(Hetero)aryl-bicyclic heteroaryl derivatives, their preparation and their use as protease inhibitors

A compound selected from

• 3-[3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4hydroxy-phenyl]-N-phenethyl-propionamide;
• 3-[4-(6-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenyl]-N-(2,3-dichloro-benzyl)-propionamide;
• 2-[4(6-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy]-N-(2,3-dichloro-benzyl)-acetamide;
• 3-[3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl]-N-[2-(2,4-dichloro-phenyl)-ethyl]-propionamide;
• 3-[3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl]-N-(2-pyridin-2-yl-ethyl)-propionamide;
• 3-[3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl]-N-(3-phenyl-propyl)-propionamide;
• 2-[4-(6-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy]-N-naphthalen-1-ylmethyl-acetamide;
• 2-(3′-Amino-5-chloro-2-hydroxy-biphenyl-3-yl)-3H-benzoimidazole-5-carboxamidine;
• 3-[3-Bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl]-propionic acid;
• 2-(3,5-Bis-hydroperoxy-2-hydroxy-phenyl)-3H-benzoimidazole -5-carboxamidine;
• 2-[4-(5-Carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy]-N-(3-chloro-benzyl)-acetamide;
• N-Benzyl-3-[3-bromo-5-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-4-hydroxy-phenyl]-propionamide;
• 2-(3,5-Dibromo-2,4-dihydroxy-phenyl)-3H-benzoimidazole-5-carboxamidine;
• 2-(2-Hydroxy-biphenyl-3-yl)-3H-benzoimidazole-5-carboxamidine;
• 2-(5-Chloro-2-hydroxy-biphenyl-3-yl)-3H-benzoimidazole-5-carboxamidine;
• 2-(2-Hydroxy-3-phenethyloxy-phenyl)-3H-benzoimidazole-5-carboxamidine;
• N-(3-Bromo-benzyl)-2-[4-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy]-acetamide;
• 2-{3-[1-(3-Amino-propionyl)-pyrrolidin-2-ylmethoxy]-2-hydroxy-phenyl}-3H-benzoimidazole-5-carboxamidine;
• 2-(5-Chloro-2-hydroxy-3-pyridin-3-yl-phenyl)-1H-benzoimidazole-5-carboxamidine;
• 2-[3-(5-Carbamimidoyl-1H-benzoimidazol-2-yl)-2-hydroxy-phenyl]-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxamidine;
• 2-[3-(1-Aminoacetyl-pyrrolidin-2-ylmethoxy)-2-hydroxy-phenyl]-3H-benzoimidazole-5-carboxamidine;
• 2-(2-Hydroxy-3-phenoxy-phenyl)-3H-benzoimidazole-5-carboxamidine;
• 2-[2-Hydroxy-3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-1H-benzoimidazole-5-carboxamidine;
• 2-[3-(1-Aminoacetyl-piperidin-3-ylmethoxy)-2-hydroxy-phenyl]-1H-benzoimidazole-5-carboxamidine;
• 2-{3-[1-(2-Amino-3-methyl-butyryl)-pyrrolidin-2-ylmethoxy]-2-hydroxy-phenyl}-1H-benzoimidazole-5-carboxamidine;
• 2-[2-Hydroxy-3-(1-hydroxyacetyl-pyrrolidin-2-ylmethoxy)-phenyl]-1H-benzoimidazole-5-carboxamidine;
• 2-(2-Hydroxy-5-iodo-3-methoxy-phenyl)-1H-benzoimidazole-5-carboxamidine;
• 2-{3-[1-(2-Amino-3-methyl-butyryl)-pyrrolidin-2-ylmethoxy]-2-hydroxy-phenyl}-3H-benzoimidazole-5-carboxamidine;
• 2-(2-Hydroxy-5-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-benzylamino}-phenyl)-3H-benzoimidazole-5-carboxamidine;
• compound with methane;
• 2-(2-Hydroxy-5-{4-[1-(1-imino-ethyl)-piperidin-3-ylmethoxy]-benzylamino}-phenyl)-3H-benzoimidazole-5-carboxamidine;
• 2-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3H-benzoimidazole-5-carboxamidine;
• 3-[2,6-Dibromo-4-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy]-propionic acid;
• 3-[2,6-Dibromo-4-(6-carbamimidoyl-1H-benzoimidazol-2-yl)-3-hydroxy-phenoxy]-propionic acid ethyl ester;
• and
• 2-[3-Bromo-2-hydroxy-5-(3-methoxy-but-3-enyl)-phenyl]-3H-benzoimidazole-5-carboxamidine;
• or a stereoisomer or pharmaceutically acceptable salt form thereof.

