Indazole derivatives useful as CB-1 inverse agonists

Patent metadata

Field	Value
Publication number	US-9682940-B2
Application number	US-201615239348-A
Country	US
Kind code	B2
Filing date	Aug 17, 2016
Priority date	Aug 25, 2015
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention is directed to indazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions mediated by the CB-1 receptor; more particularly, use in the treatment of disorders and conditions responsive to inverse agonism of the CB-1 receptor. More particularly, the compounds of the present invention are useful in the treatment of metabolic disorders.

First claim

We claim:

1. A compound of formula (I)

wherein
R 0 is selected from the group consisting of hydrogen and hydroxy;

is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, pyridyl, thiazolyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, pyridyl, thiazolyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkoxy, cyano, —C(O)OH, C(O)O—C 1-4 alkyl, —C(O)NR A R B and NR A R B ; wherein R A and R B are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy substituted C 1-2 alkyl and carboxy substituted C 1-2 alkyl; provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, pyridyl, thiazolyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, pyridyl, thiazolyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkoxy, cyano, —C(O)OH, C(O)O—C 1-4 alkyl, —C(O)NR C R D and NR C R D ; wherein R C and R D are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy substituted C 1-2 alkyl and carboxy substituted C 1-2 alkyl; provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of
(a)

wherein R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, —C(O)—(C 1-4 alkyl), —(C 1-2 alkyl)-C(O)OH, —(C 1-2 alkyl)-C(O)—O—(C 1-4 alkyl), —(C 1-2 alkyl)-O—(C 1-2 alkyl)-C(O)OH, —(C 1-2 alkyl)-C(O)—NR E R F , —SO 2 -(fluorinated C 1-2 alkyl), C 3-6 cycloalkyl and benzyl;
wherein the benzyl is optionally substituted with one substituent selected from the group consisting of —C(O)OH, —C(O)O—(C 1-4 alkyl) and —C(O)—NR E R F ;
and wherein R E and R F are each independently selected from the group consisting of hydrogen and C 1-2 alkyl;
and (b)

wherein R 2 is selected from the group consisting of C 3-6 cycloalkyl and C 1-4 alkyl;
a is an integer from 0 to 1;
b is an integer from 0 to 1; c is an integer from 0 to 1;
X is selected from the group consisting of CH and N; provided that when one or both of b or c is 0, then X is CH;
such that

is selected from the group consisting of piperazin-1,4-diyl, piperidin-1,4-diyl, pyrroldin-1,3-diyl and azetidin-1,3-diyl;
R 3 is selected from the group consisting of C 1-4 alkyl, halogenated C 1-4 alkyl, —C(O)-(fluorinated C 1-2 alkyl), —C(O)-(hydroxy substituted C 1-4 alkyl), —C(O)—(C 1-2 alkyl)-C(O)OH, —C(O)—(C 1-2 alkyl)-C(O)O—(C 1-4 alkyl), —C(O)—(C 1-4 alkyl)-C(O)—NR G R H , —C(O)O—(C 1-4 alkyl), —C(O)O—(C 3-6 cycloalkyl), —C(O)—NR G R H , —SO 2 —(C 1-4 alkyl), —SO 2 -(halogenated C 1-4 alkyl), —SO 2 —(C 1-2 alkyl)-C(O)OH, —SO 2 —(C 1-2 alkyl)-C(O)O—(C 1-4 alkyl), —SO 2 —NR G R H , —SO 2 —(C 1-2 alkyl)-C(O)—NR G R H , phenyl, pyridyl (provided that the pyridyl is bound through a carbon atom) and -L 1 -R 4 ;
wherein phenyl or pyridyl is optionally substituted with one or more (preferably one to two) substituents independently selected from the group consisting of halogen, C 1-4 alkyl, halogenated C 1-2 alkyl, C 1-4 alkoxy, —(C 1-2 alkyl)-C(O)OH, —(C 1-2 alkyl)-C(O)O—(C 1-4 alkyl), —(C 1-2 alkyl)-C(O)—NR J R K , —O—(C 1-2 alkyl)-C(O)OH, —O—(C 1-2 alkyl)-C(O)O—(C 1-4 alkyl), —O—(C 1-2 alkyl)-C(O)—NR J R K , —C(O)OH, —C(O)O—(C 1-4 alkyl) and —C(O)—NR J R K ;
wherein R G and R H are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; and wherein R J and R K are each independently selected from the group consisting of hydrogen and C 1-2 alkyl;
L 1 is selected from the group consisting of —CH 2 —, CH 2 CH 2 —, —CH(CH 3 )—, —C(O)—, —C(O)—CH 2 —, —C(O)O—, —C(O)O—CH 2 —, —C(O)—NH—, —C(O)—NH—CH 2 — and —SO 2 —;
R 4 is selected from the group consisting of C 3-6 cycloalkyl, phenyl, furanyl, thienyl, pyridyl, pyrazolyl, triazolyl, and tetrazolyl;
wherein the phenyl, furanyl, thienyl, pyridyl, pyrazolyl and triazolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —C(O)OH, —C(O)O—(C 1-4 alkyl), —C(O)—NR L R M and —SO 2 —NR L R M ; wherein R L and R M are each independently selected from the group consisting of hydrogen and C 1-2 alkyl;
or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

2. A compound as in claim 1 , wherein
R 0 is selected from the group consisting of hydrogen and hydroxy;

is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, pyridyl and thiazolyl;
wherein the phenyl, furyl, thienyl, pyridyl or thiazolyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C 1-2 alkyl, C 1-2 alkoxy, fluorinated C 1-2 alkyl, fluorinated C 1-2 alkoxy, —C(O)OH, —C(O)O—C 1-4 alkyl, —C(O)—NR A R B and —NR A R B wherein R A and R B are each independently selected from the group consisting of hydrogen, C 1-2 alkyl, hydroxy substituted C 1-2 alkyl and carboxy substituted C 1-2 alkyl; provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, pyridyl and thiazolyl;
wherein the phenyl, furyl, thienyl, pyridyl or thiazolyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C 1-2 alkyl, C 1-2 alkoxy, fluorinated C 1-2 alkyl, fluorinated C 1-2 alkoxy, —C(O)OH, —C(O)O—C 1-4 alkyl, —C(O)—NR A R B and —NR A R B wherein R A and R B are each independently selected from the group consisting of hydrogen, C 1-2 alkyl, hydroxy substituted C 1-2 alkyl and carboxy substituted C 1-2 alkyl; provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of
(a)

wherein R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, —C(O)—(C 1-4 alkyl), —(C 1-2 alkyl)-C(O)OH, —(C 1-2 alkyl)-C(O)—O—(C 1-4 alkyl), —(C 1-2 alkyl)-O—(C 1-2 alkyl)-C(O)OH, —(C 1-2 alkyl)-C(O)—NR E R F , —SO 2

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Macielag Mark J
• Zhang Rui
• Parker Michael H
• Decorte Bart L
• Greco Michael N

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D231/56 Primary

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title