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 is a bond, —O—, —S(O) n —, —NH—, —N((C 1 -C 4 )alkyl)- or (C 1 -C 2 )alkylene;
wherein B is arylene, heteroarylene, cycloalkylene or heterocycloalkylene;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene, arylene, heteroarylene or cycloalkylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
X 1 is a bond, —O—, —NH—, —N((C 1 -C 4 )alkyl)- or heterocycloalkylene;
R 1 and R 2 are independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, halo, cyano or (C 1 -C 4 )alkanoyl; or
R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—, —C(═S)— or —C(═N(C 1 -C 4 )alkyl)-;
R 3 is H or (C 1 -C 4 )alkyl which is optionally substituted with halo, cyano, hydroxy or (C 1 -C 4 )alkoxy;
R 4a and R 4b are independently H, (C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl, cycloalkyl or cycloalkyl(C 1 -C 4 )alkyl, wherein each of R 4a and R 4b is optionally substituted with one or more substituent selected from the group consisting of cyano, (C 1 -C 8 )alkoxy, —COOH, —C(O)O—(C 1 -C 8 )alkyl, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —C(O)-mono(C 1 -C 8 )alkylamino, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)— heterocycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each substituent is optionally substituted with one or more halo, heterocycloalkyl or aryl;
R 5a and R 5b are independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl or heterocycloalkyl(C 1 -C 4 )alkyl, wherein R 5a and R 5b are independently optionally substituted with one or more substituent selected from the group consisting of —N 3 , cyano, —COOH, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl, or
R 5a and R 5b together form a spirocycle having Formula (a):
wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, —NH 2 , —C(O)O—(C 1 -C 8 )alkyl, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)—(C 1 -C 8 )alkyl, —C(O)-heterocycloalkyl, —S(O) 2 R 10 , —OSi(R 10 ) 3 , (C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 8 )alkanoyl and aryl(C 1 -C 4 )alkyl;
R 6a , R 6b , R 7a and R 7b are independently H, hydroxyl, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, —CH 2 CH 2 CR 9 (═N(C 1 -C 4 )alkoxy), aryl, heterocycloalkyl, cycloalkyl, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 or —N(R 9 ) 2 , wherein each of R 6a , R 6b , R 7a and R 7b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 8 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 , —OC(O)—(C 1 -C 8 )alkyl —C(O)O—(C 1 -C 8 )alkyl and (C 1 -C 8 )alkanoyl, wherein each —OC(O)—(C 1 -C 8 )alkyl or (C 1 -C 8 )alkoxy is optionally substituted with one or more amino, —OC(O)O—(C 1 -C 8 )alkyl or —Si(R 10 ) 3 ; or
R 6a and R 6b together form a spirocycle having Formula (a);
each R 8 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein R 8 is optionally substituted with —OR, —N(R 9 ) 2 , —CON(R 9 ) 2 or cyano;
each R 9 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
each R 10 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, cycloalkyl(C 1 -C 4 )alkyl or aryl, wherein R 10 is optionally substituted with one or more halo;
each n is independently 0, 1 or 2; and
m is 1, 2, 3, 4 or 5.
2. The compound of claim 1 , wherein A is methylene.
3. The compound of claim 1 , wherein A 1 is ethenylene, propenylene, ethylene, propylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.
4. The compound of claim 1 , wherein A 1 is
5. The compound of claim 1 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene.
6. The compound of claim 1 , wherein A 2 is —CH(R 8 )-quinolinylene, —CH(R 8 )-isoquinolinylene, —CH(R 8 )-naphthyridinylene, —CH(R 8 )-cinnolinylene, —CH(R 8 )-quinoxalinylene, —CH(R 8 )-phenylene or —CH(R 8 )-halophenylene.
