Prodrugs of deoxynucleosides for treatment of diseases caused by unbalanced nucleotide pools

1 . A method for treating a disease or disorder characterized by unbalanced nucleotide pools in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one prodrug of Formula I:

wherein

Base refers to an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;

R 1 is selected from the group consisting of optionally substituted acyl, optionally substituted O-linked amino acid,

Y and Z are each independently selected from O and S;

R 4 is selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2 -24 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl (C 1-6 ) alkyl,

R 5 , R 6 and R 7 are each independently selected from optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl, optionally substituted C 3-6 cycloalkyl, and optionally substituted C 3-6 cycloalkenyl;

R 8 , R 9 , R 11 and R 12 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl and optionally substituted aryl;

R 10 and R 13 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl and optionally substituted aryl, an optionally substituted —O—C 1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-monocyclic heterocyclyl;

R 14 , R 15 and R 19 are each independently selected from hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;

R 16 and R 17 are each independently selected from —CN, optionally substituted C 2-8 organylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 organylaminocarbonyl;

R 18 is selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl; optionally substituted C 3-6 cycloalkyl and optionally substituted C 3-6 cycloalkenyl;

R 20 and R 21 are each independently selected from hydrogen, optionally substituted C 1-24 alkyl, optionally substituted C 2-24 alkenyl, optionally substituted C 2-24 alkynyl;

optionally substituted C 3-6 cycloalkyl and optionally substituted C 3-6 cycloalkenyl; and

n, m and p are each independently selected from 0, 1, 2, or 3.

2 . The method of claim 1 , wherein at least two prodrugs are administered.

3 . The method of claim 2 , wherein the weight ratio of one prodrug to another prodrug is 50/50, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10 or 95/5.

4 . The method of claim 1 , wherein the prodrug is administered in the form of a pharmaceutical composition.

5 . The method of claim 1 , wherein the disease or disorder is selected from the group consisting of TK2 deficiency, RRM2B deficiency, mutations in TYMP, SUCLA2 deficiency, SUCLG1 deficiency, MPVI 7 deficiency and DGUOK mutations.

6 . The method of claim 1 , wherein the method of administration is oral.

7 . The method of claim 1 , wherein the therapeutically effective amount administered is from about 200 mg/kg/day to about 1,000 mg/kg/day.

8 . The method of claim 1 , wherein the prodrug or a composition comprising the prodrug is administered at least once per day.