Quinazoline derivatives useful as CB-1 inverse agonists

Patent metadata

Field	Value
Publication number	US-9682955-B2
Application number	US-201514844309-A
Country	US
Kind code	B2
Filing date	Sep 3, 2015
Priority date	Sep 9, 2014
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention is directed to quinazoline derivatives, pharmaceutical compositions containing said derivatives and their use in the treatment of disorders and conditions mediated by the CB-1 receptor; more particularly, in the treatment of disorders and conditions responsive to inverse agonism of the CB-1 receptor. For example, 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

is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, 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 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 and —(C 2-4 alkyl)-O—(C 1-4 alkyl); provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, 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 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 and —(C 2-4 alkyl)-O—(C 1-4 alkyl); provided that each substituent is bound to a carbon atom of the ring;
R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, —CH═CH—(C 1-4 alkyl)-OH, —CH═CH—(C 0-3 alkyl)-CO 2 H, —CH═CH—(C 0-3 alkyl)-C(O)O—(C 1-4 alkyl), —CH═CH—(C 1-4 alkyl)-NH 2 , —CH 2 CH 2 —(C 1-4 alkyl)-OH, —CH 2 CH 2 —(C 0-3 alkyl)-CO 2 H, —CH 2 CH 2 —(C 0-3 alkyl)-C(O)O—(C 1-4 alkyl), —CH 2 CH 2 —(C 1-4 alkyl)-NH 2 , cyclopropyl, cyclobutyl, —OR 2 and —NR 3 R 4 ;
R 2 is selected from the group consisting of hydrogen, —C 1-12 alkyl, —CH 2 -(hydroxy substituted C 1-11 alkyl), —(C 1-12 alkyl)-N 3 , —(C 2-12 alkyl)-NR E R F , —(C 2-12 alkyl)-O—(C 1-12 alkyl), —(C 2-12 alkyl)-O—(C 1-12 alkyl)-OH, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-CN, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-CO 2 H, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-C(O)—O—(C 1-6 alkyl), —(C 2-12 alkyl)-O—(C 1-12 alkyl)-C(O)—NR E R F , —(C 1-12 alkyl)-CO 2 H, —(C 1-12 alkyl)-C(O)—O—(C 1-6 alkyl), —(C 2-12 alkyl)-OC(O)—(C 1-6 alkyl), —(C 2-12 alkyl)-OC(O)—NR E R F , —(C 1-12 alkyl)-C(O)—NR E R F , —(C 2-12 alkyl)-NR E —C(O)—(C 1-6 alkyl), —(C 2-12 alkyl)-NR E —C(O)—(C 1-12 alkyl)-OH and —(C 2-12 alkyl)-NR E —SO 2 —(C 1-6 alkyl); wherein R E and R F are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and —CH 2 -(hydroxy substituted C 1-5 alkyl);
R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 4 is selected from the group consisting of hydrogen, —C 1-12 alkyl, —CH 2 -(hydroxy substituted C 1-11 alkyl), —(C 1-12 alkyl)-N 3 , —(C 2-12 alkyl)-NR G R H , —(C 2-12 alkyl)-O—(C 1-12 alkyl), —(C 2-12 alkyl)-O—(C 1-12 alkyl)-OH, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-CN, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-CO 2 H, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-C(O)—O—(C 1-6 alkyl), —(C 2-12 alkyl)-O—(C 1-12 alkyl)-C(O)—NR G R H , —(C 1-12 alkyl)-CO 2 H, —(C 1-12 alkyl)-C(O)O—(C 1-6 alkyl), —(C 2-12 alkyl)-OC(O)—(C 1-6 alkyl), —(C 2-12 alkyl)-OC(O)—NR G R H , —(C 1-12 alkyl)-C(O)—NR G R H , —(C 2-12 alkyl)-NR G —C(O)—(C 1-6 alkyl), —(C 2-12 alkyl)-NR G —C(O)—(C 1-12 alkyl)-OH, —(C 2-12 alkyl)-NR G —SO 2 —(C 1-6 alkyl), —C(O)—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl) and —SO 2 -(halogenated C 1-6 alkyl); wherein R G and R H are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and —CH 2 -(hydroxy substituted C 1-5 alkyl);
R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 6 is selected from the group consisting of

a is an integer from 0 to 1;
L 1 is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 — and cycloprop-1,1-diyl;
R 7 is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl-1-oxide, thiomorpholin-4-yl-1,1-dioxide, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R 7 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-12 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —(C 1-4 alkyl)-O—(C 1-4 alkyl), —(C 1-4 alkyl)-CO 2 H, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —(C 1-4 alkyl)-C(O)—NR J R K , —O—(C 1-4 alkyl)-O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-CO 2 H, —O—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-C(O)—NR J R K , —C(O)—(C 1-4 alkyl), —C(O)-(halogenated C 1-4 alkyl), —C(O)—(C 1-4 alkyl)-CO 2 H, —C(O)—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —C(O)—NR J R K , —C(O)—(C 1-4 alkyl)-C(O)—NR J R K , —CO 2 H, —C(O)O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-OC(O)O—(C 1-4 alkyl), —C(═NR J )—NR K —C(O)O—(C 1-4 alkyl), —C(═NH)—NH 2 , —C(═N-Boc)-NH(Boc), —NR J R K , —NR J —C(O)—(C 1-4 alkyl), —NR J —SO 2 —(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl), —SO 2 -(halogenated C 1-4 alkyl), —SO 2 —(C 1-4 alkyl)-OH, —SO 2 —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —SO 2 —NR J R K and —SO 2 —(C 1-4 alkyl)-C(O)—NR J R K ; and wherein R J and R K are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and (C 2-4 alkyl)-OH;
and wherein R 7 is phenyl; the phenyl is further optionally substituted with an additional substituent selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy and halogenated C 1-4 alkoxy;
provided that when a is 0 (L 1 Is absent), then R 7 is other than piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl or thiomorpholin-4-yl-1-oxide
provided further that when the substituent group on the R 7 ring structure is selected from the group consisting of C 1-4 alkoxy, halogenated C 1-4 alkoxy, —O—(C 1-4 alkyl)-O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-CO 2 H, —O—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-C(O)—NR J R K , —NR J R K , —NR J —C(O)—(C 1-4 alkyl) and —NR J —SO 2 —(C 1-4 alkyl), then said substitutent group is bound to a carbon atom on the R 7 ring structure;

is selected from the group consisting of

wherein Z 1 is selected from the group consisting of N and CH;
b is an integer from 0 to 1;
L 2 is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —CH(CH 2 CH 3 )—, —C(O)— and —SO 2 —;
R 8 is selected from the group consisting of azetidin-3-yl, pyrrolidin-1-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R 8 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-12 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —(C 1-4 alkyl)-O—(C 1-4 a

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Macielag Mark Joseph
• Zhang Yue-Mei
• Decorte Bart L
• Greco Michael N

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D239/94

  Nitrogen atoms · CPC title

• C07D401/04

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