Compounds for the treatment of hepatitis C
The disclosure provides compounds of formula I, including pharmaceutically acceptable salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.
1. A compound of formula I
where
R 1 is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, benzyl, indanyl, or alkylcarbonyl;
R 2 is hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;
R 3 is hydrogen, alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, ((alkylcarbonyl)amino)alkyl, ((haloalkylcarbonyl)amino)alkyl, ((alkoxycarbonyl)amino)alkyl, ((benzyloxycarbonyl)amino)alkyl, alkylcarbonyl, alkoxycarbonyl, benzyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkyaminocarbonyl;
R 4 is hydrogen, alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl;
R 5 is hydrogen, alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl;
R 6 is pyrollidinyl, piperidinyl, or piperazinyl and is substituted with 0-3 substituents selected from alkyl, alkylcarbonyl, alkoxycarbonyl, and benzyloxycarbonyl;
Q is an alkylene or alkenylene chain containing 0-6 groups selected from the group consisting of 0, NR 3 , S, S(O), S(O 2 ), C(O)O, C(O)NR 4 , OC(O)NR 4 , NR 4 C(O)NR 4 , and Z, provided that any O or S atom does not directly bond to another O or S atom, such that ring A is 12-31 membered;
and where the alkylene or alkenylene chain is substituted with 0-6 substituents selected from the group consisting of alkyl, hydroxy, alkoxy, R 6 , (R 6 )alkyl, and phenyl where the phenyl substituent is further substituted with 0-4 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
X is O, CH 2 , CO, CO 2 , or C(O)NR 5 ; and
Z is C 3-7 cycloalkylene, phenylene, pyrrolidindiyl, piperidindiyl, or piperazindiyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 where:
R 1 is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, benzyl, indanyl, or alkylcarbonyl;
R 2 is cyano, hydrogen, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;
R 3 is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkyaminocarbonyl;
R 4 is hydrogen or alkyl;
R 5 is hydrogen, alkyl, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl;
Q is an alkylene or alkenylene chain containing 0-3 groups selected from the group consisting of 0, NR 3 , S, S(O), S(O 2 ), C(O)O, C(O)NR 4 , OC(O)NR 4 , NR 4 C(O)NR 4 , and Z, provided that 0, NR 3 , S, S(O), S(O 2 ), C(O)O, C(O)NR 4 , OC(O)NR 4 , and NR 4 C(O)NR 4 do not directly bond to each other or to NH or X, such that ring A is 13-24 membered; and where the alkylene or alkenylene chain is substituted with 0-3 substituents selected from the group consisting of alkyl, hydroxy, alkoxy, and phenyl where the phenyl substituent is further substituted with 0-4 cyano, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy substituents;
X is O, CO 2 , or C(O)NR 5 ; and
Z is C 3-7 cycloalkylene or phenylene;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 where R 1 is haloalkyl; R 2 is hydrogen; R 3 is hydrogen or alkylcarbonyl; R 5 is hydrogen; Q is an alkylene or alkeneylene chain containing 0-2 groups selected from the group consisting of 0, NR 3 , and Z, such that ring A is 16-31 membered; X is O or CONR 5 ; and Z is phenylene; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 where R 1 is trifluoroethyl.
5. The compound of claim 1 where X is CONN.
6. The compound of claim 1 where X is O.
7. The compound of claim 1 where X is C 1-2 .
8. The compound of claim 1 where Z is phenylene.
9. The compound of claim 1 where Z is cyclopropanediyl or cyclohexanediyl.
10. The compound of claim 1 where Z is pyrrolidindiyl or piperazindiyl.
11. The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
12. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. The composition of claim 12 further comprising at least one additional compound having therapeutic benefits for HCV wherein the compound is selected from the group consisting of interferons, cyclosporins, interleukins, HCV metalloprotease inhibitors, HCV serine protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assembly inhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5B protein inhibitors, and HCV replicon inhibitors.
14. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.
15. The method of claim 14 further comprising administering at least one additional compound having therapeutic benefits for HCV wherein the compound is selected from the group consisting of interferons, cyclosporins, interleukins, HCV metalloprotease inhibitors, HCV serine protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assembly inhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5B protein inhibitors, and HCV replicon inhibitors.