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US 2015/0175648 A1Published application
Hcv polymerase inhibitors
AssigneeMedivir AB
InventorsGenadiy KALAYANOV, Staffan TORSSELL, Horst WAHLING
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Abstract
The invention provides compounds of the formula: wherein B is a nucleobase selected from the groups (a) to (d): and the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
Claims42
A compound represented by formula I:
- wherein:
- B is a nucleobase selected from the groups (a) to (d):
- wherein Y is N or C(R19);
- R1 is selected from the groups (i) to (iv):
- R2 is H, C(═O)R30, C(═O)CHR31NH2, CR32R32′OC(═O)CHR33NH2 or CR32R32′OC(═O)R30;
- R4, R5, R7 and R8 are each independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18, SR18 or N(R18)2;
- R6, R9, R10 and R11 are each independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18, SR18, N(R18)2, NHC(O)OR18, NHC(O)N(R18)2, CN, NO2, C(O)R18, C(O)OR18, C(O)N(R18)2 and NHC(O)R18, wherein said C2-C6alkenyl group and said C2-C6alkynyl group can be optionally substituted with halo or C3-C5cycloalkyl;
- R14 is H or C1-C6alkyl, phenyl, naphthyl or a 5 to 12 membered mono or bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, which phenyl, naphthyl or heteroaryl is optionally substituted with 1, 2 or 3 R22;
- R15 and R15′ are each independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, phenyl and benzyl, or R15 and R15′ together with the carbon atom to which they are attached from a C3-C7cycloalkylene group, wherein each C1-C6alkyl is optionally substituted with a group selected from halo, OR18 and SR18, and each C3-C7cycloalkyl, C3-C7cycloalkylene, phenyl and benzyl is optionally substituted with one or two groups independently selected from C1-C3alkyl, halo and OR18;
- or
- R15′ is H and R15 and R24 together with the atoms to which they are attached, form a 5-membered ring;
- R16 is H, C1-C10alkyl, C2-C10alkenyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, benzyl, phenyl or adamantyl, any of which is optionally substituted with 1, 2 or 3 groups, each independently selected from halo, OR18 and N(R18)2;
- each R18 is independently H, C1-C6alkyl, C1-C6haloalkyl or C3-C7cycloalkyl;
- R19 is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18 or N(R18)2;
- each R20 is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, C1-C6hydroxyalkyl or C3-C7cycloalkylC1-C3alkyl;
- each R21 is independently H, C1-C24alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkenyl;
- each R22 is independently selected from halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, phenyl, hydroxyC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylcarbonyl, C3-C6cycloalkylcarbonyl, carboxyC1-C6alkyl, oxo, OR20, SR20, N(R20)2, CN, NO2, C(O)OR20, C(O)N(R20)2 and NHC(O)R20, or any two R22 groups attached to adjacent ring carbon atoms can combine to form —O—R23—O—;
- R23 is [C(R33)2]n;
- R24 is H, or R24 and R15 together with the atoms to which they are attached, form a 5-membered ring;
- each R30 is independently selected from C1-C6alkyl and C1-C6alkoxy;
- U is O or S;
- or a pharmaceutically acceptable salt and/or solvate thereof.
19 more elements
A compound represented by formula II:
- wherein:
- B is a nucleobase selected from the groups (a) to (d):
- wherein Y is N or C(R19);
- R1 is H, C(═O)R30, C(═O)CHR31NH2 or CR32R32′OC(═O)CHR33NH2;
- R2 is H, C(═O)R30, C(═O)CHR31NH2, CR32R32′OC(═O)CHR33NH2 or CR32R32′OC(═O)R30;
- R4, R5, R7 and R8 are each independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, —OR18, —SR18 or —N(R18)2;
- R6, R9, R10 and R11 are each independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18, SR18, N(R18)2, —NHC(O)OR18, —NHC(O)N(R18)2, —CN, —NO2, —C(O)R18, —C(O)OR18, —C(O)N(R18)2 and —NHC(O)R18, wherein said C2-C6alkenyl group and said C2-C6alkynyl group can be optionally substituted with halo or C3-C5cycloalkyl;
- R16 is H, C1-C10alkyl, C2-C10alkenyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, benzyl, phenyl or adamantyl, any of which is optionally substituted with 1, 2 or 3 groups, each independently selected from halo, OR18 and N(R18)2;
- each R17 is independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, phenyl and benzyl;
- or
- both R17 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic or a 5-6 membered heteroaryl ring which rings are optionally substituted with one or two groups independently selected from C1-C3alkyl, halo, C1-C3haloalkyl, amino, C1-C3alkylamino, (C1-C3alkyl)2amino;
- each R18 is independently H, C1-C6alkyl, C1-C6haloalkyl or C3-C7cycloalkyl;
- R19 is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, —OR18 or N(R18)2;
- each R30 is independently selected from C1-C6alkyl and C1-C6alkoxy;
- each R31 is independently selected from H, C1-C6alkyl, C3-C7cycloalkyl and benzyl;
- each R32 and R32′ is independently selected from H and C1-C3alkyl;
- each R33 is independently selected from H and C1-C6alkyl;
- or a pharmaceutically acceptable salt and/or solvate thereof.
