Imidazo[4,5-d]pyrimidines, their uses and methods of preparation

A compound having the general 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 represent at least 3, optionally 4 double bonds;
• R1 is selected from hydrogen, aryl, heterocycle (other than piperazinyl, piperidinyl, or either substituted with 1 or more R6), C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkyl-amino, C1-C10 dialkyl-amino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R6;
• Y is selected from a single bond, O, S(O)m (where m is an integer from 0 to 2), NR11, C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, or C1-10 alkylene, C2-20 alkenylene or C2-10 alkynylene wherein 1 to 3 methylene groups optionally are independently replaced by 1 to 3 heteroatoms selected from O, S or NR11;
• provided, however, that YR1 is not H;
• R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, 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, C7-10 cycloalkynyl, or heterocycle, provided that when one of R25 or R26 is present, then either R2 or R4 is selected from (═O), (═S), and ═NR27;
• and further provided that not both of R2 and R4 is OH, SH, thio or oxo;
• X is selected from C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or NR11, provided any such heteroatom is not adjacent to the N in the ring;
• R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl-N(R10)—, or heterocycle, where each said substituent may be optionally substituted with at least one R17, provided that for cycloalkenyl the double bond is not adjacent to a nitrogen;
• R5 independently is absent or is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, 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, C7-10 cycloalkynyl, or heterocycle;
• R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, 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, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, C1-18haloalkyl, 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, heterocycle, C1-18 hydroxyalkyl, where each may be optionally substituted with at least 1 R19;
• R7 and R8 are independently selected from hydrogen, C1-18alkyl, C1-18alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12;
• —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or where R7 and R8 together with the nitrogen form a heterocycle;
• R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, aryl, an amino acid residue linked through an amino group of the amino acid, CH2OCH(═O)R9a, or CH2C(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
• R10 and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocycle, or an amino acid residue;
• R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
• R15 and R16 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
• R17 is independently M-Q- wherein M is a ring optionally substituted with 1 or more R19, and Q is a bond or a linking group connecting M to R3 having 1 to 10 atoms selected from C and optionally 1 or more O, N or S atoms and optionally substituted with 1 or more R19;
• R19 is selected from
• (a) H;
• (b) NO2, SH, NR20R21, OH, halogen and CN;
• (c) Sulfone, sulfonamide and sulfoxide;
• (d) C1-18 alkyl, C2-18 alkenyl and C2-18 alkynyl;
• (e) C1-18 alkyl, C2-18 alkenyl and C2-18 alkynyl wherein 1 or more methylene are replaced by 1 or more O, S, NR20, C(O)NR20R21, OC(O)R12, C(O)OR12 or N(R20)C(O);
• (f) Substituents c), d) or e) substituted further by C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, aryl or heterocycle;
• (g) C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, aryl and heterocycle, or said groups substituted with C1-6 alkyl, C(O)OR12═O, halogen, CN, C(O)NR20R21, C(O)R18 or OC(O)R18;
• (h) C(O)R18, C(O)OR18, OC(O)R18, C(S)R18 and C(O)N(R12)2;
• (i) Substituents d) or e) substituted with ═O, CN, halogen, C(O)R18, C(O)NR20R21, OC(O)R18, heterocycle and heterocycle substituted with C1-C6 alkyl, C(O)OR12, ═O, CN, halogen, OC(O)R18 or C(O)NR20R21;
• (j) Substituents c) substituted further with C1-18 alkyl;
• and
• (k) Substituents f) or g) substituted further with C1-18 alkyl, ═O, NR20R21, CN, C1-18 alkoxy, heterocycle, C1-18 haloalkyl, heterocyclealkyl or halogen;
• R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, heterocycle, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, or —C(═S)R12;
• R25 and R26 are independently not present or are selected from hydrogen, C1-18 alkyl, C3-10cycloalkyl, aryl and heterocycle, where each is optionally independently substituted with 1 to 4 of C1-6 alkyl, C1-6 alkoxy, halo, CH2OH, benzyloxy, and OH;
• and
• R27 is selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, (C3-10cycloalkyl)-C1-6 alkyl, aryl, and aryl C1-18 alkyl, and
• salts, tautomers, polymorphs, isomers and solvates thereof.

