Pyrazolopyrimidine derivatives as inhibitors of nlrp3

Abstract

The invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein L, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the specification, for treatment of a disease, disorder or condition associated with NLRP3, including a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene such as cryopyrin-associated periodic syndrome (CAPS).

Description

Abstract This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in this specification, for the treatment of diseases, conditions or disorders associated with NLRP3, including diseases, conditions or disorders associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cold pyridine-associated periodic syndrome (CAPS).

Claims

WHAT IS CLAIMED IS 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein L is O or a bond; X is N or CR4; Y is N or CR5; R1is an optionally substituted C1-6alkyl group, an optionally substituted C3-8cycloalkyl group, an optionally substituted C6-14 aryl group, or an optionally substituted 4- to 6- membered heterocyclic group with the proviso that when L is a bond, then the 4- to 6- membered heterocyclic group is a 4- to 6-membered non-aromatic heterocyclic group which is linked to the pyrazolopyrimidone ring by a carbon-carbon bond; R2is a hydrogen atom, an optionally substituted C1-6 alkyl group, or an optionally substituted C3-8cycloalkyl group; R3is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, or a halogen atom; and R4, R5, R6, R7and R8are each independently a hydrogen atom, an optionally substituted C1-6alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C2-6 alkenyl group, a halogen atom, a hydroxy group, an optionally substituted C1-6 alkoxy group, or an optionally substituted 5- or 6-membered heterocyclic group a cyano group, an amino group or a nitro group; 151 55419591.1with the proviso that (1) 2,5-dihydro-6-methyl-5-(1-methylethyl)-2-(3-pyridinyl)-4H- pyrazolo[3,4-d]pyrimidin-4-one, (2) 5-ethyl-2,5-dihydro-6-methyl-2-(3-pyridinyl)-4H- pyrazolo[3,4-d]pyrimidin-4-one and (3) 5-ethyl-2,5-dihydro-2-(3-pyridinyl)-6- (trifluoromethyl)-4H-pyrazolo[3,4-d]pyrimidin-4-one are excluded.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is O or a bond; X is N or CR4; Y is N or CR5; R1is (1) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a hydroxy group, (c) an optionally halogenated C1-6 alkoxy group, (d) a di-C1-6alkylamino group, (e) a C7-16aralkyloxy group, (f) a 5- or 6-membered aromatic heterocyclic group, (g) a 5- or 6-membered non-aromatic heterocyclic group, (h) a carboxy group, (i) a 4- to 6-membered non-aromatic heterocyclyloxy group, and (j) a cyano group, (2) a C3-8cycloalkyl group optionally substituted by 1 to 3 substituents selected from (a) a C1-6alkyl group, (b) a C1-6 alkoxy group, (c) a halogen atom, (d) a cyano group, and (e) a group represented by the formula: -(CH2)a-O-(CH2)b-, wherein each of a and b is the integer of 0 to 3 and the sum of a and b is 2 to 4, (3) a C6-14aryl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, and (b) a C1-6 alkoxy group, (4) a 5- or 6-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from 152 55419591.1(a) a halogen atom, (b) a C1-6alkyl group optionally substituted by 1 to 3 substituents selected (i) halogen atom and (ii) C1-6alkoxy group, (c) a C1-6 alkoxy group, and (d) a group represented by the formula: -(CH2)a-O-(CH2)b-, together with the 5- or 6-membered aromatic heterocyclic group to which it is attached, forming a fused 8- to 10-membered heterocyclic group, wherein each of a and b is the integer of 0 to 3 and the sum of a and b is 2 to 4, or (5) a 4- to 6-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (a) an oxo group, (b) a C1-6 alkyl group, (c) a halogen atom, and (d) a C1-6 alkoxy group; R2is (1) a hydrogen atom, or (2) a C1-6 alkyl group; R3is (1) a hydrogen atom, (2) a C1-6alkyl group, or (3) a halogen atom; R4and R8are each independently (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 4 substituents selected from (i) halogen atoms, (ii) hydroxy group, and (iii) C1-6 alkoxy group, (3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (4) a halogen atom, (5) a hydroxy group, (6) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, (7) a 5- or 6-membered aromatic heterocyclic group, or (8) a cyano group; 153 55419591.1R5and R7are each independently (1) a hydrogen atom, (2) a C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a halogen atom, or (4) a C3-8 cycloalkyl group; and R6is (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a C3-8cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (4) a C2-6 alkenyl group, (5) a halogen atom, (6) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, (7) a 5- or 6-membered aromatic heterocyclic group, (8) an amino group, or (9) a nitro group.