Piperidine and azepine derivatives as prokineticin receptor modulators

• US 9,790,201 B2
• Filed: 08/07/2014
• Issued: 10/17/2017
• Est. Priority Date: 08/08/2013
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Bousba, Sarah, Goldby, Anne, Jenkins, Kerry, Kinsella, Natasha, Teall, Martin
• Primary Examiner(s): Coleman, Brenda
• Application Number:
  US14/910,377
• Publication Number:
  US 20160185752A1
• Time in Patent Office: 1,167 Days
• Field of Search: 51421704, 51421705, 51425203, 514318, 514326, 514332, 540597, 540598, 544238, 546194, 546211, 546262
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof (Formula (I)) in which m, X, R¹, R², R³ and R⁵ are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Claims

1. A compound of formula

2. A compound according to claim 1, wherein R¹ represents a C₅-C₁₀ aryl group which is optionally substituted by at least one substituent independently selected from halogen, cyano, C₁-C₂ alkyl, C₁-C₂ haloalkyl, C₁-C₂ alkoxy and C₁-C₂ haloalkoxy.

3. A compound according to claim 1, wherein, in R¹, the aryl group is phenyl.

4. A compound according to claim 1, wherein R² represents a hydrogen atom and R³ represents a hydrogen atom.

5. A compound according to claim 1, wherein m is 1.

6. A compound according to claim 1, wherein R⁴ represents a hydrogen atom.

7. A compound according to claim 1, wherein R⁵ represents a 5- to 6-membered heteroaryl group comprising a pyrindinyl group, a pyridazinyl group or a pyrazolyl group, the heteroaryl group being optionally substituted by at least one substituent independently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, —

NR¹⁰R¹¹ or C₃-C₆ cycloalkyl.

8. A compound according to claim 1, wherein the R⁵ heteroaryl group is selected from 4-pyridinyl, 4-pyridazinyl and 4-pyrazolyl.

9. A compound according to claim 1, wherein R¹⁰ and R¹¹ each independently represent a hydrogen atom or a C₁-C₃ alkyl or cyclopropyl group.

10. A compound according to claim 9, wherein R¹⁰ and R¹¹ each represent a hydrogen atom when the R⁵ heteroaryl group is 5-membered, or, wherein one of R¹⁰ and R¹¹ represents a hydrogen atom and the other of R¹⁰ and R¹¹ represents a C₁-C₃ alkyl group when the R⁵ heteroaryl group is 6-membered.

12. A process for the preparation of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof which comprises

(i) reacting a compound of formula

13. A pharmaceutical composition comprising a compound according to claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents.

14. A method for the treatment of schizophrenia, comprising administering to a patient in need thereof, a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. A method for the treatment of dementia or impaired learning, comprising administering to a patient in need thereof, a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for the treatment of pain, comprising administering to a patient in need thereof, a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1, wherein the compound comprises a racemic mixture of 5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 1, wherein the compound comprises 5-{[(3R)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine or a pharmaceutically acceptable salt thereof.

20. A compound according to claim 1, wherein the compound comprises a racemic mixture of 4-({3- [4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or a pharmaceutically acceptable salt thereof.

22. A compound according to claim 1, wherein the compound comprises 4-({(3R)-3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or a pharmaceutically acceptable salt thereof.

23. A compound according to claim 1, wherein the compound comprises 4-({(3S)-3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or a pharmaceutically acceptable salt thereof.

11. A compound being selected from:

4-{[3-(2-Fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(2,4-Dichlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-cyclopropylpyridine,

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-ethylpyridine,

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-methylpyridine,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-2-ethylpyridine,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N-(propan-2-yl)pyridin-2-amine,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-2-methoxypyridine,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-2-methylpyridine,

N-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine,

2-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

N,N-Dimethyl-4-{[3-(3-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine,

N,N-Dimethyl-4-{[3-(2-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine,

N,N-Dimethyl-4-[(3-phenylpiperidin-1-yl)carbonyl]pyridin-2-amine,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[(3 S)-3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[(3R)-3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

2-Ethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

2-(Azetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

2-(Azetidin-1-yl)-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine,

2-(Azetidin-1-yl)-4-{[3-(2-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Chloro-2-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(2-Chloro-4-fluorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2,6-dimethylpyridine,

2-Chloro-4-{[3-(4-chlorophenyl)piperidin-1-yl]carbonyl}pyridine,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-(propan-2-yl)pyridine,

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-2-methoxypyridine,

2-(Azetidin-1-yl)-4-{[3-(4-chloro-2-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

