Substituted pyrrolidines as factor XIa inhibitors for the treatment thromboembolic diseases

A method for treating a patient suffering from or susceptible to a thromboembolic disease, which method comprises administering to said patient a therapeutically effective amount of the compound of formula (I):

• wherein Cyc A represents cyclohexyl, phenyl, piperidinyl, piperazinyl, or indole;
• Cyc B represents phenyl;
• Cyc C represents pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
• each R1 may be the same or different and represents (1) —C(═NH)NH2, (2) 5- to 10-membered heteroaryl, (3) C6-C10 aryl or 5- to 10-membered heteroaryl substituted with 1 to 5 groups selected from halogen, C1-4 alkyl, C1-4 alkoxy, —C1-4 alkylene-C1-4 alkoxy, CN, —COOH, —COO-C1-4 alkyl, —CO—NH2, —OCONH2, —OCONH-C1-4 alkyl, —CONH-C1-4 alkyl, —NHCOO-C1-4 alkyl and —NHCO-C1-4 alkyl, (4) C6-C10 aryl, (5) —NH—C(═NH)NH2, (6) C1-4 alkyl, (7) C2-4 alkenyl, (8) C2-4 alkynyl, (9) —C1-4 alkylene-NH2, (10) C1-4 alkoxy, (11) CN, (12) —CO-C1-4 alkyl, (13) halogen or (14) —R10-C(═NR11)NR12R13;
• wherein R10 represents (1) a bond or (2) NH;
• R11, R12 and R13 each independently represents (1) hydrogen, (2) OH, (3) C1-4 alkyl, (4) C2-4 alkenyl, (5) C2-4 alkynyl, (6) C1-4 alkoxy, (7) —C1-4 alkylene-C1-4 alkoxy, (8) —CO-C1-4 alkyl, (9) —COO-C1-4 alkyl, (10) —OCO-C1-4 alkyl, (11) —CO—R14, (12) —COO—R15 or (13) —OCO—R16, with the proviso that R11, R12 and R13 do not all simultaneously represent hydrogen;
• wherein R14, R15 and R16 each independently represents C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl, which are substituted with 1 to 5 groups selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, trifluoromethyl, OH, —COO-C1-4 alkyl, COOH, oxo, C1-4 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl and NR17R18;
• wherein R17 and R18 each independently represents (1) hydrogen, (2) C1-4 alkyl, (3) C2-4 alkenyl or (4) C2-4 alkynyl;
• t represents an integer of 0 to 6;
• each R2 may be the same or different and represents (1) —COOH, (2) —COO-C1-4 alkyl, (3) —COO-C1-4 alkylene-C1-4 alkoxy, (4) —NH2, (5) —NH-C1-4 alkyl, (6) —NH-C1-4 alkylene-C1-4 alkoxy, (7) —NHCO-C1-4 alkyl, (8) —NHCO-C1-4 alkylene-C1-4 alkoxy, (9) —NHCOO-C1-4 alkyl, (10) —NHCOO-C1-4 alkylene-C1-4 alkoxy, (11) —CONH2, (12) —CONH-C1-4 alkyl, (13) —CONH-C2-4 alkylene-C-4 alkoxy, (14) halogen, (15) —SO2-C1-4 alkyl, (16) oxo, (17) C1-4 alkoxy, (18) —CO-C1-4 alkyl, (19) —CO-C1-4 alkylene-C1-4 alkoxy or (20) —COO— C1-4 alkyl substituted with 1 to 5 groups selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogen, trifluoromethyl, OH, —COO-C1-4 alkyl, COOH, oxo, C1-4 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl and NR19R20;
• wherein R19 and R20 each independently represents (1) hydrogen, (2) C1-4 alkyl, (3) C2-4 alkenyl or (4) C2-4 alkynyl;
• m represents an integer of 0 to 6;
• each R3 may be the same or different and represents (1) —SO2-R6-R7, (2) oxo, (3) —CO-C1-4 alkyl, (4) —CO—NH2, (5) —SO2-NH2 or (6) —COO-C1-4 alkyl;
• n represents an integer of 0 to 6;
• R6 represents (1) a bond or (2) NH;
• R7 represents (1) C1-4 alkyl, (2) Cyc D or (3) C1-4 alkyl or Cyc D substituted with 1 to 5 R8;
• wherein Cyc D represents C3-C8 cycloalkyl, 5- to 10-membered heterocycloalkyl, C6-C10 aryl or 5- to 10-membered heteroaryl;
• each R8 may be the same or different and represents (1) —COOH, (2) —COO-C1-4 alkyl, (3) —COO-C1-4 alkylene-C-4 alkoxy, (4) —NH2, (5) —NH-C1-4 alkyl, (6) —NHCO-C1-4 alkyl, (8) —CONH2, (12) —CONH-C1-4 alkyl (13) OH or (14) halogen;
• R4 represents (1) a bond, (2) C1-4 alkylene, (3) C2-4 alkenylene or (4) C2-4 alkynylene;
• R5 represents (1) —CONH—, (2) Cyc E or (3) Cyc E substituted with R9;
• wherein Cyc E represents C3-C8 cycloalkyl, 5- to 10-membered heterocycloalkyl, C6-C10 aryl or 5- to 10-membered heteroaryl;
• and
• each R9 may be the same or different and represents C1-4 alkyl or halogen;
• a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.