Cancer treatment with (2,2-bishydroxymethyl) methylenecyclopropane nucleotides

A compound represented by formula I:

• wherein:
• B is a nucleobase selected from the groups (a) to (d):
• U is O or S;
• Rx is —OC(═O)Ry, —OC(═O)CH(Ry)NH2, —OCH2OC(═O)Ry;
• or
• Rx and R1 together define a bond thus forming a cyclic phosphate;
• Ry is C1-C20alkyl or C2-C20alkenyl any of which is optionally substituted with one, two or three substituents each independently selected from fluoro, hydroxy and amino;
• or
• Ry is the side chain of a natural amino acid, which may be in the D or L configuration;
• R1 is H, or a cyclic group selected from phenyl, benzyl, naphthyl, pyridyl or indolyl, each of which cyclic groups is optionally substituted with one, two or three R22;
• or
• R1 and Rx together define a bond thus forming a cyclic phosphate;
• each R22 is independently selected from halo, hydroxy, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, hydroxyC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkylcarbonyl, C3-C6cycloalkylcarbonyl, azido, cyano, amino, or any two R22 groups attached to adjacent ring carbon atoms can combine to form —O—(CH2)1-2—O—, wherein C3-C6cycloalkyl is optionally substituted with C1-C3alkyl;
• R2 and R2′ are each independently selected from H, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkylC1-C3alkyl, phenyl, benzyl and indolyl;
• or
• R2 and R2′ together with the carbon atom to which they are attached form a C3-C7cycloalkylene group;
• wherein each C1-C6alkyl is optionally substituted with halo or OR12, and each C3-C7cycloalkyl, C3-C7cycloalkylene, phenyl and benzyl is optionally substituted with one or two groups independently selected from C1-C3alkyl, halo and OR12;
• or
• one of R2 and R2′ is H, and the other is the side chain of a natural amino acid, wherein the carboxy terminus of an Asp or Glu is optionally esterified with C1-C6 alkyl;
• R3 is C1-C10alkyl, C3-C7cycloalkyl, C1-C3alkylC3-C7cycloalkyl, phenyl or benzyl;
• any of which is optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy and N(R12)2;
• R4, R5, R7 and R8 are each independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, —OR12 or —N(R12)2;
• R6, R9, R1 and R11 are each independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, halo, OR12, —N(R12)2, —NHC(O)OR12, cyano, —C(O)OR12, —C(O)N(R12)2 or —NHC(O)R13, wherein C2-C6alkenyl and C2-C6alkynyl is optionally substituted with halo or C3-C7cycloalkyl;
• each R12 is independently H, C1-C6alkyl, haloC1-C6alkyl, C3-C7cycloalkyl or C1-C6alkyC3-C7cycloalkyl;
• R13 is R12 or CH2CH(NH2)C(═O)OH;
• or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not