US 2022/0089609 A1 · SUBSTITUTED QUINAZOLINONE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR4

Abstract

The present invention relates to novel quinazolinone derivatives of formula (I) as well as pharmaceutical compositions containing these compounds. The compounds of formula (I) as provided herein can act as positive allosteric modulators of metabotropic glutamate receptor subtype 4 (mGluR4), and can thus be used as therapeutic agents, particularly in the treatment or prevention of conditions associated with altered glutamatergic signalling and/or functions or conditions which can be affected by alteration of glutamate level or signalling.

A compound of formula (I)

wherein:
R1 is either selected from any one of the following groups:
wherein each one of the above-depicted groups is optionally substituted with one or more groups R11;
or R1 is a group
which is optionally substituted with one or more groups R11A;
each R11 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-aryl, —(C0-3 alkylene)-heteroaryl, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said —(C0-3 alkylene)-aryl, the heteroaryl moiety in said —(C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said —(C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups R12;
each R11A is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-heteroaryl, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the heteroaryl moiety in said —(C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said —(C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups R12;
each R12 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO—(C1-5 alkyl), —COOH, —CO—O—(C1-5 alkyl), —O—CO—(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO—(C1-5 alkyl), —N(C1-5 alkyl)-CO—(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), cycloalkyl, and heterocycloalkyl;
X1 is C(RX1) or N;
X2 is C(-L-RX2) or N;
X3 is C(RX3) or N;
X4 is C(RX4) or N;
wherein at least one of the ring atoms X2, X3 and X4 is not N;
RX1 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-aryl, —(C0-3 alkylene)-heteroaryl, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said —(C0-3 alkylene)-aryl, the heteroaryl moiety in said —(C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said —(C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups RX11;
each RX11 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO—(C1-5 alkyl), —COOH, —CO—O—(C1-5 alkyl), —O—CO—(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO—(C1-5 alkyl), —N(C1-5 alkyl)-CO—(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), cycloalkyl, and heterocycloalkyl;
L is selected from a covalent bond, C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene, wherein one or more —CH2— units comprised in said C1-10 alkylene, said C2-10 alkenylene, or said C2-10 alkynylene are each optionally replaced by a group independently selected from —O—, —CO—, —C(═O)O—, —O—C(═O)—, —NH—, —N(C1-5 alkyl)-, —NH—CO—, —N(C1-5 alkyl)-CO—, —CO—NH—, —CO—N(C1-5 alkyl)-, —S—, —SO—, —SO2—, —SO2—NH—, —SO2—N(C1-5 alkyl)-, —NH—SO2—, —N(C1-5 alkyl)-SO2—, carbocyclylene, and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally substituted with one or more groups independently selected from C1-4 alkyl, —OH, —O(C1-4 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)(C1-4 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), and —CN, and further wherein said C1-10 alkylene, said C2-10 alkenylene, and said C2-10 alkynylene are each optionally substituted with one or more groups independently selected from halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), and —N(C1-5 alkyl)(C1-5 alkyl);
RX2 is selected from C2-10 alkyl, carbocyclyl, heterocyclyl, and -L1-RX21, wherein said C2-10 alkyl, said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups RX22;
