapamycin analogs
The method of assembly of the series 15 bifunctional rapamycin analogs is shown in scheme 15 below. For bifunctional rapamycin analogues of this type, the J-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q 3 to 8). The amino moiety may be in R40、R16、R28、R32Or R26Attached at a position (formula I or formula I-X) to a rapamycin analog. The amino moieties can be linked by a variety of linkage fragments, including the variants in table 11. This assembly sequence begins with the reaction of a J-linker with a nucleophilic amine-containing active site inhibitor (such as those in table 2) followed by carboxylic acid deprotection to provide intermediate O1. The intermediates were then coupled to amine-containing rapamycin analogues (such as those in table 11 in the examples section) to provide the series 15 bifunctional rapamycin analogues.
Scheme 15. general Assembly of series 15 bifunctional rapamycin analogs.
Assembly of a series of 16 bifunctional rapamycin analogues
The method of assembly of the series 16 bifunctional rapamycin analogs is shown in scheme 16 below. For these types of bifunctional rapamycin analogues, the C-type linker may comprise a variant of q 0 to 30 or 0 to 10 (e.g. q1 to 9). The amine-containing rapamycin analog monomers can include those in table 11. This assembly sequence begins with the reaction of a type C linker with the carboxylic acid of an active site inhibitor (such as those in table 3) to provide intermediate P1. The intermediate is then coupled to an amine-containing rapamycin analogue (such as those in table 11 in the examples section) to provide a series 16 of bifunctional rapamycin analogues.
Scheme 16. general Assembly of series 16 bifunctional rapamycin analogs.
Pharmaceutical composition
In another aspect, a pharmaceutical composition is provided that includes a pharmaceutically acceptable excipient, and a compound or a pharmaceutically acceptable salt or tautomer thereof.
In embodiments of pharmaceutical compositions, a compound or a pharmaceutically acceptable salt or tautomer thereof may be included in a therapeutically effective amount.
Administration of the disclosed compounds or compositions can be achieved by any mode of administration of the therapeutic agent. These modes may include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical modes of administration.
Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions may be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or similar dosage forms, sometimes in unit doses and consistent with conventional pharmaceutical practice. Likewise, they can also be administered in intravenous (bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and in all use forms well known to those skilled in the art of medicine.
Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, for example, purified water, triglyceride oil (e.g., hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof), corn oil, olive oil, sunflower seed oil, safflower oil, fish oil (e.g., EPA or DHA or esters or triglycerides thereof or mixtures thereof, omega-3 fatty acids or derivatives thereof), lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine, b) a lubricant, for example, silica, talc, stearic acid, magnesium or calcium salts of stearic acid, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol, also for tablets, c) a binder, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (e.g., glucose or β -lactose), corn sweeteners, natural and synthetic MCM (e.g., acacia, tragacanth, or tragacanth), sodium alginate, and/or polyvinyl alcohol, polyethylene glycol, sorbitol, sodium carboxymethylcellulose, sodium oleate, sodium alginate, sodium.
Liquid (especially injectable) compositions can be prepared, for example, by dissolution, dispersion, and the like. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, and the like, to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins may be used to solubilize the disclosed compounds.
The disclosed compounds may also be formulated as suppositories, which may be prepared from suspensions; polyalkylene glycols, such as propylene glycol, are used as carriers.
The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, the membrane of lipid components is hydrated with an aqueous solution of the drug to form a shaped lipid layer encapsulating the drug, as described, for example, in U.S. patent No. 5,262,564, the contents of which are incorporated herein by reference.
The disclosed compounds can also be delivered by using monoclonal antibodies as a separate carrier coupled to the disclosed compounds. The disclosed compounds can also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In one embodiment, the disclosed compounds are not covalently bound to a polymer, such as a polycarboxylic acid polymer or a polyacrylate.
Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solids suitable for dissolution in liquid prior to injection.
Another aspect of the disclosure relates to a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent or surfactant.
The compositions may be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions of the present invention may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20%, by weight or volume, of the disclosed compounds.
In an embodiment of a pharmaceutical composition, the pharmaceutical composition can include a second agent (e.g., a therapeutic agent). In embodiments of pharmaceutical compositions, the pharmaceutical composition can include a second agent (e.g., a therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is an immunotherapeutic agent. In embodiments, the second agent is an immunotumoral agent. In embodiments, the second agent is an anti-autoimmune disease agent. In an embodiment, the second agent is an anti-inflammatory disease agent. In embodiments, the second agent is an anti-neurodegenerative agent. In embodiments, the second agent is an anti-metabolic disease agent. In embodiments, the second agent is an anti-cardiovascular disease agent. In an embodiment, the second agent is an anti-aging agent. In an embodiment, the second agent is a longevity agent. In an embodiment, the second agent is an agent for treating or preventing transplant rejection. In an embodiment, the second agent is an agent for treating or preventing a fungal infection. In embodiments, the second agent is an immune system suppressor. In embodiments, the second agent is an mTOR modulator. In embodiments, the second agent is an mTOR inhibitor. In embodiments, the second agent is an active site mTOR inhibitor. In embodiments, the second agent is rapamycin. In embodiments, the second agent is a rapamycin analog. In an embodiment, the second agent is a mTORC1 pathway inhibitor.
