Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9789118-B2
Application number	US-201414188647-A
Country	US
Kind code	B2
Filing date	Feb 24, 2014
Priority date	Jul 29, 2010
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The present invention provides compounds of formula (IV);

or pharmaceutically acceptable salts thereof, wherein the variables are defined as herein. The present invention provides a method for manufacturing the compounds of formula (IV), their therapeutic uses, combinations with other of pharmacologically active agents, and a pharmaceutical compositions.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IV):

wherein:
one of X 5 or X 6 is N and the other is CH; and
p is 0, 1, 2, or 3
Q is selected from the group consisting of:

wherein the symbol

indicates the point of attachment to ring B;
X 4 is —NR 4 — or —O—;
q and n are each, independently, 0, 1, 2, 3, or 4;
L 1 is —NHSO 2 —, —SO 2 NH—, —NHSO 2 NH— or —NHC(O)NH—;
R 1 may replace a hydrogen atom of any CH bond in ring A and, for each occurrence, is independently deutero, hydroxy, nitro, halo, cyano, carboxy, formyl, C 1-7 alkyl, C 3-8 carbocyclyl, C 2-7 alkenyl, C 2-7 alkynyl, C 1-7 alkoxy, C 1-7 alkylthio, C 3-8 cycloalkoxy, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 6-10 aryloxy, amino, N—C 1-7 alkylamino, N,N-di-(C 1-7 alkyl)amino, N—C 6-10 arylamino, 3- to 10-membered heterocyclyl, N-(3- to 10-membered heterocyclyl)amino, (3- to 10-membered heterocyclyl)oxy, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)C 1-4 alkyl, N-(5- to 10-membered heteroaryl)amino, (5- to 10-membered heteroaryl)oxy, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, C 1-7 alkylamido, C 6-10 arylamido, (3- to 10-membered heterocyclyl)amido, carbamoyl, N—C 1-7 alkylcarbamoyl, N,N-di-(C 1-7 alkyl)carbamoyl, C 1-7 alkoxyamido, C 1-7 alkylureido, and C 6-10 arylureido, wherein R 1 is optionally substituted on one or more carbon atom with one or more independently selected R 13 ; and wherein when R 1 comprises a heterocyclyl or a heteroaryl comprising one or more —NH—, the hydrogen of each —NH— group may be independently optionally replaced with R 22 ; or two R 1 on the same carbon atom together may form an oxo; or two R 1 on the same carbon atom together with the carbon to which they are attached form a spiro C 3-8 carbocyclyl; or two R 1 on adjacent carbon atoms together with the carbon atoms to which they are attached may form a fused C 3-8 carbocyclyl or phenyl which may be optionally substituted with one or more R 13 ; and
R 3 is selected from the group consisting of a C 1-7 alkyl, C 3-8 carbocyclyl, C 3-8 carbocyclylC 1-4 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, a 5- to 10-membered heteroaryl, a (5- to 10-membered heteroaryl)C 1-4 alkyl, a 3- to 10-membered heterocyclyl, and a (3- to 10-membered heterocyclyl)C 1-4 alkyl, wherein R 3 is optionally substituted on one or more carbon atom with one or more R 14 ; and wherein when R 3 comprises a heteroaryl or heterocyclyl comprising one or more —NH—, the hydrogen of each —NH— group may be independently optionally replaced with a C 1-7 alkyl;
R 4 is hydrogen, C 1-7 alkyl, or C 1-4 alkoxyC 1-4 alkyl; or R 3 and R 4 , together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, wherein the heterocyclyl may be optionally substituted on one or more carbon atoms with one or more R 15 ; and wherein when the heterocyclyl comprises one or more —NH—, the hydrogen of each —NH— group may be independently optionally replaced with R 16 ;
R 13 , for each occurrence, is independently deutero, nitro, halo, cyano, hydroxy, carboxy, C 1-7 alkyl, C 3-8 cycloalkyl, C 1-7 alkoxy, C 6-10 aryl, C 6-10 aryloxy, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, amino, C 1-7 alkylamino, di-(C 1-7 alkyl)amino, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, C 1-7 alkylamido, C 1-7 alkoxyamido, carbamoyl, N—C 1-7 alkylcarbamoyl, N,N-di-(C 1-7 alkyl)carbamoyl, C 1-7 alkylsufonyl, C 1-7 alkylsulfonyloxy, C 1-7 alkylsulfonamido, sulfamoyl, N—C 1-7 alkylsulfamoyl, or N,N-di-(C 1-7 alkyl)sulfamoyl, wherein R 13 is optionally substituted on one or more carbon atom with one or more independently selected R 17 ; and wherein when R 13 is a heterocyclyl or a heteroaryl comprising one or more —NH—, the hydrogen of each —NH— group may be independently optionally replaced with R 20 ; or two R 13 on the same carbon atom together may form an oxo or a spiro C 3-8 carbocyclyl; or two R 13 on adjacent carbon atoms together with the carbons to which they are attached may form a 3- to 7-membered heterocyclyl which may be optionally substituted on one or more carbon atom with one or more R 17 and if the heterocyclyl comprises one or more —NH— group, the hydrogen of each —NH— group may be independently optionally replaced with R 20 ;
