US 11,981,680 B2
Substituted thienopyrroles as PAD4 inhibitors
Daniel S. Gardner, Furlong, PA (US); John V. Duncia, Newtown, PA (US); and Joseph B. Santella, Springfield, PA (US)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Appl. No. 17/265,833
Filed by BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
PCT Filed Aug. 7, 2019, PCT No. PCT/US2019/045426
§ 371(c)(1), (2) Date Feb. 4, 2021,
PCT Pub. No. WO2020/033490, PCT Pub. Date Feb. 13, 2020.
Claims priority of provisional application 62/715,834, filed on Aug. 8, 2018.
Prior Publication US 2022/0064180 A1, Mar. 3, 2022
Int. Cl. C07D 495/04 (2006.01); A61K 45/06 (2006.01); C07D 519/00 (2006.01)
CPC C07D 495/04 (2013.01) [A61K 45/06 (2013.01); C07D 519/00 (2013.01)] 11 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is 4- to 15-membered heterocyclyl substituted with 1-4 R7;
R1 is selected from CH3 and CD3;
R2 is selected from H, C1-3 alkyl substituted with 0-5 Re, and —(CH2)r—C3-6 cycloalkyl with 0-5 Re;
R3 is selected from F, Cl, Br, and —ORb;
L is selected from —(CRdRd)0-3—, —NRa—, —S(O)p—, and —C(═O)—;
R4 is selected from H, F, Cl, Br, —CN, —ORb, C1-6 alkyl substituted with 1-5 R5, aryl substituted with 1-5 R5, C3-12 cycloalkyl substituted with 1-5 R5, and heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, NR6, O, and S and substituted with 1-5 R5;
R5, at each occurrence, is independently selected from H, F, Cl, Br, nitro, ═O, —C1-4alkyl substituted with 0-4 Re, C2-4alkenyl substituted with 0-4 Re, C2-4alkynyl substituted with 0-4 Re, —(CH2)rCN, —(CH2)rORb, (CH2)rS(O)pRc, —(CH2)rS(O)pNRaRa, —(CH2)rNRaS(O)pRc, —(CH2)rNRaRa, —(CH2)rNRaC(═O)Rb, —(CH2)rNRaC(═O)NRaRa, —(CH2)rC(═O)ORb, —(CH2)rC(═O)Rb, —(CH2)rOC(═O)Rb, —(CH2)rC(═O)NRaRa, —P(═O)(OC1-4alkyl)2, —P(═O)(C1-4alkyl)2, C3-6cycloalkyl substituted with 0-4 Re, aryl substituted with 0-4 Re, heterocyclyl substituted with 0-4 Re, and heteroaryl substituted with 0-4 Re;
R6, at each occurrence, is independently selected from H, C1-3alkyl substituted with 0-5 Re, —C(═O)Rb, —C(═O)(CH2)rNRaRa, —C(═O)(CH2)rNRaC(═O)Rb, —C(═O)ORb, —S(O)pRc, —S(O)pNRaRa, —(CH2)r—C3-6cycloalkyl substituted with 0-4 Re, —(CH2)r-aryl substituted with 0-4 Re, —(CH2)r-heterocyclyl substituted with 0-4 Re, and —(CH2)r-heteroaryl substituted with 0-4 Re;
R7 is selected from H, F, Cl, CN, C1-3 alkyl, ═N—ORb, —(CH2)rORb, —(CH2)rNRaRa, —NRaC(═NH)C1-3alkyl, —NRaC(═O)ORb, carbocyclyl, and a heterocyclyl; alternatively, two R7groups are taken together to form carbocyclyl or heterocyclyl;
Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)r—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)r-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re;
Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)r—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)r-heterocyclyl substituted with 0-5 Re;
Re, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)r—C3-6 carbocyclyl substituted with 0-5 Re, and —(CH2)r-heterocyclyl substituted with 0-5 Re;
Rd, at each occurrence, is independently selected from H and C1-6 alkyl substituted with 0-5 Re;
Re, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, —(CH2)r—C3-6 cycloalkyl, —(CH2)r-aryl, F, Cl, Br, CN, NO2, ═O, —C(═O)OH, —C(═O)OC1-4alkyl, —(CH2)rOH, and —(CH2)rOC1-4alkyl;
Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5 alkyl optionally substituted with OH, C3-6 cycloalkyl, and phenyl;
p, at each occurrence, is independently selected from zero, 1, and 2;
r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and
provided when L is selected from —NRa—, —S(O)p—, and —C(═O)—, R4 is selected from aryl substituted with 1-5 R5, C3-12 cycloalkyl substituted with 1-5 R5, and heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, NR6, O, and S and substituted with 1-5 R5.