Tetrahydroisoquinolines containing substituted azoles as inhibitors of factor XIa

摘要

A compound according to formula (I): ** Formula ** or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, wherein: ring A is independently selected from the group consisting of: carbocycle C3-10 and a 5-10 membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S (O) p, each optionally substituted with one or more R1 as allow valence; ring B is a 5-6 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, and optionally substituted with one or more R2 as valence allows; ring C is independently selected from the group consisting of: phenyl and 5-6 membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR6, O and S (O) p and optionally substituted with one or more R5 as valence allows; Q is independently selected from the group consisting of: C, CH, and N; ---- is an optional link; with the proviso that when Q is N, the optional link is absent; R1 is independently selected from the group consisting of: H, halo, NO2, OH, CN, C1-6alkyl, C1-4alkoxy, -CHF2, -CF3, -CH2NH2, -OCHF2, -CO (C1-4alkyl) , -CONH2, -COOH and 5-7 membered heterocycle; R2 is independently selected from the group consisting of: H, = O, OH, NH2, CF3, halo, C1-4alkyl (optionally substituted with OH), C1-3alkoxy, and C (O) C1-3alkyl; R3 is independently selected from the group consisting of: C1-6 alkyl substituted with 1-3 R3a, C3-10 carbocycle substituted with 1-3 R3a, and 5-10 membered heterocycle containing carbon atoms and 1-4 selected heteroatoms between N, NR7, O and S (O) p; wherein said heterocycle is substituted with 1-3 R3a; R3a is independently selected from the group consisting of: CO2H and -CO2 (C1-4alkyl); R4 is independently selected from the group consisting of: H, halo, and C1-4alkyl; R5 is independently selected from the group consisting of: H, halo, C1-4 alkyl substituted with 1-2 Rb, C2-4 alkenyl substituted with 1-2 Rb, C2-4 alkynyl substituted with 1-2 Rb, OH, CN , NH2, -NH (C1-4alkyl), N (C1-4alkyl) 2, C1-4alkoxy, -OCO (C1-4alkyl), -O-C1-4alkylene-O (C1-4alkyl) , -O-C1-4alkylene-N (C1-4alkyl) 2, -CO2H, - CO2 (C1-4alkyl), -CONH2, - (CH2) 2CONH2, -CONR9 (C1-4alkyl), -CONR9 -C1-4alkylene-O (C1-4alkyl), - CON (C1-4alkyl) 2, -CONR9-C1-4alkylene-C (C1-4alkyl) 2, -CON (C1-4alkyl) - C1-4alkylene-O (C1-4alkyl), -CONR9- C1-4alkylene-CO2 (C1-4alkyl), -NR9CO1-4-4alkyl, -NR9CO2 C1-4alkyl, -NR9CONH (C1-4alkyl), -NR9CONR9- C1-4alkylene-C1-4alkyl, -NR9-C1-4alkylene-OH, -NR9-C1-4alkylene-N (C1-4alkyl) 2, R8, -OR8, -O-C1alkylene - 4-R8, -COR8, -CO2R8, -CONR9R8, -NR9COR8, -NR9R8, -NR9CO2R8 and -NR9CONR9R8; R6 is independently selected from the group consisting of: H, C1-4alkyl, C1-4alkyl, CO C1-4alkyl, CO2C1-4alkyl, CO2Bn, phenyl and benzyl; R7 is independently selected from the group consisting of: H and C1-4alkyl; R8 is independently selected from the group consisting of: - (CH2) C3-10 n-carbocycle and - (CH2) 5-10 membered carbon-containing n-heterocycle and 1-4 heteroatoms selected from the group consisting of : N, NRa, O and S (O) p; wherein said carbocycle or heterocycle are substituted with 1-3 Rb; R9 is independently selected from the group consisting of: H and C1-4alkyl; Ra is independently selected from the group consisting of: H, C1-4alkyl substituted with 1-2 Rd, - (CH2) nOH, CO (C1-4alkyl), COCF3, CH2CF3, CO2 (C1-4alkyl), -CONH2, -CONH-C1-4-alkylene-C1-4-alkyl, C1-4-CO2-alkylene (C1-4-alkyl), Rc, CO2Rc and CONHRc; Rb is independently selected from the group consisting of: H, = O, halo, CN, OH, NO2, C1-4alkyl substituted with 1-2 Rd, C1-4alkoxy, OCF3, - (CH2) nNH2, - ( CH2) nN (C1-4alkyl) 2, CO (C1-4alkyl), CO (haloC1-4alkyl), CO2 (C1-4alkyl), - (CH2) n-CONH2, - (CH2) n-CONH (C1-4alkyl), - (CH2) n-CON (C1-4alkyl) 2, -CONH-C1-4alkylene-O (C1-4alkyl), -CONH-C1-4alkylene-C1 (C1-alkyl -4) 2, -NHCO (C1-4alkyl), -NHCO2 (C1-4alkyl), -S (O) 2NH2, - S (O) 2NH (C1-4alkyl), S (O) 2N (alkyl C1-4) 2, Rc, CORc, CO2Rc, -S (O) 2NH (C1-4alkyl) Rc, NHCONHRc and CONHRc50; optionally, Rb and Rb together with the carbon atom (s) to which they are both attached form a 5-6 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from NRa, O and S (O) p; wherein said heterocycle is optionally substituted with = O; or Ra and Rb combine to form a 5-6 membered heterocyclic ring containing carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, and optionally substituted with 1-3 Re; Rc is independently selected from the group consisting of: - (CH2) n-C3-6 cycloalkyl, - (CH2) n-phenyl, and - (CH2) n-heterocyclic 5 to 6 membered heterocycle containing 1 -4 heteroatoms selected from the group consisting of: N, NH, N (C1-4alkyl), O and S (O) p; wherein each ring moiety is substituted with 1-3 Rd; Rd is independently selected from the group consisting of: H, = O, halo, -OH, C1-4alkyl, NH2, NH (C1-4alkyl), N (C1-4alkyl) 2, optionally C1-8alkoxy substituted with OH, and -NHCO (C1-4alkyl), and heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N (C1-4alkyl), O and S ( O) p; Re is independently selected from the group consisting of: H, halo, C1-4alkyl, C1-4alkoxy, OCF3, NH2, NO2, N (C1-4alkyl) 2, CO (C1-4alkyl), CO ( halo (C1-4alkyl), CO2 (C1-4alkyl), CONH2, -CONH (C1-4alkyl), - CON (C1-4alkyl) 2, -NHCO2 (C1-4alkyl), - (CH2) n- C3-6cycloalkyl, - (CH2) n-phenyl, and - (CH2) n-5- to 6-membered heterocycle; n is independently selected from 0, 1, 2, 3 and 4; and p is independently selected from 0, 1 and 2.