15 more elements
A compound represented by formula III:
- wherein:
- B is a nucleobase selected from the groups (a) to (d):
- wherein Y is N or C(R19);
- R1 is the group (i):
- R2 is H, C(═O)R30, C(═O)CHR31NH2, CR32R32′OC(═O)CHR33NH2 or CR32R32′OC(═O)R30;
- or
- R4, R5, R7 and R8 are each independently selected from H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18, SR18 and N(R18)2;
- R6, R9, R10 and R11 are each independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18, SR18, N(R18)2, NHC(O)OR18, NHC(O)N(R18)2, CN, NO2, C(O)R18, C(O)OR18, C(O)N(R18)2 and NHC(O)R18, wherein said C2-C6alkenyl group and said C2-C6alkynyl group can be optionally substituted with halo or C3-C5cycloalkyl;
- R12 is H or (C1-C6alkylene)-T-R21, phenyl, indolyl or naphthyl which phenyl, indolyl or naphthyl group is optionally substituted with 1, 2 or 3 substituents each independently selected from halo, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, hydroxyC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylcarbonyl, C3-C6cycloalkylcarbonyl C1-C6alkoxy, C1-C6haloalkoxy, hydroxy and amino;
- R13 is (C1-C6alkylene)-T-R21;
- or
- R12 and R13 can join to form a C2-C4alkylene group between the oxygen atoms to which they are attached, wherein said C2-C4alkylene group is optionally substituted with one C6-C10aryl group;
- each R18 is independently H, C1-C6alkyl, C1-C6haloalkyl or C3-C7cycloalkyl;
- R19 is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18 or N(R18)2;
- each R20 is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, C1-C6hydroxyalkyl or C3-C7cycloalkylC1-C3alkyl;
- each R21 is independently H, C1-C24alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkenyl;
- R24 is H, or R24 and R15 together with the atoms to which they are attached, form a 5-membered ring;
- each R30 is independently selected from C1-C6alkyl and C1-C6alkoxy;
- each R31 is independently selected from H, C1-C6alkyl, C3-C7cycloalkyl and benzyl;
- each R32 and R32′ is independently selected from H and C1-C3alkyl;
- each R33 is independently selected from H and C1-C6alkyl;
- U is O;
- each T is independently S, O, SC(O), C(O)S, SC(S), C(S)S, OC(O), C(O)O and OC(O)O;
- or a pharmaceutically acceptable salt and/or solvate thereof.
21 more elements
A compound represented by formula IV:
- wherein:
- B is a nucleobase selected from the groups (a) to (d):
- wherein Y is N or C(R19);
- R1 and R2 together form a bivalent linker of formula:
- R3 is OH, C1-C6alkoxy, C3-C7cycloalkoxy, C3-C7cycloalkylC1-C3alkoxy, benzyloxy, O—(C1-C6alkylene)-T-R21 or NHC(R15)(R15′)C(═O)R16;
- R4, R5, R7 and R8 are each independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, —OR18, —SR18 or —N(R18)2;
- R6, R9, R10, R11 are each independently selected from H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR18, SR18, N(R18)2, —NHC(O)OR18, —NHC(O)N(R18)2, —CN, —NO2, —C(O)R18, —C(O)OR18, —C(O)N(R18)2 and —NHC(O)R18, wherein said C2-C6alkenyl group and said C2-C6alkynyl group can be optionally substituted with halo or C3-C5cycloalkyl;
- each R18 is independently H, C1-C6alkyl, C1-C6haloalkyl or C3-C7cycloalkyl;
- R14 is H or C1-C6alkyl, phenyl, naphthyl or a 5 to 12 membered mono or bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, which phenyl, naphthyl or heteroaryl is optionally substituted with 1, 2 or 3 R22;
- R15 and R15′ are each independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, phenyl and benzyl, or R15 and R15′ together with the carbon atom to which they are attached from a C3-C7cycloalkylene group, wherein each C1-C6alkyl is optionally substituted with a group selected from halo, OR18 and SR18, and each C3-C7cycloalkyl, C3-C7cycloalkylene, phenyl and benzyl is optionally substituted with one or two groups independently selected from C1-C3alkyl, halo and OR18;
- or
- R16 is H, C1-C10alkyl, C2-C10alkenyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, benzyl, phenyl or adamantyl, any of which is optionally substituted with 1, 2 or 3 groups, each independently selected from halo, OR18 and N(R18)2;
- R19 is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, —OR18 or N(R18)2;
- each R21 is independently H, C1-C24alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl or C3-C7cycloalkenyl;
- each T is independently S, O, SC(O), C(O)S, SC(S), C(S)S, OC(O), C(O)O and OC(O)O;
- U is O;
- or a pharmaceutically acceptable salt and/or solvate thereof.
14 more elements
Dependencies are inferred from the claim text.