Cyclic phosphate substituted nucleoside derivatives for the treatment of liver diseases

1. A compound according to Formula I or Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof wherein:

A is selected from O, S, CH 2 , CF and C═CH 2 , such that if R 2 is OH and R 3 , R 4 and V are hydrogen, then A is other than S; and if A is CF or C═CH 2 , then V is absent;

B is selected from the following groups:

each Q is independently O or S;

V is hydrogen, halogen, —N(R 13 ) 2 , —OR 13 , alkyl, alkenyl, alkynyl, haloalkyl, N 3 or CN;

W is N, CH or CF;

R 1 is —CH 2 —X—Y—R 16 ;

X is —C(R 14 ) 2 ;

Y is —C(R 15 ) 2 , or C 3 -C 6 cycloalkylene;

R 2 is fluoro, chloro, —OR 13 , —CN, —N(R 13 ) 2 , N 3 , C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 2 -C 6 alkenyl or C 2 -C 3 alkynyl;

R 3 is hydrogen;

R 4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, —OR 13 , fluoro, chloro, N 3 , —CN or —N(R 13 ) 2 ;

R 5 , R 6 , R 8 and R 9 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halogen, —OR 18 , —SR 18 and —N(R 18 ) 2 ;

R 7 , R 10 , R 11 and R 12 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 6 heteroaryl, C 9 -C 10 heteroaryl, halogen, —OR 18 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 N(R 18 ) 2 , —NHC(O)OR 18 , —NHC(O)N(R 18 ) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O(C 1 -C 6 haloalkyl), —CN, —NO 2 , —N(R 18 ) 2 , —NH(C 1 -C 6 alkylene)-(C 5 -C 6 heteroaryl), —NH(C 1 -C 6 alkylene)-(C 9 -C 10 heteroaryl), —C(O)R 18 , —C(O)OR 18 , —C(O)N(R 18 ) 2 and —NHC(O)R 18 , wherein said C 2 -C 6 alkenyl group and said C 2 -C 6 alkynyl group are optionally substituted with one or more halogen;

each occurrence of R 13 is independently selected from hydrogen, C 1 -C 6 alkyl —C(O)R 18 , or —C(O)OR 18 ;

R 14 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 6 -C 10 aryl-, OR 17 , —OC(O)R 17 , —N(R 12 )C(O)OR 17 or —C(O)OR 17 ;

each occurrence of R 15 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 6 -C 10 aryl-, OR 17 , —OC(O)R 17 , —N(R 12 )C(O)OR 17 and —C(O)OR 17 or both R 15 groups together with the carbon atom to which they are attached can join to form a 3- to 6-membered spirocyclic cycloalkyl group, such that at least one R 15 group cannot be hydrogen;

R 16 is —C(O)OR 17 ;

each occurrence of R 17 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 7 cycloalkyl and C 6 -C 10 aryl;

each occurrence of R 18 is independently selected from hydrogen, C 1 -C 15 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl), —(C 1 -C 3 alkylene) m -(C 4 -C 7 heterocycloalkyl), —(C 1 -C 3 alkylene) m -(C 5 -C 6 heteroaryl) and —(C 1 -C 3 alkylene) m -(C 9 -C 10 heteroaryl); and

each occurrence of m is independently 0 or 1.

2. The compound of claim 1 wherein A is O or S.

3. The compound of claim 1 , wherein R 1 is

and wherein R 15 and R 17 are each independently selected from C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein R 2 is fluoro or hydroxyl.

5. The compound of claim 1 , wherein R 4 is hydrogen.

6. The compound of claim 1 , wherein V is hydrogen.

7. The compound of claim 1 , wherein B is

wherein

Q is O;

W is N;

R 5 and R 6 are hydrogen;

R 7 is NH 2 or —NHC(O)—(C 6 -C 10 aryl);

R 8 is hydrogen;

R 9 is hydrogen or trifluoromethyl;

R 10 is —NH 2 or —O—C 1 -C 6 alkyl and

R 11 is —NH 2 or halogen.

8. A compound selected from the following:

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or diluent.

10. A method for treating a liver disease in a patient, the method comprising administering to the patient a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said liver disease is hepatocellular carcinoma, or HBV infection.

11. A method for treating Ebola virus infection in a patient, the method comprising administering to the patient a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.