Thieno [2, 3-b] pyridine derivatives as viral replication inhibitors

A compound according to formula (A),

• wherein,
• R1 is independently selected from alkyl;
• alkenyl;
• alkynyl;
• cycloalkyl;
• cycloalkenyl;
• cycloalkynyl;
• aryl;
• heterocycle;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl;
• or heterocycle-alkynyl;
• wherein in the cycloalkyl, cycloalkenyl, cycloalkynyl, alkyl, alkenyl or alkynyl moiety of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH3, —CH2—, —CH═ and/or ≡CH is optionally replaced by one or more —NH2, —NH—, —O—, —S—, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl, can be unsubstituted or substituted with one or more Z1;
• and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• each of R2a and R2b is independently selected from hydrogen;
• cyano;
• alkyl;
• alkenyl;
• alkynyl;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl;
• or heterocycle-alkynyl or when R2a and R2b are taken together to form vinyl or vinylalkyl;
• wherein in the alkyl, alkenyl or alkynyl moiety of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl or vinylalkyl, one or more —CH3, —CH2—, —CH═ and/or ≡CH is optionally replaced by one or more —NH2, —NH—, —O—, —S—, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, vinyl or vinylalkyl, can be unsubstituted or substituted with one or more Z1;
• and wherein optionally a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, or vinylalkyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2.
• R3 is independently selected from —COOH;
• —CN;
• —CONH2;
• —COOZ2;
• —C(O)NHCN;
• —C(O)NHOH;
• —S(O)2OH;
• —S(O)2NHZ4;
• —P(O)(OH)NH2;
• —P(O)(OH)O-alkyl;
• —P(O)(O-alkyl)2;
• —P(O)OH2;
• —NHC(O)NHS(O)2-aryl;
• —NHC(O)NHS(O)2-heteroaryl;
• —C(O)NHS(O)2-aryl;
• —C(O)NHS(O)2-heteroaryl;
• —S(O)2NHS(O)2-aryl;
• —S(O)2NHS(O)2-heteroaryl;
• or from the following structures:
• or
• R2a and R3 or R2b and R3 can be taken together to form a 4, 5, 6 or 7-membered lactone;
• R4 is independently selected from hydrogen;
• halogen;
• cyano;
• hydroxyl;
• alkyl;
• alkenyl, alkynyl;
• aryl;
• heterocycle;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl;
• heterocycle-alkynyl;
• wherein in the alkyl, alkenyl or alkynyl moiety of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl, one or more —CH3, —CH2—, —CH═ and/or δCH is optionally replaced by one or more —NH2, —NH—, —O—, —S—, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl can be unsubstituted or substituted with one or more Z1;
• and wherein optionally a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• R5 and R6 are taken together to form a 4, 5, 6, 7, or 8-membered unsaturated cycloalkyl moiety, a 4, 5, 6, 7, or 8-membered aryl moiety, or a 4, 5, 6, 7, or 8-membered mono-unsaturated, multi-unsaturated or aromatic O, S and/or N containing heterocycle together with the carbon atoms to which they are attached;
• wherein said 4, 5, 6, 7, or 8-membered unsaturated cycloalkyl moiety, 4, 5, 6, 7, or 8-membered aryl moiety, or 4, 5, 6, 7, or 8-membered mono-unsaturated, multi-unsaturated or aromatic O, S and/or N containing heterocycle can be unsubstituted or substituted with one or more Z1;
• and wherein a carbon atom or heteroatom of the 4, 5, 6, 7, or 8-membered unsaturated cycloalkyl moiety, 4, 5, 6, 7, or 8-membered aryl moiety, or 4, 5, 6, 7, or 8-membered mono-unsaturated, multi-unsaturated or aromatic O, S and/or N containing heterocycle can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2.
• each Z1 is independently selected from the group consisting of hydrogen;
• halogen;
• —OZ2;
• —SZ2;
• —S(O)Z3;
• —S(O)2Z3;
• —SO2NZ4Z5;
• trifluoromethyl;
• nitro;
• —NZ4Z5;
• —NZ2S(O)2Z3;
• cyano;
• —COOZ2;
• —C(O)NZ4Z5;
• —C(O)Z3;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl;
• heterocycle-alkynyl;
• and wherein in the alkyl, alkenyl or alkynyl moiety of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH3, —CH2—, —CH═ and/or ≡CH is optionally replaced by one or more —NH2, —NH—, —O—, —S—, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted or substituted with one or more Z11;
• and wherein optionally a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• or
• two Z1 on the same carbon atom can be taken together to form a 5, 6 or 7-membered spiro-cycloalkyl, spiro-cycloalkenyl, spiro-cycloalkynyl, or a saturated or unsaturated spiro-heterocycle together with the (4, 5, 6, 7 or 8-membered unsaturated) ring they are attached to;
• or
• two Z1 on adjacent atoms can be taken together to form a 5, 6 or 7-membered cycloalkyl, cycloalkenyl, cycloalkynyl, aryl or heterocycle fused to the (4, 5, 6, 7, or 8-membered unsaturated) ring they are attached to;
• each Z11 is independently selected from the group consisting of hydrogen;
• halogen;
• —OZ12;
• —SZ12;
• —S(O)Z13;
• —S(O)2Z13;
• —SO2NZ14Z15;
• trifluoromethyl;
• nitro;
• —NZ14Z15;
• —NZ12S(O)2Z13;
• cyano;
• —COOZ12;
• —C(O)NZ14Z15;
• —C(O)Z13;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkyl, arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl;
• heterocycle-alkynyl;
• each Z2 and Z12 is independently selected from hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl or heterocycle-alkynyl;
• and wherein in said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH3, —CH2—, —CH═ and/or ≡CH is optionally replaced by one or more —NH2, —NH—, —O—, —S—, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —COOH or NH2;
• and wherein optionally a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• each Z3 and Z13 is independently selected from hydroxyl;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl or heterocycle-alkynyl;
• and wherein in said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH3, —CH2—, —CH═ and/or ≡CH is optionally replaced by one or more —NH2, —NH—, —O—, —S—, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —COOH or NH2;
• and wherein optionally a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• each Z4, Z5, Z14 and Z15 is independently selected from hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• heterocycle;
• arylalkyl;
• arylalkenyl;
• arylalkynyl;
• heterocycle-alkyl;
• heterocycle-alkenyl or heterocycle-alkynyl;
• and wherein in said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH3, —CH2—, —CH═ and/or ≡CH is optionally replaced by one or more —NH2, —NH—, —O—, —S, —N═ and/or ≡N, respectively;
• and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —COOH or NH2;
• and wherein optionally a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
• and wherein Z4 and Z5, and Z14 and Z15 respectively can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, -OCF3, cyano, nitro, —COOH or —NH2;
• and isomers (in particular stereo-isomers or tautomers), solvates, hydrates, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof,
• provided that the compounds are not selected from
• [2-(2-methoxy-5-methylphenyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2,7-dimethyl-4-(2-furanyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [4-(2-thienyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2,7-dimethyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2,7-dimethyl-4-(m-tolyl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [4-(4-chlorophenyl)-2-methyl-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [4-(4-chlorophenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid;
• [4-(p-anisyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• Ethyl[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;
• Ethyl[2-(2-thienyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
• [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(4-ethoxyphenyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(4-iodophenyl)-4-phenyl-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(4-propoxyphenyl)-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(3,4-dipropoxyphenyl)-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(2-thienyl)-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(4-pentyloxyphenyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid;
• Ethyl[4-(p-tolyl)-2-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;
• Ethyl[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;
• [4-(3-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-methyl-4-phenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-(2-thienyl)-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid;
• [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid.