Substituted amide compounds useful as farnesoid X receptor modulators

Patent metadata

Field	Value
Publication number	US-12030835-B2
Application number	US-202017431091-A
Country	US
Kind code	B2
Filing date	Feb 14, 2020
Priority date	Feb 15, 2019
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

Disclosed are compounds of Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is a 5-membered heterocyclyl or 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, substituted with zero to 4 R 1 ; and A, X 1 , X 2 , X 3 , X 4 , Z 1 , Z 2 , R 1 , R 2 , R 3a , R 3b , a, b, and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of farnesoid X receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a salt or solvate thereof, wherein:
X 1 is CR 5a or N;
X 2 is CR 5b or N;
X 3 is CR 5c or N;
X 4 is CR 5d or N; provided that zero, 1, or 2 of X 1 , X 2 , X 3 , and X 4 are N;
Z 1 and Z 2 are independently CH 2 or O; provided that at least one of Z 1 and Z 2 is CH 2 ;
a is zero or 1;
b is zero, 1, or 2;
d is zero, 1, or 2; provided that Z 1 and Z 2 are each CH 2 when a, b, and d are each zero;
Q is C 2-6 alkenyl or C 2-6 alkynyl, each substituted with zero to 2 R 1 ;
each R 1 is independently —C(O)OR x , —C(O)NR x R x , or C 1-4 hydroxyalkyl;
each R 1a is independently halo, oxo, cyano, hydroxyl, —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, —NH(C 1-6 alkyl), —N(C 1-6 alkyl)2, or —NR x C(O)(C 1-6 alkyl), wherein each of said alkyl and alkoxy is substituted with zero to 6 R 1b ;
each R 1b is independently halo, hydroxyl, —NR w R w , oxo, cyano, C 1-3 alkoxy, C 1-3 haloalkoxy, —C(O)OR x , —C(O)NR w R w , or —NR x C(O)R y ;
or when X 1 is CR 5a , Q and R 5a can be joined together to form a —CR 1a ═CR 1 CH 2 CH 2 — bridge;
R 2 is:
(i) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or —NR v R v , wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is substituted with zero to 6 R 2a ;
(ii) C 3-8 carbocyclyl, C 6-8 spirobicyclyl, 4- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said carbocyclyl, spirobicyclyl, heterocyclyl, phenyl, and heteroaryl is substituted with zero to 3 R 2b ; or
(iii) —CH 2 (C 3-6 cycloalkyl), —CH 2 (4- to 6-membered heterocyclyl), —NR x (CH 2 ) 0-2 (C 3-6 cycloalkyl), —NR x (CH 2 ) 0-2 (C 5-8 bicycloalkyl), —NR x (CH 2 ) 0-2 (C 5-8 spirobicyclyl), —NR x (CH 2 ) 0-2 (4- to 6-membered heterocyclyl), —NR x (CH 2 ) 0-2 (5- to 6-membered heteroaryl), —NR x (CH 2 ) 0-2 (phenyl), —O(CH 2 ) 0-2 (C 3-6 cycloalkyl), —O(CH 2 ) 0-2 (C 5-8 bicycloalkyl), —O(CH 2 ) 0-2 (C 5-8 spirobicyclyl),—O(CH 2 ) 0-2 (4- to 6-membered heterocyclyl), —O(CH 2 ) 0-2 (5- to 6-membered heteroaryl), or —O(CH 2 ) 0-2 (phenyl), wherein each of said cycloalkyl, heterocyclyl, bicycloalkyl, spirobicyclyl, aryl, and heteroaryl is substituted with zero to 3 R 2b ;

each R 2a is independently halo, cyano, hydroxyl, oxo, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, —NR x R x , —C(O)(C 1-6 alkyl), —C(O)(C 3-6 cycloalkyl), —NR x C(O)R y , —C(O)(C 1-6 alkyl), —C(O)OR x , —C(O)NR w R w , —S(O) 2 R y , —S(O) 2 (C 1-3 fluoroalkyl), —NRS(O) 2 (C 1-3 alkyl), —NR x S(O) 2 (C 3-6 cycloalkyl), —S(O) 2 NR z R z , or —P(O)R y R y ;
each R 2b is independently halo, cyano, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, —NR x R x , —NR x C(O)O(C 1-3 alkyl), —C(O)(C 1-3 alkyl), or —S(O) 2 (C 1-3 alkyl), wherein each of said alkyl and alkoxy is substituted with zero to 6 R 2a ;
R 3 a and R 3b are independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl, or R 3 a and R 3b ; taken together with the carbon atom to which they are attached, form a C 3-6 cycloalkyl;
A is:
(i) cyano;
(ii) phenyl or a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of said phenyl and heteroaryl is substituted with zero to 3 R 4a ; or