mTOR and methods of treatment
The term "mTOR" may refer to a protein "mechanistic rapamycin target (serine/threonine kinase)" or a "mammalian rapamycin target". The term "mTOR" may refer to the nucleotide or protein sequence of human mTOR (e.g., Entrez2475, Uniprot P42345, RefSeq NM-004958, or RefSeq NP-004949) (SEQ ID NO: 1). The term "mTOR" may include wild-type forms of the nucleotide sequence or protein as well as any mutants thereof. In some embodiments, "mTOR" is a wild-type mTOR. In some embodiments, "mTOR" is one or more mutant forms. The term "mTOR" XYZ may refer to a nucleotide sequence or protein of mutant mTOR in which the Y-numbered amino acid of mTOR, which normally has X amino acids in the wild type, actually has Z amino acids in the mutant. In an embodiment, the mTOR is human mTOR. In an embodiment, mTOR has a nucleotide sequence corresponding to reference number GL206725550 (SEQ ID NO: 2). In embodiments, mTOR has a nucleotide sequence corresponding to RefSeq NM-004958.3 (SEQ ID NO: 2). In an embodiment, mTOR has a protein sequence corresponding to reference number GL4826730 (SEQ ID NO: 1). In embodiments, mTOR has a protein sequence corresponding to RefSeq NP-004949.1 (SEQ ID NO: 1). In an embodiment, mTOR has the following amino acid sequence:
MLGTGPAAATTAATTSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTMELREMSQEESTRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGNATRIGRFANYLRNLLPSNDPWMEMASKAIGRLAMAGDTFTAEYVEFEVKRALEWLGADRNEGRRHAAVLVLRELAISVPTFFFQQVQPFFDNIFVAVWDPKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEEAEKGFDETLAKEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYCKDLMGFGTKPRHITPFTSFQAVQPQQSNALVGLLGYSSHQGLMGFGTSPSPAKSTLVESRCCRDLMEEKFDQVCQWVLKCRNSKNSLIQMTILNLLPRLAAFRPSAFTDTQYLQDTMNHVLSCVKKEKERTAAFQALGLLSVAVRSEFKVYLPRVLDIIRAALPPKDFAHKRQKAMQVDATVFTCISMLARAMGPGIQQDIKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLLKMLSLVLMHKPLRHPGMPKGLAHQLASPGLTTLPEASDVGSITLALRTLGSFEFEGHSLTQFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQVVADVLSKLLWGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVALNDQVFEIRELAICTVGRLSSMNPAFVMPFLRKMLIQILTELEHSGIGRIKEQSARMLGHLVSNAPRLIRPYMEPILKALILKLKDPDPDPNPGVINNVLATIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVALWTLGQLVASTGYVVEPYRKYPTLLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHKVNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAVSMVALMRIFRDQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNVIRVCDGAIREFLFQQLGMLVSFVKSHIRPYMDEIVTLMREFWVMNTSIQSTIILLIEQIVVALGGEFKLYLPQLIPHMLRVFMHDNSPGRIVSIKLLAAIQLFGANLDDYLHLLLPPIVKLFDAPEAPLPSRKAALETVDRLTESLDFTDYASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLVRHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSGQGDALASGPVETGPMKKLHVSTINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSLRSCWALAQAYNPMARDLFNAAFVSCWSELNEDQQDELIRSIELALTSQDIAEVTQTLLNLAEFMEHSDKGPLPLRDDNGIVLLGERAAKCRAYAKALHYKELEFQKGPTPAILESLISINNKLQQPEAAAGVLEYAMKHFGELEIQATWYEKLHEWEDALVAYDKKMDTNKDDPELMLGRMRCLEALGEWGQLHQQCCEKWTLVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVLALHQDLFSLAQQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELEEVIQYKLVPERREIIRQIWWERLQGCQRIVEDWQKILMVRSLVVSPHEDMRTWLKYASLCGKSGRLALAHKTLVLLLGVDPSRQLDHPLPTVHPQVTYAYMKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHKQELHKLMARCFLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEAVLHYKHQNQARDEKKKLRHASGANITNATTAATTAATATTTASTEGSNSESEAESTENSPTPSPLQKKVTEDLSKTLLMYTVPAVQGFFRSISLSRGNNLQDTLRVLTLWFDYGHWPDVNEALVEGVKAIQIDTWLQVIPQLIARIDTPRPLVGRLIHQLLTDIGRYHPQALIYPLTVASKSTTTARHNAANKILKNMCEHSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPIIRIQSIAPSLQVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQLFGLVNTLLANDPTSLRKNLSIQRYAVIPLSTNSGLIGWVPHCDTLHALIRDYREKKKILLNIEHRIMLRMAPDYDHLTLMQKVEVFEHAVNNTAGDDLAKLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRHPSNLMLDRLSGKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRITCHTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDTNTKGNKRSRTRTDSYSAGQSVEILDGVELGEPAHKKTGTTVPESIHSFIGDGLVKPEALNKKAIQIINRVRDKLTGRDFSHDDTLDVPTQVELLIKQATSHENLCQCYIGWCPFW(SEQ ID NO:1)
in an embodiment, mTOR is a mutant mTOR. In embodiments, the mutant mTOR is associated with a disease that is not associated with wild-type mTOR. In embodiments, mTOR may include at least one amino acid mutation (e.g., 1,2,3,4, 5,6,7,8, 9,10, 11, 12,13,14, 15, 16, 17, 18, 19, 20, 21,22,23,24,25,26,27, 28,29, or 30 mutations) as compared to the above sequence.
The term "mTORC 1" may refer to a protein complex that includes mTOR and Raptor (a regulatory related protein of mTOR). mTORC1 may also include MLST8 (a mammalian lethal protein with SEC 13 protein 8), PRAS40, and/or DEPTOR. mTORC1 can act as a nutrient/energy/redox sensor and a regulator of protein synthesis. The term "mTORC 1 pathway" or "mTORC 1 signaling pathway" can refer to a cellular pathway that includes mTORC 1. The mTORC1 path includes path components upstream and downstream of mTORC 1. The mTORC1 path is a signaling pathway that is modulated by modulating mTORC1 activity. In an embodiment, the mTORC1 path is a signaling pathway that is modulated by modulating mTORC1 activity rather than modulating mTORC2 activity. In an embodiment, the mTORC1 pathway is a signaling pathway that is modulated to a greater extent by modulating mTORC1 activity than by modulating mTORC2 activity.
