Macrocyclic inhibitors of flaviviridae viruses
Provided are compounds of Formula: 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 Flaviviridae viral 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, 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;
A 1 is —CR 9 ═CR 9 —,
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 method of claim 1 , wherein A is methylene.
3. The method of claim 1 , wherein A 1 is ethenylene, propenylene, ethylene, propylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.
4. The method of claim 1 , wherein A 1 is
5. The method of claim 1 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene.
6. The method 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 method of claim 1 , wherein A 2 is
8. The method of claim 1 , wherein X 1 is —O— or —NH—.
9. The method 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 method of claim 1 , wherein R 3 is H.
11. The method 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 method of claim 1 , wherein R 6a and R 6b form
13. The method 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 method 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 method 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 method of claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
17. The method of claim 1 wherein the compound is
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
18. The method of claim 1 wherein compound is
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.
19. The method of claim 1 , wherein the compound of Formula I is
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 wherein the compound is
or a pharmaceutically acceptable salt thereof.
21. A method for treating a Flaviviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of 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.
22. The method of claim 21 , 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
23. A method for treating a Flaviviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of 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.
24. The method of claim 23 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 3 is —CH 2 —.
25. The method of claim 23 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 3 is —O—.
26. A method for treating a Flaviviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of 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.
27. The method of claim 26 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 4 is —O—.
28. The method of claim 26 , wherein A 2 is —CH(R 8 )-arylene or —CH(R 8 )-heteroarylene; R 3 is H; and A 4 is bond.
29. The method of claim 26 , 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)-.
30. A method for treating a Flaviviridae viral 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 thereof, wherein:
A is a bond, —O—, —S(O) n —, —NH—, —N((C 1 -C 4 )alkyl)- or (C 1 -C 2 )alkylene;
A 1 is —CR 9 ═CR 9 —,
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.