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1. WO2014164558 - PYRIDINYL AND FUSED PYRIDINYL TRIAZOLONE DERIVATIVES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

WHAT IS CLAIMED IS:

1. A compound of Formula 1,


1

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

wherein:

R1 is selected from hydrogen, halo, -CN, C1-4 alkyl, C1-4 haloalkyl, and -OR14;

R2 and R3 are each independently selected from hydrogen, halo, -CN, R6, and R7, or R2 and R3, 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, R6, and R7, and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, -CN, R6, and R7;

R4 has the formula


in which indicates a point of attachment;

L is selected from -0-, -CH20-, and -N(R4e)-;

R4a is selected from -CH2R5 and ethenyl optionally substituted with from one to three substituents independently selected from halo, cyano, and R7; and

(a) R4c is hydrogen, R4e is selected from hydrogen and C1-4 alkyl when L is -N(R4e)-, and R4b and R4d, together with a nitrogen atom and carbon atoms to which R4b, R4c, and R4d 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, C1-4 alkyl, and C1-4 haloalkyl; or

(b) R4b is selected from hydrogen and C1-4 alkyl, R4d is hydrogen, L is -N(R4e)-, and

R4c and R4e, together with the carbon atoms and a nitrogen atom to which R4c, R4d, and R4e 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, C1-4 alkyl, and C1-4 haloalkyl; or

(c) R4d is hydrogen, R4e is selected from hydrogen and C1-4 alkyl when L is -N(R4e)-, and R4b and R4c, together with the nitrogen and carbon atoms to which R4b and R4c are respectively attached, form pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl;

R5 is selected from hydrogen, halo, and C1-4 alkyl;

each R6 is independently selected from -OR8, -N(R8)R9, -NR8C(0)R9, -NHC(0)NR8R9, -NR8C(0)NHR9, -C(0)R8, -C(0)OR8, -C(0)N(R8)R9, -C(0)N(R8)OR9,

-C(0)N(R8)S(0)2R7, -N(R8)S(0)2R7, -SR8, -S(0)R7, -S(0)2R7, and -S(0)2N(R8)R9; each R7 is independently selected from

(a) Ci-6 alkyl, C2_6 alkenyl, and C2_6 alkynyl, each optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, and R10; and

(b) C3-10 cycloalkyl-(CH2)m-, C6-i4 aryl-(CH2)m-, C2_6 heterocyclyl-(CH2)m-, and

Ci-9 heteroaryl-(CH2)m-, each optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, R10, and Ci_6 alkyl optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, and R10;

each R8 and R9 is independently selected from

(a) hydrogen;

(b) Ci-6 alkyl, C2_6 alkenyl, and C2_6 alkynyl, each optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, and R10; and

(c) C3-10 cycloalkyl-(CH2)m-, C6-i4 aryl-(CH2)m-, C2_6 heterocyclyl-(CH2)m-, and

Ci-9 heteroaryl-(CH2)m-, each optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, R10, and Ci_6 alkyl optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, and R10;

each R10 is independently selected from -OR11, -N(Rn)R12, -N(Rn)C(0)R12,

-NHC(0)NRnR12, -NR11 C(0)NHR12, -C(0)Rn, -C(0)ORn, -C(0)N(Rn)R12, -C(0)N(Rn)OR12, -C(0)N(Rn)S(0)2R13, -NRnS(0)2R13, -SR11, -S(0)R13, -S(0)2R13, and -S(0)2N(Rn)R12;

each R11 and R12 is independently selected from

(a) hydrogen; and

(b) Ci-6 alkyl and C3-10 cycloalkyl-(CH2)m-, each optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, -OH, and -NH2;

each R13 is independently selected from Ci_6 alkyl and C3-10 cycloalkyl-(CH2)m-, each

optionally substituted with from one to five substituents independently selected from halo, oxo, -CN, -OH, and -NH2;

each R14 is independently selected from hydrogen, C1-4 alkyl, and C1-4 haloalkyl; and each m is independently selected from 0, 1, 2, 3, and 4;

wherein each heteroaryl and heterocyclyl of R7, R8, and R9 independently has one to four heteroatoms, each of the heteroatoms independently selected from N, O, and S.

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 any one of claims 1 and 2, wherein R2 and R3 are each independently selected from hydrogen, fluoro, chloro, and methyl.

4. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 and 2, 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 R7, and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, -CN, R6, and R7.

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 any one of claims 4 and 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 any one of the preceding claims, wherein R4a is ethenyl optionally substituted with from one to three methyl groups.

8. A compound, tautomer or pharmaceutically acceptable salt according to claim 7, wherein R4a is unsubstituted ethenyl.

9. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein R4a is -CI¾R5 and R5 is halo.

