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US 2013/0171102 A1Published application
Heterocyclic flaviviridae virus inhibitors
AssigneeGilead Sciences, Inc.
InventorsKyla Bjornson, Steven S. Bondy, You-chul Choi, Chien-Hung Chou, Ruchika Mishra, James D. Trenkle, Winston C. Tse, Randall W. Vivian, James G. Taylor
Life of this patent
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Abstract
The invention is related to anti-viral compounds of formula (A) as defined in the claims, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well to processes and intermediates useful for preparing such compounds.
Claims43
A compound of formula (A)
- wherein:
- the dotted lines represent optional double bonds, provided that no two double bonds are adjacent to one another, and that the dotted lines together represent 3 or 4 double bonds;
- U is N or CR3, T is N or CR4, A is N or CR5, W is N or CR6, V is N or CR7;
- At least one of U, V or W is N;
- and
- At least one of A and T is not N;
- X is selected from the group consisting of C1-C10 alkylene, C2-10 alkenylene and C2-10 alkynylene, wherein each of said C1-C10 alkylene, C2-10 alkenylene and C2-10 alkynylene may have one or more carbon atoms replaced by a heteroatom selected from O, S, or N and wherein each of said C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene and heteroatom may be optionally substituted with 1 or more R20;
- Y is selected from the group consisting of a single bond, O, S(O)m, NR11, C1-10 alkylene, C2-10 alkenylene and C2-10 alkynylene, wherein each of said C1-10 alkylene, C2-10 alkenylene and C2-10 alkynylene may have one or more carbon atoms replaced by a heteroatom selected from O, S, and N;
- R1 is selected from the group consisting of hydrogen, aryl, heterocycle, C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkylamino, C1-C10 dialkylamino, C3-C10 cycloalkyl, and C4-C10 cycloalkenyl, wherein each of said aryl, heterocycle, C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkylamino, C1-C10 dialkylamino, C3-C10 cycloalkyl, and C4-C10 cycloalkenyl may be optionally substituted with 1 or more R20;
- R2 is selected from the group consisting of aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, alkynyl and heterocycle, wherein each of said aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, alkynyl and heterocycle may be optionally substituted with one or more R17;
- R3 and R7 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, S(O)mR9, halogen, —OH, —CN, —NO2, —NR13R14, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, (═O), (═S), ═NR21 and heterocycle, wherein any alkyl, cycloalkyl, alkenyl, aryl and heterocycle may be optionally substituted with 1 or more R20;
- R4, R5 and R6 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, S(O)mR9, halogen, —OH, —CN, —NO2, —NR13R14, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, and heterocycle, wherein each of said alkyl, cycloalkyl, alkenyl, aryl and heterocycle may be optionally substituted with 1 or more R20;
- R9 and R18 are independently selected from the group consisting of hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, aryl, CH2OCH(═O)R9a, and CH2C(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
- R11 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, and heterocycle;
- R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, and C4-10 cycloalkenyl;
- R13 and R14 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C2-18 alkynyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12;
- S(O)mR9 and —C(═S)R12, or R13 and R14 together with the nitrogen to which they are attached form a heterocycle;
- R15 and R16 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl and an amino acid residue;
- R17 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halogenated alkyl, C2-18 halogenated alkenyl, C2-18 halogenated alkynyl, C1-18 halogenated alkoxy, C1-18 halogenated alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, halogen, OH, CN, CO2H, CO2R18, NO2, NR13R14, haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle and C1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle and C1-18 hydroxyalkyl may be optionally substituted with 1 or more R19;
- R19 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR13R14, C1-18 haloalkyl, C1-18 haloalkoxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR15R16, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocycle, C1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18alkyl)oxy, arylthio, aryl(C1-18)alkylthio and aryl(C1-18)alkyl, wherein aryl, heterocycle, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18alkyl)oxy, arylthio, aryl(C1-18)alkylthio and aryl(C1-18)alkyl may be optionally substituted with 1 or more R20;
- R20 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, heterocycle, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, halogen, OH, CN, oxo, cyanoalkyl, —CO2R18, NO2, —NR13R14, C1-18 haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio and C1-18 hydroxyalkyl;
- R21 is selected from the group consisting of hydrogen, C1-18 alkyl, C3-10 cycloalkyl, C1-18 alkoxy, (C3-10 cycloalkyl)-C1-6alkyl, aryl and arylC1-18 alkyl;
- m is an integer from 0 to 2;
- and the pharmaceutically acceptable salts thereof.
21 more elements
A compound of formula A10
- wherein:
- one of U or W is N, and the other U or W is CH;
- X is C1-C6 alkylene;
- Y is a single bond;
- R1 is phenyl optionally substituted with one to three R20;
- R2 is heterocycle optionally substituted with one to three R17.
- R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, S(O)mR9, halogen, —OH, —CN, —NO2, —NR13R14, —C(═O)R9, —C(═O)OR9, —C(═S)R9, and SH, wherein any alkyl and alkenyl may be optionally substituted with one to three R20.
- R9 and R18 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, and —NR15R16;
- R13 and R14 are independently selected from the group consisting of hydrogen, and C1-6 alkyl;
- R15 and R16 are independently selected from the group consisting of hydrogen, C1-6 alkyl, and an amino acid residue;
- R17 is phenyl optionally substituted with one to three R19;
- R19 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR13R14, C1-18 haloalkyl, C1-18 haloalkoxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR15R16, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocycle, C1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18alkyl)oxy, arylthio, aryl(C1-18)alkylthio and aryl(C1-18)alkyl, wherein aryl, heterocycle, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18alkyl)oxy, arylthio, aryl(C1-18)alkylthio and aryl(C1-18)alkyl may be optionally substituted with one to three R20;
- R20 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, heterocycle, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, halogen, OH, CN, oxo, cyanoalkyl, —CO2R18, NO2, —NR13R14, C1-18 haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio and C1-18 hydroxyalkyl;
- R21 is hydrogen or C1-6 alkyl;
- m is an integer from 0 to 2;
- and the pharmaceutically acceptable salts thereof.
13 more elements
(canceled)
(canceled)
Dependencies are inferred from the claim text.