Arilpropionamida arilacrilamida arilpropinamida or arilmetilurea derivatives as inhibitors of factor XIa. Extraction process and Pharmaceutical compositions.

摘要

This table refers to formula compound (1),There is also drug synthesis that includes these compounds and methods of treating thrombosis and / or inflammation, using the same and the same acquisition process. Item 1: a compound with formula characteristics,1. A is a c3-10 carbohydrate, which is replaced by 0-1r1 and 0-3r2, or different cycles of 5-12 members, including: carbon atom and 1-4 heteroatom selected from n, or s (or) p; Where the heterocycle is replaced by 0-1r1 and 0-3r2, the condition is that when a is a heterocycle containing one or more nitrogen atoms, a is not connected to L1; L1 es-ch2ch2 - through any nitrogen element in ring a.-CH (NR7R8) CH2--CH=CH---CSC...- er...-CR5R6NH, -CH2O-,-Sch2...-SO2CH2...-CH2N10...I am me!If L1 is - CH2O,A is then another compound different from the unsubstituted phenyl; m is a component of the formula group (2);R1 is independently each that occurs. F, Cl, Br, I, OCF3, CF3, - (CH2) rORa, - (CH2) rSRa, CN, - (CH2) rNR7R8, -C (= NR8) NR8R9, -C (O) NR8R9, -S ( O) pNR8R9, or C1-6 alkyl substituted with 0-1 R1a; R1a is F, OCF3, CF3, ORa, SRa, CN, -NR7R8, -C (O) NR8R9, -NR8C (O) Rc, -S (O) pNR8R9, NR8SO2Rc, or (CF2) rCF3; R2 is, independently each one presented, O, F, CI, Br, OCF3, CF3, CHF2, CN, NO2 (CH2) rORa, (CH2) rSRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, - (CH2) NR7R8, -C (O) NR8R9, NR8C (O) Rc, NR8C (O) ORc, NR8C (O) NR8Rc, -S (O) pNR8R9, -NR8S (O) pRc, -S (O) Rc, -S (O) 2Rc, C1-6 alkyl substituted with 0-1 R2a, (CH2) 3-7 membered r-carbocycle optionally substituted with 0-2 R2b,or - (CH2) 5-7 membered r-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, wherein the heterocycle is substituted with 0-2 R2b; alternatively, when the R1 and R2 groups are substituted into adjacent atoms which can be taken together with the atoms to which they are attached to form a 5- to 7-membered carbocycle or heterocycle comprising carbon atoms and 0-4 heteroatoms selected from N , O, and S (O) p and substituted with 0-2 Rg; R2a is F, OCF3, CF3, ORa, SRa, CN, -NR7R8, -C (O) NR8R9, -NR8C (O) Rc, - NR8C (O) ORc, -NR8C (O) NR8Rc, S (O) pNR8R9 , -NR8SO2Rc, or (CF2) rCF3; R2b is independently each that occurs, = O, F, Br, CI,OCF3, CF3, - (CH2) rORa, - (CH2) rSRa, - (CH2) rCN, - (CH2) rNR7R8, - (CH2) rC (O) ORa, (CH2) rC (O) NR8R9, - (CH2 ) rNR8C (O) Rc, - (CH2) rNR8C (O) ORc, - (CH2) rS (O) pNR8R9, - (CH2) rNR8SO2Rc, C1-4 alkyl or (CF2) rCF3; R3 is, independently at each occurrence, - (CH2) r-carboxy C3-10 substituted with 0-3 R3a and 0-1 R3d, or - (CH2) r-heterocycle with 5 to 12 members, comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, where the heterocycle is substituted with 0-3 R3a and 0-1 R3d; R3a is, independently each occurring, = O, = NR8, F, CI, Br, I, OCF3, CF3, - (CH2) rCN, NO2, - (CH2) rOR3b, - (CH2) rSR3b, - (CH2 ) rNR7R8, -NHC (O) NR8R9, - (CH2) rC (O) OR3b, -C (O) C1-4alkyl, -SO2NHR3b,-SO2NHCORc, -SO2NHCO2Rc, -CONHSO2R3c, - (CH2) rNR8C (O) R3b, - (CH2) rNR8CO2R3c, (CH2) rS (O) pNR8R9, - (CH2) rNR8S (O) pR3C, -NHS O) R3c, S (O) 2R3c, - (CH2) rC (O) NR8R9, - (CH2) rOC (O) NR8R9, -NHCOCF3, -NHSO2R3c, CONHOR3b, C1-4 haloalkyloxy, C1-4alkyl -6 substituted by R3e, C2-6 alkenyl substituted by R3e, C1-6 alkynyl substituted by R3e, C3-6 cycloalkyl substituted by 0-1 R3d, (CH2) r-carbocycle C6-10 replaced by 0-3 R3d or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, wherein the heterocycle is substituted with 0-3 R3d; alternatively,When two R3a groups are substituted into adjacent atoms, they can be taken together with the atoms to which they bond to form a 0-2 R3d-substituted C3-10 carbocycle, or a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, wherein the heterocycle is substituted with 0-2 R3d; R3b is, independently at each occurrence, H, C1-2 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) r- C3-10 carbocycle substituted with 0-3 R3d,o - (CH2) r-heterociclo de 5 hasta 10 miembros que comprende tomos de