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 compound of Formula I:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug 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, pyridylene, pyrimidinylene or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is optionally substituted with one or more (C 1 -C 4 )alkyl;
A 2 is arylene or heteroarylene, wherein A 2 is optionally 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 compound of claim 1 , wherein A 1 is ethenylene, propenylene, butenylene, ethylene, propylene, butylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene, pyridylene or pyrimidinylene.
3. The compound of claim 1 , wherein A 2 is isoquinolinylene, phenylene or halophenylene.
4. The compound of 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 compound of 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 compound of claim 1 , which is a compound of Formula II:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
A 1 is ethenylene,
A 2 is
X 1 is —O— or —NH—;
R 3a is H or methyl;
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 compound of claim 1 , 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 optionally substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or methyl; and R 4a is H, —OH or (C 1 -C 4 )alkoxy.
8. The compound of claim 1 , 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 4 )alkylene, —O—(C 2 -C 4 )alkenylene, wherein A 1 is optionally substituted with one or more (C 1 -C 4 )alkyl; R 3a is H or methyl; and R 4a is H, —OH, (C 1 -C 4 )alkoxy or halo(C 1 -C 4 )alkoxy.
9. A compound selected from:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
10. The compound of claim 1 , wherein A 2 is arylene; and A 1 is pyrazolylene, phenylene or pyridylene.
11. The compound of claim 1 , wherein A 2 is halophenylene; and A 1 is —O—(C 2 -C 4 )alkylene or —O—(C 2 -C 4 )alkenylene.
12. The compound of claim 1 , wherein A 1 is (C 2 -C 5 )alkylene or (C 2 -C 4 )alkenylene; R 5 is methyl, or R 5 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.
13. A compound selected from:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition of claim 14 , further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists; or a mixture thereof.
16. The pharmaceutical composition of claim 15 , wherein the at least one additional therapeutic agent is ribavirin, telaprevir, boceprevir or sofosbuvir.