US 12,221,459 B2
Cancer treatment with (2,2-bishydroxymethyl) methylenecyclopropane nucleotides
Björn Klasson, Huddinge (SE); and Fredrik Öberg, Huddinge (SE)
Assigned to MEDIVIR AB, Huddinge (SE)
Appl. No. 16/979,152
Filed by MEDIVIR AB, Huddinge (SE)
PCT Filed Mar. 8, 2019, PCT No. PCT/SE2019/050209
§ 371(c)(1), (2) Date Sep. 8, 2020,
PCT Pub. No. WO2019/172835, PCT Pub. Date Sep. 12, 2019.
Claims priority of application No. 1850262-5 (SE), filed on Mar. 9, 2018; and application No. 1851495-0 (SE), filed on Nov. 30, 2018.
Prior Publication US 2020/0399295 A1, Dec. 24, 2020
Int. Cl. C07F 9/06 (2006.01); A61P 35/02 (2006.01)
CPC C07F 9/062 (2013.01) [A61P 35/02 (2018.01)] 26 Claims
 
1. A compound represented by formula I:

OG Complex Work Unit Chemistry
wherein:
B is a nucleobase selected from the groups (a) to (d):

OG Complex Work Unit Chemistry
U is O or S;
Rx is —OC(═O)Ry, —OC(═O)CH(Ry)NH2, or —OCH2OC(═O)Ry;
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;
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; or
R1 and Rx together define a bond, thus forming a cyclic phosphate;
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, R10 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-C5cycloalkyl;
each R12 is independently H, C1-C6alkyl, haloC1-C6alkyl, C3-C7cycloalkyl or C1-C6alkylC3-C7cycloalkyl;
R13 is R12 or CH2CH(NH2)C(═O)OH;
or a pharmaceutically acceptable salt thereof.