TYK2 inhibitors and uses thereof

1 . A compound of Formula (A1):

or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

R A is an unsubstituted or substituted carbocycle or unsubstituted or substituted heterocycle, wherein if R A is substituted, it is substituted by 1, 2, 3, or 4 instances of R 8 ;

each R 8 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —CN, —OH, —OR 11 , —C(═O)R 10 , —CO 2 R 10 , —C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R, —SR 10 , —S(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 ;

or two R 8 groups on adjacent atoms of R A are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;

R 1 is hydrogen;

R 2 and R 3 are each independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —CN, —OH, —OR 11 , —CO 2 R 10 , —C(═O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R 11 , —SR 10 , —S(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 ;

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

R 5 is —C(═O)R 6 , —C(═O)NR 6 R 7 , —C(═O)OR 6 , or R B ;

R 6 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;

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

or R 4 and R 7 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;

R B is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if R B is substituted then R B is substituted with 1, 2, 3, or 4 instances of R 9 ;

each R 9 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —CN, —OH, —OR 11 , —C(═O)R 10 , —CO 2 R 10 , —C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R 11 , —SR 10 , —S(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 ;

or two R 9 groups on adjacent atoms of R B are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle;

each R 10 is independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;

or two R 10 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; and

each R 11 is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;

wherein each substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R S groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, monocyclic carbocycle, monocyclic heterocycle, —CN, —CH 2 CN, —OR 12 , —CH 2 OR 12 , —CO 2 R 12 , —CH 2 CO 2 R 12 , —C(═O)N(R 12 ) 2 , —CH 2 C(═O)N(R 12 ) 2 , —N(R 12 ) 2 , —CH 2 N(R 12 ) 2 , —NR 12 C(═O)R 12 , —CH 2 NR 12 C(═O)R 12 , —NR 12 SO 2 R 13 , —CH 2 NR 12 SO 2 R 13 , —SR 12 , —CH 2 SR 12 , —S(═O)R 13 , —CH 2 S(═O)R 13 , —SO 2 R 13 , —CH 2 SO 2 R 13 , —SO 2 N(R 12 ) 2 , and —CH 2 SO 2 N(R 12 ) 2 ;

each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl;

or two R 12 groups are taken together with the N atom to which they are attached to form a N-containing heterocycle;

each R 13 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; and

wherein when R 5 is —C(═O)R 6 and R 6 is cyclopropyl, each R 8 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, —CN, —OH, —OR 11 , —C(═O)R 10 , —CO 2 R 10 , —C(═O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R 11 , —SR 10 , —S(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 .

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

R 2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, —OR 11 , or —N(R 10 ) 2 ;

R 3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, —OR 11 , or —N(R 10 ) 2 ; and

R 4 is hydrogen or C 1 -C 4 alkyl.

3 . The compound of claim 1 , having the structure of Formula (I):

or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

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

R 2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, —OR 11 , or —N(R 10 ) 2 ;

R 3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, —OR 11 , or —N(R 10 ) 2 ; and

R 4 is hydrogen or C 1 -C 4 alkyl.

5 . The compound of claim 3 , having the structure of Formula (II):

or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

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

R B is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle, wherein if R B is substituted then R B is substituted with 1, 2, 3, or 4 instances of R 9 .

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

R B is

where p is 0-4.

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

each R 9 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, —CN, —OH, —OR 11 , —CO 2 R 10 , —C(═O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 .

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

R 5 is —C(═O)R 6 , —C(═O)NR 6 R 7 , or —C(═O)OR 6 .

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

R 2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, —OR 11 , or —N(R 10 ) 2 ;

R 3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CN, —OH, —OR 11 , or —N(R 10 ) 2 ;

R 4 is hydrogen or C 1 -C 4 alkyl;

R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted 4- to 8-membered heterocycloalkyl; and

R 7 is hydrogen or C 1 -C 4 alkyl.

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

R A is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if R A is substituted then R A is substituted with 1, 2, 3, or 4 instances of R 8 .

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

R A is unsubstituted or substituted phenyl or unsubstituted or substituted pyridinyl, wherein if R A is substituted then R A is substituted with 1, 2, 3, or 4 instances of R 8 ;

or R A is an unsubstituted or substituted C 3 -C 7 cycloalkyl or an unsubstituted or substituted unsubstituted or substituted 4- to 8-membered heterocycloalkyl, wherein if R A is substituted then R A is substituted with 1, 2, 3, or 4 instances of R 8 .

13 . The compound of claim 1 , having the structure of Formula (VIII):

or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:

V is CH or N;

W is CH, CR 9 , or N;

p is 0-3; and

q is 0-4.

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

each R 8 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C 3 -C 7 cycloalkyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, unsubstituted or substituted 4- to 8-membered heterocycloalkyl, —CN, —OH, —OR 11 , —C(═O)R 10 , —CO 2 R 10 , —C(═O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R 11 , —SR 10 , —S(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 ;

or two R 8 groups on adjacent atoms of R A are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle.

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

each R 8 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, unsubstituted or substituted monocyclic 5-membered heteroaryl, 4- to 8-membered heterocycloalkyl, —CN, —OH, —OR 11 , —C(═O)R 10 , —CO 2 R 10 , —C(═O)N(R 10 ) 2 , —N(R 10 ) 2 , —NR 10 C(═O)R 11 , —SO 2 R 11 , or —SO 2 N(R 10 ) 2 .

16 . A compound selected from:

or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

17 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

18 . A method of treating a TYK2-mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Bechet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

19 . A method of treating an inflammatory disease or condition or autoimmune disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein the inflammatory disease or condition is selected from intestinal bowel disease, Crohn's disease, ulcerative colitis, and celiac disease: wherein the autoimmune disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, Bechet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.