Purine nucleoside monophosphate prodrugs for treatment of cancer and viral infections

A compound of Formula (I):

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• R1 is selected from the group consisting of halogen, OR′, N(R′)2, SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, and NHCOOR′,
• each R′ is independently H, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of hydroxyalkyl, aminoalkyl, and alkoxyalkyl,
• W is, independently, N, CH, CF, CCN, CC≡CH, or CC(O)N(R′)2;
• Sugar is ribose or modified ribose of the general formula (II):
• wherein:
• Y is O or S;
• Z is selected from the group consisting of CL2, CL2CL2, CL2OCL2, CL2SCL2, CL2O, OCL2 and CL2NHCL2, wherein L independently is selected from the group consisting of H, F, alkyl, alkenyl, and alkynyl, wherein alkyl, alkenyl, and alkynyl may each optionally contain one or more heteroatoms;
• A is O, S, CH2, CHF, CF2, C═CH2, C═CHF, or C═CF2;
• R4′, R5, R5′, R6′, R6′, and R7′ are independently selected from the group consisting of H, F, Cl, Br, I, OH, SH, NH2, NHOH, NHNH2, N3, C(O)OH, CN, C(O)NH2, C(S)NH2, C(O)OR, R, OR, SR, SSR, NHR, and NR2;
• wherein for formula (I) where sugar is formula (II), when A is O, and R4′, R5, R5′, R6, R7′ are H, R6′ cannot be N3;
• wherein for formula (I) where sugar is formula (II), when A is O or S R7′ cannot be OH, SH, NH2, NHOH, NHNH2, OR, SR, SSR, NHR, or NR2;
• R is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of hydroxyalkyl, aminoalkyl, and alkoxyalkyl,
• R2 is O-phenyl, where phenyl is substituted with (CH2)1-6CO2R9a, and, optionally, one or two substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, (CH2)1-6CO2R9a, halogen, C1-6 haloalkyl, —N(R9a)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R9a)2, —SO2C1-6 alkyl, COR9b, nitro and cyano;
• R3 is selected from:
• (a) OR8 where R8 is H, C1-20 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, aryl, or heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, (CH2)1-6CO2R9a, halogen, C1-6 haloalkyl, —N(R9a)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R9a)2, —SO2C1-6 alkyl, COR9b, nitro and cyano;
• R9a is independently H or C1-6 alkyl;
• R9b is —OR9a or —N(R9a)2;
• (b)
• where R10a and R10b are:
• (i) independently selected from the group consisting of H, C1-10 alkyl, —(CH2)rNR9a2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)pMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)mCOR9b, aryl and aryl-C1-3 alkyl, said aryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro, and cyano;
• (ii) R10a is H and R10b and R12 together are (CH2)2-4 to form a ring that includes the adjoining N and C atoms;
• (iii) R10a and R10b together are (CH2)n to form a ring;
• (iv) R10a and R10b both are C1-6 alkyl;
• or
• (v) R10a is H and R10b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2—CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
• p is 0 to 2;
• r is 1 to 6;
• n is 4 or 5;
• m is 0 to 3;
• R11 is H, C1-10 alkyl, or C1-10 alkyl substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, fluoro, or C3-10 cycloalkyl;
• R12 is H, C1-3 alkyl, or R10a, or R10b and R12 together are (CH2)2-4 so as to form a ring that includes the adjoining N and C atoms;
• (c) an O attached lipid, an N or O attached peptide, an O attached cholesterol, or an O attached phytosterol;
• (d) R2 and R3 may come together to form a ring
• where W2 is selected from the group consisting of phenyl and monocyclic heteroaryl, optionally substituted with one to three substituents independently selected from the group consisting of C1-6 alkyl, CF3, C2-6 alkenyl, C1-6 alkoxy, OR9c, CO2R9a, COR9a, halogen, C1-6 haloalkyl, —N(R9a)2, C1-6 acylamino, CO2N(R9a)2, SR9a, —NHSO2C1-6 alkyl, —SO2N(R9a)2, —SO2C1-6 alkyl, COR9b, and cyano, and wherein said monocyclic heteroaryl and substituted monocyclic heteroaryl has 1-2 heteroatoms that are independently selected from the group consisting of N, O, and S, with the provisos that:
• a) when there are two heteroatoms and one is O, then the other can not be O or S, and
• b) when there are two heteroatoms and one is S, then the other can not be O or S;
• R9a is independently H or C1-6 alkyl;
• R9b is —OR9a or —N(R9a)2;
• R9c is H or C1-6 acyl;
• (e)
• where R13 is selected from the group consisting of H, C1-10 alkyl, C1-10 alkyl optionally substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl;
• f) R2 and R3 may come together to form a ring
• where R14 is:
• (i) independently selected from the group consisting of H, C1-10 alkyl, —(CH2)rNR29a, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)pMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)mCOR9b, aryl, aryl-C1-3 alkyl, heteroaryl and heteroaryl-C1-3 alkyl, said aryl and heteroaryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro, and cyano;
• (ii) R14 is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or C3-6 cycloalkyl;
• p is 0 to 2;
• r is 1 to 6;
• m is 0 to 3,
• Q1 is NR9a, O, or S,
• Q2 is selected from the group consisting of C1-10 alkyl, C1-6 hydroxyalkyl, aryl, aryl-C1-3 alkyl, heteroaryl and heteroaryl-C1-3 alkyl, said aryl and heteroaryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C1-10 alkyl, C1-6 alkoxy, fluoro, and chloro;
• R11 is H, C1-10 alkyl, C1-10 alkyl optionally substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl C1-6 alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl;
• R12 is H or C1-3 alkyl, or R14b and R12 together are (CH2)2-4 so as to form a ring that includes the adjoining N and C atoms;
• alternatively Sugar is a modified ribose of the general formula (III):
• wherein:
• A, R2, R3, Y, Z, R4′, R5′, R6′, and R7′ are as defined above;
• wherein for formula (I) where sugar is formula (III), when A is O or S R7′ cannot be OH, SH, NH2, NHOH, NHNH2, OR, SR, SSR, NHR, and NR2
• R is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of hydroxyalkyl, aminoalkyl, and alkoxyalkyl,
• alternatively Sugar is a dioxolane or an oxathiolane of the general formulas (IV), (V), (VI), and (VII):
• wherein:
• V is S or Se
• R2, R3, Y, and Z are as defined above,
• alternatively Sugar is a phosphonylmethoxyalkyl of the general formula (VIII):
• wherein:
• R2, R3, and Y are as defined above;
• R15 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, heteroaryl, arylalkyl, and alkylaryl;
• alternatively Sugar is of the general formulas (IX) or (X):
• wherein:
• R2, R3, and Y are as defined above;
• Y2 is O, S, Se, or NR;
• R is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of hydroxyalkyl, aminoalkyl, and alkoxyalkyl;
• R16 and R17 are defined as H, CH3, or CH2OR18;
• R18 is H or C1-C6 acyl,
• alternatively Sugar is a modified ribose of the general formulas (XI):
• wherein:
• R2, R3, and Y are as defined above;
• R4′, R5, R5′, R6, and R6′ are as defined above;
• R19 is H, F, Cl, Br, I, N3, C(O)OH, CN, C(O)NH2, C(S)NH2, C(O)OR, or R,
• R is independently a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents selected from the group consisting of hydroxyalkyl, aminoalkyl, and alkoxyalkyl,
• wherein the compounds can be in the form of the β-L- or β-D-configuration, or a mixture thereof.