L1 is selected from a covalent bond, C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene, wherein one or more —CH2— units comprised in said C1-10 alkylene, said C2-10 alkenylene, or said C2-10 alkynylene are each optionally replaced by a group independently selected from —O—, —CO—, —C(═O)O—, —O—C(═O)—, —NH—, —N(C1-5 alkyl)-, —NH—CO—, —N(C1-5 alkyl)-CO—, —CO—NH—, —CO—N(C1-5 alkyl)-, —S—, —SO—, —SO2—, —SO2—NH—, —SO2—N(C1-5 alkyl)-, —NH—SO2—, and —N(C1-5 alkyl)-SO2—, and further wherein said C1-10 alkylene, said C2-10 alkenylene, and said C2-10 alkynylene are each optionally substituted with one or more groups independently selected from halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), and —N(C1-5 alkyl)(C1-5 alkyl);
RX21 is selected from C2-5 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups RX22;
each RX22 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-SO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-aryl, —(C0-3 alkylene)-heteroaryl, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said —(C0-3 alkylene)-aryl, the heteroaryl moiety in said —(C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said —(C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups RX23;
each RX23 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO—(C1-5 alkyl), —COOH, —CO—O—(C1-5 alkyl), —O—CO—(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO—(C1-5 alkyl), —N(C1-5 alkyl)-CO—(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), —SO—(C1-5 alkyl), —SO2—(C1-5 alkyl), cycloalkyl, and heterocycloalkyl;
RX3 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-aryl, —(C0-3 alkylene)-heteroaryl, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said —(C0-3 alkylene)-aryl, the heteroaryl moiety in said —(C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said —(C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups RX31;
each RX31 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO—(C1-5 alkyl), —COOH, —CO—O—(C1-5 alkyl), —O—CO—(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO—(C1-5 alkyl), —N(C1-5 alkyl)-CO—(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), cycloalkyl, and heterocycloalkyl;
RX4 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —(C0-3 alkylene)-OH, —(C0-3 alkylene)-O(C1-5 alkyl), —(C0-3 alkylene)-SH, —(C0-3 alkylene)-S(C1-5 alkyl), —(C0-3 alkylene)-NH2, —(C0-3 alkylene)-NH(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-halogen, —(C0-3 alkylene)-(C1-5 haloalkyl), —(C0-3 alkylene)-O—(C1-5 haloalkyl), —(C0-3 alkylene)-CN, —(C0-3 alkylene)-CHO, —(C0-3 alkylene)-CO—(C1-5 alkyl), —(C0-3 alkylene)-COOH, —(C0-3 alkylene)-CO—O—(C1-5 alkyl), —(C0-3 alkylene)-O—CO—(C1-5 alkyl), —(C0-3 alkylene)-CO—NH2, —(C0-3 alkylene)-CO—NH(C1-5 alkyl), —(C0-3 alkylene)-CO—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—CO—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-CO—(C1-5 alkyl), —(C0-3 alkylene)-SO2—NH2, —(C0-3 alkylene)-SO2—NH(C1-5 alkyl), —(C0-3 alkylene)-SO2—N(C1-5 alkyl)(C1-5 alkyl), —(C0-3 alkylene)-NH—SO2—(C1-5 alkyl), —(C0-3 alkylene)-N(C1-5 alkyl)-SO2—(C1-5 alkyl), —(C0-3 alkylene)-aryl, —(C0-3 alkylene)-heteroaryl, —(C0-3 alkylene)-cycloalkyl, and —(C0-3 alkylene)-heterocycloalkyl, wherein the aryl moiety in said —(C0-3 alkylene)-aryl, the heteroaryl moiety in said —(C0-3 alkylene)-heteroaryl, the cycloalkyl moiety in said —(C0-3 alkylene)-cycloalkyl, and the heterocycloalkyl moiety in said —(C0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups RX41;
each RX41 is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, —OH, —O(C1-5 alkyl), —SH, —S(C1-5 alkyl), —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)(C1-5 alkyl), halogen, C1-5 haloalkyl, —O—(C1-5 haloalkyl), —CN, —CHO, —CO—(C1-5 alkyl), —COOH, —CO—O—(C1-5 alkyl), —O—CO—(C1-5 alkyl), —CO—NH2, —CO—NH(C1-5 alkyl), —CO—N(C1-5 alkyl)(C1-5 alkyl), —NH—CO—(C1-5 alkyl), —N(C1-5 alkyl)-CO—(C1-5 alkyl), —SO2—NH2, —SO2—NH(C1-5 alkyl), —SO2—N(C1-5 alkyl)(C1-5 alkyl), —NH—SO2—(C1-5 alkyl), —N(C1-5 alkyl)-SO2—(C1-5 alkyl), cycloalkyl, and heterocycloalkyl;
or a pharmaceutically acceptable salt thereof;
with the proviso that the following compounds are excluded from formula (I):
and with the further proviso that the following compound is excluded:

25 more elements

Substituted quinazolinone derivatives and their use as positive allosteric modulators of mglur4

Life of this patent

Substituted quinazolinone derivatives and their use as positive allosteric modulators of mglur4

Life of this patent

Abstract

Claims21