US 12,227,496 B2
Substituted bicyclic compounds as farnesoid X receptor modulators
Dean A. Wacker, Yardley, PA (US); Susheel Jethanand Nara, Mumbai (IN); Srinivas Cheruku, Bangalore (IN); Kandhasamy Sarkunam, Hosur (IN); Firoz Ali Jaipuri, Bangalore (IN); Rishikesh Narayan, Mumbai (IN); Subba Reddy Bandreddy, Bangalore (IN); and Srinivas Jogi, Bangalore (IN)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Appl. No. 17/431,006
Filed by BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
PCT Filed Feb. 14, 2020, PCT No. PCT/US2020/018210
§ 371(c)(1), (2) Date Aug. 13, 2021,
PCT Pub. No. WO2020/168148, PCT Pub. Date Aug. 20, 2020.
Claims priority of provisional application 62/806,042, filed on Feb. 15, 2019.
Prior Publication US 2022/0162201 A1, May 26, 2022
Prior Publication US 2023/0109670 A9, Apr. 6, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 413/12 (2006.01); C07D 217/06 (2006.01); C07D 271/06 (2006.01); C07D 403/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01); C07D 417/14 (2006.01)
CPC C07D 413/12 (2013.01) [C07D 217/06 (2013.01); C07D 271/06 (2013.01); C07D 403/12 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01)] 11 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a stereoisomer, a tautomer, or a salt thereof, wherein:
X1 is CR5a or N;
X2 is CR5b or N;
X3 is CR5c or N;
X4 is CR5d or N; provided that zero, 1, or 2 of X1, X2, X3, and X4 are N;
Z1 and Z2 are independently CH2 or O; provided that at least one of Z1 and Z2 is CH2;
a is zero or 1;
b is zero, 1, or 2;
d is zero, 1, or 2; provided that Z1 and Z2 are each CH2 when a, b, and d are each zero;
Q is a cyclic group selected from 3- to 8-membered carbocyclyl, 6- to 10-membered aryl, 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein said cyclic group is substituted with zero to 4 R1;
each R1 is independently hydrogen, halo, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —C(O)(C1-6 alkyl), —C(O)(C3-6 cycloalkyl), —NRxC(O)Ry, —C(O)ORx, —C(O)NRwRw, —S(O)2(C1-6 alkyl), —S(O)2(C3-6 cycloalkyl), —NRxS(O)2(C1-6 alkyl), —NRxS(O)2(C3-6 cycloalkyl), —S(O)2NRzRz, —P(O)RyRy, —(CH2)0-3(C3-6 carbocyclyl), —O(C3-6 cycloalkyl), —O(4- to 6-membered heterocyclyl), —(CH2)0-3(4- to 6-membered heterocyclyl), or —(CH2)0-3(5- or 6-membered heteroaryl), wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is substituted with zero to 4 R1a and each of said cycloalkyl, heterocyclyl, and heteroaryl is substituted with zero to 4 R1b;
each R1a is independently halo, hydroxyl, —NRwRw, oxo, cyano, C1-3 alkoxy, C1-3 haloalkoxy, —C(O)ORx, —C(O)NRwRw, or —NRxC(O)Ry;
each R1b is independently halo, oxo, cyano, hydroxyl, —NH2, C1-6 alkyl, C1-6 alkoxy, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, or —NRxC(O)(C1-6 alkyl), wherein each of said alkyl and alkoxy is substituted with zero to 6 R1a,
R2 is C6-8 carbocyclyl, 6- to 7-membered heterocyclyl, phenyl, or 6-membered heteroaryl, wherein each of said carbocyclyl, heterocyclyl, phenyl, and heteroaryl is substituted with zero to 3 R2b;