The term "mTORC 2" may refer to a protein complex comprising mTOR and RICTOR (a rapamycin insensitive partner of mTOR.) mTORC2 may also include G β L, mSIN1 (mammalian stress activated protein kinase interacting protein 1), Protor 1/2, DEPTOR, TTI1, and/or tel2 mTORC2 may modulate cellular metabolism and cytoskeleton the term "mTORC 2 pathway" or "mTORC 2 signal transduction pathway" may refer to a cellular pathway that includes mTORC 2. mTORC2 pathway includes pathway components upstream and downstream of mTORC 2. mTORC2 pathway is a signaling pathway that is modulated by modulating mTORC2 activity.
The term "rapamycin" or "sirolimus" may refer to a macrolide produced by streptomyces hygroscopicus. Rapamycin may prevent activation of T cells and B cells. Rapamycin has the IUPAC name (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS) -9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34 a-hexadecahydro-9, 27-dihydroxy-3- [ (1R) -2- [ (1S,3R,4R) -4-hydroxy-3-methoxycyclohexyl ] -1-methylethyl ] -10, 21-dimethoxy-6, 8,12,14,20, 26-hexamethyl-23, 27-epoxy-3H-pyrido [2,1-c ] [1,4] -oxa-triundecy clo-1, 5,11,28,29(4H,6H,31H) -pentanone. Rapamycin has a CAS number of 53123-88-9. Rapamycin can be produced synthetically (e.g., by chemical synthesis) or by using production methods that do not include the use of streptomyces hygroscopicus.
"analog" is used according to its ordinary meaning in chemistry and biology and may refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, for example, in that one atom is replaced by an atom of a different element, or a particular functional group is present, or one functional group is replaced by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound (including isomers thereof). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but not in structure or origin.
The term "rapamycin analogue/rapalog" may refer to an analogue or derivative (e.g., a prodrug) of rapamycin.
The terms "active site mTOR inhibitor" and "ATP mimetic" may refer to a compound that inhibits mTOR activity (e.g., kinase activity) and binds to the mTOR active site (e.g., ATP binding site, overlapping ATP binding site, blocking ATP access to the ATP binding site of mTOR). Examples of active site mTOR inhibitors may include, but are not limited to, Γ NK128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, Torin 1, Torin 2, WYE 687 salts (e.g., hydrochloride salt), PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, and PKI-587. In an embodiment, the active site mTOR inhibitor is asTORi. In some embodiments, an "active site inhibitor" may refer to an "active site mTOR inhibitor".
The term "FKBP" may refer to a protein peptidyl-prolyl cis-trans isomerase. For non-limiting examples of FKBP, see in Cell Mol Life sciences (Cell Mol Life Sci.) 2013, month 9; 70(18):3243-75. In embodiments, "FKBP" may refer to "FKBP-12" or "FKBP 1A". In embodiments, "FKBP" may refer to a human protein. The term "FKBP" includes both wild-type and mutant forms of the protein. In embodiments, "FKBP" may refer to a wild-type human protein. In embodiments, "FKBP" may refer to a wild-type human nucleic acid. In embodiments, the FKBP is a mutant FKBP. In embodiments, the mutant FKBP is associated with a disease that is not associated with wild-type FKBP. In embodiments, the FKBP includes at least one amino acid mutation (e.g., 1,2,3,4, 5,6,7,8, 9,10, 11, 12,13,14, 15, 16, 17, 18, 19, 20, 21,22,23,24,25,26,27, 28,29, or 30 mutations) as compared to a wild-type FKBP.
The term "FKBP-12" or "FKBP 1A" may refer to the protein "peptidyl-prolyl cis-trans isomerase FKBP 1A". In embodiments, "FKBP-12" or "FKBP 1A" may refer to a human protein. The terms "FKBP-12" or "FKBP 1A" include wild-type and mutant forms of the protein. In embodiments, "FKBP-12" or "FKBP 1A" may refer to a protein (SEQ ID NO:3) associated with Entrez Gene 2280, OMIM 186945, UniProtP62942, and/or RefSeq (protein) NP-000792. In embodiments, reference numbers immediately above may refer to proteins and related nucleic acids known as of the filing date of this application. In embodiments, "FKBP-12" or "FKBP 1A" may refer to a wild-type human protein. In embodiments, "FKBP-12" or "FKBP 1A" may refer to a wild-type human nucleic acid. In an embodiment, FKBP-12 is a mutant FKBP-12. In embodiments, the mutant FKBP-12 is associated with a disease that is not associated with wild-type FKBP-12. In embodiments, FKBP-12 can include at least one amino acid mutation (e.g., 1,2,3,4, 5,6,7,8, 9,10, 11, 12,13,14, 15, 16, 17, 18, 19, 20, 21,22,23,24,25,26,27, 28,29, or 30 mutations) as compared to wild-type FKBP-12. In an example, FKBP-12 has a protein sequence corresponding to reference number GI: 206725550. In an example, FKBP-12 has a protein sequence corresponding to RefSeqNP-000792.1 (SEQ ID NO: 3).
