Pharmacologically active aryl-substituted pyrazolo[1,5-a]pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-10960007-B2
Application number	US-201816493018-A
Country	US
Kind code	B2
Filing date	Mar 12, 2018
Priority date	Mar 13, 2017
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

The present invention relates to new pyrazolo[1,5-a]pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof that serve as GABA B receptor positive allosteric modulators. The invention also relates to the process for producing such compounds. The invention further relates to pharmaceutical compositions comprising such compounds optionally in combination with two or more different therapeutic agents and the use of such compounds in methods for treating diseases and conditions mediated and modulated by the GABA B receptor positive allosteric mechanism. The invention also provides a method for manufacture of medicaments useful in the treatment of such disorders.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
A is an optionally substituted phenyl or pyridyl group;
B is hydrogen or halogen atom, methyl, cyano group;
C is C 1-6 alkyl,
D is C 1-6 alkyl optionally substituted by a halogen atom or halogen atoms, C 3-5 cycloalkyl; C 3-5 cycloalkylC 1-6 alkyl, dialkylamino, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkylthio group, tetrahydrofuranyl, tetrahydrofuranylC 1-6 alkyl, tetrahydropyranyl, tetrahydropyranylC 1-6 alkyl; or C and D together form a 3 to 7-membered saturated ring, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur, and wherein the 3 to 7-membered saturated ring is unsubstituted or substituted by one or more of C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, and C 1-3 alkylcarbonyl; and
R 1 is hydrogen, halogen atom, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, haloC 1-6 alkyl, or an amino group;
or pharmaceutically acceptable salts, pro-drugs, racemates, enantiomers, diastereomers, thereof.

2. A compound according to claim 1 wherein C is C 1-6 alkyl; and D is C 1-6 alkyl optionally substituted by a halogen atom or halogen atoms, C 3-5 cycloalkyl, C 3-5 cycloalkylC 1-6 alkyl, dialkylamino, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, or C 1-6 alkylthio groups.

3. A compound according to claim 1 wherein C and D together form a 3 to 7-membered saturated ring, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur, and wherein the 3 to 7-membered saturated ring is unsubstituted or substituted by one or more of C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, and C 1-3 alkylcarbonyl.

4. A compound according to claim 1 wherein C is methyl; and D is isopropyl or C 1-6 alkoxyC 1-6 alkyl.

5. A compound according to claim 1 selected from the group of
(3S)-1-[2-(4-Chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid;
(3S)-3-Ethyl-1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3R)-3-Ethyl-1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3S)-1-[2-(4-Chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3S)-1-[5-Methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3R)-1-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3S)-3-Methyl-1[5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3S)-1-{2-[2-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid;
(3S)-3-Ethyl-1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3S)-3-Ethyl-1[3-fluoro-5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3R)-1-[2-(4-chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid;
(3R)-1-[2-(4-chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3R)-1-[5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3S)-1-[2-(2,4-dichlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3R)-1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}-3-(propan-2-yl)piperidine-3-carboxylic acid; and
(3S)-1-[3-fluoro-5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

7. A combination comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 and one or more therapeutically active co-agents.

8. A process for manufacturing a pharmaceutical composition having GABA B receptor positive allosteric modulator effect comprising mixing a therapeutically effective amount of a compound of formula (I) according to claim 1 and carriers.

9. A compound according to claim 5 selected from the group consisting of:
(3S)-1-[2-(4-Chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid; and
(3S)-3-Ethyl-1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid.

10. A compound according to claim 5 selected from the group consisting of:
(3R)-3-Ethyl-1-{2-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid; and
(3S)-1-[2-(4-Chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid.

11. A compound according to claim 5 selected from the group consisting of:
(3S)-1-[5-Methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid; and
(3R)-1-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}-3-(propan-2-yl)piperidine-3-carboxylic acid.

12. A compound according to claim 5 selected from the group consisting of:
(3S)-3-Methyl-1-[5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid; and
(3S)-1-{2-[2-Chloro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid.

13. A compound according to claim 5 selected from the group consisting of:
(3S)-3-Ethyl-1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid; and
(3S)-3-Ethyl-1-[3-fluoro-5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid.

14. A compound according to claim 5 selected from the group consisting of:
(3R)-1-[2-(4-chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid; and
(3R)-1-[2-(4-chlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid.

15. A compound according to claim 5 selected from the group consisting of:
(3R)-1-[5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid; and
(3S)-1-[2-(2,4-dichlorophenyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid.

16. A compound according to claim 5 selected from the group consisting of:
(3R)-1-{2-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl}-3-(propan-2-yl)piperidine-3-carboxylic acid; and
(3S)-1-[3-fluoro-5-methyl-6-(propan-2-yl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid.

Assignees

• Richter Gedeon Nyrt

Inventors

• Borza István
• Román Viktor
• Éles János
• Hadady Zsuzsa
• Huszár József

Classifications

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D239/00 Primary

  Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/28

  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 title