each R 4a is independently halo, cyano, hydroxyl, —NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —(CH 2 ) 0-3 NH(C 1-6 alkyl), —(CH 2 ) 0-2 N(C 1-6 alkyl) 2 , —(CH 2 ) 0-3 (C 3-6 cycloalkyl), or —(CH 2 ) 0-3 (4- to 6-membered heterocyclyl), wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is substituted with zero to 6 R 4d and each of said cycloalkyl and heterocyclyl is substituted with zero to 3 R 4e ;
R 4b is C 1-6 alkyl, —(CH 2 ) 0-3 (C 3-6 cycloalkyl), or —(CH 2 ) 0-3 (4- to 6-membered heterocyclyl), wherein each of said alkyl is substituted with zero to 6 R 4d and each of said cycloalkyl and heterocyclyl is substituted with zero to 3 R 4e ;
each R 4 , is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl;
each R 4d is independently halo, hydroxyl, —NR x R x , oxo, cyano, C 1-3 alkoxy, or C 1-3 haloalkoxy;
each R 4e is independently halo, oxo, cyano, hydroxyl, —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, —NH(C 1-6 alkyl), or —N(C 1-6 alkyl) 2 , wherein each of said alkyl and alkoxy is substituted with zero to 6 R 4d ;
each of R 5a , R 5b , R 5c , and R 5d is independently hydrogen, halo, hydroxy, cyano, C 1-6 alkyl substituted with zero to 6 R 5e , C 1-6 alkoxy substituted with zero to 6 R 5e , —C(O)OR x , —C(O)NR w R w , —S(O) 2 R y , —S(O) 2 NR z R z , or phenyl substituted with zero to 3 R 5f ;
each of R 5e is independently halo, hydroxyl, —NR x R x , oxo, cyano, C 1-3 alkoxy, or C 1-3 haloalkoxy;
each R 5f is independently halo, oxo, cyano, hydroxyl, —NH 2 , C 1-6 alkyl, C 1-6 alkoxy, —NH(C 1-6 alkyl), or —N(C 1-6 alkyl) 2 , wherein each of said alkyl and alkoxy is substituted with zero to 6 R 5e ;
each R is independently hydrogen, C 1-6 alkyl, or alternatively, two R, taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered bicyclic or spirocyclic ring moiety containing zero to 2 additional heteroatoms independently selected from N, O, and S, wherein each ring can be substituted with zero to 6 R 2a ;
each R w is independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or alternatively, two R w , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O, and S;
each R x is independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R y is C 1-6 alkyl or C 3-6 cycloalkyl; and
each R z is independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or alternatively, two R z , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O, and S.

2. The compound according to claim 1 or a stereoisomer, a tautomer, or a salt or solvate thereof, wherein:
Q is —CR 1c ═CR 1c R 1 or —C≡CR 1 ;
R 1 is —C(O)OR x , —C(O)NR x R x or C 1-4 hydroxyalkyl;
each R 1c is independently H or —CH 3 ;
or when X 1 is CR 5a , X 2 is CR 5b , X 3 is CR 5c , X 4 is CR 5d , then Q and R 5a can be joined together to form a —CR 1a ═CR 1 CH 2 CH 2 — bridge;
R 2 is:
(i) C 1-4 alkyl, C 1-4 alkoxy, or —NR R, wherein each of said alkyl and alkoxy is substituted with zero to 4 R 2a ;
(ii) C 3-8 carbocyclyl, C 6-8 spirobicyclyl, phenyl, or 4- to 7-membered heterocyclyl, wherein each of said carbocyclyl, spirobicyclyl, and heterocyclyl is substituted with zero to 3 R 2b ; or
(iii) —CH 2 (C 3-5 cycloalkyl), —CH 2 (4- to 6-membered heterocyclyl), —NR x (CH 2 ) 0-2 (C 3-5 cycloalkyl), —NR x (CH 2 ) 0-2 (4- to 6-membered heterocyclyl), —NR x (CH 2 ) 0-2 (phenyl), —O(phenyl), or —S(O) 2 (C 3-6 cycloalkyl), wherein each of said cycloalkyl, heterocyclyl, and phenyl is substituted with zero to 3 R 2b ;

each R 2a is independently F, Cl, hydroxyl, —NR x R x , oxo, cyano, C 1-3 alkoxy, C 1-3 haloalkoxy, or —C(O)OH;
each R 2 b is independently F, Cl, cyano, hydroxyl, C 1-4 alkyl, C 1-3 alkoxy, —NR x R x , —NR x C(O)O(C 1-3 alkyl), —C(O)(C 1-2 alkyl), or

Assignees

• Bristol Myers Squibb Co

Inventors

• Wacker Dean A
• Nara Susheel Jethanand
• Cheruku Srinivas
• Sarkunam Kandhasamy
• Jaipuri Firoz Ali
• Thangavel Soodamani
• Narayan Rishikesh
• Bandreddy Subba Reddy
• Jogi Srinivas
• Kathi Pavan Kalyan

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D309/04

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D295/04

  with substituted hydrocarbon radicals attached to ring nitrogen atoms · CPC title