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is O or bond; X is CR4; Y is CR5; R1is a C1-6 alkyl group optionally substituted by an optionally halogenated C1-6 alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4and R8are each independently (1) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or (2) a halogen atom; R5and R7are both hydrogen atoms; and R6is (1) a C3-8cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (2) a halogen atom, or (3) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein 154 55419591.1L is O; X is N or CR4; Y is N or CR5; R1is an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-14 aryl group, or an optionally substituted 4- to 6- membered heterocyclic group; R2is a hydrogen atom, or an optionally substituted C1-6 alkyl group; R3is a hydrogen atom, an optionally substituted C1-6 alkyl group, or a halogen atom; R4and R8are each independently a hydrogen atom, an optionally substituted C1-6alkyl group, an optionally substituted C3-8 cycloalkyl group, a halogen atom, a hydroxy group, an optionally substituted C1-6 alkoxy group, an optionally substituted 5- or 6-membered heterocyclic group or a cyano group; R5and R7are each independently a hydrogen atom, an optionally substituted C1-6alkyl group, or a halogen atom; and R6is a hydrogen atom, an optionally substituted C1-6alkyl group, an optionally substituted C3-8cycloalkyl group, an optionally substituted C2-6alkenyl group, a halogen atom, an optionally substituted C1-6 alkoxy group, or an optionally substituted 5- or 6-membered heterocyclic group.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is O; X is N or CR4; Y is N or CR5; R1is (1) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a hydroxy group, (c) an optionally halogenated C1-6 alkoxy group, (d) a di-C1-6alkylamino group, and (e) a C7-16 aralkyloxy group, (2) a C3-8 cycloalkyl group optionally substituted by 1 to 3 substituents selected from (a) a C1-6 alkoxy group, (b) a cyano group, and 155 55419591.1(c) a group represented by the formula: -(CH2)a-O-(CH2)b-, wherein each of a and b is the integer of 0 to 3 and the sum of a and b is 2 to 4, (3) a C6-14aryl group, or (4) a 4- to 6-membered non-aromatic heterocyclic group; R2is (1) a hydrogen atom, or (2) a C1-6 alkyl group; R3is (1) a hydrogen atom, (2) a C1-6 alkyl group, or (3) a halogen atom; R4and R8are each independently (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 4 substituents selected from (i) halogen atoms, (ii) hydroxy group, and (iii) C1-6 alkoxy group, (3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (4) a halogen atom, (5) a hydroxy group, (6) a C1-6 alkoxy group, (7) a 5- or 6-membered aromatic heterocyclic group, or (8) a cyano group; R5and R7are each independently (1) a hydrogen atom, (2) a C1-6alkyl group, or (3) a halogen atom; and R6is (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (4) a C2-6 alkenyl group, (5) a halogen atom, 156 55419591.1(6) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, or (7) a 5- or 6-membered aromatic heterocyclic group.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is O; X is CR4; Y is CR5; R1is a C1-6 alkyl group optionally substituted by 1 to 3 C1-6 alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4and R8are each independently (1) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or (2) a halogen atom; R5and R7are both hydrogen atoms; and R6is (1) a C3-8cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (2) a halogen atom, or (3) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is O; X is CR4; Y is CR5; R1is a C1-6 alkyl group; R2is a hydrogen atom; R3is a hydrogen atom; R4and R8are both C1-6 alkyl groups; R5and R7are both hydrogen atoms; and R6is a C3-8cycloalkyl group.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is a bond; X is N or CR4; 157 55419591.1Y is N or CR5; R1is an optionally substituted C1-6alkyl group, an optionally substituted C3-8cycloalkyl group, an optionally substituted C6-14aryl group, or an optionally substituted 4- to 6- membered non-aromatic heterocyclic group; R2is a hydrogen atom, or an optionally substituted C1-6 alkyl group; R3is a hydrogen atom, an optionally substituted C1-6alkyl group, or a halogen atom; R4and R8are each independently a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, a halogen atom, a hydroxy group, an optionally substituted C1-6alkoxy group, an optionally substituted 5- or 6-membered heterocyclic group or a cyano group; R5and R7are each independently a hydrogen atom, an optionally substituted C1-6 alkyl group, a halogen atom, or an optionally substituted C3-8 cycloalkyl group; and R6is a hydrogen atom, an optionally substituted C1-6alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C2-6 alkenyl group, a halogen atom, an optionally substituted C1-6alkoxy group, an optionally substituted 5- or 6-membered heterocyclic group, an amino group, or a nitro group.

9. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is a bond; X is CR4; Y is CR5; R1is (1) a C1-6alkyl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a hydroxy group, (c) an optionally halogenated C1-6alkoxy group, (d) a C7-16 aralkyloxy group, (e) a 5- or 6-membered aromatic heterocyclic group, (f) a 5- or 6-membered non-aromatic heterocyclic group, (g) a carboxy group, (h) a 4- to 6-membered non-aromatic heterocyclyloxy group, and (i) a cyano group, (2) a C3-8cycloalkyl group optionally substituted by 1 to 3 substituents selected from 158 55419591.1(a) a C1-6 alkyl group, (b) a C1-6alkoxy group, (c) a halogen atom, and (d) a cyano group, (3) a C6-14 aryl group optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, and (b) a C1-6 alkoxy group, or (4) a 4- to 6-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (a) an oxo group, (b) a C1-6 alkyl group, (c) a halogen atom, and (d) a C1-6alkoxy group; R2is (1) a hydrogen atom, or (2) a C1-6alkyl group; R3is (1) a hydrogen atom, or (2) a C1-6alkyl group; R4and R8are each independently (1) a hydrogen atom, (2) a C1-6alkyl group optionally substituted by 1 to 4 halogen atoms, (3) a halogen atom, (4) a hydroxy group, or (5) a C1-6 alkoxy group; R5and R7are each independently (1) a hydrogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a halogen atom, or (4) a C3-8 cycloalkyl group; and R6is (1) a hydrogen atom, (2) a C1-6alkyl group 159 55419591.1(3) a C3-8 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, (4) a halogen atom, (5) an amino group, or (6) a nitro group.

10. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L is bond; X is CR4; Y is CR5; R1is a C1-6 alkyl group optionally substituted by an optionally halogenated C1-6 alkoxy group; R2is a hydrogen atom; R3is a hydrogen atom; R4and R8are both C1-6alkyl groups optionally substituted by 1 to 3 halogen atoms; R5and R7are both hydrogen atoms; and R6is a C3-8cycloalkyl group.

11. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4- one; 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one; 2-[2-bromo-4-(difluoromethoxy)-6-methylphenyl]-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one; 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin- 4-one; 2-[4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl]-6-(2-methoxyethoxy)-2,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one; 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-[(difluoromethoxy)methyl]-2,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one; 2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one; and 160 55419591.12-[4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl]-6-(methoxymethyl)-2,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one.

12. A method of treating a disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is associated with NLRP3.

13. A method of treating a disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1, wherein the disease, disorder or condition is associated with a heterozygous gain of function mutation in the NLRP3 gene.

14. A method of treating a cryopyrin-associated periodic syndrome (CAPS) in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1.

15. The method according to claim 14, wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

16. A method of treating a neurodegenerative disease, disorder or condition in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1.

17. A method of treating Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or prion disease in a subject, which comprises administering to the subject an effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1. 161 55419591.

118. A medicament comprising a compound or pharmaceutically acceptable salt as defined in claim 1.

19. The medicament according to claim 18, which is an agent for the treatment of disease, disorder or condition associated with NLRP3.

20. The medicament according to claim 18, which is an agent for the treatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

21. The medicament according to claim 18, which is an agent for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

22. The medicament according to claim 21, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

23. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of disease, disorder or condition associated with NLRP3.

24. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene. 162 55419591.

125. Use of a compound or pharmaceutically acceptable salt thereof as defined in claim 1 for the manufacture of a medicament for the treatment of a cryopyrin-associated periodic syndrome (CAPS).

26. The use according to claim 25 wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle- Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

27. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a disease, disorder or condition associated with NLRP3.

28. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a disease, disorder or condition associated with a heterozygous gain of function mutation in the NLRP3 gene.

29. A compound or pharmaceutically acceptable salt thereof as defined in claim 1 for use in treating a cryopyrin-associated periodic syndrome (CAPS).

30. The compound according to claim 29, wherein the cryopyrin-associated periodic syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS). 163 55419591.1