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

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, COR 1 , or COOR 1 ;

X 2 is hydrogen, COR 1 , or COOR 1

wherein each is, independently, CH 2 —O(CO)—X 5 ; CH 2 —O(CO)O—X 5 , C 1-20 alkyl, the carbon chain derived from a fatty alcohol, or C 1-20 alkyl substituted with a C 1 -C 6 alkyl, alkoxy, di(C 1 -C 6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are selected from the group consisting of C 1-6 alkyl, and substituted C 1-6 alkyl, wherein the substituents are C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, fluoro, or C 3-10 cycloalkyl,

X 5 is independently, C 1-20 alkyl, the carbon chain derived from a fatty alcohol, or C 1-20 alkyl substituted with a C 1 -C 6 alkyl, alkoxy, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl or substituted heteroaryl; wherein the substituents are C 1-6 alkyl, or C 1-6 alkyl substituted with a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, fluoro, or C 3-10 cycloalkyl,

each X 3 and X 4 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, alkylaryl, halogen, NH 2 , OH, SH, CN, or NO 2 ,

and wherein sugar has the general Formula

wherein:

Y is O or S;

Z is CH 2 ,

A is O,

R 4′ , R 5 , R 5′ , R 6 , R 6′ , and R 7 are independently selected from the group consisting of H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, NHNH 2 , N 3 , C(O)OH, CN, CH 2 OH, C(O)NH 2 , C(S)NH 2 , C(O)OR, R, OR, SR, SSR, NHR, and NR 2 ;

R 5′ and R 6′ can come together to form a ring

provided that when A is O, R 7′ cannot be OH, SH, NH 2 , NHOH, NHNH 2 , OR, SR, SSR, NHR, or NR 2 , and

R is independently a C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, C 3 -C 6 cycloalkyl, aryl, alkylaryl, or arylalkyl, wherein the groups are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and substituted C 1-6 alkyl, wherein the substituents are C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, fluoro, or C 3-10 cycloalkyl,

R 2 is OR 8 where R 8 is aryl, optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH 2 ) 0-6 CO 2 R 9a , halogen, C 1-6 haloalkyl, —N(R 9a ) 2 , C 1-6 acylamino, —NHSO 2 C 1-6 alkyl, —SO 2 N(R 9a ) 2 , —SO 2 C 1-6 alkyl, COR 9b , nitro, cyano and

wherein R 21 is selected from the group consisting of H, C 1-20 alkyl, C 1-20 alkenyl, the carbon chain derived from a fatty acid, and C 1-20 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, C 3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, or C 3-10 cycloalkyl alkyl,

and R 3 is

 where R 10a and R 10b are:

(i) independently selected from the group consisting of H, C 1-10 alkyl, —(CH 2 ) r NR 9a 2 , C 1-6 hydroxyalkyl, —CH 2 SH, —(CH 2 ) 2 S(O) p Me, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH 2 ) m COR 9b , aryl and aryl-C 1-3 alkyl, wherein said aryl groups are optionally substituted with a group selected from the group consisting of hydroxyl, C 1-10 alkyl, C 1-6 alkoxy, halogen, nitro, and cyano;

(ii) R 10a is H and R 10b and R 12 together are (CH 2 ) 2-4 to form a ring that includes the adjoining N and C atoms;

(iii) R 10a and R 10b together are (CH 2 ) n to form a ring;

(iv) R 10a and R 10b both are C 1-6 alkyl; or

(v) R 10a is H and R 10b is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, —CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 —CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or C 3-10 cycloalkyl;

p is 0 to 2;

r is 1 to 6;

n is 4 or 5;

m is 0 to 3;

R 11 is H, C 1-10 alkyl, or C 1-10 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, C 3-10 cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-5 alkyl, or C 1-5 alkyl substituted with a C 1-6 alkyl, C 1-6 alkoxy, di(C 1-6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, or C 3-10 cycloalkyl alkyl;

R 12 is H or C 1-3 alkyl,

or R 10a .

2. The compound of claim 1 , wherein each R 1 is, independently, C 1-20 alkyl, the carbon chain derived from a fatty alcohol, or C 1-20 alkyl substituted with a C 1 -C 6 alkyl, alkoxy, di(C 1 -C 6 alkyl)-amino, fluoro, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl; wherein the substituents are C 1-6 alkyl, or C 1-6 alkyl substituted with a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, di(C 1 -C 6 alkyl)-amino, fluoro, or C 3-10 cycloalkyl.

3. The compound of claim 1 , wherein R 7′ is independently selected from the group consisting of H, F, Cl, Br, I, N 3 , C(O)OH, CN, CH 2 OH, C(O)NH 2 , C(S)NH 2 , C(O)OR, and R.

4. The compound of claim 1 , wherein the compounds are described herein are in the form of the β-L- or β-D-configuration, or a mixture thereof.

5. The compound of claim 1 , wherein when the phosphorous portion of the compound described herein contains a chiral center, such chiral center is in the form of the R p - or S p -configuration or a mixture thereof.

6. A compound of one of the following formulas:

or a pharmaceutically acceptable salt thereof.

7. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

8. A compound of one of the following formulas:

or a pharmaceutically acceptable salt thereof.

9. A method for treating a host infected with hepatitis C viral infections in a host in need thereof, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.

10. The method of claim 9 , wherein the compound is administered in combination with another anti-HCV agent selected from the group consisting of interferons, anti-fibrotics, inosine monophosphate dehydrogenase inhibitors, apotosis regulators, vaccines, monoclonal antibodies, immunomodulators, antisense therapeutics, caspase inhibitors, polymerase inhibitors, anti-phospholipid agents, serine protease inhibitors, and immunomodulators.

11. The method of claim 9 , wherein the compounds have been shown in previous test hosts to be converted in vivo to a mixture of compounds comprising mixture C or D of 4-NHOH, 4-NH 2 and 4-OH pyrimidine triphosphates: