Benzylamine derivatives as inhibitors of plasma kallikrein

A compound of formula I

• wherein:
• R1 is H, alkyl, —COalkyl, —COaryl, —COheteroaryl, —CO2alkyl, —(CH2)aOH, —(CH2)bCOOR10, —(CH2)cCONH2, —SO2alkyl, —SO2aryl, —SO2(CH2)hR13, —CO(CH2)iR14, —COcycloalkyl, —COCH═CHR15, —CO(CH2)jNHCO(CH2)kR16, or —CONR17R18;
• R2 is H, or alkyl;
• R3 is H, alkyl, —(CH2)daryl, —(CH2)eheteroaryl, —(CH2)fcycloalkyl, —(CH2)gheterocycloalkyl, —CH(cycloalkyl)2, —CH(heterocycloalkyl)2, or —(CH2)laryl-O—(CH2)m-aryl;
• R4 and R6 are independently H or alkyl;
• R5 is H, alkyl, alkoxy, or OH;
• or R4 and R5, together with the atoms to which they are attached, may join to form a 5- or 6-membered azacycloalkyl structure;
• R7 and R8 are independently H, alkyl, alkoxy, CN, halo, or CF3;
• R9 is aryl or heteroaryl;
• R10 is H or alkyl;
• a, b, c, d, e, f g, h, i, j, l and m are independently 1, 2 or 3;
• k is 0, 1, 2 or 3;
• *1 and *2 denote chiral centres;
• alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10);
• alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR11, fluoro and NR11R12;
• cycloalkyl is a mono- or bi-cyclic saturated hydrocarbon of between 3 and 10 carbon atoms optionally fused to an aryl group;
• heterocycloalkyl is a C-linked or N-linked 3 to 10 membered saturated, mono- or bi-cyclic ring, wherein said heterocycloalkyl ring contains, where possible, 1, 2 or 3 heteroatoms independently selected from N, NR11 and O;
• alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6) in either case optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, OH, CN, CF3, COOR11, fluoro and NR11R12;
• aryl is phenyl, biphenyl or naphthyl optionally substituted with up to 5 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3 and NR11R12;
• heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR11, S and O;
• optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR11, CF3, NR11R12 and NHR19;
• R11 and R12 are independently H, or alkyl;
• R13 is aryl or heteroaryl;
• R14 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
• R15 is H, alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
• R16 is H, aryl or heteroaryl;
• R17 is H, alkyl, aryl, heteroaryl or heterocycloalkyl;
• R18 is —(CH2)mR21, where m is 0, 1, 2 or 3 and R21 is H, aryl or heteroaryl;
• R19—COalkyl, —COaryl or —COheteroaryl;
• or a tautomer, isomer, stereoisomer (including an enantiomer, diastereoisomer or racemic and scalemic mixture thereof), a pharmaceutically acceptable salt or solvate thereof.