US 11,053,247 B2
Pyrimidinones as factor XIA inhibitors
Andrew K. Dilger, Ewing, NJ (US); James R. Corte, Yardley, PA (US); Indawati De Lucca, Pennington, NJ (US); Tianan Fang, Newtown, PA (US); Wu Yang, Princeton Junction, NJ (US); Yufeng Wang, Belle Mead, NJ (US); Kumar Balashanmuga Pabbisetty, Piscataway, NJ (US); William R. Ewing, Yardley, PA (US); Yeheng Zhu, Stockton, NJ (US); Ruth R. Wexler, Belle Mead, NJ (US); Donald J. P. Pinto, Churchville, PA (US); Michael J. Orwat, New Hope, PA (US); and Leon M. Smith, II, Somerset, NJ (US)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Filed by Bristol-Myers Squibb Company, Princeton, NJ (US)
Filed on Jun. 25, 2019, as Appl. No. 16/451,873.
Application 16/451,873 is a continuation of application No. 15/903,671, filed on Feb. 23, 2018, granted, now 10,336,754, issued on Jul. 2, 2019.
Application 15/903,671 is a continuation of application No. 15/221,142, filed on Jul. 27, 2016, abandoned.
Application 15/221,142 is a continuation of application No. 14/872,546, filed on Oct. 1, 2015, granted, now 9,453,018, issued on Sep. 27, 2016.
Claims priority of provisional application 62/058,316, filed on Oct. 1, 2014.
Claims priority of provisional application 62/058,293, filed on Oct. 1, 2014.
Prior Publication US 2020/0055854 A1, Feb. 20, 2020
Int. Cl. C07D 471/18 (2006.01); C07F 7/08 (2006.01); C07D 519/00 (2006.01); C07D 471/08 (2006.01); C07D 487/08 (2006.01)
CPC C07D 471/18 (2013.01) [C07D 471/08 (2013.01); C07D 487/08 (2013.01); C07D 519/00 (2013.01); C07F 7/0814 (2013.01)] 9 Claims
 
1. A compound having Formula (IIa):

OG Complex Work Unit Chemistry
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is a 6-membered aryl or a 6-membered heteroaryl;
ring B is a 6-membered heteroaryl substituted with, where valence allows, one or more R3 groups comprising carbon atoms and 1-3 heteroatoms selected from N and NR3c;
G1 is

OG Complex Work Unit Chemistry
wherein G3 is CR8a and G4 is CR8e;
W is independently selected from (CR1R2)1-2, O, NH, and N(C1-4 alkyl);
Y is independently selected from —CHR13NH—, —NHC(═O)— and —C(═O)NH—;
R1 and R2 are independently selected from H, D, halogen, haloalkyl, C1-6 alkyl (optionally substituted with R6), hydroxyl, and alkoxy (optionally substituted with R6), and C3-5 cycloalkyl optionally substituted with R6;
R3 is independently selected from H, ═O, halogen, C1-4 alkyl (optionally substituted with R6), CN, —(CH2)n—OR5, —(CH2)n—NR5R5, —(CH2)n—C(═O)R5, and —(CH2)n—C(═O)OR5;
R3c is independently selected from H, haloalkyl, and C1-4 alkyl (optionally substituted with R6);
R4 is independently selected from H, OH, halogen, CN, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy;
R5 is independently selected from H, C1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), C3-10 carbocyclyl and 4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R6;
R6 is independently selected from H, —(CH2)n—OH, ═O, —(CH2)nNH2, —(CH2)nCN, halogen, C1-6 alkyl, —(CH2)n—C(═O)OH, —(CH2)n—C(═O)OC1-4 alkyl, —(CH2)n—OC1-4 alkyl, —(CH2)n—C(═O)NH2, —(CH2)n—C3-10 carbocyclyl, —(CH2)n-4- to 10-membered heterocyclyl, and —O—(CH2)n-4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R10;
R7 is independently selected from H, hydroxyl, halogen, C1-2haloalkyl, and C1-2alkyl;
R8a is a 5-membered heterocyclyl with at least 3 nitrogen atoms optionally substituted with R10;
R8b is independently selected from H and F;
R8c is independently selected from H, F, Cl, methyl, ethyl, isopropyl, OCHF2, and OCH3;
R8d is independently selected from H, F, and Cl;
R8e is H;
R10 is independently selected from H, C1-6 alkyl (optionally substituted with R11), C2-6 alkenyl, C2-6 alkynyl, aryl (optionally substituted with R11), —(CH2)n—C3-6 cycloalkyl (optionally substituted with R11), —(CH2)n—O-4- to 10-membered heterocyclyl (optionally substituted with R11), F, Cl, Br, —(CH2)nCN, NO2, ═O, C(═O)N12R12, —(CH2)nC(═O)OR12, Si(C1-4 alkyl)3, —(CH2)n—OR12, —(CH2)n—NR12R12, —S(═O)pC1-6 alkyl, NR12S(═O)pC1-6 alkyl, and S(═O)pNR12R12;
R11, at each occurrence, is independently selected from H, halogen, C1-5 alkyl, —(CH2)n—OH, C3-6 cycloalkyl, and phenyl;
R12, at each occurrence, is independently selected from H, C1-5 alkyl optionally substituted with R11, C3-6 cycloalkyl, phenyl, and heterocyclyl, or R12 and R12 together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1-4alkyl;
R13 is, independently at each occurrence, selected from H, CF3, C(═O)OH, C(═O)O(C1-4 alkyl), and —C(═O)NH2(C1-4 alkoxy);
n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is an integer independently selected from 0, 1, and 2.