2-Methoxy-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

4-{[3-(4-Methylphenyl)piperidin-1-yl]carbonyl}-2-(pyrrolidin-1-yl)pyridine,

4-{[(3S)-3-(3-Methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

N-Ethyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine,

2-(3,3-Difluoroazetidin-1-yl)-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridine,

N-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}-N-propylpyridin-2-amine,

N-Methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}-N-(propan-2-yl)pyridin-2-amine,

1-(4-{[3-(4-Methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-yl)azetidin-3-ol,

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-ethoxypyridine,

N-Cyclopropyl-N-methyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine,

N,N-Dimethyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine,

N,N-Dimethyl-4-({3-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine,

4-{[3-(2-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(2-Methoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

N,N-Dimethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine,

N,N-Dimethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (R Enantiomer),

N,N-Dimethyl-4-{[3-(4-methylphenyl)piperidin-1-yl]carbonyl}pyridin-2-amine (S Enantiomer),

4-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-2-ethylpyridine,

N-Methyl-4-({3-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine,

N-Methyl-4-({3-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine,

4-{[3-(4-Methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-{[3-(2-Methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridin-2-amine,

2-Ethyl-4-({3-[2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridine,

2-Ethyl-4-{[3-(2-methoxyphenyl)piperidin-1-yl]carbonyl}pyridine,

N,N-Dimethyl-4-({3-[2-(trifluoromethoxy)phenyl]piperidin-1-yl}carbonyl)pyridin-2-amine,

4-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridin-2-amine,

4-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-({3-[2-(Difluoromethoxy)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridin-2-amine,

2-(1-{[2-(Dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-yl)benzonitrile,

4-{[3-(4-Chloro-2,6-dimethylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

5-{[3-(4-Chlorophenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine,

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine,

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[(3R)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[(3S)-3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-3-methoxypyridazine,

5-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridazin-3-amine,

5-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine,

3-(Azetidin-1-yl)-5-({3-[4-chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)pyridazine,

5-({3-[2-Methoxy-4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine,

5-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine,

5-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N-methylpyridazin-3-amine,

5-({3-[4-Methoxy-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-N,N-dimethylpyridazin-3-amine,

5-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[3-(4-Chloro-2-ethoxyphenyl)piperidin-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine,

5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-3-methylpyridazine,

5-{[3-(2-Methoxyphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine,

3-(4-Chloro-2-methylphenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-(4-Chlorophenyl)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-(4-Chlorophenyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-(4-Chlorophenyl)-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-(4-Chlorophenyl)-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine,

3-(4-Chloro-2-methylphenyl)-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-(4-Chloro-2-methylphenyl)-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine,

3-(4-Chloro-2-methylphenyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine,

4-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-amine,

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1H-pyrazol-4-yl)carbonyl]piperidine,

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidine,

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-{[1-(propan-2-yl)-1H-pyrazol-4-yl]carbonyl}piperidine,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine,

1-[(1,3-Dimethyl-1H-pyrazol-4-yl)carbonyl]-3-(4-methoxy-2-methylphenyl)piperidine,

4-{[3-(4-Methoxy-2-methylphenyl)piperidin-1-yl]carbonyl}-1-methyl-1H-pyrazol-3-amine,

3-[4-Chloro-2-(trifluoromethyl)phenyl]-1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]piperidine,

4-{[5-(4-Chlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[5-(4-Chloro-2-methylphenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[5-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydropyridin-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

N,N-Dimethyl-4-[(3-phenylazepan-1-yl)carbonyl]pyridin-2-amine,

4-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridin-2-amine,

4-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridin-2-amine,

4-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridin-2-amine,

5-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N-methylpyridazin-3-amine,

5-{[3-(4-Methoxyphenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine,

5-{[3-(4-Chlorophenyl)azepan-1-yl]carbonyl}-N,N-dimethylpyridazin-3-amine,

3-(4-Chloro-2-methylphenyl)-1-{[2-(dimethylamino)pyridin-4-yl]carbonyl}piperidin-3-ol,

1-{[2-(Dimethylamino)pyridin-4-yl]carbonyl}-3-(4-fluorophenyl)piperidin-3-ol,

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (R Enantiomer),

4-({3-[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine (S Enantiomer),

and pharmaceutically acceptable salts thereof.

18. A compound comprising a mixture of the R and S enantiomers of 5-{[3-(4-Chloro-2-methylphenyl)piperidin-1-yl]carbonyl}-N-methylpyridazin-3-amine or pharmaceutically acceptable salts thereof.

21. A compound comprising a mixture of the R and S enantiomers of 4-({3[4-Chloro-2-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)-1-methyl-1H-pyrazol-3-amine or pharmaceutically acceptable salts thereof.