A compound having the general formula (B),

• wherein:
• R1 is selected from aryl, heterocycle, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each are optionally substituted with 1 or 2 R6;
• Y is a bond;
• R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, 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, C7-10 cycloalkynyl, or heterocycle, provided that when one of R25 or R26 is present, then either R2 or R4 is selected from (═O), (═S), and ═NR27;
• provided that R2 is not OH, SH, thio or oxo;
• X is selected from C1-C3 alkylene, C2-3 alkenylene or C2-3 alkynylene;
• R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl-N(R10)—, or heterocycle, where each is optionally substituted with at least one R17, provided that for cycloalkenyl the double bond is not adjacent to a nitrogen;
• R5 independently is absent or is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, 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, C7-10 cycloalkynyl, or heterocycle;
• R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, 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, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, 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, heterocycle, C1-18 hydroxyalkyl, where each may be optionally substituted with at least 1 R19;
• R7 and R8 are independently selected from hydrogen, C1-18alkyl, C1-18alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12;
• —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or where R7 and R8 together with the nitrogen form a heterocycle;
• R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, aryl, an amino acid residue linked through an amino group of the amino acid, CH2OCH(═O)R9a, or CH2C(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
• R10 and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocycle, or an amino acid residue;
• R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
• R15 and R16 are independently selected from hydrogen, C1-18alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
• R17 is independently selected from the group consisting of (a) 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, C7-10 cycloalkynyl, halogen, OH, CN, CO2H, CO2R18, NO2, NR7R8, haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, heterocycle, 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, or C1-18 hydroxyalkyl is optionally substituted with 1 or more R19;
• R19 is selected from
• (a) H;
• (b) NO2, SH, NR20R21, OH, halogen and CN;
• (c) Sulfone, sulfonamide and sulfoxide;
• (d) C1-18 alkyl, C2-18 alkenyl and C2-18 alkynyl;
• (e) C1-18 alkyl, C2-18 alkenyl and C2-18 alkynyl wherein 1 or more methylene are replaced by 1 or more O, S, NR20, C(O)NR20R21, OC(O)R12, C(O)OR12 or N(R20)C(O);
• (f) Substituents c), d) or e) substituted further by C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, aryl or heterocycle;
• (g) C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, aryl and heterocycle, or said groups substituted with C1-6 alkyl, C(O)OR12═O, halogen, CN, C(O)NR20R21, C(O)R18 or OC(O)R18;
• (h) C(O)R18, C(O)OR18, OC(O)R18, C(S)R18 and C(O)N(R12)2;
• (i) Substituents d) or e) substituted with ═O, CN, halogen, C(O)R18, C(O)NR20R21, OC(O)R18, heterocycle and heterocycle substituted with C1-C6 alkyl, C(O)OR12, ═O, CN, halogen, OC(O)R18 or C(O)NR20R21,
• (j) Substituents c) substituted further with C1-18 alkyl;
• and
• (k) Substituents f) or g) substituted further with C1-18 alkyl, ═O, NR20R21, CN, C1-18 alkoxy, heterocycle, C1-18 haloalkyl, heterocyclealkyl or halogen;
• R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, heterocycle, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, or —C(═S)R12;
• R25 and R26 are independently not present or are selected from hydrogen, C1-18 alkyl, C3-10cycloalkyl, aryl and heterocycle, where each is optionally independently substituted with 1 to 4 of C1-6 alkyl, C1-6 alkoxy, halo, CH2OH, benzyloxy, and OH;
• and
• R27 is selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, (C3-10 cycloalkyl)-C1-6 alkyl, aryl, and aryl C1-18 alkyl, and
• salts, tautomers, polymorphs, isomers and solvates thereof.

A method for structure-activity determination of analogues of compounds of WO 2004/005286 having the general structure

• wherein the R, X and Y groups are defined in WO 2004/005286, comprising
• (A) preparing an analogue of a compound falling within the scope of WO 2004/005286 wherein C7 is replaced by N;
• and
• (B) determining the anti-HCV activity of the compound of step (A).