TYK2 INHIBITORS AND USES THEREOF

1 . A compound of Formula (II):

a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

L is a 4-10 atom linker; optionally substituted with one or more R L ;

each R L is independently deuterium, halogen, —CN, —OR, —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR, —OC(═O)OR, —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R L on the same carbon are taken together to form an oxo, a cycloalkyl, or heterocycloalkyl; or two R L on different carbons are taken together to form a cycloalkyl or heterocycloalkyl;

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

each R A is independently deuterium, halogen, —CN, —OR, —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR, —OC(═O)OR, —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R A1 ; or two R A on the same carbon are taken together to form an oxo;

each R A1 is independently deuterium, halogen, —CN, —OR, —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR, —OC(═O)OR, —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R A1 on the same carbon are taken together to form an oxo

n is 0-4;

is a single bond or a double bond;

X 1 and X 2 are —N— or —C═; provided that one of X 1 or X 2 is —N— and the other is —C═;

Y 8 is CR 8 or N;

Y 6 is CR 6 or N;

Y 3 is CR 3 or N;

Y 9 is CR 9 or N;

R 3 , R 6 , R 8 , and R 9 are independently hydrogen, deuterium, halogen, —CN, —OR, —SR b , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR c R d , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR, —OC(═O)OR, —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 4a ;

each R 4a is independently deuterium, halogen, —CN, —OR, —NR c R d , —C(═O)R a , —C(═O)OR, —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 4a on the same carbon are taken together to form an oxo;

R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

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 or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH 2 , —C(═O)Me, —C(═O)OH, —C(═O)OMe, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

2 . The compound of claim 1 , wherein the compound of Formula (II) is a compound of Formula (IIa):

or a pharmaceutically acceptable salt or stereoisomer thereof.

3 . The compound of claim 1 , wherein the compound of Formula (II) is a compound of Formula (IIb):

or a pharmaceutically acceptable salt or stereoisomer thereof.

4 . The compound of claim 1 wherein:

Y 9 is N.

5 . The compound of claim 1 , wherein:

Y 6 is CR 6 and R 6 is hydrogen.

6 . (canceled)

7 . The compound of claim 1 , wherein:

Y 3 is CR 3 and R 3 is hydrogen.

8 . (canceled)

9 . The compound of claim 1 , wherein:

Y 8 is N.

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

Y 8 is CR 8 , and R 8 is hydrogen.

11 . (canceled)

12 . The compound of claim 1 , wherein:

R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

13 . The compound of claim 1 , wherein:

R 4 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.

14 . The compound of claim 1 , wherein:

R 5 is hydrogen.

15 . The compound of claim 1 , wherein:

R 7 is hydrogen or C 1 -C 6 alkyl.

16 . The compound of claim 1 , wherein:

Ring A is heterocycloalkyl, aryl, or heteroaryl.

17 . The compound of claim 1 , wherein:

Ring A is aryl.

18 . The compound of claim 1 , wherein:

Ring A is heteroaryl.

19 . The compound of claim 1 , wherein:

each R A is independently deuterium, halogen, —CN, —OR, —NR c R d , —C(═O)R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.

20 . The compound of claim 1 , wherein:

L is a 4-8 atom linker; optionally substituted with one or more R L .

21 . (canceled)

22 . The compound of claim 1 , wherein:

L is a 4-10 atom linker comprising between 4 and 10 carbons and between 0 and 4 heteroatoms selected from oxygen and nitrogen; the linker being optionally substituted with one or more R L .

23 - 27 . (canceled)

28 . The compound of claim 1 , wherein:

each R L is independently deuterium, halogen, —CN, —OR b , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R L on the same carbon are taken together to form an oxo.

29 . The compound of claim 1 , wherein:

each R L is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R L on the same carbon are taken together to form an oxo or a cycloalkyl; or two R L on different carbons are taken together to form a cycloalkyl.

30 . The compound of claim 1 , wherein:

each R L is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; or two R L on the same carbon are taken together to form an oxo.

31 . The compound of claim 1 , wherein:

L is

32 . The compound of claim 1 , wherein:

L is

33 . The compound of claim 1 , wherein:

L is

34 . The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

35 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

36 . A method of inhibiting a TYK2 enzyme in a patient or biological sample comprising contacting said patient or biological sample with a compound of claim 1 .

37 . A method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof a compound of claim 1 .

38 . The method of claim 37 , wherein the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

39 . The method of claim 37 , wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.