Antipicornaviral compounds, compositions containing them, and methods for their use

A compound of the formula (I):

• wherein:
• M is O or S;
• R1 is H, F, an alkyl group, OH, SH, or an O-alkyl group;
• R2 and R5 are independently selected from H,
• or an allyl group, wherein said alkyl group is different from
• with the proviso that at least one of R2 or R5 must be
• and wherein, when R2 or R5 is
• X is ═CH or ═CF and Y1 is ═CH or ═CF,
• or X and Y1 together with Q′ form a three-membered ring in which Q′ is —C(R10)(R11)— or —O—, X is —CH— or —CF—, and Y1 is —CH—, —CF—, or —C(alkyl)-, where R10 and R11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
• or X is —CH2—, —CF2—, —CHF—, or —S—, and Y1 is —O—, —S—, —NR12—, —C(R13)(R14)—, —C(O)—, —C(S)—, or —C(CR13R14)—,
• wherein R12 is H or alkyl, and R13 and R14 independently are H, F, or an alkyl group, or, together with the atoms to which they are bonded, form a cycloalkyl group or a heterocycloalkyl group;
• A1 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), P—OR15, or P—NR15R16,
• wherein R15 and R16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are bonded, form a heterocycloalkyl group;
• D1 is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
• and
• B1 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR17, —SR17, —NR17R18, —NR19NR17R18, or —NR17OR18,
• wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
• and with the provisos that when D1 is the moiety □N with a lone pair of electrons capable of forming a hydrogen bond, B1 does not exist;
• and when A1 is an sp3 carbon, B1 is not —NR17R18 when D1 is the moiety —NR25R26 with a lone pair of electrons capable of forming a hydrogen bond, wherein R25 and R26 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
• and wherein D1-A1-B1 optionally forms a nitro group where A1 is N;
• and further wherein, when R2 or R5 is
• X is ═CH or ═CF and Y2 is =C, ═CH, or ═CF,
• or X and Y2 together with Q′ form a three-membered ring in which Q′ is —C(R10)(R11)— or —O—, X is —CH— or —CF—, and Y2 is —CH—, —CF—, or —C(alkyl)-, where R10 and R11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
• or X is —CH2—, —CF2—, —CHF—, or —S—, and Y2 is —O—, —S—, —N(R′12)—, —C(O)—, —C(R′13)(R14)—, —C(S)—, or —C(CR′13R′14)—,
• wherein R′12 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR′13, —NR′13R′14, —C(O)—R′13, —SO2R′13, or —C(S)R′13, and R′13 and R′14, independently are H, F, or an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
• A2 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), P—OR15, or P—NR15R16,
• wherein R15 and R16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are bonded, form a heterocycloalkyl group;
• D2 is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
• and
• B2 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR17, —SR17, —NR17R18, —NR19NR17R18, or —NR17OR18,
• wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloakyl group, an aryl group, a heteroaryl group, or an acyl group;
• and further wherein any combination of Y2, A2, B2, and D2 optionally can form a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
• R3 and R6 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R17, —OR17, —SR17, —NR17R18, —NR19NR17R18, or —NR17OR18,
• wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
• or, R3 and R6, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
• R7 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR17, —SR17, —NR17R18, —NR19NR17R18, or —NR17OR18,
• wherein R17, R18, and R19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
• or R7, together with R3 or R6 and the atoms to which they are attached, forms a heterocycloalkyl group;
• R20 is H, OH, or any suitable organic moiety;
• and
• Z and Z1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R21, —CO2R21, —CN, —C(O)NR21R22, —C(O)NR21OR22, —C(S)R21, —C(S)NR21R22, —NO2, —SOR21, —SO2R21, —SO2NR21R22, —SO(NR21)(OR22), —SONR21, —SO3R21, —PO(OR21)2, —PO(R21)(R22), —PO(NR21R22)(OR23), PO(NR21R22)(NR23R24), —C(O)NR21NR22R23, or —C(S)NR21NR22R23,
• wherein R21, R22, R23, and R24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R21, R22, R23, and R24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
• or Z1, as defined above, together with R1, as defined above, and the atoms to which Z1 and R1 are bonded, form a cycloalkyl or heterocycloalkyl group,
• or Z and Z1, both as defined above, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group;
• or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof;
• and wherein said compound, or pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof, has antipicornaviral activity with an EC50 less than or equal to 10 μM in the HI-HeLa cell culture assay.