PYRIDINYL AND FUSED PYRIDINYL TRIAZOLONE DERIVATIVES

• US 20140256734A1
• Filed: 03/10/2014
• Published: 09/11/2014
• Est. Priority Date: 03/11/2013
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Lawson, John David, Sabat, Mark, Scorah, Nicholas, Smith, Christopher, Vu, Phong H., Wang, Haixia
• Granted Patent: US 9,402,841 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are compounds of Formula 1,

or pharmaceutically acceptable salts thereof, wherein R¹, R², R³, and R⁴ are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, non-malignant proliferative disorders, and other conditions associated with BTK.

Claims

1. A compound of Formula 1,

2. A compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R¹ is hydrogen.

3. A compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R² and R³ are each independently selected from hydrogen, fluoro, chloro, and methyl.

4. A compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein R² and R³, 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, R⁶, and R², and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, —

CN, R⁶, and R².

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 R² and R³, together with the carbon atoms to which they are attached, form a benzene ring which is optionally substituted.

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 —

CH₂R⁵ and R⁵ is halo.

10. A compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein 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 the nitrogen atom and the 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.

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^4c, 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.

13. 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.

14. 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^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 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.

15. A compound, tautomer or pharmaceutically acceptable salt according to claim 14, 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.

17. A compound, tautomer or pharmaceutically acceptable salt according to claim 14, 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.

18. 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.

19. A compound, tautomer or pharmaceutically acceptable salt according to claim 18, 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.

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

22. A compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein L is —

N(R^4e)—

.

23. A compound, tautomer or pharmaceutically acceptable salt according to claim 1, wherein L is selected from —

O— and

—

CH₂O—

.

24. A compound, tautomer or pharmaceutically acceptable salt according to claim 23, wherein L is —

O—

.

25. A compound according to claim 1, 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.

26. A pharmaceutical composition comprising:

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

a pharmaceutically acceptable excipient.

28. A method for inhibiting BTK in a subject, the method comprising administering to the subject a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1.

29. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is associated with BTK.

30. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is selected from Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, and non-malignant proliferative disorders.

31. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Sjö

gren'"'"'s syndrome, ankylosing spondylitis, Behcet'"'"'s disease, graft versus host disease, pemphigus vulgaris, idiopathic plasmacytic lymphadenopathy, atherosclerosis, myocardial infarction, and thrombosis.

32. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound, tautomer or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is selected from B-cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

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

34. A combination according to claim 33, wherein the additional pharmacologically active agent is a disease modifying antirheumatic drug (DMARD).

35. A combination according to claim 34, wherein the DMARD is methotrexate.

12. (canceled)

16. (canceled)

20. (canceled)

27. (canceled)