Potent and selective inhibitors of hepatitis C virus
The present invention is directed to compounds, compositions and methods for treating or preventing hepatitis C virus (HCV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment or prevention of HCV infection.
1. A compound of Formula (I):
R 1 is, independently, H, C 1-6 alkyl, aryl-C 1-6 -alkyl, C 1-6 alkyl-aryl, or aryl,
R 2 is, independently, H, aryl-C 1-6 -alkyl, C 1-6 alkyl-aryl, aryl, C 1-6 alkyl-guanidine, C 1-6 alkylamino, C 1-6 alkyl-S—C 1-6 alkyl, C 1-6 alkylthiol, C 1-6 alkyl-hydroxy, C 1-6 alkyl-amide, C 1-6 alkyl-phenoxy, C 1-6 alkyl-carboxy heteroaryl, and heteroaryl-C 1-6 alkyl, wherein aryl rings can be substituted with from 1 to 3 substituents Z as defined herein,
R 3 is, independently, H or Cl, with the proviso that at least one R 3 is Cl,
R 4 is, independently, H or —S(O) x R 1 , with the proviso that at least one R 4 is —S(O) x —R 1 ,
Z is selected from the group consisting of C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl heterocyclyl, aryl, heteroaryl, arylalkoxycarbonyl, carboxy, halo, haloalkyl, —OR′, —NR′R″, hydroxy, hydroxy-C 1-6 alkyl, alkoxyalkyl(C 2-8 ), alkoxycarbonyl, —CF 3 , —CN, —NO 2 , —C 2 R′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, —NR′SO 2 R″, N(R′) 2 , SR′, OCOR′, N(COR′)R′, N(COR′)COR′, and SCOR′,
Each R′ and R″ are, independently, H, a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, aryl-C 1-6- alkyl; or if two R′ reside on the same nitrogen atom they can come together to form an alkyl ring (C 3-6 ) containing none or one heteroatom independently selected from N, O, and S; wherein the R′ groups can be substituted with one or more Z substituents as defined above,
j is 0-4, and
x is 0-2, or a pharmaceutically acceptable salt or prodrug thereof,
wherein the compound is in the form of the R- or S-configuration at any chiral center.
2. The compounds of claim 1 , of the formula:
wherein R 1 , R 2 , Z, R′, R″, j, and x are as defined with respect to Formula (I).
3. The compound of claim 1 , wherein one or both of the R 2 substituents are phenyl or phenyl substituted with one or more substituents Z as defined herein.
4. The compound of claim 1 , wherein one or two of the R 1 substituents are —CH 3 .
5. The compound of claim 1 , wherein each R 1 is —CH 3 and both of the R 2 substituents are phenyl or phenyl substituted with one or more substituents Z.
6. A compound having one of the following formulas:
or a pharmaceutically acceptable salt or prodrug thereof.
7. A compound having one of the following formulas:
or a pharmaceutically acceptable salt or prodrug thereof.
8. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.
9. The composition of claim 8 , further comprising one, two, or three additional compounds having anti-HCV activity.
10. A method for treating a host infected with HCV comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.
11. The method of claim 10 , wherein the compound is administered in combination with one, two, or three other anti-HCV agent(s).
12. The compound of claim 1 , wherein one or both of R 2 are aryl, wherein each aryl ring can be substituted with from 1 to 3 substituents Z.
13. A compound of Formula (I):
R 1 is, independently, H, C 1-6 alkyl, aryl-C 1-6 -alkyl, C 1-6 alkyl-aryl, or aryl,
R 2 is, independently, H, C 1-6 alkyl, aryl-C 1-6 -alkyl, C 1-6 alkyl-aryl, aryl, C 1-6 alkyl-guanidine, C 1-6 alkylamino, C 1-6 alkyl-S—C 1-6 alkyl, C 1-6 alkylthiol, C 1-6 alkyl-hydroxy, C 1-6 alkyl-amide, C 1-6 alkyl-phenoxy, C 1-6 alkyl-carboxy heteroaryl, and heteroaryl-C 1-6 alkyl, wherein aryl rings can be substituted with from 1 to 3 substituents Z as defined herein,
R 3 is, independently, H or Cl, with the proviso that at least one R 3 is Cl,
R 4 is, independently, H or —S(O)R 1 , with the proviso that at least one R 4 is —S(O)R 1 ,
Z is selected from the group consisting of C 1-8 alkyl, C 2-6 alkenyl, C 2-6 alkynyl heterocyclyl, aryl, heteroaryl, arylalkoxycarbonyl, carboxy, halo, haloalkyl, —OR′, —NR′R″, hydroxy, hydroxy-C 1-6 alkyl, alkoxyalkyl(C 2-8 ), alkoxycarbonyl, —CF 3 , —CN, —NO 2 , —C 2 R′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, —NR′SO 2 R″, N(R′) 2 , SR′, OCOR′, N(COR′)R′, N(COR′)COR′, and SCOR′,
Each R′ and R″ are, independently, H, a C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, aryl-C 1-6- alkyl; or if two R′ reside on the same nitrogen atom they can come together to form an alkyl ring (C 3-6 ) containing none or one heteroatom independently selected from N, O, and S; wherein the R′ groups can be substituted with one or more Z substituents as defined above,
j is 0-4, or a pharmaceutically acceptable salt or prodrug thereof.