Substituted pyrazolo[1,5-a]pyrimidines as TYK2 pseudokinase ligands

1. A compound having Formula (I′):

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein:

X is N;

Y is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl is optionally substituted by 1, 2, 3, or 4 independently selected R 7 substituents; or

Y is

L 1 is a bond, —CH 2 NR 9 —, —C(O)—, —NR 9 —, —NR 9 CH 2 —, or —O—;

R 1 is C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is substituted by 1, 2, or 3 independently selected R 13 substituents;

R 2 is hydrogen, deuterium, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;

R 3 is hydrogen, deuterium, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;

R 4 is hydrogen, deuterium, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;

R 5 is hydrogen or C 1 -C 6 alkyl;

R 6 is hydrogen, deuterium, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;

each R 7 is independently deuterium, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —C(O)R 11 , —C(O)NR 10 R 10 , —C(O)OR 10 , —NR 10 R 10 , —NR 10 C(O)R 11 , —NR 10 S(O) 2 R 11 , —OR 10 , ═O, —S(O) 2 R 11 , —S(O) 2 NR 10 R 10 , C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl, wherein each C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 2 -C 9 heteroaryl is optionally and independently substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR 12 R 12 , —C(O)OR 12 , —NR 12 R 12 , —OR 12 , C 2 -C 9 heterocycloalkyl, and C 2 -C 9 heteroaryl; or two R 7 , together with the carbon atom(s) to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl or a 5-, 6-, or 7-membered heterocycloalkyl;

R 8 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl;

R 9 is hydrogen or C 1 -C 6 alkyl;

each R 10 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, or phenyl, wherein each phenyl is optionally and independently substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR 12 R 12 , —C(O)OR 12 , —NR 12 R 12 , —OR 12 , C 2 -C 9 heterocycloalkyl, and C 2 -C 9 heteroaryl;

each R 11 is independently C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl;

each R 12 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R 13 is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —C(O)R 11 , —C(O)NR 10 R 10 , —C(O)OR 10 , —NR 10 R 10 , —NR 10 C(O)R 11 , —NR 10 S(O) 2 R 11 , —OR 10 , ═O, —S(O) 2 R 11 , —S(O) 2 NR 10 R 10 , C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, or C 2 -C 9 heteroaryl, wherein each C 3 -C 6 cycloalkyl, C 2 -C 9 heterocycloalkyl, C 6 -C 10 aryl, and C 2 -C 9 heteroaryl is optionally and independently substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR 12 R 12 , —C(O)OR 12 , —NR 12 R 12 , —OR 12 , C 2 -C 9 heterocycloalkyl, and C 2 -C 9 heteroaryl; and

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

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is phenyl, wherein the phenyl is optionally substituted by 1, 2, or 3 independently selected R 7 substituents.

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

4. The compound of claim 3 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 13 is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, or ═O.

5. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 13 is independently halogen, —CN, or —OH.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is cyclopropyl, wherein the cyclopropyl is substituted by 1 R 13 substituent, and R 13 is halogen, —CN, or —OH.

7. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is

8. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 1 is a bond.

9. The compound of claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 1 is —NH—.

10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is hydrogen or C 1 -C 6 alkyl; and R 4 is hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is hydrogen; and R 4 is C 1 -C 6 alkyl.

12. The compound of claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 is hydrogen.

13. The compound of claim 12 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is hydrogen.

14. The compound of claim 13 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is hydrogen.

15. The compound of claim 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is hydrogen.

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

17. A method for inhibiting tyrosine kinase 2 activity in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The method of claim 17 , wherein the patient has a disease selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, intestinal bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

19. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.