each R2a is independently halo, cyano, hydroxyl, oxo, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, —NRxRx, —C(O)(C1-6 alkyl), —C(O)(C3-6 cycloalkyl), —NRxC(O)Ry, —C(O)(C1-6 alkyl), —C(O)ORx, —C(O)NRwRw, —S(O)2Ry, —S(O)2(C1-3 fluoroalkyl), —NRxS(O)2(C1-3 alkyl), —NRxS(O)2(C3-6 cycloalkyl), —S(O)2NRzRz, or —P(O)RyRy;
each R2b is independently halo, cyano, hydroxyl, oxo, C1-6 alkyl, C1-6 alkoxy, —NRxRx, —NRxC(O)O(C1-3 alkyl), —C(O)(C1-4 alkyl), —C(O)O(C1-4 alkyl), or —S(O)2(C1-3 alkyl), wherein each of said alkyl and alkoxy is substituted with zero to 6 R2a;
each R2b is independently halo, cyano, hydroxyl, oxo, C1-6 alkyl, C1-6 alkoxy, —NRxRx, —NRxC(O)O(C1-3 alkyl), —C(O)(C1-4 alkyl), —C(O)O(C1-4 alkyl), —C(O)NRwRw, —NRxC(O)Ry, —NRxS(O)2(C1-3 alkyl), —NRxS(O)2(C3-6 cycloalkyl), —S(O)2NRzRz, or —S(O)2(C1-3 alkyl), wherein each of said alkyl and alkoxy is substituted with zero to 6 R2a,
R3a and R3b are independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, or C3-6 cycloalkyl, or R3a and R3b taken together with the carbon atom to which they are attached, form a C3-6 cycloalkyl;
A is:
(i) cyano;
(ii) a 5-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, substituted with zero to 3 R4a, or

OG Complex Work Unit Chemistry
each R4a is independently halo, cyano, hydroxyl, —NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, —(CH2)0-3NH(C1-6 alkyl), —(CH2)0-2N(C1-6 alkyl)2, —(CH2)0-3(C3-6 cycloalkyl), or —(CH2)0-3(4- to 6-membered heterocyclyl), wherein each of said alkyl, alkoxy, alkenyl, and alkynyl is substituted with zero to 6 R4d and each of said cycloalkyl and heterocyclyl is substituted with zero to 3 R4e;
R4b is C1-6 alkyl, —(CH2)0-3(C3-6 cycloalkyl), or —(CH2)0-3(4- to 6-membered heterocyclyl), wherein each of said alkyl is substituted with zero to 6 R4d and each of said cycloalkyl and heterocyclyl is substituted with zero to 3 R4e;
each R4c is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, —S(O)2(C1-3 alkyl), 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl;
each R4d is independently halo, hydroxyl, —NRxRx, oxo, cyano, C1-3 alkoxy, or C1-3 haloalkoxy;
each R4e is independently halo, oxo, cyano, hydroxyl, —NH2, C1-6 alkyl, C1-6 alkoxy, —NH(C1-6 alkyl), or —N(C1-6 alkyl)2, wherein each of said alkyl and alkoxy is substituted with zero to 6 R4d;
each of R5a, R5b, R5c, and R5d is independently hydrogen, halo, hydroxy, cyano, C1-6 alkyl substituted with zero to 6 R5e, C1-6 alkoxy substituted with zero to 6 R5e, —C(O)ORx, —C(O)NRwRw, —S(O)2Ry, —S(O)2NRzRz, or phenyl substituted with zero to 3 R5f;
each of R5e is independently halo, hydroxyl, —NRxRx, oxo, cyano, C1-3 alkoxy, or C1-3 haloalkoxy;
each R5f is independently halo, oxo, cyano, hydroxyl, —NH2, C1-6 alkyl, C1-6 alkoxy, —NH(C1-6 alkyl), or —N(C1-6 alkyl)2, wherein each of said alkyl and alkoxy is substituted with zero to 6 R5e;
each Rw is independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or alternatively, two Rw, 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 Rx is independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl;
Ry is C1-6 alkyl or C3-6 cycloalkyl; and
each Rz is independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or alternatively, two Rz, 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.