Substituted pyrazolopyrimidines and method of use

Patent metadata

Field	Value
Publication number	US-9828381-B2
Application number	US-201615133851-A
Country	US
Kind code	B2
Filing date	Apr 20, 2016
Priority date	Apr 20, 2015
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

Compounds of formula (I)

and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , L 1 and G 1 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by positive allosteric modulation of the γ-aminobutyric acid B (GABA-B) receptor. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or isotopically labeled form thereof, wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl,C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl, wherein
the C 1 -C 6 alkyl and the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a independently selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, amido, carboxy, cyano, halogen, hydroxy, and oxo; and
the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1b independently selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl, amido, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, carboxy, cyano, halogen, haloC 1 -C 6 alkyl, hydroxy, hydroxyC 1 -C 6 alkyl, and oxo;

R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl; or
R 1 , R 2 and the nitrogen to which they are attached form a saturated 4-7-membered N-bound heterocycle, which in addition to the nitrogen atom may have one further heteroatom selected from O, S and N as a ring member, wherein:
each such 4-7-membered heterocycle is unsubstituted or substituted with one or more identical or different substituents R 1c , where R 1c is selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkylsulfonylamino, amido, carboxy, cyano, halogen, haloC 1 -C 6 alkyl, amino, hydroxy, hydroxyC 1 -C 6 alkyl, oxo, spirocyclic bound C 3 -C 6 cycloalkyl; and spirocyclic bound saturated 4-6-membered heterocycle; wherein
each spirocyclic bound C 3 -C 6 cycloalkyl and spirocyclic bound 4-6-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, cyano, halogen, haloC 1 -C 6 alkyl, hydroxy, and hydroxyC 1 -C 6 alkyl;

R 3 is hydrogen;
R 4 is C 1 -C 6 alkyl;
L 1 is (CR 5 R 6 ) m , wherein m is 1 and
R 5 and R 6 , are, at each occurrence, independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
and

G 1 is selected from the group consisting of C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, and phenyl; wherein
each C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, and phenyl is unsubstituted or substituted with one or more identical or different substituents R G , where R G is selected from the group consisting of C 1 -C 6 alkyl, cyano, haloC 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy and haloC 1 -C 6 alkoxy.

2. The compound or pharmaceutically acceptable salt of claim 1 wherein R 5 is hydrogen and R 6 is C 1 -C 6 alkyl.

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein
G 1 is selected from the group consisting of 5-6-membered heteroaryl and phenyl; wherein the 5-6-membered heteroaryl and phenyl are unsubstituted or carry 1, 2, 3 or 4 radicals R G .

4. The compound or pharmaceutically acceptable salt of claim 1 , wherein
G 1 is selected from the group consisting of phenyl, 3-chlorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, pyridine-2-yl and 5-chloropyridin-2-yl.

5. The compound or pharmaceutically acceptable salt of claim 1 , wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl, wherein
the C 1 -C 6 alkyl and the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a ; and
the C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl, 4-7-membered heterocycle are unsubstituted or substituted with one or more substituents R 1b ; and

R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl.

6. The compound or pharmaceutically acceptable salt of claim 5 , wherein:
R 1 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted or substituted with one or more halogen atoms; and
R 2 is hydrogen.

7. The compound or pharmaceutically acceptable salt of claim 5 , wherein:
R 1 is selected from the group consisting of C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkylC 1 -C 6 alkyl, wherein
the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl is unsubstituted or substituted with one or more substituents R 1a , and
the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1b ; and

R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl.

8. The compound or pharmaceutically acceptable salt of claim 1 , wherein:
R 1 , R 2 and the nitrogen to which they are attached form a 4-7-membered heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl wherein azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and azepanyl are unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c .

9. The compound or pharmaceutically acceptable salt of claim 8 , wherein:
R 1 , R 2 and the nitrogen to which they are attached form a 4-5-membered heterocycle selected from the group consisting of azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c .

10. The compound or pharmaceutically acceptable salt of claim 8 , wherein:
R 1 , R 2 and the nitrogen to which they are attached form a 6-7-membered heterocycle selected from the group consisting of piperidinyl, piperazinyl, and azepanyl wherein piperidinyl, piperazinyl, and azepanyl are unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c .

11. The compound or pharmaceutically acceptable salt of claim 1 , wherein the moiety NR 1 R 2 is selected from the group consisting of azetidin-1-yl, 3-ethyl-2-carboxylazetidin-1-yl, pyrroldin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-(acetylamino)pyrrolidin-1-yl, 3-(methylsulfonylamino)pyrrolidin-1-yl, 3-aminocarbonylpyrrolidin-1-yl, piperidin-1-yl, 3-fluoropiperidin-1-yl, 4-fluoropiperidin-1-yl, 2-(2-hydroxyethyl)piperidin-1-yl, 2-ethylpiperidin-1-yl, 2-(hydroxymethyl)piperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl, 2-oxopiperidin-1-yl, 3-(methylsulfonylamino)piperidin-1-yl, 2-(2-hydroxyethyl)-3-oxopiperazin-1-yl, 3,3-difluorpiperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxy-3,3-difluoropiperidin-1-yl, 2,2,2-trifluoroethylamino, tert-butylamino, 1-(trifluoromethyl)-ethylamino, 1-methylcyclopropylamino, 1-(trifluoromethyl)cyclopropylamino, 3-fluorocyclobutylamino, 3,3-difluorocyclobutylamino, 3-hydroxycyclobutylamino, (3,3-difluorocyclobutyl)methylamino, 2-oxa-6-azaspiro[3.4]oct-6-yl, 2-oxa-7-azaspiro-[3.5]non-7-yl, 7-oxa-2-azaspiro[3.5]non-2-yl and 3-hydroxy-7-azaspiro[3.4]oct-7-yl.

12. A compound, selected from the group consisting of:
2-{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}ethanol;
{1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]piperidin-2-yl}methanol;
2-(4-chlorobenzyl)-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine;
2-(4-chlorobenzyl)-7-(3,3-difluoropiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine;
1-[2-(4-chlorobenzyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-3,3-difluoropiperidin-4-ol;
(3S)-1-[2

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Faghih Ramin
• Moeller Achim
• Ochse Michael
• Pohlki Frauke
• Schmidt Martin
• Sippy Kevin
• Turner Sean
• Van Der Kam Elizabeth Louise

Classifications

• A61K31/519

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title