Substituted pyrazolopyrimidines and method of use

Patent metadata

Field	Value
Publication number	US-2016304527-A1
Application number	US-201615133851-A
Country	US
Kind code	A1
Filing date	Apr 20, 2016
Priority date	Apr 20, 2015
Publication date	Oct 20, 2016
Grant date	—

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 labelled form thereof, wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl, 4-7-membered heterocycle and 4-7-membered heterocycleC 1 -C 6 alkyl, wherein each of the 4-7-membered heterocycles in the two last mentioned radicals are saturated or have one endocyclic double bond;
a) the C 1 -C 6 alkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl, and the C 1 -C 6 alkyl of 4-7-membered heterocycleC 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;
b) 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, and the 4-7-membered heterocycle of 4-7-membered heterocycleC 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, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl;
R 4 is hydrogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl; or
R 3 and R 4 are joined to form a C 3 -C 7 alkylene;
L 1 is selected from the group consisting of —(CR 5 R 6 ) m —, —(CH 2 ) n CR 5a ═CR 6a (CH 2 ) p —, and

wherein
c) R 5 , R 5a , R 5b , R 6 , R 6a and R 6b are, at each occurrence, independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, fluorine, haloC 1 -C 6 alkyl and phenyl, wherein;
phenyl is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halogen, or haloC 1 -C 6 alkyl; or

d) R 5 or R 6 is a C 2 -C 4 alkylene attached to G 1 ;
e) m is 1, 2, 3 or 4;
f) n is, at each occurrence, independently 0, 1, or 2;
g) p is, at each occurrence, independently 0, 1, or 2; and

G 1 is selected from the group consisting of C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, 5-6-membered heterocycle, which is saturated or has one endocyclic double bond, and phenyl; wherein
each C 5 -C 10 cycloalkyl, 5-6-membered heteroaryl, 5-6-membered heterocycle, 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:
L 1 is —(CR 5 R 6 ) m —, wherein m is 1 and wherein R 5 and R 6 are, at each occurrence, independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl.

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

4 . 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 .

5 . 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.

6 . The compound or pharmaceutically acceptable salt of claim 1 , wherein:
R 3 is hydrogen; and R 4 is C 1 -C 6 alkyl.

7 . 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 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl, 4-7-membered heterocycle and 4-7-membered heterocycleC 1 -C 6 alkyl;
a) the C 1 -C 6 alkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl, the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl, and the C 1 -C 6 alkyl of 4-7-membered heterocycleC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a ;
b) 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, and the 4-7-membered heterocycle of 4-7-membered heterocycleC 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 7 , wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, the C 2 -C 6 alkenyl, the C 2 -C 6 alkynyl are unsubstituted or substituted with one or more halogen atoms; and R 2 is hydrogen.

9 . The compound or pharmaceutically acceptable salt of claim 7 , wherein:
R 1 is selected from the group consisting of C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl, 4-7-membered heterocycle and 4-7-membered heterocycleC 1 -C 6 alkyl;
a) the C 1 -C 6 alkyl of C 3 -C 6 cycloalkylC 1 -C 6 alkyl and the C 1 -C 6 alkyl of 4-7-membered heterocycleC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1a ;
b) 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, and the 4-7-membered heterocycle of 4-7-membered heterocycleC 1 -C 6 alkyl are unsubstituted or substituted with one or more substituents R 1b ; and
R 2 is selected from hydrogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl.

10 . 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 .

11 . The compound or pha

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

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

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title