Therapeutic compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10457654-B2
Application number	US-201715799771-A
Country	US
Kind code	B2
Filing date	Oct 31, 2017
Priority date	Oct 17, 2016
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

The invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables X, Y 1 —Y 5 , R 1 , R 2 , R 3 , R 4 , and Het 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:
R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, C 1 -C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, hydroxy, C 1 -C 6 alkoxy, nitro, and halo, wherein any C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, and phenyl; and Z is selected from —N(R 5 )—, —O—, —S—, —S(O)—,and —S(O) 2 —;
or
R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, cyano, halo, and C 1 -C 6 haloalkyl; and R 4 and Z together with the benzene ring to which they are both attached form a 9- or 10-membered heterobicycle;
Het is 5- or 6-membered heteroaryl optionally substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, cyano, halo, and C 1 -C 6 haloalkyl;
X is selected from —N(R 6 ) 2 and —N(R 7 ) 3 +− W and amine oxides thereof;
Y 1 is —C(R 8 ) 2 —; and Y 2 is selected from —(C(R 8 ) 2 ) n —, —N(R 9 )—, —O —, —C(R 8 ) 2 —N(R 9 )—, —N(R 9 )—C(R 8 ) 2 —, —C(R 8 ) 2 —O—, and —O—C(R 8 ) 2 —;
or
Y 1 is selected from —N(R 9 )—and —O—; and Y 2 is —(C(R 8 ) 2 ) n —;
n is selected from 0, 1, and 2;
Y 3 and Y 6 are each —C(R 8 ) 2—;
Y 4 and Y 5 are each —C(R 8 )—;
R 5 is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each R 6 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkanoyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, and C 6 -C 12 aryl, wherein any C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkanoyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, and C 6 -C 12 aryl is optionally substituted with one or more groups independently selected from deuterium, halo, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, —NR a R b , —C(═O) NR a R b R c , and phenyl, wherein any C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkanoyl is optionally substituted with C 3 -C 6 cycloalkyl; or two R 6 groups together with the nitrogen to which they are both attached form a 4- to 10-membered heterocycle that is optionally substituted with one or more groups independently selected from deuterium, halo, cyano, hydroxy, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl, which C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl is optionally substituted with one or more groups independently selected from hydroxy and halo;
each R 7 is independently selected from C 1 -C 6 alkyl; or two R 7 groups together with the nitrogen to which they are both attached form a 4- to 7-membered heterocycle;
each R 8 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, benzyl, 5-15 membered heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkoxy, hydroxy, halo, cyano, and -L-C 6 -C 12 aryl;
wherein each C 3 -C 6 cycloalkyl, -L-C 6 -C 12 aryl, benzyl, 5-15 membered heteroaryl, and C 1 -C 6 alkoxy, is optionally substituted with one to three substituents R x each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, halo, hydroxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 halocycloalkyl, —S(C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O) 2 (C 1 -C 6 alkyl), —NH 2 —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , 4-6 membered heterocycle, and C 1 -C 6 haloalkyl or two R 8 that are on adjacent carbons taken together form a double bond; and R 9 is selected from hydrogen, C 1 -C 6 alkyl and C 6 -C 12 aryl, which C 6 -C 12 aryl is optionally substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, halo, and C 1 -C 6 haloalkyl; or one R 8 or R 9 taken together with another R 8 or R 9 and the atoms to which they are attached form a 3-8 membered fused, bridged or spirocyclic ring, which 3-8 membered ring is optionally substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, halo, and C 1 -C 6 haloalkyl; and L is selected from a bond, —O—, —S—, —S(O)—, and —S(O) 2 —;
each R a and R b is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkanoyl;
each R c is independently selected from 4-7 membered heterocycle that is optionally substituted with one or more groups independently selected from halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
W − is a counterion.

2. The compound of claim 1 wherein:
R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, C 1 -C 6 alkyl, cyano, C 3 -C 6 cycloalkyl, halo, and C 1 -C 6 haloalkyl; and Z is selected from —N(R 5 )—, —O —, —S—, —S(O)—, and —S(O) 2 —;
or
R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, cyano, halo, and C 1 -C 6 haloalkyl; and R 4 and Z together with the benzene ring to which they are both attached form a 9- or 10-membered heterobicycle;
Het is 5- or 6-membered heteroaryl optionally substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, cyano, halo, and C 1 -C 6 haloalkyl;
X is selected from —N(R 6 ) 2 and —N(R 7 ) 3 +− W;
Y 1 is —C(R 8 ) 2 —; and Y 2 is selected from —(C(R 8 ) 2 ) n—, —N(R 9 )—, —O —,
—C(R 8 ) 2 —N(R 9 )—, —N(R 9 )—C(R 8 ) 2 —, —C(R 8 ) 2 —O—, and —O—C(R 8 ) 2 —;
or
Y 1 is selected from —N(R 9 )—and —O —; and Y 2 is —(C(R 8 ) 2 ) n —;
n is selected from 0, 1, and 2;
Y 3 and Y 6 are each —C(R 8 ) 2 —;
Y 4 and Y 5 are each —C(R 8 )—;
R 5 is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each R 6 is independently selected from hydrogen, C 2 -C 6 alkoxyalkyl, C 1 -C 6 alkyl, benzyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, and phenyl; or two R 6 groups together with the nitrogen to which they are both attached form a 4- to 7-membered heterocycle;
each R 7 is independently selected from C 1 -C 6 alkyl; or two R 7 groups together with the nitrogen to which they are both attached form a 4- to 7-membered heterocycle;
each R 8 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, hydroxyl, halo, cyano, benzyl and phenyl; wherein each benzyl or phenyl is optionally substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, cyano, halo, and C 1 -C 6 haloalkyl or two R 8 that are on adjacent carbons taken together form a double bond; and R 9 is selected from hydrogen and C 1 -C 6 alkyl; or one R 8 or R 9 taken together with another R 8 or R 9 and the atoms to which they are attached form a 3-8 membered fused, bridged or spirocyclic ring; and
W is a counterion; or a pharmaceutically acceptable salt thereo.

3. The compound of claim 1 which is a compound of formula (Ik):

wherein:
n is 1, 2, or 3; and
each R x is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, halo, hydroxy, C 3 -C 6 cycloalkoxy, C 3 -C 6 halocycloalkyl, —S(C 1 -C 6 alkyl), —S(O)(C 1 -C 6 alkyl), —S(O) 2(C 1 -C 6 alkyl), —NH 2 —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , 4-6 membered heterocycle, and C 1 -C 6 haloalkyl;
or a pharmaceutically acceptable salt thereof.

4. The com

Assignees

• Genentech Inc
• Xenon Pharmaceuticals Inc

Inventors

• Sutherlin Daniel
• Mckerrall Steven
• Wilson Michael Scott
• Lai Kwong Wah
• Bergeron Philippe
• Zhang Birong
• Beveridge Ramsay
• Leclerc Jean-Philippe
• Lemire Alexandre
• Zhao Liang
• Sturino Claudio

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P17/04

  Antipruritics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D417/12

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

• C07D403/12

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