Autotaxin inhibitors and uses thereof

1. A compound of Formula (I′), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

X 1 is CR 13 ;

X 2 is CR 14 ;

X 3 is N or CR 15 ;

W is

Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

L is —O—, —S—, or —NR 19 —;

R 11 is L 1 -R 20 ;

L 1 is absent or C 1 -C 6 alkylene optionally substituted with deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , or —C(═O)NR c R d ;

R 20 is halogen, —CN, —OR 21 , —SR 21 , —S(═O)R 22 , —S(═O) 2 R 22 , —NO 2 , —NR 23 R 24 , —NR 21 S(═O) 2 R 22 , —S(═O) 2 NR 23 R 24 , —C(═O)R 22 , —OC(═O)R 22 , —C(═O)C(═O)R 22 , —C(═O)OR 21 , —C(═O)NR 21 OR 21 , —OC(═O)OR 21 , —C(═O)NR 23 R 24 , —OC(═O)NR 23 R 24 , —NR 21 C(═O)NR 23 R 24 —NR 21 S(═O) 2 NR 23 R 24 , —NR 21 C(═O)R 22 , —NR 21 C(═)OR 21 , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 1 ;

each R 21 is independently hydrogen, —CN, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 1a ;

R 22 is hydrogen, —CN, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 1b ;

R 23 and R 24 are independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 1c ;

or R 23 and R 24 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 1d ;

each R 12 is independently deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 2 ;

or two R 12 on the same carbon are taken together to form an oxo;

R 13 is hydrogen, deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 3 ;

R 14 is deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 4 ;

R 15 is hydrogen, deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 5 ;

or R 14 and R 15 are taken together to form a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are independently optionally substituted with one, two, or three R 6 ;

R 16 is hydrogen, deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 7 ;

each R 17 is independently deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR a , —C(═O)NR c R d , —NR a C(═O)R b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 8 ;

or two R 17 on the same carbon are taken together to form an oxo;

each R 18 is independently deuterium, halogen, —CN, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR a , —C(═O)NR c R d , —NR a C(═O)R b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R 9 ;

or two R 18 on the same carbon are taken together to form an oxo;

R 19 is hydrogen, —S(═O)R b , —S(═O) 2 R b , —S(═O) 2 NR c R d , —C(═O)R b , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;

each R 1a , R 1b , R 1c , and R 1d are independently oxo, halogen, —CN, —OR a , —S(═O) 2 R b , —NR c R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —C(═O)OR a , —OC(═O)OR a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or phenyl;

each R 1 is independently oxo, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)R a , —C(═O)NR c R d , —S(═O) 2 R b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, or phenyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, and phenyl are independently optionally substituted with one, two, or three halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or phenyl;

each R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently oxo, halogen, —CN, —OR a , —NR c R d , —C(═O)OR a , —C(═O)R a , —C(═O)NR e R d , —S(═O) 2 R b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, or phenyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, and phenyl are independently optionally substituted with one, two, or three halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or phenyl;

each R a is independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, —OH, —NH 2 , or C 1 -C 6 alkyl;

each R b is independently C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, —OH, —NH 2 , or C 1 -C 6 alkyl;

each R c and R d are independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three halogen, —OH, —NH 2 , or C 1 -C 6 alkyl;

or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, —OH, —NH 2 , or C 1 -C 6 alkyl;

n is 0-3;

m is 0-3; and

p is 0-3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 13 is hydrogen, deuterium, halogen, —CN, —OR a , —NR c R d , or C 1 -C 6 alkyl optionally substituted with one, two, or three halogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 14 is deuterium, halogen, —CN, —OR a , —NR c R d , or C 1 -C 6 alkyl optionally substituted with one, two, or three halogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

X 3 is CR 15 and R 15 is hydrogen, deuterium, halogen, —CN, —OR a , —NR c R d , or C 1 -C 6 alkyl optionally substituted with one, two, or three halogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 16 is C 1 -C 6 alkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

L is —NR 19 — and R 19 is hydrogen or C 1 -C 6 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

Ring B is a 5-membered heteroaryl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

Ring C is aryl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the compound is a compound of Formula (Ic):

10. The compound of claim 9 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 17 is —CN.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

each R 18 is independently halogen, or C 1 -C 6 alkyl optionally substituted with one, two, or three halogen.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

Ring A is heterocycloalkyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

L 1 is C 1 -C 6 alkylene.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 20 is —CN, —S(═O) 2 R 22 , —C(═O)R 22 , —C(═O)OR 21 , —C(═O)NR 23 R 24 , heterocycloalkyl, or heteroaryl; wherein the heterocycloalkyl and heteroaryl are independently optionally substituted with one, two, or three R 1 .

15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 20 is —C(═O)NR 23 R 24 .

16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

R 23 and R 24 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three oxo, halogen, —CN, —OR a , —S(═O) 2 R b , —NR c R d , —S(═O) 2 NR c R d , —C(═O)R b , —OC(═O)R b , —C(═O)OR a , —OC(═O)OR a , —C(═O)NR c R d , —OC(═O)NR c R d , —NR a C(═O)NR c R d , —NR a C(═O)R b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:

18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

19. A method of treating fibrotic diseases, cancers, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurological diseases, and metabolic diseases, the method comprising administering a therapeutic amount of a compound of claim 1 .

20. A method of treating Idiopathic Pulmonary Fibrosis (IPF), scleroderma, or nonalcoholic steatohepatitis (NASH), the method comprising administering a therapeutic amount of a compound of claim 1 .