The term "4E-BP 1" or "4 EBP 1" or "EIF 4EBP 1" may refer to the protein "eukaryotic translation initiation factor 4E binding protein 1". In embodiments, "4E-BP 1" or "4 EBP 1" or "EIF 4EBP 1" may refer to a human protein. The terms "4E-BP 1" or "4 EBP 1" or "EIF 4EBP 1" include both wild-type and mutant forms of the protein. In embodiments, "4E-BP 1" or "4 EBP 1" or "EIF 4EBP 1" may refer to proteins related to Entrez Gene 1978, OMIM 602223, UniProt Q13541 and/or RefSeq (protein) NP-004086 (SEQ ID NO: 4). In embodiments, reference numbers immediately above may refer to proteins and related nucleic acids known as of the filing date of this application. In embodiments, "4E-BP 1" or "4 EBP 1" or "EIF 4EBP 1" may refer to a wild-type human protein. In embodiments, "4E-BP 1" or "4 EBP 1" or "EIF 4EBP 1" may refer to a wild-type human nucleic acid. In an embodiment, 4EBP1 is mutant 4EBP 1. In the examples, the mutant 4EBP1 is associated with a disease that is not associated with wild-type 4EBP 1. In embodiments, the 4EBP1 can include at least one amino acid mutation (e.g., 1,2,3,4, 5,6,7,8, 9,10, 11, 12,13,14, 15, 16, 17, 18, 19, 20, 21,22,23,24,25,26,27, 28,29, or 30 mutations) as compared to wild-type 4EBP 1. In an example, 4EBP1 has a protein sequence corresponding to reference number GL 4758258. In the examples, 4EBP1 has a protein sequence corresponding to RefSeq NP-004086.1 (SEQ ID NO: 4).
The term "Akt" can refer to serine/threonine specific protein kinases involved in cellular processes (e.g., glucose metabolism, apoptosis, proliferation) and other functions, also known as "protein kinase B" (PKB) or "Akt 1". In embodiments, "Akt" or "AM" or "PKB" may refer to a human protein. The term "Akt" or "Akt 1" or "PKB" includes both wild-type and mutant forms of the protein. In embodiments, "Akt" or "Akt 1" or "PKB" may refer to proteins related to Entrez Gene 207, OMIM 164730, UniProtP31749 and/or RefSeq (protein) NP-005154 (SEQ ID NO: 5). In embodiments, reference numbers immediately above may refer to proteins and related nucleic acids known as of the filing date of this application. In embodiments, "Akt" or "Akt 1" or "PKB" may refer to a wild-type human protein. In embodiments, "Akt" or "Akt 1" or "PKB" can refer to a wild-type human nucleic acid. In the examples, Akt is a mutant Akt. In the examples, mutant Akt is associated with a disease not associated with wild-type Akt. In embodiments, Akt can include at least one amino acid mutation (e.g., 1,2,3,4, 5,6,7,8, 9,10, 11, 12,13,14, 15, 16, 17, 18, 19, 20, 21,22,23,24,25,26,27, 28,29, or 30 mutations) as compared to a wild-type Akt. In an embodiment, Akt has a protein sequence corresponding to reference number GI: 62241011. In the examples, Akt has a protein sequence corresponding to RefSeq NP-005154.2 (SEQ ID NO: 5).
The present disclosure provides a method of treating a disease or disorder mediated by mTOR, the method comprising administering to an individual suffering from or susceptible to a disease or disorder mediated by mTOR a therapeutically effective amount of one or more of the disclosed compositions or compounds. The present disclosure provides a method of preventing a disease or disorder mediated by mTOR, the method comprising administering to an individual suffering from or susceptible to a disease or disorder mediated by mTOR a therapeutically effective amount of one or more of the disclosed compositions or compounds. The present disclosure provides a method of reducing the risk of an mTOR-mediated disease or condition, the method comprising administering to an individual suffering from or susceptible to an mTOR-mediated disease or condition a therapeutically effective amount of one or more of the disclosed compositions or compounds.
In some embodiments, the disease is cancer or an immune-mediated disease. In some embodiments, the cancer is selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer (kidney cancer), kidney cancer (renal cancer), liver cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, a hematoproliferative disorder, lymphoma, leukemia, endometrial cancer, cervical cancer, vulval cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, biliary tract cancer, eye cancer, gastrointestinal stromal tumor, and neuroendocrine tumor. In some embodiments, the disorder is cirrhosis. In some embodiments, the immune-mediated disease is selected from resistance resulting from transplantation of heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine (intestinum tenue), limb, muscle, nerve, duodenum, small intestine (small-bowel), or islet cells; graft versus host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
The present disclosure provides a method of treating cancer comprising administering to an individual a therapeutically effective amount of one or more of the disclosed compositions or compounds. In some embodiments, the cancer is selected from brain and neurovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphoma, gastric cancer, kidney cancer, liver cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, neural cancer, spleen cancer, pancreatic cancer, a hematologic proliferative disorder, lymphoma, leukemia, endometrial cancer, cervical cancer, vulval cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal or rectal cancer, anal cancer, bladder cancer, biliary tract cancer, eye cancer, gastrointestinal stromal tumor, and neuroendocrine tumor. In some embodiments, the disorder is cirrhosis.
The present disclosure provides a method of treating an immune-mediated disease comprising administering to an individual a therapeutically effective amount of one or more of the disclosed compositions or compounds. In some embodiments, the immune-mediated disease is selected from resistance resulting from transplantation of cardiac, renal, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or pancreatic islet cells; graft versus host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.
The present disclosure provides a method of treating an age-related condition comprising administering to an individual a therapeutically effective amount of one or more of the disclosed compositions or compounds. In certain embodiments, the age-related condition is selected from sarcopenia, skin atrophy, muscle atrophy, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, decreased life expectancy, impaired renal function and age-related hearing loss, age-related behavioral dysfunction (e.g., weakness), cognitive decline, age-related dementia, memory impairment, tendon stiffness, cardiac dysfunction (e.g., cardiac hypertrophy and contractile and diastolic dysfunction), immune aging, cancer, obesity, and diabetes.
