Substituted bicyclic compounds as farnesoid X receptor modulators

Patent metadata

Field	Value
Publication number	US-11713312-B2
Application number	US-202117544490-A
Country	US
Kind code	B2
Filing date	Dec 7, 2021
Priority date	Feb 15, 2019
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

Disclosed are compounds of Formula (I):or a stereoisomer, a tautomer, or a salt or solvate thereof, wherein all the variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. Also disclosed are 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 a cyclic group selected from cyclopropyl, spiro[3.3]heptenyl, bicyclo[2.2.2]octanyl, azetidinyl, morpholinyl, oxaazaspiro[3.3]heptanyl, piperazinyl, piperidinyl, [1,2,4]triazolo[1,5-a] pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 1H-pyrazolo[3,4-b] pyridinyl, 2,3-dihydrobenzo[d]oxazolyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, benzo[d][1,3]dioxolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazolyl, indazolyl, indolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[2,1-f] [1,2,4]triazinyl, quinolinyl, tetrahydropyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[5,4-b] pyridinyl, thiazolyl, thieno[3,2-b]pyridinyl, and triazolyl, wherein said cyclic group is substituted with zero to 2 R 1 ;
each R 1 is independently hydrogen, halo, cyano, hydroxyl, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(O)(C 1-6 alkyl), —C(O)(C 3-6 cycloalkyl), —NR x C(O)R y , —C(O)OR x , —C(O)NR w R w , —S(O) 2 (C 1-6 alkyl), —S(O) 2 (C 3-6 cycloalkyl), —NR x S(O) 2 (C 1-6 alkyl), —NR x S(O) 2 (C 3-6 cycloalkyl), —S(O) 2 NR z R z , —P(O)R y R y , —(CH 2 ) 0-3 (C 3-6 carbocyclyl), —O(C 3-6 cycloalkyl), —O(4- to 6-membered heterocyclyl), (CH 2 ) 0-3 (4- to 6-membered heterocyclyl), or —(CH 2 ) 0-3 (5- or 6-membered heteroaryl), wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is substituted with zero to 4 R 1a and each of said cycloalkyl, heterocyclyl, and heteroaryl is substituted with zero to 4 R 1b ;
each R 1a 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 ;
each R 1b 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 1a ;
R 2 is:
(i) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, or —NR v R y , wherein each of said alkyl, alkenyl, alkynyl, and alkoxy is substituted with zero to 6 R 2a ;
(ii) C 3-5 carbocyclyl, C 6-8 spirobicyclyl, or 4- to 5-membered heterocyclyl, wherein each of said carbocyclyl, spirobicyclyl, and heterocyclyl 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), —NR x S(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 1-4 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 3a and R 3b are independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl, or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C 3-6 cycloalkyl;
A is oxadiazolyl substituted with zero to 3R 4a ;
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 ;
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 v is independently hydrogen, C 1-6 alkyl, or alternatively, two R v , 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;
each R y is independently 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:
each R 1 is independently F, Cl, Br, cyano, hydroxyl, oxo, —NR x R x , C 1-5 alkyl, C 1-4 alkoxy, —NR x (C 1-4 alkyl), —NR x C(O)R y , —C(O)(C 1-4 alkyl), —C(O)OR x , —C(O)NR w R w , —S(O) 2 (C 1-4 alkyl), —S(O) 2 (C 3-6 cycloalkyl), —NR x S(O) 2 (C 1-4 alkyl), —NR x S(O) 2 (C 3-6 cycloalkyl), —S(O) 2 NR z R z , —P(O)R y R y , —(CH 2 ) 0-3 (C 3-6 carbocyclyl), —O(C 3-6 cycloalkyl), —O(4- to 6-membered heterocyclyl), —(CH 2 ) 0-3 (4- to 6-membered heterocyclyl), or —(CH 2 ) 0-3 (5- or 6-membered heteroaryl), wherein each of said alkyl and alkoxy is substituted with zero to 4 R 1a and each of said cycloalkyl,

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• C07D413/12 Primary

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D271/06 Primary

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• C07D217/06 Primary

  with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D403/12

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