Macrocyclic inhibitors of flaviviridae viruses
Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
1. A method for treating a hepatitis C virus infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, wherein:
A 1 is (C 2 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, —O—(C 2 -C 4 )alkylene, —O—(C 2 -C 4 )alkenylene, arylene, aryl(C 1 -C 2 )alkylene, heterocycloalkylene, pyrazolylene, pyrimidinylene,
or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is unsubstituted or substituted with one or more (C 1 -C 4 )alkyl;
A 2 is arylene or heteroarylene, wherein A 2 is unsubstituted or substituted with halo;
X 1 is —O—, —NH—or —N((C 1 -C 4 )alkyl)-;
R 1a and R 1b are independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
R 2 is H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
R 3a and R 3b are independently H or (C 1 -C 8 )alkyl;
R 4a and R 4b are independently H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl;
R 5 is H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl, or
R 5 forms a cyclic moiety along with —N((C 1 -C 4 )alkyl)- of X 1 or arylene of A 2 ; and
R 6 is H or (C 1 -C 4 )alkyl.
2. The method according to claim 1 , wherein A 1 is ethenylene, propenylene, butenylene, ethylene, propylene, butylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.
3. The method according to claim 1 , wherein A 2 is isoquinolinylene, phenylene or halophenylene.
4. The method according to claim 1 , wherein X 1 is —O— or —NH—; one of R 1a and R 1b is H and the other is methyl; R 2 is iso-propyl; R 5 is methyl and R 6 is H or methyl.
5. The method according to claim 1 , wherein R 3a is H or methyl; R 3b is H; R 4a is H, —OH, methoxy, trifluoroethoxy; and R 4b is H.
6. The method according to claim 1 , wherein the compound of formula I is a compound of Formula II:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer, thereof, wherein:
A 1 is ethenlene,
A 2 is
X 1 is —O—or —NH—;
R 3a is H or (C 1 -C 4 )alkyl;
R 4a is H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl; and
R 5 is H or (C 1 -C 4 )alkyl.
7. The method according to claim 6 , wherein A 2 is heteroarylene; A 1 is (C 2 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, wherein A 1 is unsubstituted or substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or (C 1 -C 8 )alkyl; and R 4a is H, —OH or (C 1 -C 4 )alkoxy.
8. The method according to claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
9. The method according to claim 6 , wherein A 2 is arylene; and A 1 is (C 2 -C 5 )alkylene, (C 2 C 5 )alkenylene, (C 2 -C 5 )alkynylene, —O—(C 2 -C 5 )alkylene, —O—(C 2 -C 4 )alkenylene, wherein A 1 is unsubstituted or substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or (C 1 -C 4 )alkyl; and R 4a is H, —OH, (C 1 -C 4 )alkoxy or halo(C 1 -C 4 )alkoxy.
10. The method according to claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
11. The method of claim 6 , wherein A 2 is arylene; and A 1 is pyrazolylene, phenylene or pyrimidinylene.
12. The method according to claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
13. The method according to claim 1 , wherein A 2 is haloarylene; and A 1 is —O—(C 2 -C 5 )alkylene or —O—(C 2 -C 4 )alkenylene.
14. The method according to claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer thereof.
15. The method of claim 1 , wherein A 1 is (C 2 -C 5 )alkylene or (C 2 -C 5 )alkenylene; R 5 is methyl, or R 6 form
along with arylene of A 2 , or R 5 form
along with —N((C 1 -C 4 )alkyl)- of X 1 ; and R 6 is H or methyl.
16. The method according to claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.