HCV protease inhibitors and uses thereof
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2a is —OH or —NHSO 2 R 2 ;
R 2 is —N(R) 2 or an optionally substituted group selected from C 3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or:
two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 is selected from the group consisting of:
R w is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur: or
R w and R x are taken together to form an optionally substituted C 3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or:
R w and R y are taken together to form an optionally substituted C 3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R x is -T-R z , wherein:
T is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, or —SO 2 N(R)—; and
R z is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x′ is hydrogen, or R x′ and R x are taken together with their intervening atoms to form an optionally substituted spiro-fused 5-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R y is hydrogen, or R x and R y are taken together to form an optionally substituted C 3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R 4 is H, —NHC(O)R 5 , —NHC(O)OR 6 ,
a natural or unnatural amino acid side-chain group; or R 4 and Rx are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R 5 is independently —N(R) 2 or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 6 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 7 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
wherein when R 3 is
R 4 is an unnatural amino acid side-chain group of threonine substituted with one, two, or three methyl groups.
2. The compound according to claim 1 , wherein said compound is of formula II-a or II-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2 is —N(R) 2 or an optionally substituted group selected from C 3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x is -T-R z , wherein:
T is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, or —SO 2 N(R)—; and
R z is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R y is hydrogen or R x and R y are taken together to form an optionally substituted C 3-7 membered carbocycle;
R 4 is H, —NHC(O)R 5 , —NHC(O)OR 6 , a natural or unnatural amino acid side-chain group; or R 4 and R x are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R 5 is independently —N(R) 2 or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 6 is an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
3. The compound according to claim 1 , wherein said compound is of formula III-a or III-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2 is —N(R) 2 or an optionally substituted group selected from C 3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x is -T-R z , wherein:
T is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, or —SO 2 N(R)—; and
R z is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 6-10 membered monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 4 is H, —NHC(O)OR 6 , a natural or unnatural amino acid side-chain group; or R 4 and Rx are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 6 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
4. The compound according to claim 1 , wherein said compound is of formula IV-a or IV-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2 is an optionally substituted group selected from C 3-7 cycloalkyl, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x is -T-R z , wherein:
T is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, or —SO 2 N(R)—; and
R z is an optionally substituted group selected from 6-10 membered monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 4 is H, —NHC(O)OR 6 , a natural or unnatural amino acid side-chain group; or R 4 and R x are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 6 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
5. The compound according to claim 1 , wherein said compound is of formula V-a or V-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2 is —N(R) 2 ;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x is -T-R z , wherein:
T is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, or —SO 2 N(R)—; and
R z is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 4 is H, —NHC(O)OR 6 , a natural or unnatural amino acid side-chain group; or R 4 and R x are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 6 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
6. The compound according to claim 1 , wherein said compound is of formula VI-a or VI-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2 is an optionally substituted group selected from C 3-7 cycloalkyl, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x and R y are taken together to form an optionally substituted C 3-7 membered carbocycle;
R 4 is H, —NHC(O)R 5 , a natural or unnatural amino acid side-chain group; or R 4 and R x are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 5 is —N(R) 2 .
7. The compound according to claim 1 , wherein said compound is of formula VII-a or VII-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic;
R 2 is an optionally substituted group selected from C 3-7 cycloalkyl, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x′ and R x are taken together with their intervening atoms to form an optionally substituted spiro-fused 5-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 4 is H,
a natural or unnatural amino acid side-chain group; or R 4 and R x are taken together with their intervening atoms to form an optionally substituted, saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 5 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 7 is an optionally substituted group selected from C 1-6 aliphatic, bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
8. The compound according to claim 1 , wherein said compound is of formula VII-a or VII-b:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 1′ are independently hydrogen or optionally substituted C 1-6 aliphatic, or R 1 and R 1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R 2 is —N(R) 2 or an optionally substituted group selected from C 3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C 1-6 aliphatic, or:
two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R x is -T-R z , wherein:
T is a covalent bond or a C 1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, or —SO 2 N(R)—; and
R z is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a bridged bicyclic, 6-10 membered monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R x′ is hydrogen, or R x′ and R x are taken together with their intervening atoms to form an optionally substituted spiro-fused 5-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
9. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
11. The composition according to claim 10 , in combination with an additional therapeutic agent.
12. The composition according to claim 11 , wherein the additional therapeutic agent is an antiviral agent.
13. A method for inhibiting HCV protease, or a mutant thereof, activity comprising administering to a patient in need thereof a compound according to claim 1 .
14. The method according to claim 13 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly.
15. The method according to claim 14 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying a cysteine residue conserved at an equivalent position to Cys159 of HCV protease subtype Ib.
16. The method according to claim 14 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys16.
17. A method for treating a hepatitis C viral infection, comprising administering to a patient in need thereof a compound according to claim 1 .
18. The method of claim 17 , wherein the step of administering occurs once daily.
19. The method of claim 17 , wherein the compound irreversibly inhibits HCV protease by covalently modifying a cysteine residue conserved at an equivalent position to Cys159 of HCV protease subtype 1b.
20. The method of claim 19 , wherein the HCV protease genotype or subtype is selected from the group consisting of 1a, 1b, 1c, 2a, 2b, 2c,21,2k,3a, 3b, 3k, 4a, 4d, 4f, 5a, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6l, 6j, 6k, 6l, 6m, 6n, 6o, 6p, 6q, 6t, and 7a.
21. The method of claim 20 , wherein the HCV protease genotype or subtype is 1a, 1b, 2a, or 3a.
22. The method of claim 17 , wherein the compound irreversibly inhibits HCV protease by covalently modifying Cys16 of HCV protease.
23. The compound according to claim 1 , wherein R w is hydrogen, and R 1 and R 1′ are taken together to form:
wherein R o is an optionally substituted group selected from C 1-6 aliphatic.
24. The compound according to claim 23 , wherein R o is vinyl.
25. The compound according to claim 23 , wherein R o is ethyl.
26. The compound according to claim 1 , wherein R 2a is —NHSO 2 R 2 and R 2 is cyclopropyl.
27. The compound according to claim 1 , wherein R w , R x′ , and R y are hydrogen, T is —O—, and R z is
28. The compound according to claim 1 , wherein R 4 is —NHC(O)OR 6 and R 6 is C 1-6 aliphatic.
29. The compound according to claim 1 , wherein R 4 is an unnatural amino acid side-chain group of threonine substituted with one, two, or three methyl groups.
30. A covalent adduct formed by reacting a compound of claim 1 with HCV protease.
31. The covalent adduct of claim 30 , wherein the adduct is formed via a covalent bond between substituent R 3 and a cysteine sulfhydryl group of HCV protease, which cysteine is conserved at an equivalent position to Cys159 of the HCV protease subtype Ib polypeptide chain.
32. The covalent adduct of claim 30 , wherein the adduct is formed via a covalent bond between substituent R 3 and a cysteine sulfhydryl group of HCV protease, which cysteine is present at position 16 of the HCV protease polypeptide chain.
33. A method for inhibiting HCV protease, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound according to claim 1 .
34. The method according to claim 33 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly.
35. The method according to claim 34 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying a cysteine residue conserved at an equivalent position to Cys159 of HCV protease subtype 1b.
36. The method according to claim 34 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys16.