Therapeutic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10787446-B2
Application number	US-201815939112-A
Country	US
Kind code	B2
Filing date	Mar 28, 2018
Priority date	Sep 28, 2015
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

Abstract

The invention provides a compound of formula:

or a salt thereof, wherein the variables R AA , n, ring A, ring B, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —C(═O)OR A1 , —SO 2 R A1 , —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 3-15 membered carbocyclyl, 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, and C 1-4 (halo)alkoxy; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
ring “A” is a 5-6 membered heterocycle;
R 1a is H or C 1-4 alkyl;
R 1b is H or C 1-4 alkyl;
R 2 is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and aryl(C 1-4 alkyl); and R 7 is selected from the group consisting of 3-15 membered heterocyclyl, 5-12 membered heteroaryl, —C(O)N(R c ) 2 and —C(═NCN)N(R c ) 2 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-15 membered heterocyclyl or 5-12 membered heteroaryl: wherein any C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aryl(C 1-4 alkyl), 3-15 membered heterocyclyl, and 5-12 membered heteroaryl is optionally substituted with one or more groups R d that are independently selected from the group consisting of F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
each R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, phenyl and benzyl; and
n is 0, 1, 2, 3, 4, 5, or 6;
provided at least one of R 2 , R 3 , R 4 , and R 5 is not H.

2. A compound of formula (Ix):

or a pharmaceutically acceptable salt thereof; wherein,
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —C(═O)OR A1 , —SO 2 R A1 , —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 3-15 membered carbocyclyl, 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 (halo)alkoxy, and —C(O)N(R c ) 2 ; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
ring “A” is a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl;
Ring B is a 5, 6, or 7 membered carbocyclyl or a 5, 6, or 7 membered heterocyclyl, which 5, 6, or 7 membered carbocyclyl and 5, 6, or 7 membered heterocyclyl is optionally substituted with one or more groups independently selected from C 1-4 alkyl, halo, and haloC 1-4 alkyl;
R 1b is H or C 1-4 alkyl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and aryl(C 1-4 alkyl); and R 7 is selected from the group consisting of C 1-8 alkyl, 3-15 membered heterocyclyl, 5-12 membered heteroaryl, —C(O)N(R c ) 2 and —C(═NCN)N(R c ) 2 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-15 membered heterocyclyl or 5-12 membered heteroaryl; wherein any C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aralkyl, 3-15 membered heterocyclyl, and 5-12 membered heteroaryl is optionally substituted with one or more groups R d that are independently selected from the group consisting of F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino; each R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, phenyl and benzyl; and
n is 0, 1, 2, 3, 4, 5, or 6.

3. The compound of formula (Ix) of claim 2 :

or a pharmaceutically acceptable salt thereof; wherein,
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said (3-15 membered carbocyclyl), 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino, and C 1-4 (halo)alkoxy; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl;
R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-8 alkylamino and C 1-4 dialkylamino;
ring “

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Bergeron Philippe
• Burford Kristen
• Chowdhury Sultan
• Dehnhardt Christoph Martin
• Focken Thilo
• Grimwood Michael Edward
• Hasan Abid
• Lai Kwong Wah
• Liu Zhiguo
• Mckerrall Steven
• Nguyen Teresa Phuongtram
• Safina Brian
• Sutherlin Daniel
• Wang Tao

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P17/04

  Antipruritics · CPC title

• C07D401/12

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

• C07D417/12 Primary

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title