Pyridinone and pyrimidinone derivatives as factor XIa inhibitors

摘要

A compound represented by formula (I): ** (See formula) ** wherein Cyc1 represents C3-C8 cycloalkyl, 5 to 10 membered heterocycloalkyl, or a 5 to 10 membered heteroaryl; Cyc2 represents C3-C8 cycloalkyl, 5 to 10 membered heterocycloalkyl, C5-C10 aryl or 5 or 6 membered heteroaryl; Cyc3 represents C3-C8 cycloalkyl, 5 to 10 membered heterocycloalkyl, C5-C10 aryl, or a 5 to 10 membered heteroaryl; R1 represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) nitro, (6) cyano, (7) oxo, (8) amidino , (9) -C 1-8 alkyl-OR8, (10) -OR9, (11) -COOR10, (12) -C 1-4 alkyl-COOR11, (13) -NHC (O) -C 1-4 alkyl, ( 14) -C 1-4 alkyl-OC (O) -C 1-8 alkyl or (15) -NHC (O) O-R12, wherein each of R8, R9, R10, R11, and R12 independently represents (1) hydrogen , (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5- to 10-membered heterocycloalkyl, (7) C5-C10 aryl , (8) 5 to 10 membered heteroaryl or (9) C 1-4 alkyl substituted with 1 to 5 groups selected from C3-C8 cycloalkyl, 5 to 10 membered heterocycloalkyl, C5-C10 aryl and 5 to 10 membered heteroaryl; s represents an integer from 0 to 6, where s represents an integer from 2 to 6, each R1 can be the same or different; R2 represents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc4 or (6) C1-8 alkyl, C2-8 alkenyl or alkynyl C2-8, which are substituted with 1 to 5 groups selected from halogen, nitro, trifluoromethyl, cyano, Cyc5, -NR13R14, -OR15, -SR16, -NHC (O) -Cyc6, -NHC (O) -C1 alkyl -8, -NHC (O) O-R17 and Cyc5 substituted with 1 to 3 groups selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, amidino and -OR18 , wherein R13, R14, R15, R16, R17 and R18 each independently represent (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5 to 10 membered heterocycloalkyl, (7) C5-C10 aryl, (8) 5 to 10 membered heteroaryl or (9) C1-4 alkyl substituted with 1 to 5 groups selected from cycloalkyl C3-C8, 5 to 10 membered heterocycloalkyl, C5-C10 aryl and 5 to 10 membered heteroaryl; Cyc4, Cyc5 and Cyc6 each independently represent C3-C8 cycloalkyl, 5 to 10 membered heterocycloalkyl, C5-C10 aryl or a 5 to 10 membered heteroaryl; R3 represents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc7 or (6) C1-8 alkyl, C2-8 alkenyl or alkynyl C2-8, which are substituted with 1 to 5 groups selected from halogen, nitro, trifluoromethyl, cyano, Cyc8, -NR19R20, -OR21, -SR22, -NHC (O) -Cyc9, -NHC (O) -C1 alkyl- 8, -NHC (O) O-R23 and Cyc8 substituted with 1 to 3 groups selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, amidino and -OR24, wherein each of R19, R20, R21, R22, R23 and R24 independently represents (1) hydrogen, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5 to 10 membered heterocycloalkyl, (7) C5-C10 aryl, (8) 5 to 10 membered heteroaryl or (9) C1-4 alkyl substituted with 1 to 5 groups selected from cycloalkyl C3-C8, 5 to 10 membered heterocycloalkyl, C5-C10 aryl and 5 to 10 membered heteroaryl; Cyc7, Cyc8 and Cyc9 each independently represent C3-C8 cycloalkyl, 5 to 10 membered heterocycloalkyl, C5-C10 aryl, or 5 to 10 membered heteroaryl; Y represents N or C (R5); R4 and R5 each independently represent (1) hydrogen, (2) halogen, (3) C1-4 alkyl, (4) C3-C8 cycloalkyl, (5) 5 to 10 membered heterocycloalkyl, (6) C5 aryl -C10, (7) 5- to 10-membered heteroaryl or (8) C1-4 alkyl substituted with 1 to 5 groups selected from C3-C8 cycloalkyl, 5 to 10-membered heterocycloalkyl, C5-C10 aryl, and 5 to 10-membered heteroaryl ; ...