Viral polymerase inhibitors

An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula I:

• 1308
• wherein:
• either A or B is N and the other B or A is C, wherein - - - between two C-atoms represents a double bond and - - - between a C-atom and a N-atom represents a single bond,
• the group —C(═Y1)-Z is covalently linked to either M2 or M3,
• M1 is CR4a,
• M2 or M3, when not linked to —C(═Y1)-Z, is CR5,
• M4 is CR4b,
• and in addition one or two of the groups selected from M1, M2, M3 and M4 may also be N, with the proviso that the group M2 or M3 to which —C(═Y1)-Z is linked is an C-atom,
• Sp is a spacer group selected from —(CR51R52)k1—, wherein
• k1 is 1, 2 or 3;
• R51, R52 are independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl, or
• R51 and R52 are covalently bonded together and to the carbon-atom to which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms selected from N, O or S;
• said alkyl, cycloalkyl, alkyl-cycloalkyl or cyclic system being optionally substituted by halogen, hydroxy, (C1-6)alkoxy, cyano, amino, —NH(C1-4-alkyl) and/or —N(C1-4-alkyl)2;
• Y0 is O, S, NR11 or CR12R13, wherein
• R13, R12, R13 are each independently defined as RO;
• R13 may also be COORO or SO2RC;
• wherein RC and each RO is optionally substituted with R150;
• or both R12 and R13 are covalently bonded together and to the carbon-atom to which they are attached to form a 3, 4, 5, 6 or 7-membered saturated or 5, 6 or 7-membered unsaturated cyclic system whereby the 5, 6 or 7-membered saturated or unsaturated cyclic system may contain 1 to 3 heteroatoms selected from N, O or S;
• said cyclic systems being optionally substituted with R150;
• L is C1-6alkyl, (C3-6)cycloalkyl, C1-6alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, (C1-6alkyl)aryl, Het, (C1-6)alkyl-Het, all of which being optionally substituted with R60;
• or Y0 and L are covalently bonded to form a 5, 6, 7 or 8-membered mono- or a 8, 9, 10 or 11 -membered bicyclic group which may be unsaturated or aromatic and which may contain 1, 2 or 3 heteroatoms selected from N, O and S, wherein the mono- or bicyclic group is optionally substituted with R60;
• or if Y0 is CR12R13, then L may also be H;
• or if Y0 is O, then L may also be ORC,
• wherein RC is optionally substituted with R60;
• or if Y0 is O, S or NR11, then L may also be N(RN2)RN1, NRN3—N(RN2)RN1,
• NRN3—NRN2—CO—RC, NRN4—NRN3—CO—N(RN2)RN1, NRN2—SO2—RC, NRN2—CO—RC, NRN3—CO—N(RN2)RN1 or N(RN1)ORO;
• said RN1, including any heterocycle or heterobicycle formed by RN1, RN2 and/or RN3, and RCand RO being optionally substituted with R60;
• or if Y0 is O or S, then L may also be OR6a or N(R5a)R6a, wherein R5a is defined as RN2,
• and wherein R6a is:
• 1309
• or R6ais:
• 1310
• wherein R7a and R8a are each independently defined as RO, COORO or CON(RN2)RN1, wherein said RO is optionally substituted with R60;
• or
• R7a and R8a are covalently bonded together to form a (C3-7)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S;
• and when L is N(R5a)R6a, either of R7a, or R8a may be covalently bonded to R5a to form a nitrogen-containing 5-or 6-membered heterocycle, wherein said cycloalkyl or heterocycle being optionally substituted by R150;
• and
• W1 is selected from
• a) a single bond;
• b) —CH2—;
• c) —CH2—CH2—;
• and
• d) —CH═CH—;
• wherein the alkylene and alkenylene groups according to b), c) and d) may be substituted with (C1-3) alkyl;
