US 12,492,202 B2
Macrocyclic PAD4 inhibitors useful as immunosuppressant
Khehyong Ngu, Pennington, NJ (US); Christopher Annunziato, North Lawrence, NJ (US); John V. Duncia, Newtown, PA (US); and Daniel S. Gardner, Furlong, PA (US)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Appl. No. 17/760,309
Filed by BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
PCT Filed Feb. 5, 2021, PCT No. PCT/US2021/016698
§ 371(c)(1), (2) Date Aug. 8, 2022,
PCT Pub. No. WO2021/158840, PCT Pub. Date Aug. 12, 2021.
Claims priority of provisional application 62/970,832, filed on Feb. 6, 2020.
Prior Publication US 2023/0203039 A1, Jun. 29, 2023
Int. Cl. C07D 471/22 (2006.01); A61K 45/06 (2006.01); C07D 487/22 (2006.01); C07D 498/22 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/22 (2013.01) [A61K 45/06 (2013.01); C07D 487/22 (2013.01); C07D 498/22 (2013.01); C07D 519/00 (2013.01)] 21 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
Q is selected from the group consisting of N and CH;
A is 4- to 15-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
A1 is C1-4 alkylene substituted with 0-3 R1; optionally, one or more of the methylene units of said C1-4 alkylene are replaced by O, S(O)p, NH, N(C1-4 alkyl), and C(═O);
A2 is selected from the group consisting of C3-6 carbocyclyl and 4- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, each substituted with 0-4 R2;
A3 is selected from the group consisting of C3-6 carbocyclyl and 4- to 6-membered heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, each substituted with 0-4 R2;
A4 is selected from the group consisting of C3-8 alkylene and C3-8 alkenylene, each substituted with 0-5 R1; optionally, one or more of the methylene units of said C3-8 alkylene except for the one that is directly bonded to the nitrogen atom of the indole or pyrrolopyridine moiety are replaced by O, S(O)p, NH, N(C1-4 alkyl), and C(═O);
provided that when A2 is absent, A1 is bonded directly to A3; when A3 is absent, A2 is bonded directly to A4; when A2 and A3 are both absent, A1 is bonded directly to A4 and at least two methylene units of A4 are replaced by O, S(O)p, NH, N(C1-4 alkyl), and C(═O);
R1 is selected from the group consisting of F, Cl, —ORb, and C1-3 alkyl substituted with 0-5 Rc;
R2 is selected from the group consisting of F, Cl, CN, =O, C(═O)NRaRa, and C1-3 alkyl substituted with 0-5 Rc;
R3 is selected from the group consisting of F, Cl, Br, —ORb, and C1-3 alkyl substituted with 0-5 Rc;
R4 is selected from the group consisting of F, Cl, Br, and C1-6 alkyl substituted with 0-5 Rc;
R5 is selected from the group consisting of F, Cl, CN, C1-3 alkyl, ═N—ORb, —(CH2)rORb, —OC(═O)NRaRa, —(CH2)rNRaRa, —NRaC(═NH)C1-3alkyl, —C(═O)ORb, —NRaC(═O)ORb, carbocyclylyl substituted with 0-5 Rc, and heterocyclylyl substituted with 0-5 Rc; alternatively, two R5 groups are taken together to form carbocyclyl or heterocyclyl;
R6, at each occurrence, is independently selected from the group consisting of F, Cl, Br, and C1-4alkyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl;
Ra, at each occurrence, is independently selected from the group consisting of H, C1-6 alkyl substituted with 0-5 Rc, C2-6 alkenyl substituted with 0-5 Rc, C2-6 alkynyl substituted with 0-5 Rc, —(CH2)r—C3-10carbocyclyl substituted with 0-5 Rc, and —(CH2)r-heterocyclyl substituted with 0-5 Rc; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Rc;
Rb, at each occurrence, is independently selected from the group consisting of H, C1-6 alkyl substituted with 0-5 Rc, C2-6 alkenyl substituted with 0-5 Rc, C2-6 alkynyl substituted with 0-5 Rc, —(CH2)r—C3-10carbocyclyl substituted with 0-5 Rc, and —(CH2)r-heterocyclyl substituted with 0-5 Rc;
Rc, at each occurrence, is independently selected from the group consisting of F, Cl, Br, CN, ═O, OH, OC1-4 alkyl, CO2H, C1-6 alkyl substituted with 0-5 Rd, —(CH2)r—C3-6 cycloalkyl substituted with 0-5 Rd, —(CH2)r-aryl substituted with 0-5 Rd, —(CH2)r-heterocyclyl substituted with 0-5 Rd,
Rd, at each occurrence, is independently selected from the group consisting of F, Cl, Br, CN, OH, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl, and phenyl;
p, at each occurrence, is an integer selected from zero, 1, and 2; and
r, at each occurrence, is an integer selected from zero, 1, 2, 3, and 4.