In certain embodiments, the disclosed compositions or compounds may be used with a method for immunosenescence. Immunosenescence can refer to a reduction in immune function, resulting in a diminished immune response, e.g., to cancer, vaccination, infectious pathogens, etc. It is involved in both the ability of the host to respond to infection and in the generation of long-term immunological memory, particularly by vaccination. This immunodeficiency is prevalent and is found in both long-lived and short-lived species as a function of age of the species relative to life expectancy rather than time-sequential time. It is considered to be a major factor causing an increase in the frequency of illness and death of the elderly. Immunosenescence is not a random worsening phenomenon, but rather appears to repeat the evolutionary pattern in reverse, and most parameters affected by immunosenescence appear to be under genetic control. Immunosenescence can also sometimes be assumed to occur due to the continuing challenge of unavoidable exposure to multiple antigens (e.g., viruses and bacteria). Immune aging is a multifactorial disease that causes many pathologically significant health problems, for example in the elderly population. Age-dependent biological changes, such as hematopoietic stem cell depletion, increased PD1+ lymphocytes, decreased total numbers of phagocytic and NK cells, and humoral immune decline, contribute to the development of immunosenescence. In one aspect, immunosenescence of an individual can be measured by measuring telomere length in immune cells (see, e.g., U.S. patent No. 5,741,677). Immunosenescence of individuals greater than or equal to 65 years can also be determined by recording a sub-normal number of naive CD4 and/or CD 8T cells, a T cell bank, the number of PD 1-expressing T cells (e.g., a sub-normal number of PD-1 negative T cells), or the response to vaccination in an individual. In certain embodiments, selective modulation of mTORC1 of certain T cell populations can improve vaccine efficacy in aging populations and enhance the effectiveness of cancer immunotherapy. The present disclosure provides a method of treating immunosenescence comprising administering to an individual a therapeutically effective amount of one or more of the disclosed compositions or compounds.
In one aspect, a method of treating a disease associated with abnormal levels of mTORC1 activity in an individual in need of such treatment is provided. The disease may be caused by upregulation of mTORC 1. The methods may comprise administering to the individual one or more compositions or compounds described herein. The methods can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, there is provided one or more compositions or compounds as described herein for use as a medicament. In an embodiment, the agent is suitable for treating a disease caused by upregulation of mTORC 1. Use may include administering to the individual one or more of the compositions or compounds described herein. Use can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, one or more compositions or compounds as described herein are provided for use in treating a disease caused by abnormal levels of mTORC1 activity in an individual in need of such treatment. The disease may be caused by upregulation of mTORC 1. Use may include administering to the individual one or more of the compositions or compounds described herein. Use can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
Upregulation of mTORC1 results in increased mTORC1 activity compared to normal levels of mTORC1 activity in a particular individual or population of healthy individuals. Increased mTORC1 activity can lead to, for example, excessive cell proliferation, leading to disease states.
The individual treated for the disease is typically a mammal. The mammal treated with a compound (e.g., a compound described herein, a mTORC1 modulator (e.g., inhibitor)) can be a human, a non-human primate, and/or a non-human mammal (e.g., a rodent, a canine).
In another aspect, there is provided a method of treating a disease associated with mTORC1 activity in an individual in need of such treatment, the method comprising administering to the individual one or more compositions or compounds as described herein (e.g., claims, examples, tables, figures, or claims) including an example.
In another aspect, there is provided one or more compositions or compounds as described herein for use as a medicament. In embodiments, the agents may be suitable for treating disorders associated with mTORC1 activity in an individual in need of such treatment. In embodiments, using can include administering to the individual one or more compositions or compounds as described herein (e.g., aspects, embodiments, examples, tables, figures, or claims) including the embodiments.
In another aspect, one or more compositions or compounds are provided for treating a disease associated with mTORC1 activity in an individual in need of such treatment. In embodiments, using can include administering to the individual one or more compositions or compounds as described herein (e.g., aspects, embodiments, examples, tables, figures, or claims) including the embodiments.
In embodiments, the disease associated with mTORC1 activity or with an abnormal level of mTORC1 activity is cancer. In embodiments, the disease associated with mTORC1 activity or with abnormal levels of mTORC1 activity is an autoimmune disease. In embodiments, the disease associated with mTORC1 activity or with an abnormal level of mTORC1 activity is an inflammatory disease. In embodiments, the disease associated with mTORC1 activity or with abnormal levels of mTORC1 activity is a neurodegenerative disease. In embodiments, the disease associated with mTORC1 activity or with an abnormal level of mTORC1 activity is a metabolic disease. In embodiments, the disease associated with mTORC1 activity or with an abnormal level of mTORC1 activity is transplant rejection. In embodiments, the disease associated with mTORC1 activity or with abnormal levels of mTORC1 activity is a fungal infection. In embodiments, the disease associated with mTORC1 activity or with abnormal levels of mTORC1 activity is a cardiovascular disease.
In embodiments, the disease associated with mTORC1 activity or with an abnormal level of mTORC1 activity is aging. In embodiments, the disease associated with mTORC1 activity or with abnormal levels of mTORC1 activity is death from an age-related disease. In embodiments, the disease associated with mTORC1 activity or associated with abnormal levels of mTORC1 activity is an age-related condition. In certain embodiments, the age-related condition is selected from the group consisting of: sarcopenia, skin atrophy, muscle atrophy, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, huntington's disease, alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, shortened life expectancy, impaired renal function and age-related hearing loss, age-related behavioral dysfunction (e.g., weakness), cognitive decline, age-related dementia, memory impairment, tendon stiffness, cardiac dysfunction (e.g., cardiac hypertrophy and systolic and diastolic dysfunction), immune aging, cancer, obesity, and diabetes. In certain embodiments, selective modulation of mTORC1 of certain T cell populations can improve vaccine efficacy in aging populations and enhance the effectiveness of cancer immunotherapy. The present disclosure provides a method of treating immunosenescence comprising administering to an individual a therapeutically effective amount of one or more of the disclosed compounds.
