Cap/endo dual inhibitors and their use in the treatment, amelioration or prevention of a viral disease

A method of treating, ameliorating or preventing a viral disease, comprising:

• administering to a patient in need thereof an effective amount of a compound having the general formula (V), or a pharmaceutically acceptable salt, racemate, enantiomer, or diastereomer or mixture thereof:
• and
• administering to the patient at least one further medicament selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (V);
• a neuraminidase inhibitor;
• an M2 channel inhibitor;
• an alpha-glucosidase inhibitor;
• a ligand of another influenza target;
• an antibiotic;
• an anti-inflammatory agent;
• an lipoxygenase inhibitor;
• an EP ligand;
• a bradykinin ligand, and a cannabinoid ligand;
• wherein:
• R51 is selected from —H, -(optionally substituted C1-6 alkyl) and —C(O)-(optionally substituted C1-6 alkyl);
• or
• R51 is selected from —C(O)—R, —C(O)—OR, —PO(ORA)(ORB) and —OC(O)OR, where R, RA and RB are independently selected from C1-6 alkyl, aryl, and heteroaryl, where the C1-6 alkyl, aryl, or heteroaryl can be optionally substituted with —OH or —O—C1-6 alkyl,
• R52 is selected from —H, -(optionally substituted C1-6 alkyl), —(CH2)q-(optionally substituted heterocyclyl), —(CH2)q-(optionally substituted carbocyclyl), —(CH2)p—OR55, and —(CH2)p—NR56R57;
• R53 is selected from —R54 and —X51R54;
• R54 is a bicyclic fused ring system comprising from 10 to 14 ring atoms and 1 to 4 nitrogen atoms as ring atoms, wherein the bicyclic fused ring system can optionally be substituted;
• R55 is selected from —H, —C1-6 alkyl, and —(CH2CH2O)rH;
• R56 is selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• R57 is selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• R58 is selected from —H and —C1-6 alkyl;
• X51 is -L1-(A-(L2)m)n;
• X52 is selected from NR56, N(R56)C(O), C(O)NR56, O, C(O), C(O)O, OC(O);
• N(R56)SO2, SO2N(R56), S, SO, and SO2;
• L1 is selected from NR56, N(R56)C(O), C(O)NR56, O, C(O), C(O)O, OC(O);
• N(R56)SO2, SO2N(R56), N(R56)SO2N(R56), S, SO, SO2 and (optionally substituted heterocyclyl having 3 to 7 ring atoms)-NR56;
• L2 is selected from NR56, N(R56)C(O), C(O)NR56, O, C(O), C(O)O, OC(O);
• N(R56)SO2, SO2N(R56), N(R56)SO2N(R56), S, SO, SO2 and (optionally substituted heterocyclyl having 3 to 7 ring atoms)-NR56;
• A is selected from (CR*R**)t, optionally substituted C3-7 carbocyclyl, optionally substituted heterocyclyl having 3 to 7 ring atoms and combinations thereof;
• R* is independently for each occurrence selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• R** is independently for each occurrence selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• or R* and R** can optionally form an optionally substituted C3-7 carbocyclyl group or optionally substituted heterocyclyl group having 3 to 7 ring atoms;
• R*** is independently for each occurrence selected from —H, a —C1-6 alkyl group, and a —C1-6 alkyl group which is substituted by one or more halogen atoms;
• m is 0 or 1;
• n is 0 or 1;
• p is 1 to 4;
• q is 0 to 4;
• r is 1 to 3;
• s is 0 to 4;
• and
• t is 1 to 6;
• the alkyl group can be optionally substituted with one or more substituents which are independently selected from halogen, —CN, —NR56R57, —OH, and —O—C1-6 alkyl;
• the bicyclic fused ring system can be optionally substituted with one or more substituents which are independently selected from (═O), halogen, —CN, —CF3, —(CH2)s—X52—R58, —C1-6 alkyl, —C3-7 carbocyclyl, —C1-4 alkyl-C3-7 carbocyclyl, -(heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(heterocyclyl having 3 to 7 ring atoms);
• and
• the hydrocarbon group, heterocyclyl group, and/or carbocyclyl group can be optionally substituted with one or more substituents which are independently selected from halogen, —CN, —CF3, —(CH2)s—X52—R58, —C1-6 alkyl, —C3-7 carbocyclyl, —C1-4 alkyl-C3-7 carbocyclyl, -(heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(heterocyclyl having 3 to 7 ring atoms).