R 14 , for each occurrence, is independently halo, hydroxy, carboxy, C 1-7 alkoxycarbonyl, C 1-7 alkyl, C 1-7 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein R 14 may be optionally substituted on one or more carbon atoms with one or more independently selected R 24 ; or two R 14 on the same carbon atom together may form an oxo, a spiro C 3-8 carbocyclyl or a 3- to 7-membered spiro heterocyclyl; or two R 14 on adjacent carbon atoms together with the carbon atoms to which they are attached may form a phenyl which may be optionally substituted on one or more carbon atoms with one or more R 24 ;
R 15 , for each occurrence, is independently selected from the group consisting of hydroxy, carboxy, C 1-7 alkyl, C 1-7 alkoxy, C 3-8 carbocyclyl, phenyl, and C 1-7 alkoxycarbonyl; wherein R 15 may be optionally substituted on one or more carbon atoms with one or more substituent independently selected from halo, hydroxy, C 1-4 alkoxy; or two R 15 on the same carbon atom together form an oxo or together with the carbon atom to which they are attached form a C 2-8 cycloalkyl or a 3- to 10-membered heterocyclyl; or two R 15 on adjacent carbon atoms together with the carbon atoms to which they are attached may form a fused phenyl;
R 16 , for each occurrence, is independently selected from the group consisting of C 1-7 alkyl, C 3-8 carbocyclyl, C 1-7 alkanoyl, C 1-7 alkoxycarbonyl, or 5- to 10-membered heteroaryl;
R 17 , for each occurrence, is independently selected from cyano, halo, hydroxy, carboxy, C 1-7 alkyl, C 1-7 alkoxy, amino, C 1-7 alkylamino, di-(C 1-7 alkyl)amino, C 6-10 arylamino, C 6-10 arylC 1-4 alkylamino, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, 3- to 10-membered heterocyclyl, wherein R 17 may be optionally substituted on one or more carbon atoms with one or more independently selected halo, amino, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 haloalkyl, carboxy, or C 1-7 alkyoxycarbonyl; and wherein when R 17 is a heterocyclyl comprising one or more —NH—, the hydrogen of each —NH— group may be independently optionally replaced with R 23 ; or two R 17 on the same carbon atom together may form an oxo;
R 18 is a C 1-7 alkyl, C 3-8 cycloalkyl, phenyl or a C 1-7 alkoxyC 1-7 alkyl;
R 20 , R 22 , and R 23 , for each occurrence, are independently deutero, halo, carboxy, C 1-7 alkyl, C 1-7 alkoxy, C 6-10 aryloxy, C 6-10 arylC 1-4 alkoxy, or C 1-7 alkoxycarbonyl; and
R 24 , for each occurrence, is independently hydroxy, halo, carboxy, C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 alkoxy, amino, N—C 1-7 alkylamino, N,N-di-(C 1-7 alkyl)amino, C 1-7 alkoxycarbonyl, C 1-7 alkanoyloxy, phosphonooxy, C 1-7 alkoxy(hydroxy)phosphoryloxy or di-(C 1-7 alkoxy)phosphoryloxy; wherein R 24 may be optionally substituted on one or more carbon atom with a group independently selected from amino, N—C 1-7 alkylamino, and phenyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IVa):

wherein “*” indicates a carbon where the sulfamoyl group may be attached.

Assignees

• Barnes David Weninger
• Bebernitz Gregory Raymond
• Clairmont Kevin
• Cohen Scott Louis
• Damon Ii Robert Edson
• Day Robert Francis
• Dodd Stephanie Kay
• Gaul Christoph
• Gulgeze Efthymiou Hatice Belgin
• Jain Monish
• Karki Rajeshri Ganesh
• Kirman Louise Clare
• Lin Kai
• Mao Justin Yik Ching
• Patel Tajesh Jayprakash
• Raymer Brian Kenneth
• Liansheng Su
• Novartis Ag

Inventors

• Barnes David Weninger
• Bebernitz Gregory Raymond
• Clairmont Kevin
• Cohen Scott Louis
• Damon Ii Robert Edson
• Day Robert Francis
• Dodd Stephanie Kay
• Gaul Christoph
• Gulgeze Efthymiou Hatice Belgin
• Jain Monish
• Karki Rajeshri Ganesh
• Kirman Louise Clare
• Lin Kai
• Mao Justin Yik Ching
• Patel Tajesh Jayprakash
• Raymer Brian Kenneth
• Liansheng Su

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title