In embodiments, the disease associated with mTORC1 activity or a disease associated with an abnormal level of mTORC1 activity is cancer (e.g., carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, solid cancer, lymphoma; kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, gastrointestinal cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, esophageal cancer, liver cancer; testicular cancer, glioma, liver cancer, lymphoma (including B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma) (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma), leukemia (including AML, ALL, and CML), multiple myeloma, and breast cancer (e.g., triple negative breast cancer).
In embodiments, the disease associated with mTORC1 activity or associated with an abnormal level of mTORC1 activity is Acute Disseminated Encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukotrichia, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic abnormalities, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, Autoimmune Inner Ear Disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, Autoimmune Thrombocytopenic Purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, autoimmune diseases, Axonal or neuronal neuropathy, Barlow's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Casleman's disease, celiac disease, Chagas ' disease, chronic fatigue syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Relapsing Multifocal Osteomyelitis (CRMO), Churg-Schuis syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogan syndrome, congealing syndrome, congenital heart conduction block, Coxsackie myocarditis (Coxsackie myocarpis), CREST's disease, primary cryoglobulinemia, demyelinating neuropathy, dermatitis, dermatomyositis, herpes (Devices), myelitis disopneumoniae (lupus), myxoviridis, Grave's disease, Graves Descemet's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, Granulomatosis Polyangiitis (GPA) (formerly Wegener's granulomatosis), Graves ' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henschel-Schonlein purpura, purpura, herpes gestationis, thrombocytopenia, glomerulonephritis, Graves's thyroiditis, Graves ' disease, Hashimoto's disease, thrombocytopenia, Graves's purpura, IgA nephropathy, thrombocytopenia, IgA nephropathy, Graves's purpura, Graves's disease, Graves's purpura, Graves's disease, Graves's purpura, Graves IgG 4-related sclerosing disease, immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leubert-Eaton syndrome, Leukotic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, Linear IgA disease (LAD), lupus (SLE), Chronic Lyme disease (Lyme disease), Meniere's disease, microscopic polyangiitis, Mixed Connective Tissue Disease (MCTD), Mooren's ulcer, Murch-Hadamann disease (Mucha-Haermann disease), multiple sclerosis, myasthenia gravis, myositis, narcolepsy, optic neuritis (Devicker's), neutropenia, ocular cicatricial dermatitis, cicatrix, Optic neuritis, recurrent rheumatism, PANDAS (a streptococcal associated pediatric autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, Paroxysmal Nocturnal Hemoglobinuria (PNH), Parry rob syndrome, parsonand syndrome, Parsonnage-Turner syndrome, parsonentitis, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune multiple endocrine gland syndromes type I, II and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progestational dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, gangrenous dermatosis, pure dyserythrocytic development, idiopathic pulmonary fibrosis, paraneoplastic cerebellar degeneration, paroxysmal hemoglobinopathy, acute nocturnal hemoglobinuria (PNH), Parry nocturnal hemoglobinuria, paraneoplastic nocturnal hemoglobinuria, periencephritis, peripheral encephalomyelitis, peripheral encephalomyeli, Raynaud's phenomenon (Raynauds phenomenon), reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, recurrent polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome (Schmidt syndrome), scleritis, scleroderma, Sjogren's syndrome, autoimmune disease of sperm and testis, stiff person syndrome, Subacute Bacterial Endocarditis (SBE), susacks's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/giant cell arteritis, thrombocytopenic purpura (TTP), tossa-hunter syndrome (Tolosa-hunter), synusitis, type 1 diabetes, ulcerative colitis, non-connective tissue (td) differentiation, Uveitis, vasculitis, blistering dermatoses, vitiligo, wegener's granulomatosis (i.e., Granulomatous Polyangiitis (GPA), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, guillain-barre syndrome, hashimoto's encephalitis, hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, behcet's disease, crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, Celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, atopic dermatitis, Alexander's disease, Alper's disease, alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as schlemeter-woggett-huggen-Batten disease), Bovine Spongiform Encephalopathy (BSE), Canavan disease, Cockayne syndrome (Cockayne syndrome), corticobasal degeneration, keletye-jakoff disease, dementia, guillain-Straussler syndrome (guillain-strandler-stra), alzheimer's disease, cretayan syndrome (Cockayne syndrome), corticobasal degeneration, crohn's disease (schutzkokukokukoff disease), dementia, guillain-Straussler-strandler syndrome (guillain-strandler-strander syndrome), alzheimer's disease, Huntington's Disease, HTV-associated dementia, Kennedy's Disease, Krabe's Disease, Kuru (kuru), Lewy body dementia, Machado-Joseph Disease (Machado-Joseph Disease) (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's Disease, Peizaeus-Merzbacher Disease, Pick's Disease, Primary lateral sclerosis, prion Disease, Refsum's Disease, Sandhs Disease, Schildder's Disease, subacute combined degeneration secondary to pernicious anemia, schizophrenia, multiple types of spinal cord atrophy, Richardson's Disease, Sphingese-Schedule Disease (Ochros Disease), Skinson-Schedulis Disease, Skinson's Disease, Sphingese Disease, Sphingesenberg Disease, Sphingese Disease, Sphingeseler's Disease, Sphingesenekutson Disease, Sphingeseler-Josephsheson's Disease, Sphingese Disease, Sphingeseler's Disease, Sphingesenekstroemia, Sphingese Disease, Sphingeseler's Disease, Sphingeserviosis, Sphingeseler's Disease, Spiesis, Sphingeseler, Tuberculosis, diabetes (e.g., type I or type II), obesity, metabolic syndrome, mitochondrial disease (e.g., mitochondrial dysfunction or mitochondrial dysfunction), fungal infection, graft rejection, or cardiovascular disease (e.g., congestive heart failure, arrhythmic syndrome (e.g., paroxysmal tachycardia, delayed posterior depolarization, ventricular tachycardia, sudden tachycardia, exercise-induced arrhythmia, long QT syndrome, or bilateral tachycardia), thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders within the heart cavity), atherosclerosis, restenosis, peripheral arterial disease, coronary bypass surgery, carotid arterial disease, arteritis, myocarditis, cardiovascular inflammation, vascular inflammation, Coronary Heart Disease (CHD), Unstable Angina (UA), unstable refractory angina, Stable Angina (SA), Slow Angina (SA) Stable angina pectoris; acute Coronary Syndrome (ACS); myocardial infarction (incipient or recurrent); acute Myocardial Infarction (AMI); myocardial infarction; non-Q wave myocardial infarction; non-STE myocardial infarction; coronary artery disease; ischemic heart disease; myocardial ischemia; ischemia; ischemic sudden death; transient ischemic attacks; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolization; coronary thrombosis; cerebral arterial thrombosis, cerebral embolism; renal embolism; pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e.g., associated with atherosclerosis, surgery, long-term immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, hormones, or pregnancy); or an arrhythmia (e.g., supraventricular arrhythmia, atrial flutter, or atrial fibrillation).
