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

Patent metadata

Field	Value
Publication number	US-11026946-B2
Application number	US-201816493453-A
Country	US
Kind code	B2
Filing date	Mar 12, 2018
Priority date	Mar 13, 2017
Publication date	Jun 8, 2021
Grant date	Jun 8, 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 GABAB receptor positive allosteric modulators. The invention al so 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 GABAB receptor positive allosteric mechanism. The invention al so 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:

R 1 and R 2 are independently selected from hydrogen, halogen atom, C 1-6 alkyl, or haloC 1-6 alkyl;
R 3 is hydrogen, halogen atom, C 1-6 alkyl, or cyano group;
R 4 is C 1-6 alkyl;
R 5 is C 1-6 alkyl optionally substituted by a halogen atom, 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, or tetrahydropyranylC 1-6 alkyl;
or R 4 and R 5 together form a 3 to 7-membered saturated ring, wherein the 3 to 7-membered saturated ring is unsubstituted or substituted by one or more C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, or C 1-3 alkylcarbonyl, and wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;
R 6 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, hydrolysable esters, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

2. A compound according to claim 1 wherein R 1 and R 2 are independently selected from hydrogen, halogen atom, C 1-6 alkyl, or haloC 1-6 alkyl;
R 3 is hydrogen, halogen atom, C 1-6 alkyl, or cyano group;
R 4 is C 1-6 alkyl;
R 5 is C 1-6 alkyl optionally substituted by a halogen atom, 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, or tetrahydropyranylC 1-6 alkyl;
R 6 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, hydrolysable esters, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

3. A compound according to claim 1 wherein
R 1 and R 2 are independently selected from hydrogen, halogen atom, C 1-6 alkyl, or haloC 1-6 alkyl;
R 3 is hydrogen, halogen atom, C 1-6 alkyl, or cyano group;
R 4 and R 5 together form a 3 to 7-membered saturated ring, wherein the 3 to 7-membered saturated ring is unsubstituted or substituted by one or more C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, or C 1-3 alkylcarbonyl, and wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;
R 6 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, hydrolysable esters, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

4. A compound according to claim 1 wherein R 4 is methyl; and R 5 is isopropyl or C 1-6 alkoxyC 1-6 alkyl.

5. A compound according to claim 1 selected from the group consisting of
(3S)-1[5-Methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3S)-1[5-Methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3R)-3-Methyl-1-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3R)-1-[5-Methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo [1,5-a]pyrimidin-7-yl]-3-propylpiperidine-3-carboxylic acid;
(3S)-1-[5-Methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-propylpiperidine-3-carboxylic acid;
(3R)-3-(Fluoromethyl)-1-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl) cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3S)-3-(Fluoromethyl)-1-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl) cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3R)-3-Methyl-1-[(8S)-8-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]-5H,6H,7H,8H-pyrazolo[3, 2-b]quinazolin-9-yl]piperidine-3-carboxylic acid;
(3R)-3-Methyl-1-[(8R)-8-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]-5H,6H,7H,8H-pyrazolo[3, 2-b]quinazolin-9-yl]piperidine-3-carboxylic acid;
(3R)-1-[5-Methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo [1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3S)-3-Methyl-1-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3S)-3-Ethyl-1-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3R)-3-Ethyl-1-[5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3R)-1-[5-Methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo [1,5-a]pyrimidin-7-yl]-3-(propan-2-yl)piperidine-3-carboxylic acid;
(3S)-1-[3-Fluoro-5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid;
(3R)-1-[3-Fluoro-5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid;
(3S)-3-Ethyl-1-[3-fluoro-5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl) cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3R)-3-Ethyl-1-[3-fluoro-5-methyl-6-(propan-2-yl)-2-[trans-4-(trifluoromethyl) cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl]piperidine-3-carboxylic acid;
(3S)- 1-{3-Fluoro-6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid;
(3R)- 1-{3-Fluoro-6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid;
(3S)-3-Ethyl-1-{6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3R)-3-Ethyl-1-{6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3S)-1-{3-Fluoro-6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid;
(3R)- 1-{3-Fluoro-6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl)cydohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid;
(3S)-3-Ethyl-1-{3-fluoro-6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl) cydohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3R)-3-Ethyl-1-{3-fluoro-6-methoxy-5-methyl-2-[trans-4-(trifluoromethyl) cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3R)-1-{6-Ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-a]pyrimidin-7-yl}-3-methylpiperidine-3-carboxylic acid;
(3R)-3-Ethyl-1-{6-ethyl-5-methyl-2-[trans-4-(trifluoromethyl)cyclohexyl]pyrazolo [1,5-a]pyrimidin-7-yl}piperidine-3-carboxylic acid;
(3S)-1-[2-(4,4-Difluorocydohexyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid;
(3R)-1-[2-(4,4-Difluorocyclohexyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid;
(3S)-1-[2-(4,4-Difluorocydohexyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid;
(3R)-1-[2-(4,4-Difluorocyclohexyl)-5-methyl-6-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-ethylpiperidine-3-carboxylic acid;
(3R)-1-[2-(4,4-Difluorocydohexyl)-5,6-diethylpyrazolo[1,5-a]pyrimidin-7-yl]-3-methylpiperidine-3-carboxylic acid;
(3R)-3-Methyl-1-{2-[trans-4-(trifluoromethyl)cyclohexyl]-5H,6H,7H,8H-pyrazolo [3,2-b]quinazolin-9-yl}piperi

Assignees

• Richter Gedeon Nyrt

Inventors

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

Classifications

• A61K31/519 Primary

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

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D239/00 Primary

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title