Tetrahydrofuro [3,4-D] dioxolane compounds for use in the treatment of viral infections and cancer
View Patent ↗The invention provides compounds of formula (I), as described herein, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the compounds, and synthetic methods and intermediates that are useful for preparing the compounds. The compounds of formula (I) are useful as anti-viral agents and/or as anti-cancer agents.
1. A compound of formula I:
wherein:
B is selected from:
W is O, S, or NH;
X is N, Y is N and Z is CH; or X is N, Y is CR 23 and Z is CH; or X is C, Y is CR 23 and Z is O;
R is OR 3 , SR 3 , NR 3 R 4 , NR 3 NR 4 R 5 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH 2 ) n —CH(NHR 3 )CO 2 R 4 , (CH 2 ) n —S-alkyl, (CH 2 ) n —S-aryl, Cl, F, Br, I, CN, COOR 3 , CONR 3 R 4 , NHC(═NR 3 )NHR 4 , NR 3 OR 4 , NR 3 NO, NHCONHR 3 , NR 3 N═NR 4 , NR 3 N═CHR 4 , NR 3 C(O)NR 4 R 5 , NR 3 C(S)NR 4 R 5 , NR 3 C(O)OR 4 , CH═N—OR 3 , NR 3 C(═NH)NR 4 R 5 , NR 3 C(O)NR 4 NR 5 R 6 , O—C(O)R 3 , OC(O)—OR 3 , ONH—C(O)O-alkyl, ONHC(O)O-aryl, ONR 3 R 4 , SNR 3 R 4 , S—ONR 3 R 4 , or SO 2 NR 3 R 4 ; and R 23 is H, CN, NO 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH═CF 2 , CH(═NR 3 )OR 4 , CHO, CH═CH—OCH 3 , NHCONH 2 , NHCSNH 2 , CONR 3 R 4 , CSNR 3 R 4 , CO 2 R 3 , alkoxy, NH 2 , alkylamino, dialkylamino, halogen, (1,3-oxazol-2-yl), (1,3-oxazol-5-yl), (1,3-thiazol-2-yl), (imidazol-2-yl), (2-oxo[1,3]dithiol-4-yl), (furan-2-yl), (2H[1,2,3]triazol-4-yl), C(═NH)NH 2 , C(═NH)NHOH, C(═NOH)NH 2 , acyl, substituted acyl, OR 3 , C(═NR 3 )R 4 , CH═NNR 3 R 4 , CH═NOR 3 , CH(OR 3 ) 2 , B(OR 3 ) 2 , C≡C—C(═O)NR 3 R 4 , or N(═NHNH 2 )NHNH 2 ; or R and R 23 together with atoms to which they are attached may form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl;
n is 0-5;
R 1 is H, NR 3 R 4 , Cl, F, OR 3 , SR 3 , NHCOR 3 , NHSO 2 R 3 , NHCONHR 3 , CN, alkyl, aryl, ONR 3 R 4 , or NR 3 C(O)OR 4 ;
R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO 2 -alkyl and NO; or R 3 and R 4 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring; or R 4 and R 5 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino ring;
R a is selected from the group consisting of hydrogen, C 1-16 alkylcarbonyl, C 2-18 alkenylcarbonyl, C 1-10 alkyloxycarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 cycloalkyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, an amino acyl residue of structural formula —C(═O)CH(R 11 )NH—R 12 , or a residue of structural formula: —P(═O)(O—Ar)—NHCH(R 13 )—C(═O)OR 14 , wherein alkylcarbonyl, alkyloxycarbonyl, cycloalkylcarbonyl, and cycloalkyloxycarbonyl are unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, carboxy, C 1-4 alkoxy, amino, C 1-4 alkylamino, and di (C 1-4 alkyl)amino and wherein arylcarbonyl, aryloxycarbonyl, heteroarylcarbonyl, and heteroaryloxycarbonyl are unsubstituted or substituted with one to five substituents independently selected from R 9 ;
Ar is phenyl unsubstituted or substituted with one to three substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl;
each R 9 is independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfonyl, cyano, nitro, amino, phenyl, carboxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkylcarbonyl, C 1-4 alkylcarbonyloxy, and C 1-4 alkyloxycarbonyl;
R 11 is hydrogen, C 1-5 alkyl, or phenyl C 0-2 alkyl;
R 12 is hydrogen, C 1-4 alkyl, C 1-4 acyl, benzoyl, C 1-4 alkyloxycarbonyl, phenyl C 0-2 alkyloxycarbonyl, C 1-4 alkylaminocarbonyl, phenyl C 0-2 alkylaminocarbonyl, C 1-4 alkylsulfonyl, or phenyl C 0-2 alkylsulfonyl;
R 13 is hydrogen, C 1-5 alkyl, phenyl or benzyl; wherein alkyl is unsubstituted or substituted with one substituent selected from the group consisting of hydroxy, methoxy, amino, carboxy, carbamoyl, guanidino, mercapto, methylthio, 1H-imidazolyl, and 1H-indol-3-yl; and wherein phenyl and benzyl are unsubstituted or substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, and methoxy;
R 14 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl; wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkoxy; and wherein phenyl and benzyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, cyano, C 1-4 alkoxy, and trifluoromethyl;
R b is selected from the group consisting of C 1-12 alkyl, C 3-8 cycloalkyl, aryl, and heteroaryl; wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, and C 1-4 alkoxy; and aryl and heteroaryl are unsubstituted or substituted with one to five substituents independently selected from R 9 ; and
R c is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more substituents independently selected from halo, amino, hydroxy, and alkoxy;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein W is O.
