Certain imidazopyridines as cyclic AMP response element binding (CREB) binding protein (CBP) inhibitors and uses thereof
This disclosure relates to compounds that are CBP inhibitor and methods of using such compounds in the treatment and diagnosis of diseases and disorders.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
L is (CR a R b ) n ;
R a and R b are each independently selected from H, C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl;
n is 0, 1, 2, or 3;
R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 haloalkyl, C(O)H, C(O)(C 1-8 alkyl), C(O)OH, C(O)O(C 1-8 alkyl), C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkylene, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl, and 5-10 membered heteroaryl-C 1-4 alkylene; wherein the 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-4 alkylene, 5-10 membered heteroaryl, and 5-10 membered heteroaryl-C 1-4 alkylene each has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; and wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkylene, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl, and 5-10 membered heteroaryl-C 1-4 alkylene are each optionally substituted with 1, 2, or 3 substituents selected from halo, C(O)H, C(O)(C 1-8 alkyl), C(O)OH, and C(O)O(C 1-8 alkyl);
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from H, halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, OH, and O-C 1-8 alkyl;
R 7 is selected from Cy, C 2-8 alkenyl, and C 2-8 alkynyl;
R 8 is selected from H, C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl; and
Cy is selected from 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl;
wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; and wherein the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from oxo, C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl.
2. The compound of claim 1 , wherein the compound is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is a compound of Formula IV:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein the compound is a compound of Formula V:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein n is 0.
7. The compound of claim 1 , wherein n is 2.
8. The compound of claim 1 , wherein R a is H.
9. The compound of claim 1 , wherein R b is H.
10. The compound of claim 1 , wherein R 1 is C 1-8 alkyl optionally substituted with 1, 2, or 3 substituents selected from halo, C(O)H, C(O)(C 1-8 alkyl), C(O)OH, and C(O)O(C 1-8 alkyl).
11. The compound of claim 1 , wherein R 1 is C 3-10 cycloalkyl.
12. The compound of claim 1 , wherein R 1 is 4-10 membered heterocycloalkyl-C 1-4 alkylene.
13. The compound of claim 1 , wherein R 1 is C 6-10 aryl or C 6-10 aryl-C 1-4 alkylene.
14. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , and R 6 are H.
15. The compound of claim 1 , wherein R 2 , R 5 , and R 6 are each H.
16. The compound of claim 1 , wherein R 3 is halo, C 1-8 alkyl, OH, and O-C 1-8 alkyl.
17. The compound of claim 1 , wherein R 4 is halo, C 1-8 alkyl, OH, and O-C 1-8 alkyl.
18. The compound of claim 1 , wherein R 7 is Cy.
19. The compound of claim 18 , wherein Cy is 5-10 membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from oxo, C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl.
20. The compound of claim 18 , wherein Cy is isoxazolyl, indazolyl, 3,4-dihydroquinazolin-2(1H)-onyl, or 3a,7a-dihydrobenzo[d]isoxazolyl.
21. The compound of claim 1 , wherein R 8 is H.
22. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
24. A method of inhibiting CBP activity, said method comprising contacting a compound of claim 1 , or a pharmaceutically acceptable salt thereof with CBP.
25. A process of preparing a compound of Formula I of claim 1 , or a pharmaceutically acceptable salt thereof, comprising converting a compound of Formula D:
to afford a compound of Formula I, or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 , wherein n is 1.