7. The compound of claim 1 , wherein A 2 is
8. The compound of claim 1 , wherein X 1 is —O— or —NH—.
9. The compound of claim 1 , wherein R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—.
10. The compound of claim 1 , wherein R 3 is H.
11. The compound of claim 1 , wherein R 6a is H and R 6b is H or (C 1 -C 4 )alkyl, or R 6a and R 6b together form a spirocycle having Formula (a).
12. The compound of claim 1 , wherein R 6a and R 6b form
13. The compound of claim 1 , wherein R 3 is H; R 5a is H; R 5b is H, (C 1 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, azido(C 1 -C 8 )alkyl, aryl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl or arylheterocycloalkyl(C 1 -C 4 )alkyl; R 6a is H; and R 6b is H, (C 1 -C 4 )alkyl or hydroxy(C 1 -C 4 )alkyl.
14. The compound of claim 1 , wherein X 1 is —O— or —NH—; R 1 and R 2 , when taken together with the carbon to which they are both attached, form —C(═O)—; R 3 is H; R 4a is H; R 4b is methyl; R 5a is H and R 5b is iso-propyl, propenyl or propynyl; and R 8 is methyl.
15. 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 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene or cycloalkylene;
X 1 is a bond, —O—, —NH, —N(CH 3 )—,
R 3 is H or (C 1 -C 4 )alkyl;
R 4a and R 4b are independently H, (C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl, cycloalkyl or cycloalkyl(C 1 -C 4 )alkyl, wherein each of R 4a and R 4b is optionally substituted with one or more substituent selected from the group consisting of cyano, (C 1 -C 8 )alkoxy, —COOH, —C(O)O—(C 1 -C 8 )alkyl, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —C(O)-mono(C 1 -C 8 )alkylamino, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)— heterocycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each substituent is optionally substituted with one or more halo, heterocycloalkyl or aryl;
R 5 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl or heterocycloalkyl(C 1 -C 4 )alkyl, wherein R 5 is optionally substituted with one or more substituent selected from —N 3 , cyano, —COOH, halo, hydroxyl, amino, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl,
R 6a and R 6b are independently H, hydroxyl, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, —CH 2 CH 2 CR 9 (═N(C 1 -C 4 )alkoxy), aryl, heterocycloalkyl, cycloalkyl, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 or —N(R 9 ) 2 , wherein each of R 6a and R 6b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 8 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 , —OC(O)—(C 1 -C 8 )alkyl —C(O)O—(C 1 -C 8 )alkyl and (C 1 -C 8 )alkanoyl, wherein each —OC(O)—(C 1 -C 8 )alkyl or (C 1 -C 8 )alkoxy is optionally substituted with one or more amino, —OC(O)O—(C 1 -C 8 )alkyl or —Si(R 10 ) 3 ; or
R 6a and R 6b together form a spirocycle having Formula (a);
wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, —NH 2 , —C(O)O—(C 1 -C 8 )alkyl, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)—(C 1 -C 8 )alkyl, —C(O)-heterocycloalkyl, —S(O) 2 R 10 , —OSi(R 10 ) 3 , (C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 8 )alkanoyl and aryl(C 1 -C 4 )alkyl;
R 8 is H or (C 1 -C 4 )alkyl;
each R 9 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl; and
each R 10 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, cycloalkyl(C 1 -C 4 )alkyl or aryl, wherein R 10 is optionally substituted with one or more halo.
16. The compound of claim 1 , which is a compound of Formula IIa:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein:
R 6a and R 6b are independently H, hydroxyl, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, —CH 2 CH 2 CR 9 (═N(C 1 -C 4 )alkoxy), aryl, heterocycloalkyl, cycloalkyl, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 or —N(R 9 ) 2 , wherein each of R 6a and R 6b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 8 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 , —OC(O)—(C 1 -C 8 )alkyl —C(O)O—(C 1 -C 8 )alkyl and (C 1 -C 8 )alkanoyl, wherein each —OC(O)—(C 1 -C 8 )alkyl or (C 1 -C 8 )alkoxy is optionally substituted with one or more amino, —OC(O)O—(C 1 -C 8 )alkyl or —Si(R 10 ) 3 ; or
R 6a and R 6b together form a spirocycle having Formula (a);
wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, —NH 2 , —C(O)O—(C 1 -C 8 )alkyl, —C(O)-di(C 1 -C 8 )alkylamino, —C(O)—(C 1 -C 8 )alkyl, —C(O)-heterocycloalkyl, —S(O) 2 R 10 , —OSi(R 10 ) 3 , (C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 8 )alkanoyl and aryl(C 1 -C 4 )alkyl;
each R 9 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl; and
each R 10 is independently H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, cycloalkyl(C 1 -C 4 )alkyl or aryl, wherein R 10 is optionally substituted with one or more halo.
