Kinase inhibitors and methods of use thereof
The present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting kinase (e.g., GSK3 (e.g., GSK3α or GSK3β) or CK1) activity. The present invention further provides methods of using the compounds described herein for treating kinase-mediated disorders, such as neurological diseases, psychiatric disorders, metabolic disorders, and cancer.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein
R 1 and R 2 are independently selected from the group consisting of optionally substituted aliphatic, optionally substituted aryl, and optionally substituted heteroaryl; or R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted 3- to 7-membered saturated carbocyclic or heterocyclic ring, wherein the ring formed by R 1 and R 2 may be optionally fused to an aryl or heteroaryl ring;
R 3 is selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —OC(═O)R A , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —OC(═O)N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R B is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
R 4a and R 4b are hydrogen;
R 5a and R 5b are independently selected from the group consisting of hydrogen, halo, —CN, —OR A , —N(R B ) 2 , and optionally substituted aliphatic, or R 5a and R 5b are taken together with their intervening atoms to form an optionally substituted 3- to 7-membered saturated carbocyclic or heterocyclic ring; and
R 6a and R 6b are hydrogen.
2. The compound of claim 1 , wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof,
wherein
each R 7 is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —OC(═O)R A , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —OC(═O)N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; or two adjacent R 7 groups are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic fused ring; or R 2 and R 7 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic fused ring; and
n is 0, 1, 2, 3, 4, or 5.
3. The compound of claim 1 , wherein the compound is of formula III:
or a pharmaceutically acceptable salt thereof,
wherein
Ring A is a 5- to 6-membered heteroaryl, 4- to 6-membered carbocyclyl, or 4- to 6-membered heterocyclyl;
each R 7 is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted aliphatic, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —OC(═O)R A , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —OC(═O)N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ; or two adjacent R 7 groups are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic fused ring; or R 2 and R 7 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic fused ring; and
n is 0, 1, 2, 3, or 4, as valency allows.
4. The compound of claim 1 , wherein R 3 is hydrogen.
5. The compound of claim 1 , wherein R 3 is optionally substituted aliphatic.
6. The compound of claim 1 , wherein R 3 is trifluoromethyl.
7. The compound of claim 1 , wherein R 2 is optionally substituted aliphatic.
8. The compound of claim 1 , wherein R 5a and R 5b are methyl.
9. The compound of claim 2 , wherein n is 0, 1, or 2.
10. The compound of claim 1 , wherein the compound is one of the following:
or a pharmaceutically acceptable salt thereof.
11. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
12. A method of inhibiting GSK3 comprising contacting GSK3 with an effective amount of a compound of claim 1 .
13. The compound of claim 1 , wherein R 1 is optionally substituted pyridyl.
14. The compound of claim 1 , wherein R 1 is unsubstituted 3-pyridyl.
15. The compound of claim 1 , wherein R 2 is methyl.
16. The compound of claim 1 , wherein R 3 is methyl.
17. The compound of claim 1 , wherein R 3 is optionally substituted alkynyl or —CN.
18. The compound of claim 1 , wherein R 3 is optionally substituted alkyl.
19. The compound of claim 1 , wherein R 3 is substituted or unsubstituted cycloalkyl.
20. The compound of claim 1 , wherein R 3 is cyclopropyl.
21. The compound of claim 1 , wherein R 2 is optionally substituted alkyl.
22. The compound of claim 1 , wherein R 2 is ethyl.