Macrocyclic inhibitors of
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 disease selected from the group consisting of dengue fever, yellow fever, hepatitis C virus, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis or West Nile encephalitis, comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer 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 (C 1 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aryl(C 1 -C 2 )alkylene, heteroaryl(C 1 -C 2 )alkylene, cycloalkyl(C 1 -C 2 )alkylene or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is optionally replaced by —O—, —S(O) n —, —NH— or —N((C 1 -C 4 )alkyl)-, and wherein a sp 3 or sp 2 carbon atom of A 1 is optionally substituted with one or more groups selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl, arylheterocycloalkyl(C 1 -C 4 )alkyl, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 and —N(R 9 ) 2 ;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene, arylene, cycloalkylene, (C 1 -C 3 )alkylene, (C 2 -C 3 )alkenylene or (C 2 -C 3 )alkynylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
L 1 is —O—C(O)—, —O—CH 2 —, —NR 11 —CH 2 —, —NH—C(R 10 ) 2 — or —NH—S(O) 2 —, wherein each R 10 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl; and R 11 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl;
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(O)—(C 1 -C 4 )alkyl; 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, hydroxyl 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 R 4a and R 4b is optionally substituted with one or more substituents selected from the group consisting of cyano, —COOH, halo, hydroxyl, amino, (C 1 -C 8 )alkoxy, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl;
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 each R 5a and R 5b is optionally substituted with one or more substituents 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, (C 1 -C 8 )alkoxy, 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) optionally has one or more substituents selected from the group consisting of oxo, ═N(C 1 -C 4 )alkoxy, halo, hydroxyl, —NH 2 , (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —OC(O)R 9 , —C(O) 2 R 9 , and —S(O) 2 R 9 ;
R 6a and R 6b are independently H, hydroxyl, (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 and —N(R 9 ) 2 , wherein each of R 6a and R 6b is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 and (C 1 -C 8 )alkanoyl; 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, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
each n is independently 0, 1 or 2; and
m is 1, 2, 3, 4 or 5.
2. The method of claim 1 , wherein the disease is Hepatitis C virus.
3. A method for providing immunomodulation to 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, or tautomer 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 (C 1 -C 5 )alkylene, (C 2 -C 5 )alkenylene, (C 2 -C 5 )alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aryl(C 1 -C 2 )alkylene, heteroaryl(C 1 -C 2 )alkylene, cycloalkyl(C 1 -C 2 )alkylene or heterocycloalkyl(C 1 -C 2 )alkylene, wherein a sp 3 carbon atom of A 1 is optionally replaced by —O—, —S(O) n —, —NH— or —N((C 1 -C 4 )alkyl)-, and wherein a sp 3 or sp 2 carbon atom of A 1 is optionally substituted with one or more groups selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocycloalkyl, cycloalkyl, aryl(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 4 )alkyl, heterocycloalkyl(C 1 -C 4 )alkyl, arylheterocycloalkyl(C 1 -C 4 )alkyl, —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 and —N(R 9 ) 2 ;
A 2 is —CH(R 8 )-arylene, —CH(R 8 )-heteroarylene, —CH(R 8 )-heterocycloalkylene, —CH(R 8 )-cycloalkylene, arylene, cycloalkylene, (C 1 -C 3 )alkylene, (C 2 -C 3 )alkenylene or (C 2 -C 3 )alkynylene, wherein A 2 is optionally substituted with one or more substituents selected from the group consisting of —OR 9 , —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —N(R 9 ) 2 , halo, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano and (C 1 -C 8 )alkyl;
L 1 is —O—C(O)—, —O—CH 2 —, —NR 11 —CH 2 —, —NH—C(R 10 ) 2 — or —NH—S(O) 2 —, wherein each R 10 is independently H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl; and R 11 is (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkenyl or cycloalkyl;
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(O)—(C 1 -C 4 )alkyl; 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, hydroxyl 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 R 4a and R 4b is optionally substituted with one or more substituents selected from the group consisting of cyano, —COOH, halo, hydroxyl, amino, (C 1 -C 8 )alkoxy, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, aryl and heteroaryl;
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 each R 5a and R 5b is optionally substituted with one or more substituents 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, (C 1 -C 8 )alkoxy, 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) optionally has one or more substituents selected from the group consisting of oxo, ═N(C 1 -C 4 )alkoxy, halo, hydroxyl, —NH 2 , (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —OC(O)R 9 , —C(O) 2 R 9 , and —S(O) 2 R 9 ;
R 6a and R 6b are independently H, hydroxyl, (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 and —N(R 9 ) 2 , wherein each of R 6a and R 6b is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, —NHS(O)R 9 , —NHC(O)R 9 and (C 1 -C 8 )alkanoyl; 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, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl or (C 2 -C 4 )alkynyl;
each n is independently 0, 1 or 2; and
m is 1, 2, 3, 4 or 5.
4. The method of claim 1 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof.
5. The method of claim 1 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
6. The method of claim 1 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
7. The method of claim 1 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 2 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
10. The method of claim 2 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
11. The method of claim 2 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 2 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 3 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, or tautomer thereof.
14. The method of claim 3 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
15. The method of claim 3 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.
16. The method of claim 3 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 3 , wherein the compound of Formula I is:
or a pharmaceutically acceptable salt thereof.