Benzamide derivative useful as FASN inhibitors for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9562035-B2
Application number	US-201414550349-A
Country	US
Kind code	B2
Filing date	Nov 21, 2014
Priority date	Dec 3, 2013
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention is directed to benzamide derivatives, pharmaceutical compositions containing them, and their use as FASN inhibitors, in for example, the treatment of cancer, obesity related disorders, liver related disorders and viral infections. Such compounds are represented by formula (I) as follows:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , m, n,

 are defined herein.

First claim

We claim:

1. A compound of formula (I)

wherein
R 1 is selected from the group consisting of C 1-6 alkyl, fluorinated C 1-3 alkyl, C 3-6 cycloalkyl, —(C 1-2 alkyl)-C 3-6 cycloalkyl, aryl, 5 to 6 membered heteroaryl, 9 to 10 membered heteroaryl, 4 to 6 membered saturated heterocyclyl and 9 to 10 membered saturated, partially unsaturated or benzo-fused heterocyclyl;
wherein the C 3-6 cycloalkyl, aryl, 5 to 6 membered heteroaryl, 9 to 10 membered heteroaryl, 4 to 6 membered saturated heterocyclyl or 9 to 10 membered saturated, partially unsaturated or benzo-fused heterocyclyl is optionally substituted with one to three R 0 substituents;
wherein each R 0 is independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy, —NR A R B , —C(O)—(C 1-4 alkyl), —S—(C 1-4 alkyl), —SO—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl), —C 3-6 cycloalkyl, —(C 1-2 alkyl)-C 3-6 cycloalkyl, —C(O)—C 3-6 cycloalkyl, —(C 1-2 alkyl)-phenyl and 5 to 6 membered saturated heterocyclyl;
wherein the C 3-6 cycloalkyl or 5 to 6 membered saturated heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl and hydroxy substituted C 1-2 alkyl;
wherein R A is selected from the group consisting of hydrogen and C 1-4 alkyl; and wherein R B is selected from the group consisting of hydrogen, formyl, C 1-6 alkyl, C 3-6 cycloalkyl and 5 to 6 membered saturated heterocyclyl; wherein the R B 5 to 6 membered saturated heterocyclyl is optionally substituted with C 1-4 alkyl;
R 2 is selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, fluorinated C 1-3 alkyl, C 1-4 alkoxy, benzyloxy and —NR X R Y ;
wherein R X is selected from the group consisting of hydrogen, C 1-4 alkyl and (C 2-4 alkyl)-O—(C 1-2 alkyl); and wherein R Y is selected from the group consisting of hydrogen, C 1-4 alkyl, —(C 2-4 alkyl)-O—(C 1-2 alkyl), C 3-6 cycloalkyl and C(O)—C 3-6 cycloalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, methyl and trifluoromethyl;
n is 1; and m is 1; such that

 is piperidin-1,4-diyl;
R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl;
R 5 is selected from the group consisting of hydrogen, hydroxy and C 1-3 alkyl;

 is selected from the group consisting of,

wherein R 6 is selected from the group consisting of aryl, 5 to 6 membered heteroaryl and 9 to 10 membered heteroaryl;
wherein the aryl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, trifluoromethyl, hydroxy substituted C 1-3 alkyl, C 1-4 alkoxy, NR P R Q , —(C 1-2 alkyl)-NR P R Q , C 3-6 cycloalkyl, —(C 1-2 alkyl)-C 3-6 cycloalkyl, 5 to 6 membered saturated heterocyclyl and 5 to 6 membered hereroaryl; wherein R P and R Q are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
wherein R 7 is selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl and trifluoromethyl;
wherein

 represents a 9 to 10 membered bicyclic, partially unsaturated or aromatic heterocyclyl; and wherein the

 is optionally substituted with one to three substituents independently selected from the group consisting of halogen, oxo, cyano, C 1-4 alkyl, trifluoromethyl, C 1-4 alkoxy, NR S R T and cyclopropyl; wherein R S and R T are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

2. A compound as in claim 1 , wherein
R 1 is selected from the group consisting of C 1-6 alkyl, fluorinated C 1-3 alkyl, C 3-6 cycloalkyl, aryl, 5 to 6 membered heteroaryl, 9 to 10 membered heteroaryl, 4 to 6 membered saturated heterocyclyl and 9 to 10 membered benzo-fused heterocyclyl;
wherein the C 3-6 cycloalkyl, aryl, 5 to 6 membered heteroaryl, 9 to 10 membered heteroaryl, 4 to 6 membered saturated heterocyclyl or 9 to 10 membered benzo-fused heterocyclyl is optionally substituted with one to three R 0 substituents;
wherein each R 0 is independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy, —NR A R B , —C(O)—(C 1-4 alkyl), —S—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl), —C 3-6 cycloalkyl, —(C 1-2 alkyl)-C 3-6 cycloalkyl, —C(O)—C 3-6 cycloalkyl, —(C 1-2 alkyl)-phenyl and 5 to 6 membered saturated heterocyclyl;
wherein the C 3-6 cycloalkyl or 5 to 6 membered saturated heterocyclyl is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 alkyl and hydroxy substituted C 1-2 alkyl;
wherein R A is selected from the group consisting of hydrogen and C 1-4 alkyl; and wherein R B is selected from the group consisting of hydrogen, formyl, C 1-6 alkyl, C 3-6 cycloalkyl and 5 to 6 membered saturated, nitrogen containing heterocyclyl; wherein the R B 5 to 6 membered saturated, nitrogen containing heterocyclyl is optionally substituted with C 1-4 alkyl;
R 2 is selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy, benzyloxy and —NR X R Y ;
wherein R X is selected from the group consisting of hydrogen, C 1-4 alkyl and —(C 2-4 alkyl)-O—(C 1-2 alkyl); and wherein R Y is selected from the group consisting of hydrogen, C 1-4 alkyl, —(C 2-4 alkyl)-O—(C 1-2 alkyl), C 3-6 cycloalkyl and —C(O)—C 3-6 cycloalkyl;
R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl and trifluoromethyl;
R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl;
R 5 is selected from the group consisting of hydrogen, hydroxy and C 1-3 alkyl;

 is selected from the group consisting of,

wherein R 6 is selected from the group consisting of aryl, 5 to 6 membered heteroaryl and 9 to 10 membered heteroaryl;
wherein the aryl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C 1-4 alkyl, trifluoromethyl, hydroxy substituted C 1-2 alkyl, C 1-4 alkoxy, NR P R Q , —(C 1-2 alkyl)-NR P R Q , C 3-6 cycloalkyl, —(C 1-2 alkyl)-C 3-6 cycloalkyl, 5 to 6 membered saturated, nitrogen containing heterocyclyl and 5 to 6 membered nitrogen containing hereroaryl; wherein R P and R Q are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
wherein R 7 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, C 1-4 alkyl and trifluoromethyl;
wherein

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Connolly Peter J
• Lu Tianbao

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/02

  specific for leukemia · CPC title