17. The compound of claim 15 , wherein R 4a and R 4b are independently H, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl;
R 5 is H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl or heterocycloalkyl(C 1 -C 4 )alkyl, wherein R 5 is optionally substituted with one or more substituent selected from the group consisting of —N 3 , halo, hydroxyl, di(C 1 -C 8 )alkylamino, aryl or heteroaryl; and
R 6a and R 6b are independently H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl, wherein each of R 6a and R 6b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, (C 1 -C 4 )alkyl, aryl, cycloalkyl, heterocycloalkyl, di(C 1 -C 8 )alkylamino and (C 1 -C 8 )alkanoyl; or
R 6a and R 6b together form
18. The compound of claim 1 , which is
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
19. The compound of claim 1 , which is a compound of Formula III:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene or cycloalkylene;
A 3 is —CH 2 — or —O—;
X 1 is —O—, —N(CH 3 )— or —NH—;
R 3 is H or (C 1 -C 4 )alkyl;
R 4a is H;
R 4b is H, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl;
R 5 is H, (C 1 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, azido(C 1 -C 8 )alkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl or heteroarylheteroaryl(C 1 -C 4 )alkyl;
R 6a and R 6b are independently H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl, wherein each of R 6a and R 6b is optionally substituted with one or more substituent selected from the group consisting of halo, (C 1 -C 4 )alkyl, aryl, cycloalkyl, heterocycloalkyl, di(C 1 -C 8 )alkylamino and (C 1 -C 8 )alkanoyl; or
R 6a and R 6b together form
and
R 8 is H or (C 1 -C 4 )alkyl.
20. The compound of claim 19 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 3 is —CH 2 —.
21. The compound of claim 19 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 3 is —O—.
22. The compound of claim 19 , which is
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
23. The compound of claim 1 , which is a compound of Formula IV:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene or cycloalkylene;
A 4 is bond or —O—;
X 1 is —O—, —N(CH 3 )— or —NH—;
R 3 is H or (C 1 -C 4 )alkyl;
R 4a is H;
R 4b is H, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl;
R 5 is H, (C 1 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, azido(C 1 -C 8 )alkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl or heteroarylheteroaryl(C 1 -C 4 )alkyl;
R 6a and R 6b are independently H, —OH, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy or (C 1 -C 8 )alkyl, wherein each of R 6a and R 6b is optionally substituted with one or more substituent selected from the group consisting of halo, (C 1 -C 4 )alkyl, aryl, cycloalkyl, heterocycloalkyl, di(C 1 -C 8 )alkylamino and (C 1 -C 8 )alkanoyl; and
R 8 is H or (C 1 -C 4 )alkyl.
24. The compound of claim 23 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 4 is —O—.
25. The compound of claim 23 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 4 is bond.
26. The compound of claim 23 , wherein A 1 is ethenylene; A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene or cycloalkylene; X 1 is —O—, —NH— or —N((C 1 -C 4 )alkyl)-.
27. The compound of claim 23 , which is
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
28. A pharmaceutical composition comprising a therapeutically effective amount of 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.
29. The pharmaceutical composition of claim 28 , 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.
30. The pharmaceutical composition of claim 29 , wherein the at least one addition therapeutic agent is ribavirin, telaprevir, boceprevir or sofosbuvir.