• Y2is O or S;
• R9a is defined as RO, wherein said RO is optionally substituted with R60;
• or
• R9a is covalently bonded to either of R7a or R8a to form a 5- or 6-membered heterocycle;
• Q1 is aryl, Het, (C1-6)alkyl-aryl, (C1-6)alkyl-Het, (C1-6)alkyl-CONH-aryl or (C1-6) alkyl-CONH-Het, all of which being optionally substituted with R60;
• Y1 is O, S or NR14, wherein R14 is H or (C1-6) alkyl;
• Z is defined as
• a) ORO;
• b) SO2RC;
• c) N(RN2)RN1;
• d) NRN3—N(RN2)RN1;
• e) NRN3—NRN2—CO—RC;
• f) NRN4—NRN3—CO—N(RN2)RN1;
• g) NRN2—SO2—RC or
• h) NRN3—SO2—N(RN2)RN1;
• i) NRN2—CO—RC;
• j) COORO;
• k) N(RN1)ORO;
• wherein RO and RC are optionally substituted with R60;
• and
• said RN1, including any heterocycle or heterobicycle formed by RN1, RN2, and/or RN3, being optionally substituted with R60;
• or Z is OR6b or N(R5b)R6b wherein R5bis defined as RN2 and R6b is:
• 1311
• or R6b is:
• 1312
• wherein R7b, R8b, Y3, R9b, W2 are defined as R7a, R8a, Y2, R9a, W1 respectively;
• and
• Q2 is aryl, Het, (C1-6) alkyl-aryl, (C1-6) alkyl-Het, (C1-6) alkyl-CONH-aryl or (C1-6) alkyl-CONH-Het, all of which being optionally substituted with R60 or Q2 is R160
• or Q2 is selected from the group consisting of O—C1-4alkyl, S—C1-4-alkyl, C1-4-alkyl, C2-4-alkenyl and C2-4-alkynyl, all of which being optionally substituted with R160;
• and
• R2 is selected from:
• halogen or R21, wherein R21 is aryl or Het, said R21 is optionally substituted with R150;
• R3 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C1-3)alkyl-(C3-7)cycloalkyl, (C5-7)cycloalkenyl, (C1-3)alkyl-(C5-7)cycloalkenyl, (C6-10)bicycloalkyl, (C1-3)alkyl-(C6-10)bicycloalkyl, (C6-10)bicycloalkenyl, (C1-3)alkyl-(C6-10)bicycloalkenyl, HCy or (C1-3)alkyl-HCy,
• wherein HCy is a saturated or unsaturated 4 to 7-membered heterocyclic group with 1 to 3 heteroatoms selected from O, S and N;
• said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, HCy and alkyl-HCy being optionally substituted with from 1 to 4 substituents selected from:
• a) halogen;
• b) (C1-6)alkyl optionally substituted with:
• 1 to 3 substituents selected from halogen;
• OR31 or SR31 wherein R31 is H, (C1-6alkyl), (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl;
• or
• N(R32)2 wherein each R32 is independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl;
• or both R32 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
• c) OR33 or SR33 wherein R33 is H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl;
• d) N(R35)2 wherein each R35 is independently H, (C1-6)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl;
• or both R35 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
• R4a, R4b, R5 each are independently H or defined as R150;
• R60 is each defined as 1 to 4 substituents independently selected from:
• 1 to 3 substituents selected from halogen;
• one of each substituent selected from:
• OPO3H, NO2, cyano, azido, C(═NH)NH2, C(═NH)NH(C1-6)alkyl or C(═NH)NHCO(C1-6)alkyl, SO3H;
• and
• 1to 3 substituents selected from:
• a) (C1-6) alkyl, (C3-7)cycloalkyl, C3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms selected from N, O and S;
• (C2-6)alkenyl, (C2-8)alkynyl, (C1-6)alkyl-(C3-7)cycloalkyl, all of which optionally being substituted with R150;
• b) ORO;
• c) OC(O)RO;
• d) SRO, SO2RC, SO2N(RN2)RN1, SO2N(RN2)C(O)RC, CONRN3SO2N(RN2)RN1, or CONRN2SO2RC;
• e) N(RN2)RN1, N(RN2)COORC, N(RN2)SO2RC or N(RN1)RO;
