Pyrimidine nucleosides and their monophosphate prodrugs for the treatment of viral infections and cancer

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, COR1, or COOR1;
• X2 is hydrogen, COR1, or COOR1
• wherein each is, independently, CH2—O(CO)—X5;
• CH2—O(CO)O—X5, C1-20 alkyl, the carbon chain derived from a fatty alcohol, or C1-20 alkyl substituted with a C1-C6 alkyl, alkoxy, di(C1-C6 alkyl)-amino, fluoro, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are selected from the group consisting of C1-6 alkyl, and substituted C1-6 alkyl, wherein the substituents are C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl,
• X5 is independently, C1-20 alkyl, the carbon chain derived from a fatty alcohol, or C1-20 alkyl substituted with a C1-C6 alkyl, alkoxy, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl or substituted heteroaryl;
• wherein the substituents are C1-6 alkyl, or C1-6 alkyl substituted with a C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl,
• each X3 and X4 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, alkylaryl, halogen, NH2, OH, SH, CN, or NO2,
• and wherein sugar has the general Formula
• wherein:
• Y is O or S;
• Z is CH2,
• A is O,
• 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, CH2OH, C(O)NH2, C(S)NH2, C(O)OR, R, OR, SR, SSR, NHR, and NR2;
• R5′ and R6′ can come together to form a ring
• provided that when A is O, R7′ cannot be OH, SH, NH2, NHOH, NHNH2, OR, SR, SSR, NHR, or NR2, and
• R is independently a C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, C3-C6 cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl and substituted C1-6 alkyl, wherein the substituents are C1-C6 alkyl, C1-C6 alkoxy, di(C1-C6 alkyl)-amino, fluoro, or C3-10 cycloalkyl,
• R2 is OR8 where R8 is aryl, 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)0-6CO2R9a, halogen, C1-6 haloalkyl, —N(R9a)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R9a)2, —SO2C1-6 alkyl, COR9b, nitro, cyano and
• wherein R21 is selected from the group consisting of H, C1-20 alkyl, C1-20 alkenyl, the carbon chain derived from a fatty acid, and C1-20 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, or C3-10 cycloalkyl alkyl,
• and R3 is
• 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, wherein said aryl groups are 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 C3-10 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 C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, C3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
• wherein the substituents are C1-5 alkyl, or C1-5 alkyl substituted with a C1-6 alkyl, C1-6 alkoxy, di(C1-6 alkyl)-amino, fluoro, C3-10 cycloalkyl, or C3-10 cycloalkyl alkyl;
• R12 is H or C1-3 alkyl,
• or R10a.