Pyridinyl and fused pyridinyl triazolone derivatives

1. A compound of Formula 1,

a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:

R 1 is selected from hydrogen, halo, —CN, C 1-4 alkyl, C 1-4 haloalkyl, and —OR 14 ;

R 2 and R 3 are each independently selected from hydrogen, halo, —CN, R 6 , and R 7 , or R 2 and R 3 , together with carbon atoms to which they are attached, form a benzene ring or a pyridine ring in which the benzene ring is optionally substituted with from one to four substituents independently selected from halo, —CN, R 6 , and R 7 , and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, —CN, R 6 , and R 7 ;

R 4 has the formula

in which \ indicates a point of attachment;

L is selected from —O—, —CH 2 O—, and —N(R 4e )—;

R 4a is selected from —CH 2 R 5 and ethenyl optionally substituted with from one to three substituents independently selected from halo, cyano, and R 7 ; and

(a) R 4c is hydrogen, R 4e is selected from hydrogen and C 1-4 alkyl when L is —N(R 4e )—, and R 4b and R 4d , together with a nitrogen atom and carbon atoms to which R 4b , R 4c , and R 4d are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl; or

(b) R 4b is selected from hydrogen and C 1-4 alkyl, R 4d is hydrogen, L is —N(R 4e )—, and R 4c and R 4e , together with the carbon atoms and a nitrogen atom to which R 4c , R 4d , and R 4e are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl; or

(c) R 4d is hydrogen, R 4e is selected from hydrogen and C 1-4 alkyl when L is —N(R 4e )—, and R 4b and R 4c , together with the nitrogen and carbon atoms to which R 4b and R 4c are respectively attached, form pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl;

R 5 is selected from hydrogen, halo, and C 1-4 alkyl;

each R 6 is independently selected from —OR 8 , —N(R 8 )R 9 , —NR 8 C(O)R 9 , —NHC(O)NR 8 R 9 , —NR 8 C(O)NHR 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 )R 9 , —C(O)N(R 8 )OR 9 , —C(O)N(R 8 )S(O) 2 R 7 , —N(R 8 )S(O) 2 R 7 , —SR 8 , —S(O)R 7 , —S(O) 2 R 7 , and —S(O) 2 N(R 8 )R 9 ;

each R 7 is independently selected from

C 1-6 alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R 8 and R 9 is independently selected from

(a) hydrogen; and

(b) C 1-6 alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

and each R 14 is independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.

2. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is hydrogen.

3. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 2 and R 3 are each independently selected from hydrogen, fluoro, chloro, and methyl.

4. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a benzene ring or a pyridine ring in which the benzene ring is optionally substituted with from one to four substituents independently selected from halo, —CN, R 6 , and R 7 , and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, —CN, R 6 , and R 7 .

5. A compound, tautomer or pharmaceutically acceptable salt according to claim 4 , wherein the benzene ring or the pyridine ring is optionally substituted with one or two substituents independently selected fluoro, chloro, and methyl.

6. A compound, tautomer or pharmaceutically acceptable salt according to claim 5 , wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a benzene ring which is optionally substituted with one or two substituents independently selected fluoro, chloro, and methyl.

7. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 4a is ethenyl optionally substituted with from one to three methyl groups.

8. A compound, tautomer or pharmaceutically acceptable salt according to claim 7 , wherein R 4a is unsubstituted ethenyl.

9. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 4a is —CH 2 R 5 and R 5 is halo.

10. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 4a is hydrogen, R 4e is selected from hydrogen and C 1-4 alkyl when L is —N(R 4e )—, and R 4b and R 4d , together with the nitrogen atom and the carbon atoms to which R 4b , R 4a , and R 4d are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl.

11. A compound, tautomer or pharmaceutically acceptable salt according to claim 10 , wherein R 4b and R 4d , together with the nitrogen atom and the carbon atoms to which R 4b , R 4a , and R 4d are respectively attached, form a pyrrolidine ring which is optionally substituted with from one to four substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl.

12. A compound, tautomer or pharmaceutically acceptable salt according to claim 10 , wherein the ring formed by R 4b and R 4d , together with the nitrogen atom and the carbon atoms to which R 4b , R 4c , and R 4d are respectively attached, is unsubstituted.

13. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 4b is selected from hydrogen and C 1-4 alkyl, R 4d is hydrogen, L is —N(R 4e )—, and R 4e and R 4e , together with the carbon atoms and the nitrogen atom to which R 4c , R 4d , and R 4e are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl.

14. A compound, tautomer or pharmaceutically acceptable salt according to claim 13 , wherein R 4c and R 4e , together with the carbon atoms and the nitrogen atom to which R 4c , R 4d , and R 4e are respectively attached, form a pyrrolidine ring which is optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl.

15. A compound, tautomer or pharmaceutically acceptable salt according to claim 13 , wherein the ring formed by R 4c and R 4e , together with the carbon atoms and the nitrogen atom to which R 4c , R 4d , and R 4e are respectively attached, is unsubstituted.

16. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein R 4d is hydrogen, R 4e is selected from hydrogen and C 1-4 alkyl when L is —N(R 4e )—, and R 4b and R 4c , together with the nitrogen and carbon atoms to which R 4b and R 4c are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl.

17. A compound, tautomer or pharmaceutically acceptable salt according to claim 16 , wherein R 4b and R 4c , together with the nitrogen and carbon atoms to which R 4b and R 4c are respectively attached, form a pyrrolidine ring which is optionally substituted with from one to six substituents independently selected from halo, C 1-4 alkyl, and C 1-4 haloalkyl.

18. A compound, tautomer or pharmaceutically acceptable salt according to claim 16 , wherein the ring formed by R 4b and R 4c , together with the nitrogen and carbon atoms to which R 4b and R 4c are respectively attached, is unsubstituted.

19. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein L is —N(R 4e )—.

20. A compound, tautomer or pharmaceutically acceptable salt according to claim 1 , wherein L is selected from —O— and —CH 2 O—.

21. A compound, tautomer or pharmaceutically acceptable salt according to claim 20 , wherein L is —O—.

22. A compound which is selected from the following compounds:

(R)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(R)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(R,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

N-(1-(3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)pyrrolidin-3-yl)acrylamide;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-(((1-acryloylpyrrolidin-2-yl)methyl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(R)-3-(1-((1-acryloylpyrrolidin-2-yl)methoxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-methacryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)(methyl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-methacryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-(((1-acryloylpyrrolidin-3-yl)oxy)methyl)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S,E)-5-(1-((1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S,E)-3-(1-((1-(but-2-enoyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

3-(1-((trans-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

3-(1-(((3R,4S)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

3-(1-(((3S,4R)-1-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-methoxyisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-3-(6-((1-acryloylpyrrolidin-3-yl)oxy)-5-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one;

(S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-5-(1-((1-(2-chloroacetyl)pyrrolidin-3-yl)amino)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-5-(1-((1-acryloylpiperidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-5-(1-((1-acetylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

(S)-5-(1-((1-propionylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

a tautomer of any one of the aforementioned compounds;

a stereoisomer of any one of the aforementioned compounds or tautomers; and

a pharmaceutically acceptable salt of any one of the aforementioned compounds, tautomers or stereoisomers.

23. A pharmaceutical composition comprising:

a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1 ; and

a pharmaceutically acceptable excipient.

24. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

25. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

26. A compound according to claim 1 , which is (S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

27. A compound according to claim 1 , which is (S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

28. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

29. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

30. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

31. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

32. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

33. A compound according to claim 1 , which is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

34. A combination comprising an effective amount of a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1 , and at least one additional pharmacologically active agent.

35. A combination according to claim 34 , wherein the additional pharmacologically active agent is a disease modifying antirheumatic drug (DMARD).

36. A combination according to claim 35 , wherein the DMARD is methotrexate.