• f) N(R2N)CORC;
• g) N(RN3)CON(RN2)RN1;
• h) N(RN3)COCORC, N(RN3)COCOORO or N(RN3)COCON(RN2)RN1;
• i) CORO;
• j) COORO;
• k) CON(RN2)RN1;
• l) aryl, Het, (C1-4alkyl)aryl or (C1-4alkyl)Het, all of which optionally being substituted with R150;
• wherein said RN1, RC and RO are each independently optionally substituted with R150 as defined,
• R150 is each defined as 1 to 4 substituents independently selected from:
• 1 to 3 substituents selected from halogen;
• one of each substituent selected from:
• OPO3H, NO2, cyano, azido, C(═NH)NH2, C(═NH)NH(C1-6)alkyl or C(=NH)NHCO(C1-6)alkyl;
• and
• 1 to 3 substituents selected from:
• a) (C1-6) alkyl, (C3-7)cycloalkyl, C3-7 spirocycloalkyl optionally containing 1 or 2 heteroatoms selected from N, O and S;
• (C2-6)alkenyl, (C2-6)alkynyl, (C1-3)alkyl-(C3-7)cycloalkyl, all of which optionally substituted with R160;
• b) ORO;
• c) OC(O)RO;
• d) SRO, SO2RC, SO2N(RN2)RN1, SO2N(RN2)C(O)RC or CON(RN2) SO2RC;
• e) N(RN2)RN1, N(RN2)COORC, N(RN2)SO2RC, or N(RN1)RO;
• f) N(RN2)CORC;
• g) N(RN3)CON(RN2)RN1;
• h) N(RN3)COCORC, N(RN3)COCOORO, N(RN3)COCON(RN2)OH, N(RN3)COCON(RN2)OC1-4-alkyl or N(RN3)COCON(RN2)RN1;
• i) CORO;
• j) COORO;
• k) tetrazole, triazole, CONRN3—SO2N(RN2)RN1;
• or CON(RN2)RN1;
• wherein said RN1, RC and/or RO are optionally substituted with R160 as defined;
• R160 is each defined as 1, 2 or 3 substituents independently selected from:
• 1, 2 or 3 fluorine substituents;
• and
• one of each substituent selected from tetrazole, triazole, chlorine, bromine, iodine, CN, nitro, C1-4alkyl, CF3, COOR161, SO3H, SR161, SCF3, SO2R163, OR161, OCF3, N(R162)2, SO2N(R162)2, NR162SO2RC, NR162COR162CON(R162)2, —NR161—CO—COOR161, —NR161—CO—CO(NR162)2, —CONR161SO2RC, CONR161—SO2N(R162)2 or —SO2—NR161—CORC, wherein R161, R163and each R162 is independently (C1-4)alkyl, (C3-7)cycloalkyl or (C1-3)alkyl-(C3-7)cycloalkyl;
• and R161 and each R162 may each independently also be H;
• or both R162 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
• RO, RC are independently defined as (C1-6)alkyl, (C3-6)cycloalkyl, (C1-4)alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl and (C1-4)alkyl-Het;
• and RO may also be H;
• RN1 is independently selected from H, (C1-6)alkyl, (C3-7)cycloalkyl, (C1-4)alkyl-(C3-6)cycloalkyl, (C2-6)alkenyl, aryl, Het, (C1-4)alkyl-aryl, (C1-4)alkyl-Het;
• or
• RN2, RN3, RN4 are independently H, CH3, (C2-6)alkyl, (C3-6)cycloalkyl, (C1-4) alkyl-(C36)cycloalkyl;
• wherein said alkyl, cycloalkyl or alkylcycloalkyl is optionally substituted with hydroxy, halogen, carboxy, C1-6-alkoxycarbonyl, C1-6-alkyl, C1-6alkoxy, amino, —NH(C1-4-alkyl) and/or —N(C1-6-alkyl)2;
• and wherein said CH3 is optionally substituted with halogen, carboxy or C1-6-alkoxycarbonyl;
• and
• in the case
• a) of a group N(RN2)RN1 the substituents RN2 and RN1;
• or
• b) of a group NRN3—N(RN2)RN1 the substituents RN3 and RN1, or RN2 and RN1;
• may be covalently bonded together to form a 4-, 5-, 6- or 7-membered saturated or unsaturated N-containing heterocycle or a 8-, 9-, 10- or 11-membered N-containing heterobicycle each may have additionally from 1 to 3 heteroatoms selected from O, N, and S;
• wherein Het is defined as a 4-, 5-, 6- or 7-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, or a 8-, 9-, 10- or 11-membered heterobicycle having 1 to 5 heteroatoms selected from O, N and S;
• or a salt thereof.