Kinase inhibitors and methods of use thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is selected from the group consisting of optionally substituted aliphatic, optionally substituted aryl, and optionally substituted heteroaryl;

R 2 is optionally substituted aliphatic;

or R 1 and R 2 are taken together with their intervening atoms to form a ring, wherein:

the ring formed by R 1 and R 2 is an optionally substituted 3- to 7-membered saturated carbocyclic ring; an unsubstituted 3- to 7-membered saturated heterocyclic ring; an optionally substituted 3- to 7-membered saturated heterocyclic ring, wherein one to four ring atoms are independently oxygen or sulfur; or a 3- to 7-membered saturated heterocyclic ring that has ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and is substituted with:

(i) one or more carbon atom substituents independently selected from the group consisting of halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ) 3 + X − , —N(OR cc )R bb , —SH, —SR aa , —SSR cc , —C(═O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R aa , —S(═O)R aa , —OS(═O)R aa , —C(═O)SR aa , —SC(═O)SR aa , —OC(═O)SR aa , —SC(═O)OR aa , —SC(═O)R aa , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; and optionally two geminal hydrogens on a carbon atom of the ring formed by R 1 and R 2 are replaced with the group ═O; and/or

(ii) one or more nitrogen atom substituents independently selected from the group consisting of —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═O)SR cc , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

wherein:

each instance of R aa is independently selected from the group consisting of C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R bb is independently selected from the group consisting of hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R cc is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R dd is independently selected from the group consisting of halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR ee , —ON(R ff ) 2 , —N(R ff ) 2 , —N(R ff ) 3 + X − , —N(OR ee )R ff , —SH, —SR ee , —SSR ee , —C(═O)R ee , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , —NR ff CO 2 R ee , —NR ff C(═O)N(R ff ) 2 , —NR ff SO 2 R ee , —SO 2 N(R ff ) 2 , —SO 2 R ee , —SO 2 OR ee , —OSO 2 R ee , —S(═O)R ee , —C(═O)SR ee , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents are joined to form ═O;

each instance of R ee is independently selected from the group consisting of C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

each instance of R ff is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

each instance of R gg is independently halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X − , —NH(C 1-6 alkyl) 2 + X − , —NH 2 (C 1-6 alkyl)+X − , —NH 3 + X − , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C(═O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC(═O)(C 1-6 alkyl), —OCO 2 (C 1-6 alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6 alkyl) 2 , —OC(═O)NH(C 1-6 alkyl), —NHC(═O)(C 1-6 alkyl), —N(C 1-6 alkyl)C(═O)(C 1-6 alkyl), —NHCO 2 (C 1-6 alkyl), —NHC(═O)N(C 1-6 alkyl) 2 , —NHC(═O)NH(C 1-6 alkyl), —NHC(═O)NH 2 , —OC(NH)NH(C 1-6 alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6 alkyl) 2 , —NHSO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 OC 1-6 alkyl, —OSO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —C(═O)S(C 1-6 alkyl), C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal R gg substituents are joined to form ═O; and

X − is a counterion; and

the ring formed by R 1 and R 2 is optionally fused to an optionally substituted, 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 , —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 independently selected from the group consisting of hydrogen, halo, and unsubstituted methyl;

R 5a and R 5b are independently selected from the group consisting of hydrogen, halo, —CN, —OR A , —N(R B ) 2 , or 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 independently selected from the group consisting of hydrogen, halo, and unsubstituted methyl.

2. The compound of claim 1 , wherein the compound is of formula I-a:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1′ is optionally substituted aryl; and

R 2′ is optionally substituted aliphatic.

3. 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 , S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;

optionally two adjacent R 7 groups are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic, fused ring;

provided that R 2 and one R 7 are taken together with their intervening atoms to form an optionally substituted, carbocyclic or heterocyclic, fused ring; and

n is 1, 2, 3, 4, or 5.

4. 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;

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 , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;

optionally two adjacent R 7 groups are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic, fused ring;

optionally R 2 and one 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.

5. The compound of claim 4 , wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt thereof,

wherein:

R 2′ is optionally substituted aliphatic.

6. The compound of claim 5 , wherein the compound is of formula III-a-ii:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted aliphatic.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted alkyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted methyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are each unsubstituted methyl.

12. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A method of inhibiting glycogen synthase kinase 3 (GSK3) comprising contacting GSK3 with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method of treating a disorder comprising administering to a subject suffering from the disorder an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is Fragile X syndrome.

15. A method of inhibiting casein kinase 1 (CK1) comprising contacting CK1 with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are taken together with their intervening atoms to form a ring, wherein the ring formed by R 1 and R 2 is an optionally substituted 3- to 7-membered saturated carbocyclic ring; an unsubstituted 3- to 7-membered saturated heterocyclic ring; an optionally substituted 3- to 7-membered saturated heterocyclic ring, wherein one to four ring atoms are independently oxygen or sulfur; or a 3- to 7-membered saturated heterocyclic ring that has ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur and is substituted with:

(i) one or more carbon atom substituents as defined in claim 1 ; and/or

(ii) one or more nitrogen atom substituents as defined in claim 1 .

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are taken together with their intervening atoms to form a ring, wherein the ring formed by R 1 and R 2 is an optionally substituted 3- to 7-membered saturated carbocyclic ring; an unsubstituted 3- to 7-membered saturated heterocyclic ring; an optionally substituted 3- to 7-membered saturated heterocyclic ring, wherein one to four ring atoms are independently oxygen or sulfur; or a 3- to 7-membered saturated heterocyclic ring that has ring carbon atoms and 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur and is substituted with:

(i) one or more carbon atom substituents as defined in claim 1 ; and/or

(ii) one or more nitrogen atom substituents as defined in claim 1 ;

and the ring formed by R 1 and R 2 is fused to an optionally substituted, aryl or heteroaryl ring.

19. 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 , —S(═O)R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;

optionally two adjacent R 7 groups are taken together with their intervening atoms to form an optionally substituted, monocyclic, carbocyclic or heterocyclic ring; and

n is 0, 1, 2, 3, 4, or 5.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted alkyl, haloalkyl, unsubstituted cycloalkyl, or cycloalkyl substituted with one or more fluoro.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted ethyl.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is fluorine.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b are each hydrogen.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are each hydrogen.

25. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.

27. A method of treating a disorder comprising administering to a subject suffering from the disorder an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is autism.

28. A method of treating a disorder comprising administering to a subject suffering from the disorder an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is bipolar disorder.

29. A method of treating a disorder comprising administering to a subject suffering from the disorder an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is acute myeloid leukemia.

30. The compound of claim 19 , wherein the compound is of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein:

R 2' is optionally substituted aliphatic.

31. The compound of claim 30 wherein the compound is of formula II-b-ii:

or a pharmaceutically acceptable salt thereof.