A method for treating or preventing a arterial thromboembolism, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula:

• A—B
• or pharmaceutically acceptable salts thereof, wherein
• A represents
• B represents
• X and Y independently at each occurrence are selected from NH, N, C, or CH, such that at least one of X and Y always represents N or NH;
• and
• Z represents C or N;
• provided that, (i) when Z represents N, R7 represents H or C(═NH)NH2;
• R1 represents OH, halogen, COOH, COO—O1-4 alkyl, O—(CH2)0-1—Ph, N(R10)2, CH2OR10, C1-6-halogenated alkyl, O—(CH2)1-4—CO—N(R10)2, SC1-4 alkyl, NHSO2C1-4alkyl, SO2—OH, O—SO2—OH, O—SO2—O—C1-4 alkyl, OP(O)(OH)2, or OP(O)(OH)OC1-4 alkyl;
• R2, R3, R4, and R5 independently at each occurrence represent H, SH, OR10, halogen, COOR10, CONR11R12, optionally substituted aryl, optionally substituted heterocyclyl, C4-14 cycloalkyl-C1-4 alkyl, C1-4 alkyl aryl, optionally substituted C1-14 straight chain, branched or cyclo alkyl, O—(CH2)2-6—NR10—(CH2)0-3—R24, NR10R24, (CH2)1-4—NR33R34, (CH2)1-4—COOR33, O—(CH2)1-3—N—CO-het, O—(CH2)1-2—NH—CO-aryl, O—(CH2)1-2—NR10—CO—NR10R33, O—(CH2)0-2—C(O)—NR33R34, O—(CH2)1-4—COOR10, O—(CH2)1-3-het—R32, O-optionally substituted cycloalkyl, O—(CH2)1-4—NR10—COO-t-butyl, O—(CH2)1-4—NR10R33, O—(CH2)1-4—NR10—C(O)—C0-3-alkyl-optionally substituted aryl, O-substituted cycloalkyl, O—(CH2)0-6-optionally substituted aryl, (CH2)1-4—NH—C(O)O—(CH2)1-4—PhR13R14, NO2, O—(CH2)0-4—C(O)—NH-tetrahydro carboline, NR10R28, O—(CH2)1-3-optionally substituted het, CH2COOCH3, CH═CH—COOCH3, 5-amidino benzimidazole,
• alternatively R2 and R3 taken together form
• R6 and R9 independently at each occurrence represents H, halogen, cyano, C1-4 alkyl, C1-4 halogenated alkyl, NO2, O-aryl or OR11;
• R7 and R8 independently at each occurrence represent OH, CF3, H, NO2, C1-4 alkyl, OC1-4 alkyl, O-aryl, halogen, or cyano, or a basic group selected from guanidino, C(═NH)N(R10)2, C(═NH)—NH—NH2, C(═O)NH2, 2-imidazoline, N-amidinomorpholine, N-amidino piperidine, 4-hydroxy-N-amidino piperidine, N-amidino pyrrolidine, tetrahydro pyrimidine, and thiazolidin-3-yl-methylideneamine;
• with the proviso that one, but not both, of R7 and R8 represents a basic group;
• R10 independently at each occurrence represents H, (CH2)0-2-aryl, C1-4 halo alkyl, or C1-14 straight chain, branched or cyclo alkyl, and alternatively, when one atom is substituted with two R10 groups, the atom alone with the R10 groups can form a five to 10 membered rind structure;
• R11 and R12 independently at each occurrence represent H or C1-4 alkyl;
