Compounds for inhibition of alpha 4 beta 7 integrin

Patent metadata

Field	Value
Publication number	US-11224600-B2
Application number	US-201916667373-A
Country	US
Kind code	B2
Filing date	Oct 29, 2019
Priority date	Oct 30, 2018
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 and X 2 are each independently selected from CR 10 and N;
X 3 and X 5 are each independently selected from NR 11 , O, S, C(O), and C(R 10 ) 2 ;
each X 4 is independently selected from NR 11 , O, S, C(O), and C(R 10 ) 2 ;
R 1 is selected from -L-A 1 , -L-A 2 , -L-A 3 , and -L-A 4 ;
L is selected from a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and —N(H)—C(O)—*; wherein * indicates a point of attachment of L to A 1 , A 2 , A 3 , or A 4 ;
A 1 is C 6-10 aryl optionally substituted with one to six R a ;
A 2 is 5-10 membered heteroaryl containing one to five heteroatoms independently selected from S, N, and O, and optionally one or two C(O); wherein A 2 is optionally substituted with one to six R a ;
A 3 is 5-10 membered cycloalkyl or 5-14 membered heterocyclyl; wherein A 3 is optionally substituted with one to six R a ; and
A 4 is —NR a1 R a2 ;
wherein each R a is independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, —S(O) m —C 1-6 alkyl, C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, —O-(3-6 membered heterocyclyl), —O—C 1-4 alkylene-C 3-8 cycloalkyl, —O-phenyl, and —O—C 3-8 cycloalkyl;
each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, and —S(O) m —C 1-6 -alkyl of R a are optionally substituted with one to three R a3 ; wherein each R a 3 is independently selected from hydroxyl, cyano, —NR a1 R a2 , C 1-6 alkoxyl, C 3-8 cycloalkyl, phenyl, and 3-6 membered heterocyclyl; wherein each C 3-8 cycloalkyl, phenyl, and 3-6 membered heterocyclyl of R a3 is independently optionally substituted with one to three R a4 ; wherein each R a4 is independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 3-8 cycloalkyl, and 3-6 membered heterocyclyl; and
each C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, —O-(3-6 membered heterocyclyl), —O—C 1-4 alkylene-C 3-8 cycloalkyl, —O-phenyl, and —O—C 3-8 cycloalkyl of R a is independently optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;

each R 2 , R 3 , R 4 , R 5 , and R 6 is independently selected from H, halo, cyano, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-8 haloalkyl, C 1-8 haloalkoxyl, —NR b1 R b2 , —R b3 S(O) m R b4 , —S(O) m R b4 , —NR b1 S(O) v R b4 , —COOR b1 , —CONR b1 R b2 , —NR b1 COOR b2 , —NR b1 COR b4 , —R b3 NR b1 R b2 , —S(O) v NR b1 R b2 , C 3-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 3-12 membered heterocyclyl;
each C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, C 1-8 haloalkyl, and C 1-8 haloalkoxyl of R 2 , R 3 , R 4 , R 5 , and R 6 is independently optionally substituted with one to two R c ; wherein each R c is independently selected from azido, oxo, cyano, halo, hydroxyl, —NR a1 R a2 , C 1-4 alkoxyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein each C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl of R c is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, —NR a1 R a2 , C 1-4 alkyl, C 1-6 haloalkyl, C 1-4 alkoxyl, and C 3-6 cycloalkyl;
each C 6-10 aryl and 5-6 membered heteroaryl of R 2 , R 3 , R 4 , R 5 , and R 6 is independently optionally substituted with one to five R b ; and

