Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors

1. A compound of Formula (XVII):

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

Z is —NR 10 — or —O—;

X 1 is CR 11 or N;

X 2 is CR 11 or N;

X 3 is CR 11 or N;

B 1 is N or CR 12a ;

B 2 is N or CR 12b ;

R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 ;

or R 2 is —C(═O)R 14 , —C(═O)NR 14 R 15 , or —C(═O)OR 14 ;

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

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

each R 7 is independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl;

or one R 6 and one R 7 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form —C(═O)— or C 3 -C 4 cycloalkyl;

each R 8 is independently hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 deuteroalkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR 17 , —C(═O)R 16 , C(═O)OR 16 , or —C(═O)N(R 16 ) 2 ;

wherein each substituted C 1 -C 6 alkyl and substituted C 1 -C 6 deuteroalkyl is independently substituted with one or two groups independently selected from halogen , —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 3 , and —OCF 3 ; and

wherein each substituted carbocyclyl and substituted heterocyclyl is independently substituted with one or two groups independently selected from halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;

R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or a monocyclic heterocyclyl;

each R 11 is independently hydrogen, halogen, C 1 -C 6 fluoroalkyl, —CN, —OH, —OR 17 , or —N(R 16 ) 2 ;

R 12a is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN;

R 12b is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or —CN;

each R 13 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, —CN, —OH, —OR 17 , —C(═O) 16 , —C(═O)OR 16 , —C(═O)N(R 16 ) 2 , —N(R 16 ) 2 , —NR 16 C(═O)R 17 , —S(═O) 2 R 17 , or —S(═O) 2 N(R 16 ) 2 ;

wherein each substituted C 1 -C 6 alkyl is independently substituted with one or two groups independently selected from halogen, —NC, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —OCH 3 , —OCHF 2 , and —OCF 3 ; and

wherein each substituted carbocyclyl and substituted heterocyclyl is independently substituted with one or two groups independently selected from halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;

R 14 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein each substituted C 1 -C 6 alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more groups independently selected from the group consisting of deuterium, halogen, —CN, —NH 2 , —OH, —NH(CH 3 ), —N(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCHF 2 , and —OCF 3 ;

R 15 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;

each R 16 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl;

or two R 16 on the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered nitrogen-containing heterocycloalkyl;

each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl;

n is 1 or 2; and

q is 1 or 2;

with the provisos that:

(i) if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, —C(═O)R 16 , —C(═O)OR 16 , or —C(═O)N(R 16 ) 2 ; and

(ii) the compound of Formula (XVII) is not selected from the group consisting of: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-methylpyridazine-3-carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide, and 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-methylnicotinamide.

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

(i) X 1 is CR 11 ;

X 2 is CR 11 ; and

X 3 is CR 11 ; or

(ii) X 1 is CR 11 ;

X 2 is CR 11 ; and

X 3 is N; or

(iii) X 1 is CR 11 ;

X 2 is N; and

X 3 is CR 11 ; or

(iv) X 1 is N;

X 2 is CR 11 ; and

X 3 is CR 11 .

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

X 1 is CR 11 ;

X 2 is CR 11 ;

X 3 is CR 11 ; and

each R 11 is independently hydrogen or F.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 8 is independently hydrogen, —Cl, —F, CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CD 3 , —CH 2 OH, —CF 3 , cyclopropyl, oxetanyl, azetidinyl, —C(═O)OH, or —C(═O)OCH 3 ; with the proviso that if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CD 3 , —CH 2 OH, —CF 3 , cyclopropyl, oxetanyl, azetidinyl, —C(═O)OH, or —C(═O)OCH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 8 is independently hydrogen, —CH 3 , —CD 3 , —OH, —CH 2 OH, —CF 3 , oxetanyl, —CN, or —C(═O)OCH 3 ; with with the proviso that if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, —CH 3 , —CD 3 , —CH 2 OH, oxetanyl, or —C(═O)OCH 3 .

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

Z is —NR 10 —;

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

each R 7 is independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; and

R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 is —C(═O)R 14 , —C(═O)NR 14 R 15 , or —C(═O)OR 14 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 is —C(═O)R 14 .

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

(i) B 1 is CR 12a ; and

B 2 is CR 12b ; or

(ii) B 1 is N; and

B 1 is CR 12b ; or

(iii) B 1 is CR 12a ; and

B 2 is N; or

(iv) B 1 is N; and

B 2 is N.

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

(i) B 1 is CH; and

B 2 is CH; or

(ii) B 1 is N; and

B 2 is CH.

12. The compound of claim 1 , wherein the compound is a compound of Formula (VIa-1):

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

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

B 1 is CH; and

B 2 is CH; or

(ii) B 1 is N; and

B 2 is CH; and

Z is —NR 10 —;

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

each R 7 is independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl;

each R 8 is independently hydrogen, —CH 3 , —CD 3 , —OH, —CH 2 OH, —CF 3 , oxetanyl, —CN, or —C(═O)OCH 3 ;

R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl; and

each R 11 is independently hydrogen or F;

with the proviso that if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, —CH 3 , —CD 3 , —CH 2 OH, oxetanyl, or —C(═O)OCH 3 .

14. The compound of claim 13 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted, then Ring B is substituted with q instances of R 13 .

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

R 2 is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted, then Ring B is substituted with q instances of R 13 ;

each R 13 is independently —F, —Cl, —CH 3 , or —CF 3 .

16. The compound of claim 13 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 is —C(═O)R 14 .

17. The compound of claim 16 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 14 is —CH 3 , —CD 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —CH 2 CF 3 , cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,

18. The compound of claim 1 , wherein the compound is selected from the group consisting of:

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

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

20. A method of inhibiting tyrosine-protein kinase 2 activity in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

21. The method of claim 20 , wherein the patient has a tyrosine-protein kinase 2 mediated disease or condition selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, Sjogen'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.