Antiviral phosphoramidates
The invention provides novel nucleoside compounds of formula I wherein R 1 , R 2a , R 2b , R 3 , R 4 , R 5 R 6 , R 8a , R 9 and R 10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
1. A compound according to formula I
wherein:
R 1 is hydrogen or aryl wherein said aryl is phenyl or naphthyl 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, halogen, C 1-6 haloalkyl, —N(R 1a ) 2 , C 1-6 acylamino, —NHSO 2 C 1-6 alkyl, —SO 2 N(R 1a ) 2 , —SO 2 C 1-6 alkyl, COR 1b , nitro and cyano;
R 1a is independently hydrogen or C 1-6 alkyl;
R 1b is —OR 1a or —N(R 1a ) 2 ;
R 2a and R 2b are (i) independently selected from the group consisting of hydrogen, C 1-10 alkyl, —(CH 2 ) r NR 1a 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 1b , aryl and aryl C 1-3 alkyl, said aryl groups 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 2a is hydrogen and R 2b and R 4 together are (CH 2 ) 3 ; (iii) R 2a and R 2b together are (CH 2 ) n ; or, (iv) R 2a and R 2b both are C 1-6 alkyl;
R 3 is hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, aryl or aryl-C 1-3 alkyl wherein said aryl is phenyl;
R 4 is hydrogen, C 1-3 alkyl, or R 2b and R 4 together are (CH 2 ) 3 ;
R 5 is azide, C≡CH or -(Z)-CH═CHCl;
R 6 is A, B, C or D wherein R 11 is hydrogen or C 1-3 alkyl;
R 7 is hydrogen, methyl, halomethyl or halogen;
either
(a) R 9 is OR 8b and R 10 is hydrogen wherein R 8a and R 8b are (i) independently hydrogen, benzoyl or C 1-6 acyl or (i) together R 8a and R 8b are C(Me) 2 , C(CH 2 ) 4 , CHPh, or
(b) R 9 is hydrogen and R 10 is OR 8b wherein R 8a and R 8b are independently hydrogen or C 1-6 acyl;
m is 0 to 3;
n is 4 or 5;
p is 0 to 2;
r is 1 to 6; and,
pharmacologically acceptable salts thereof.
2. A compound according to claim 1 wherein R 3 is hydrogen, C 1-10 alkyl, aryl or aryl-C 1-3 alkyl wherein said aryl is phenyl and R 11 is hydrogen.
3. A compound according to claim 2 wherein:
R 2a and R 2b are (i) independently hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 SH, —CH 2 CH 2 S(O) p Me, —(CH 2 ) m COR 1b wherein m is 1 or 2, —(CH 2 ) r —NH 2 wherein r is 3 or 4, —(CH 2 ) 3 —NHC(═NH)NH 2 , —CH 2 C 6 H 5 , —CH 2 -p-C 6 H 4 —OH, (3-indolinyl)methylene, (4-imidazolyl)methylene; (ii) R 2a and R 2b together are (CH 2 ) n ; or, (iii) R 2a and R 2b both are C 1-3 alkyl;
R 3 is hydrogen, C 1-10 alkyl or benzyl;
R 9 is OR 8b ; and,
R 4 , R 7 , R 8a , R 8b and R 10 are hydrogen.
4. A compound according to claim 3 wherein:
R 2a is hydrogen and R 2b is selected from the group consisting of hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 SH, —CH 2 CH 2 SMe, —(CH 2 ) m COR 1b wherein m is 1 or 2, —(CH 2 ) r —NH 2 where r is 3 or 4, —(CH 2 ) 3 —NHC(═NH)NH 2 , —CH 2 C 6 H 5 , —CH 2 -p-C 6 H 4 —OH, (3-indolinyl)methylene, and (4-imidazolyl)methylene; and,
R 5 is azide or C≡CH.
5. A compound according to claim 4 wherein R 2b is hydrogen, -Me, —CH 2 CH(Me) 2 , —CH(Et)Me or —CHMe 2 .
6. A compound according to claim 3 wherein both R 2a and R 2b are Me or R 2a and R 2b together are (CH 2 ) 4 and R 5 is azide or C≡CH.
7. A compound according to claim 2 wherein:
R 2a and R 2b are (i) independently hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 SH, —CH 2 CH 2 S(O) p Me, —(CH 2 ) m COR 1b wherein m is 1 or 2, —(CH 2 ) r —NH 2 wherein r is 3 or 4, —(CH 2 ) 3 —NHC(═NH)NH 2 , —CH 2 C 6 H 5 , —CH 2 -p-C 6 H 4 —OH, (3-indolinyl)methylene, (4-imidazolyl)methylene; (ii) R 2a and R 2b together are (CH 2 ) n ; or, (iii) R 2a and R 2b both are C 1-3 alkyl;
R 3 is C 1-10 alkyl or benzyl;
R 10 is OR 8b ; and,
R 4 , R 7 , R 8a , R 8b and R 9 are hydrogen.
8. A compound according to claim 7 wherein:
R 2a is hydrogen and R 2b is selected from the group consisting of hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 SH, —CH 2 CH 2 SMe, —(CH 2 ) m COR 1b wherein m is 1 or 2, —(CH 2 ) r —NH 2 wherein r is 3 or 4, —(CH 2 ) 3 —NHC(═NH)NH 2 , —CH 2 C 6 H 5 , —CH 2 -p-C 6 H 4 —OH, (3-indolinyl)methylene, and (4-imidazolyl)methylene; and,
R 5 is azide or C≡CH.
9. A compound according to claim 8 wherein R 2b is hydrogen, -Me, —CH 2 CH(Me) 2 , —CH(Et)Me or —CHMe 2 .
10. A compound according to claim 7 wherein both R 2a and R 2b are Me or R 2a and R 2b together are (CH 2 ) 4 and R 5 is azide or C≡CH.
11. A method for inhibiting HCV replication in a cell comprising administering an effective amount of a compound according to claim 1 .
12. A method for inhibiting HCV replication in a cell comprising administering an effective amount of a compound according to claim 4 .
13. A pharmaceutical composition comprising an effective quantity of a compound according to claim 1 admixed with at least one pharmaceutically acceptable carrier, diluent, or excipient.