carbono y 1-4 hetero tomos seleccionados de NO y S (O) p en donde el heterociclo est substituido con 0-3 R3d R3c es independientemente cada que se -C (O) ORa, -OC (O) Ra, NR8C (O) Rc, -C (O) NR8R9, - S (O) 2NR8R9, -NR7R8, NR8S (O) 2NR8R9, NR8S (O) 2Rc, - S (O) pRc, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) r -C3-10 carbocycle substituted with 0-3 Rd, or (CH2) r 5 to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S (O) p, where the heterocycle is substituted with 0-3 Rd; R3e is, independently each one presented, H, - (CH2) rORa, F, = O, CN, NO2, - (CH2) rNR7R8, -C (O) Ra, -C (O) ORa, - OC (O ) Ra, NR8C (O) Rc, -C (O) NR8R9, -S (O) 2NR8R9, NR8S (O) 2NR8R9, NR8S (O) 2Rc, -S (O) pRc, (CF2) rCF3,(CH2) C3-10 r-carbocycle substituted with 0-3 Rd, or - (CH2) 5-10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S (O ) p, where the heterocycle is substituted with 0-3 Rd; R4 is, independently each occurring, H, F, CI, Br, I, OCF3, CF3, CN, NO2, ORa, SRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR8R9, -NR8C (O) Rc, - S (O) pNR8R9, -NR8S (O) pRc, -S (O) 2Rc, or C1-4 alkyl substituted with 0-2 R4a; R4a is, independently each occurring, H, F, = O, C1-6 alkyl, ORa, SRa, CF3, CN, NO2, -C (O) Ra, -C (O) ORa, -NR7R8, -C (O) NR8R9, -NR8C (O) Rc, -S (O) pNR8R9, -NR8S (O) pRc, - S (O) Rc, or -S (O) 2Rc; R5 is,independently each occurring, H, F, CF3, - (CH2) rORa, = O, - (CH2) r-NR7R8, -S (O) pNR8R9, - (CH2) r-CO2Ra, - (CH2) r- CONR8R9, or C1-4 alkyl; R6 is, independently each occurring, H, F, or C1-4alkyl; R7 is, independently each occurring, H, C1-6alkyl, - (CH2) n-carbocycle C3-10, - (CH2) n- (5- to 10-membered heteroaryl),C (O) Rc, -CHO, -C (O) 2Rc, -S (O) 2Rc, -CONR8Rc, -OCONHRc, -C (O) O- (C1-4alkyl) OC (O) - (C1alkyl -4),O-C (o) or - (C1-4 tar) OC (o) - (arilo C6-10);Where 0-2 RF is used to replace tar, carbohydrate, isopropene and arilo, isopropene includes: carbon atom and 1-4 heteroatoms selected from n, O, y (o) p; R8 is, regardless of each case, h, C1-6, n-fenilo, O-2, N-Heterocycle, consisting of 5 to 10 members: carbon atom And 1-4 heteroatoms selected from n, O, and S (o) P, in which tar, phenyl, and heteroatoms can be replaced by 0-2 RF; or, R7 and R8, when combined with the same nitro group, can be combined into a different cycle of 5-10 members, including: carbon atoms and 0-3 extra heteroatoms selected from n.O. And S (o) P, in which the heterocycle is replaced by 0-2 RF; R8a is h or C1-4 tar; R9 is independently occurring C1-6 or N - (CH2) phenyl; where tar and phenyl are replaced by 0-2 RF; on the other hand, R8 and R9, when they are linked to the same nitro group, are combined into a heterocycle. It is composed of 5 to 10 members: carbon atom and other 0-2 heteroatom selected from n, O, and S (o) P, in which case, heterocycle is replaced by 0-2rd; R10 is h or C1-6 tar, regardless of each case, it is replaced by 0-3r10a; r10a is, regardless of each case, H = or C1-4 tar, ora,F, CF3, CN, NO2, -C (O) Ra, -C (O) ORa, -C (O) NR8R9, -NR8C (O) Rc, -S (O) pNR8R9, - NR8S (O) pRc, or S (O) pRc; R11 is C1-4 haloalkyl, -C (O) NR8R9, -CH2C (O) NR8R9, -CH2CH2C (O) NR8R9, -C (O) Ra, -CH2C (O) Ra, -CH2CH2C (O) Ra, - C (O) ORa, -CH2C (O) ORa, -CH2CH2C (O) ORa, C1-3 alkyl substituted with 0-3 R11c, C2-6 alkenyl substituted with 0-3 R11a, C2-6 alkynyl or substituted with 0 -3 R11a, - (CH2) r-C3-10 carbocycle substituted with 0-3 R11b, or - (CH2) r-heterocycle with 5 to 10 members, comprising: carbon atoms and 1-4 heteroatoms selected from N, O , and S (O) p, where the heterocycle is substituted with 0-3 R11b; R11a is, independently every H, = O, ORa, SRa, F, CF3, CN, NO2, -C (O) Ra,-, or 1-1, or 1-carbon-1-1-1-1 atoms, including 1, or carbon-1-1-carbon-1, or carbon - heteromorphic atoms selected from n, O, and S (o) P, and C1C (or (or) PRC, C1C, c1c1c, any kind of C1C, any kind of C6, or C1C, any kind of C3-6, C1-4 halide, C1-4 halide,-(CH2) r-carbocyclo c3-10 is changed to 0-3 Rd, or - (CH2) r-heterocycle is composed of 5 to 10 members, including carbon atoms and 1-4 heteroatoms selected from n, O, s (o) P, and replaced by 0-3 Rd; or