• R20 represents R24, C1-4-alkyl, (CH2)1-3-biphenyl, (CH2)1-4—Ph—N(SO2—C1-2-alkyl)2, (CH2)1-4—NH—C(O)—R24, (CH2)1-4—NH—SO2—R24, halogen, COOR10, (CH2)1-4—Ph—N(SO2—C1-2alkyl), (CH2)1-4—NR10—C(O)—R24, (CH2)1-4—NR10—SO2—R24, (CH2)1-4-het, (CH2)1-4—CON(R10)2, (CH2)1-4—N(R10)—C(O)—NR10R24, (CH2)1-4—N(R10)—C(S)—NR10R24, or (CH2)1-3—COOH;
• R24 represents R10, (CH2)1-4-optionally substituted aryl, (CH2)0-4OR10, CO—(CH2)1-2—N(R10)2, CO(CH2)1-4—OR10, (CH2)1-4—COOR10, (CH2)0-4—N(R10)2, SO2R10, COR10, CON(R10)2, (CH2)0-4-aryl-COOR10, (CH2)0-4-aryl-N(R10)2, or (CH2)1-4-het-aryl;
• R28 represents (CH2)1-2—Ph—O—CH2)0-2-het—R30, C(O)-het, CH2—Ph—CH2-het-(R30)1-3;
• (CH2)1-4-cyclohexyl-R31, CH2—Ph—O—Ph—(R30)1-2, CH2—(CH2OH)-het—R30, CH2—Ph—O-cycloalkyl-R31, CH2-het-C(O)—CH2-het-R30, or CH2—Ph—O—(CH2)—O-het-R30;
• R30 represents SO2N(R10)2, H, NHOH, amidino, or C(═NH)CH3;
• R31 represents R30, amino-amidino, NH—C(═NH)CH3 or R10;
• R32 represents H, C(O)—CH2—NH2, or C(O)—CH(CH(CH3)2)—NH2;
• R33 and R34 independently at each occurrence represent R10, (CH2)0-4—Ar, optionally substituted aryl, (CH2)0-4 optionally substituted heteroaryl, (CH2)1-4—CN, (CH2)1-4—N(R10)2, (CH2)1-4—OH, (CH2)1-4—SO—N(R10)2;
• alternatively,
• R33 and R34 along with the nitrogen atom that they are attached form a 4 to 14 atom ring structure selected from tetrahydro-1H-carboline;
• 6,7-dialkoxyoxy-2-substituted 1,2,3,4-tetrahydro-isoquinoline,
• R35 represents R10, SO2—R10, COR10, or CONHR10;
• E represents a bond, S(O)0-2, O or NR10;
• W1, W2, W3 and W4 independently represent C or N;
• and
• Q, Q1, Q2, Q3, L1, L2, L3 and L4 independently at each occurrence represent N-natural or unnatural amino acid side chain, CHR10, O, NH, S(O)0-2, N—C(O)—NHR10, SO2—N(R10)2, N—C(O)—NH—(CH2)1-4—R26, NR10, N-heteroarl, N—C(═NH)—NHR10, or N—C(═NH)C1-4 alkyl;
• R26 represents OH, NH2, or SH;
• provided that, (i) when R1=OH;
• R7=amidine;
• R2, R6, R8, R9, and R20 each represent H;
• and R3, R4, R5 are independently chosen from H, CH3, and halogen, then only one of R3, R4, and R5 represents H;
• (ii) when R1=OH;
• R7=amidine;
• R2, R3, R4, R5, and R20 each represent H;
• and R6, R8, R9 are independently chosen from H, CH3, and halogen, then only one of R6, R8, and R9 represents H;
• (iii) at least two of W1, W2, W3 and W4 represent C and at least one of W1, W2, W3 and W4 represent N;
• and (iv) when R1=OH;
• R7=amidine;
• and R2, R3, R4, R5, R6, R8, and R9, represent H, R20 cannot be CH3, or a pharmaceutically acceptable salt thereof.