A method of treating, ameliorating or preventing a viral disease, comprising:

• administering to a patient in need thereof an effective amount of a compound having the general formula (V), or a pharmaceutically acceptable salt, racemate, enantiomer, or diastereomer or mixture thereof:
• and
• administering to the patient at least one further medicament selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (V);
• a neuraminidase inhibitor;
• an M2 channel inhibitor;
• an alpha-glucosidase inhibitor;
• a ligand of another influenza target;
• an antibiotic;
• an anti-inflammatory agent;
• an lipoxygenase inhibitor;
• an EP ligand;
• a bradykinin ligand, and a cannabinoid ligand;
• wherein:
• R51 is selected from —H, -(optionally substituted C1-6 alkyl) and —C(O)-(optionally substituted C1-6 alkyl);
• or
• R51 is selected from —C(O)—R, —C(O)—OR, —PO(ORA)(ORB) and —OC(O)OR, where R, RA and RB are independently selected from C1-6 alkyl, aryl, and heteroaryl, where the C1-6 alkyl, aryl, or heteroaryl can be optionally substituted with —OH or —O—C1-6 alkyl,
• R52 is selected from —H, -(optionally substituted C1-6 alkyl), —(CH2)q-(optionally substituted heterocyclyl), —(CH2)q-(optionally substituted carbocyclyl), —(CH2)p—OR55, and —(CH2)p—NR56R57;
• R53 is selected from —R54 and —X51R54;
• R54 is a bicyclic fused ring system comprising from 10 to 14 ring atoms and 1 to 4 nitrogen atoms as ring atoms, wherein the bicyclic fused ring system can optionally be substituted;
• R55 is selected from —H, —C1-6 alkyl, and —(CH2CH2O)rH;
• R56 is selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• R57 is selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• R58 is selected from —H and —C1-6 alkyl;
• X51 is -L1-(A-(L2)m)n-;
• X52 is selected from NR56, N(R56)C(O), C(O)NR56, O, C(O), C(O)O, OC(O);
• N(R56)SO2, SO2N(R56), S, SO, and SO2;
• L1 is selected from NR56, N(R56)C(O), C(O)NR56, O, C(O), C(O)O, OC(O);
• N(R56)SO2, SO2N(R56), N(R56)SO2N(R56), S, SO, SO2 and (optionally substituted heterocyclyl having 3 to 7 ring atoms)-NR56;
• L2 is selected from NR56, N(R56)C(O), C(O)NR56, O, C(O), C(O)O, OC(O);
• N(R56)SO2, SO2N(R56), N(R56)SO2N(R56), S, SO, SO2 and (optionally substituted heterocyclyl having 3 to 7 ring atoms)-NR56;
• A is selected from (CR*R**)t, optionally substituted C3-7 carbocyclyl, optionally substituted heterocyclyl having 3 to 7 ring atoms and combinations thereof;
• R* is independently for each occurrence selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• R** is independently for each occurrence selected from —H, -(optionally substituted C1-6 alkyl), -(optionally substituted C3-7 carbocyclyl), —C1-4 alkyl-(optionally substituted C3-7 carbocyclyl), -(optionally substituted heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(optionally substituted heterocyclyl having 3 to 7 ring atoms);
• or R* and R** can optionally form an optionally substituted C3-7 carbocyclyl group or optionally substituted heterocyclyl group having 3 to 7 ring atoms;
• R*** is independently for each occurrence selected from —H, a —C1-6 alkyl group, and a —C1-6 alkyl group which is substituted by one or more halogen atoms;
• m is 0 or 1;
• n is 0 or 1;
• p is 1 to 4;
• q is 0 to 4;
• r is 1 to 3;
• s is 0 to 4;
• and
• t is 1 to 6;
• the alkyl group can be optionally substituted with one or more substituents which are independently selected from halogen, —CN, —NR56R57, —OH, and —O—C1-6 alkyl;
• the bicyclic fused ring system can be optionally substituted with one or more substituents which are independently selected from (═O), halogen, —CN, —CF3, —(CH2)s—X52—R58, —C1-6 alkyl, —C3-7 carbocyclyl, —C1-4 alkyl-C3-7 carbocyclyl, -(heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(heterocyclyl having 3 to 7 ring atoms);
• the hydrocarbon group, heterocyclyl group, and/or carbocyclyl group can be optionally substituted with one or more substituents which are independently selected from halogen, —CN, —CF3, —(CH2)s—X52—R58, —C1-6 alkyl, —C3-7 carbocyclyl, —C1-4 alkyl-C3-7 carbocyclyl, -(heterocyclyl having 3 to 7 ring atoms), and —C1-4 alkyl-(heterocyclyl having 3 to 7 ring atoms);
• and
• wherein the at least one further medicament is administered concurrently with, sequentially with or separately from the compound having the general formula (V).