In one aspect, there is provided a method of treating a disease comprising administering an effective amount of one or more compositions or compounds as described herein. In one aspect, there is provided one or more compositions or compounds as described herein for use as a medicament (e.g., for treating a disease). In one aspect, one or more compositions or compounds as described herein are provided for use in treating a disease (e.g., comprising administering an effective amount of one or more compositions or compounds as described herein). In an embodiment, the disease is cancer. In embodiments, the disease is an autoimmune disease. In an embodiment, the disease is an inflammatory disease. In an embodiment, the disease is a neurodegenerative disease. In an embodiment, the disease is a metabolic disease. In an embodiment, the disease is a fungal infection. In an embodiment, the disease is transplant rejection. In an embodiment, the disease is a cardiovascular disease.
In embodiments, the disease is cancer (e.g., carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, solid cancer, lymphoma; kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, esophagus, liver, testis, glioma, liver, lymphoma (including B-cell acute lymphoblastic lymphoma, non-hodgkin's lymphoma (e.g., burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), hodgkin's lymphoma), leukemia (including AML, ALL, and CML), multiple myeloma, and breast cancer (e.g., triple negative breast cancer).
In embodiments, the disease is Acute Disseminated Encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalopathy, addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, anti-phospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic abnormalities, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, Autoimmune Inner Ear Disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, Autoimmune Thrombocytopenic Purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, barlow's disease, behcet's disease, bullous pemphigoid, herpes zoster, herpes simplex virus, and other diseases, Cardiomyopathy, Cashmere's disease, celiac disease, Chagas' disease, chronic fatigue syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Relapsing Multifocal Osteomyelitis (CRMO), churg-Stachys syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Kupffer syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, primary mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devkker's disease (neuromyelitis optica), discoid lupus, Descemera syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, illicit syndrome, fibromyalgia, fibrositis, giant cell arteritis (temporal arteritis), Giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, Granulomatous Polyangiitis (GPA) (previously known as Wegener's granulomatosis), Graves ' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henry-Schneider purpura, herpes gestationis, hypogammaglobulinemia, Idiopathic Thrombocytopenic Purpura (ITP), IgA nephropathy, IgG 4-associated sclerosing diseases, immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lanbert-Eton syndrome, leukocyte fragmenting vasculitis, lichen planus, sclerosing moss, woody conjunctivitis, Linear IgA disease (LAD), lupus (SLE), Lyme disease, and the like, Meniere's disease, microscopic polyangiitis, Mixed Connective Tissue Disease (MCTD), Munich's ulcer, Muscohal's disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devicker), neutropenia, ocular cicatricial pemphigoid, optic neuritis, recurrent rheumatism, PANDAS (a pediatric autoimmune neuropsychiatric disorder associated with streptococcus), paraneoplastic cerebellar degeneration, Paroxysmal Nocturnal Hemoglobinuria (PNH), Parlo syndrome, Paget's syndrome, pars plana (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, type II and type III autoimmune multiple endocrine syndromes, polymyalgia rheumatica, polymyositis, multiple sclerosis, myasthenia gravis, myasthe, Post-myocardial infarction syndrome, post-pericardiotomy syndrome, progestogenic dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell dysplasia, raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, reiter's syndrome, recurrent polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, schmidt syndrome, scleritis, scleroderma, sjogren's syndrome, sperm and testicular autoimmune disease, stiff man syndrome, Subacute Bacterial Endocarditis (SBE), suza syndrome, sympathetic ophthalmia, takayasu arteritis, temporal arteritis/giant cell arteritis, thrombocytopenic purpura (TTP), tossa-Hunter syndrome, Transverse myelitis, type 1 diabetes, ulcerative colitis, Undifferentiated Connective Tissue Disease (UCTD), uveitis, vasculitis, blistering skin disease, vitiligo, Wegener's granulomatosis (i.e., Granulomatous Polyangiitis (GPA), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Levens's ophthalmopathy, inflammatory bowel disease, Addison's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves's ophthalmopathy, inflammatory bowel disease, Addison Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, atopic dermatitis, alexander's disease, alper's disease, alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, pavosis (also known as schermamee-woguet-huggen-buerger-barthason disease), Bovine Spongiform Encephalopathy (BSE), kawanner's disease, cockayne syndrome, corticobasal degeneration, creutzfeldt-jakob disease, frontotemporal dementia, guillain-stosler-scheinker syndrome, huntington's disease, HTV-related dementia, kennedy's disease, krabbe's disease, kuru, lewy body dementia, mado-joseph disease (type 3 spinocerebellar ataxia), spinocerebellar ataxia, Multiple sclerosis, multiple system atrophy, narcolepsy, neuroleptic disease, parkinson's disease, pemphigus disease, pick's disease, primary lateral sclerosis, prion disease, refsum's disease, sandhoff's disease, schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, still-richardson-olzves disease, tabes spinosus, diabetes (e.g., type I or type II), obesity, metabolic syndrome, mitochondrial disease (e.g., mitochondrial dysfunction or mitochondrial dysfunction), fungal infection, transplant rejection or cardiovascular disease (e.g., congestive heart failure; arrhythmic syndrome (e.g., paroxysmal tachycardia, delayed post-depolarization depolarizer syndrome, delayed onset tachycardia, delayed onset, ventricular tachycardia, sudden tachycardia, exercise-induced arrhythmia, long QT syndrome, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders within the heart chamber); atherosclerosis; restenosis; peripheral arterial disease; coronary artery bypass surgery; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; inflammation of