3. The compound of claim 1 wherein W is S.
4. The compound of claim 1 wherein R is OR 3 ,Cl, SR 3 , NR 3 R 4 , or NR 3 NR 4 R 5 .
5. The compound of claim 1 wherein R is hydroxy, chloro, methoxy, mercapto, amino, methylamino, isopropylamino, propylamino, ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino, 1-(2-hydroxyethyl)hydrazino, hydrazino, 1-methylhydrazino, azetidino, or pyrrolidino.
6. The compound of claim 1 wherein R 1 is H or NR 3 R 4 .
7. A compound of formula Ia:
wherein R b is selected from:
or a pharmaceutically acceptable salt thereof.
8. A compound of formula Ib:
wherein R b is selected from:
or a pharmaceutically acceptable salt thereof.
9. A compound of formula (Ic):
wherein R a is selected from
or a pharmaceutically acceptable salt thereof.
10. A compound of formula (Id):
wherein R a is selected from
or a pharmaceutically acceptable salt thereof.
11. A compound of formula (Ie):
wherein R b is selected from:
or a pharmaceutically acceptable salt thereof.
12. A compound of formula (If):
wherein R b is selected from:
or a pharmaceutically acceptable salt thereof.
13. A compound of formula (Ig):
wherein R a is selected from
or a pharmaceutically acceptable salt thereof.
14. A compound of formula (Ih):
wherein R a is selected from
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound as described in claim 1 and a pharmaceutically acceptable carrier.
16. The composition of claim 15 which further comprises one or more additional anti-viral agents.
17. The composition of claim 16 wherein the one or more anti-viral agents are selected from ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of serine proteases, an inhibitor of inosine monophosphatedehydrognease, interferon-α, and pegylated interferon-α(peginterferon-α).
18. The composition of claim 15 which further comprises one or more additional HCV polymerase inhibitors.
19. The composition of claim 15 which further comprises one or more protease inhibitors.
20. The composition of claim 17 which further comprises ribavirin.
21. The composition of claim 17 which further comprises interferon-αor pegylated interferon-α(peginterferon-α).
22. The composition of claim 15 which further comprises one or more anti-cancer agents.
23. The composition of claim 22 wherein the one or more anti-cancer agents are selected from alkylating agents, antimetabolites, natural products, and hormonal agents.
24. A method for therapeutically treating a viral infection in an animal having a viral infection comprising administering to the animal a pharmaceutically effective amount of a compound as described in claim 1 .
25. The method of claim 24 wherein the viral infection is selected from the group consisting of: hepatitis B, hepatitis C, human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo, small pox, Ebola, and West Nile virus.
26. The method of claim 24 wherein the viral infection is HCV.
27. The method of claim 24 which further comprises administering to the animal one or more additional HCV polymerase inhibitors.
28. The method of claim 24 which further comprises administering to the animal one or more protease inhibitors.
29. The method of claim 24 which further comprises administering ribavirin to the animal.
30. The method of claim 24 which further comprises administering interferon-αor pegylated interferon-α(peginterferon-α) to the animal.
31. A method for therapeutically treating cancer in an animal having cancer comprising administering to the animal a pharmaceutically effective amount of a compound as described in claim 1 .
32. The method of claim 31 wherein one or more additional anti-cancer agents are administered.
33. The method of claim 24 wherein the animal is a human.
34. A method for inhibiting a viral RNA or DNA polymerase comprising contacting the polymerase in vitro or in vivo with an effective inhibitory amount of a compound as described in claim 1 .
35. The method of claim 34 wherein the viral polymerase is an RdRp.
36. A pharmaceutical composition comprising a compound as described in claim 7 and a pharmaceutically acceptable carrier.
37. A pharmaceutical composition comprising a compound as described in claim 8 and a pharmaceutically acceptable carrier.
38. A pharmaceutical composition comprising a compound as described in claim 9 and a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising a compound as described in claim 10 and a pharmaceutically acceptable carrier.
40. A pharmaceutical composition comprising a compound as described in claim 11 and a pharmaceutically acceptable carrier.
41. A pharmaceutical composition comprising a compound as described in claim 12 and a pharmaceutically acceptable carrier.
42. A pharmaceutical composition comprising a compound as described in claim 13 and a pharmaceutically acceptable carrier.
43. A pharmaceutical composition comprising a compound as described in claim 14 and a pharmaceutically acceptable carrier.
44. The method of claim 24 , wherein the animal is a mammal.
45. The method of claim 31 , wherein the animal is a mammal.
46. The method of claim 31 , wherein the animal is a human.