each C 3-12 cycloalkyl and 3-12 membered heterocyclyl of R 2 , R 3 , R 4 , R 5 , and R 6 is independently optionally substituted with one to six groups independently selected from ═CR b1 R b2 , and R b ;
wherein each R b is independently selected from azido, cyano, halo, hydroxyl, —NR a1 R a2 , C 1-6 alkyl, C 1-8 haloalkyl, C 1-6 alkoxyl, C 3-6 cycloalkyl, C 3-6 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocycly; wherein each C 3-6 cycloalkyl, C 3-6 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl of R b is independently optionally substituted with one to three groups independently selected from halo, hydroxyl, cyano, —NR a1 R a2 , C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxyl;
each R b1 and R b2 is independently selected from H, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 3-8 membered heterocyclyl;
each C 1-8 alkyl and C 1-6 haloalkyl of R b1 and R b2 is optionally substituted with one to two R b5 ; and
each C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 3-8 membered heterocyclyl of R b1 and R b2 is independently optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-8 alkyl, C 1-8 haloalkyl, C 1-6 alkoxyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl;

R b3 is C 1-4 alkylene;
R b4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and the 4-6 membered heterocyclyl of R b4 is optionally substituted with one to three R b6 ;
each R b5 is independently selected from cyano, hydroxyl, C 1-4 alkoxyl, C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl; wherein each C 3-8 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, and 4-6 membered heterocyclyl of R b5 is optionally substituted with one to three groups independently selected from halo, cyano, hydroxyl, —NR a1 R a2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, and phenyl; and
each R b6 is independently selected from halo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, C 3-6 cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein each C 3-6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of R b6 is independently optionally substituted with one to three groups independently selected from halo, cyano, —NR a1 R a2 , C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxyl; or
R 2 and R 3 , R 3 and R 4 , or R 5 and R 6 together with the atoms to which they are attached may form a C 1-6 aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 5-6 membered heterocyclyl;

wherein each C 6-10 aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 5-6 membered heterocyclyl is optionally substituted with one to three groups independently selected from halo, cyano, —NR a1 R a2 , C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 -aryl, 5-6 membered heteroaryl, C 1-4 alkylene-C 3-8 cycloalkyl, C 1-4 alkylene-C 6-10 aryl, and C 1-4 alkylene-(5-6 membered heteroaryl);
R 7 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;
R 8 is selected from H, C 1-4 alkyl, and C 1-4 haloalkyl;
R 9 is selected from H, C 1-6 alkyl, —C 1-4 alkylene-NR a1 R a2 , —C 1-4 alkylene-C(O)NR a1 R a2 , —C 1-4 alkylene-O—C(O)—C 1-4 alkyl, —C 1-4 alkylene-O—C(O)—O—C 1-4 alkyl, —C 1-4 alkylene-O—C(O)—C 1-4 alkylene-NR a1 R a2 , —C 1-4 alkylene-O—C 1-4 alkyl, C 3-8 cycloalkyl, —C 1-4 alkylene-C 3-8 cycloalkyl, 4-6 membered heterocyclyl, and —C 1-4 alkylene-(4-6 membered heterocyclyl);
wherein each C 3-8 cycloalkyl, —C 1-4 alkylene-C 3-8 cycloalkyl, 4-6 membered heterocyclyl and —C 1-4 alkylene-(4-6 membered heterocyclyl) of R 9 is optionally substituted with one to three groups independently selected from halo, C 1-4 alkyl, C 1-4 alkoxyl, and C 1-4 haloalkyl; or
R 9 together with th

Assignees

• Gilead Sciences Inc

Inventors

• Blomgren Peter A
• Campbell Taryn
• Chandrasekhar Jayaraman
• Clark Christopher T
• Codelli Julian A
• Currie Kevin S
• Kropf Jeffrey E
• Moazami Yasamin
• Nava Nicole
• Patel Leena
• Perreault Stephane
• Perry Jason K
• Sedillo Kassandra F
• Seeger Natalie
• Stevens Kirk L
• Treiberg Jennifer Anne
• Yeung Suet C
• Zhao Zhongdong

Classifications

• C07D307/87

  Benzo [c] furans; Hydrogenated benzo [c] furans · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D311/58

  other than with oxygen or sulphur atoms in position 2 or 4 · CPC title