blood vessels; coronary Heart Disease (CHD); unstable Angina (UA); unstable refractory angina pectoris; stable angina pectoris (SA); chronic stable angina pectoris; acute Coronary Syndrome (ACS); myocardial infarction (incipient or recurrent); acute Myocardial Infarction (AMI); myocardial infarction; non-Q wave myocardial infarction; non-STE myocardial infarction; coronary artery disease; ischemic heart disease; myocardial ischemia; ischemia; ischemic sudden death; transient ischemic attacks; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolization; coronary thrombosis; cerebral arterial thrombosis, cerebral embolism; renal embolism; pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e.g., associated with atherosclerosis, surgery, long-term immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, hormones, or pregnancy); or an arrhythmia (e.g., supraventricular arrhythmia, atrial flutter, or atrial fibrillation). In an embodiment, the disease is a polycystic disease. In an embodiment, the disease is polycystic kidney disease. In an embodiment, the disease is stenosis. In an embodiment, the disease is restenosis. In an embodiment, the disease is neointimal proliferation. In an embodiment, the disease is neointimal hyperplasia.
In another aspect, there is provided a method of treating aging in an individual in need of such treatment, the method comprising administering to the individual one or more compositions or compounds as described herein (e.g., claims, examples, tables, figures, or claims) including examples. The present disclosure provides a method of treating immunosenescence comprising administering to an individual a therapeutically effective amount of one or more of the disclosed compounds or compositions.
In another aspect, there is provided one or more compositions or compounds as described herein for use as a medicament. In embodiments, the agent may be suitable for treating aging in an individual in need of such treatment. In embodiments, using can include administering to the individual one or more compositions or compounds as described herein (e.g., aspects, embodiments, examples, tables, figures, or claims) including the embodiments.
In another aspect, there is provided one or more compositions or compounds as disclosed herein for use in treating aging in a subject in need of such treatment. In embodiments, using can include administering to the individual one or more compositions or compounds as described herein (e.g., aspects, embodiments, examples, tables, figures, or claims) including the embodiments.
In another aspect, there is provided a method of prolonging mean life or inducing longevity in an individual in need of such treatment, the method comprising administering to the individual one or more compositions or compounds as described herein (e.g., claims, examples, tables, figures, or claims) including examples.
In another aspect, there is provided one or more compositions or compounds as described herein for use as a medicament. In embodiments, the agent may be suitable for extending the mean life span or inducing longevity in an individual in need of such treatment. In embodiments, using can include administering to the individual one or more compositions or compounds as described herein (e.g., aspects, embodiments, examples, tables, figures, or claims) including the embodiments.
In another aspect, one or more compositions or compounds are provided for use in extending the mean life span or inducing longevity in an individual in need of such treatment. In embodiments, using can include administering to the individual one or more compositions or compounds as described herein (e.g., aspects, embodiments, examples, tables, figures, or claims) including the embodiments.
In one aspect, a method of treating polycystic disease in an individual in need of such treatment is provided. The polycystic disease can be polycystic kidney disease. The methods may comprise administering to the individual one or more compositions or compounds described herein. The methods can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, there is provided one or more compositions or compounds as described herein for use as a medicament. In embodiments, the medicament is suitable for treating polycystic diseases. The polycystic disease can be polycystic kidney disease. Use may include administering to the individual one or more of the compositions or compounds described herein. Use can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, there is provided one or more compositions or compounds as described herein for use in treating polycystic disease in a subject in need of such treatment. The polycystic disease can be polycystic kidney disease. Use may include administering to the individual one or more of the compositions or compounds described herein. Use can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, a method of treating stenosis in an individual in need of such treatment is provided. The stenosis may be restenosis. The methods may comprise administering to the individual one or more compositions or compounds described herein. In embodiments, one or more compositions or compounds are administered in a drug eluting stent. The methods can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, there is provided one or more compositions or compounds as described herein for use as a medicament. In embodiments, the agent is suitable for treating stenosis. The stenosis may be restenosis. Use may include administering to the individual one or more of the compositions or compounds described herein. In embodiments, the compound is administered in a drug eluting stent. Use can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In one aspect, there is provided one or more compositions or compounds as described herein for use in treating stenosis in an individual in need of such treatment. The stenosis may be restenosis. Use may include administering to the individual one or more of the compositions or compounds described herein. In embodiments, one or more compositions or compounds are administered in a drug eluting stent. Use can include administering to the individual a therapeutically effective amount of one or more of the compositions or compounds described herein (e.g., a mTORC1 modulator (e.g., inhibitor) as described above).
In embodiments, the disease is a disease described herein, and the compound is a compound described herein, and the composition is a composition described herein.
Exemplary embodiments
Some embodiments of the present disclosure, embodiments are example I, presented below.
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