10. A compound, tautomer or pharmaceutically acceptable salt according to any one of the preceding claims, wherein R4c is hydrogen, R4e is selected from hydrogen and C1-4 alkyl when L is -N(R4e)-, and R4b and R4d, together with the nitrogen atom and the carbon atoms to which R4b, R4c, and R4d 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, Ci-4 alkyl, and C1-4 haloalkyl.

11. A compound, tautomer or pharmaceutically acceptable salt according to claim 10, wherein R4b and R4d, together with the nitrogen atom and the carbon atoms to which R4b, R4c, and R4d are respectively attached, form a pyrrolidine ring which is optionally substituted with from one to four substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl.

12. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R4c is hydrogen, R4e is hydrogen when L is -N(R4e)-, and R4b and R4d, together with the nitrogen atom and the carbon atoms to which R4b, R4c, and R4d are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to four substituents independently selected from halo, C1-4 alkyl, and Ci-4 haloalkyl.

13. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 10-12, wherein the ring formed by R4b and R4d, together with the nitrogen atom and the carbon atoms to which R4b, R4c, and R4d are respectively attached, is unsubstituted.

14. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R4b is selected from hydrogen and C1-4 alkyl, R4d is hydrogen, L is -N(R4e)-, and R4c and R4e, together with the carbon atoms and the nitrogen atom to which R4c, R , and R e 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, Ci-4 alkyl, and C1-4 haloalkyl.

15. A compound, tautomer or pharmaceutically acceptable salt according to claim 14, wherein R4c and R4e, together with the carbon atoms and the nitrogen atom to which R4c, R4d, and R4e are respectively attached, form a pyrrolidine ring which is optionally substituted with from one to six substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl.

16. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R4b is hydrogen, R4d is hydrogen, L is -N(R4e)-, and R4c and R4e, together with the carbon atoms and the nitrogen atom to which R4c, R4d, and R4e are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to four substituents independently selected from halo, Ci-4 alkyl, and Ci-4 haloalkyl.

17. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 14-16, wherein the ring formed by R4c and R4e, together with the carbon atoms and the nitrogen atom to which R4c, R4d, and R4e are respectively attached, is unsubstituted.

18. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R4d is hydrogen, R4e is selected from hydrogen and C1-4 alkyl when L is -N(R4e)-, and R4b and R4c, together with the nitrogen and carbon atoms to which R4b and R4c 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, Ci-4 alkyl, and Ci-4 haloalkyl.

19. A compound, tautomer or pharmaceutically acceptable salt according to claim 18, wherein R4b and R4c, together with the nitrogen and carbon atoms to which R4b and R4c are respectively attached, form a pyrrolidine ring which is optionally substituted with from one to six substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl.

20. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R4d is hydrogen, R4e is hydrogen when L is -N(R4e)-, and R4b and R4c, together with the nitrogen and carbon atoms to which R4b and R4c are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to four substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl.

21. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 18-20, wherein the ring formed by R4b and R4c, together with the nitrogen and carbon atoms to which R4b and R4c are respectively attached, is unsubstituted.

22. A compound, tautomer or pharmaceutically acceptable salt according to any one of the preceding claims, wherein L is -N(R4e)-.

23. A compound, tautomer or pharmaceutically acceptable salt according to any one of claims 1-13 and 18-21, wherein L is selected from -O- and -CH20-.

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;

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

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

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

(5)-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;

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

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

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

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

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

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

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

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

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

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

3 -( 1 -(((3R,45)- 1 -acryloyl-4-methylpyrrolidin-3 -yl)oxy)isoquinolin-3 -yl)- IH- 1 ,2,4- triazol-5(4H)-one;

3-(l-(((35',4R)-l-acryloyl-4-methylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-lH-l,2,4- triazol-5(4H)-one;

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

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

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

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

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

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

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

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

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

(5)-3 -(6-(( 1 -acryloylpyrrolidin-3 -yl)oxy)pyridin-2-yl)- IH- 1 ,2,4-triazol-5 (4H)-one; (5)-3-(6-((l-acryloylpyrrolidin-3-yl)oxy)-5-methylpyridin-2-yl)-lH-l,2,4-triazol- 5(4H)-one;

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

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

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

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

(5)-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 any one of claims 1-25; and

a pharmaceutically acceptable excipient.

27. A compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1-25, for use as a medicament.

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 any one of claims 1-25.

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 any one of claims 1-25, 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 any one of claims 1-25, 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 any one of claims 1-25, 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, Sj5gren'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 any one of claims 1-25, wherein the disease, disorder or condition is selected from B-cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

33. A combination of an effective amount of a compound, tautomer or pharmaceutically acceptable salt as defined in any one of claims 1-25, 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.