HCV protease inhibitors and uses thereof
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
1. A conjugate of the formula Cys159-linker-inhibitor moiety, wherein the Cys159 is Cys159 of HCV protease, wherein the inhibitor moiety is of formula A:
or a pharmaceutically acceptable salt thereof, wherein:
one of R a and R b is hydrogen and the other is —OH or —OC(O)R′, or R a and R b are taken together to form an oxo group;
R′ is an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloalkyl, 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 1 is an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl(C 1-3 alkyl);
R 2 is hydrogen or an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl;
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 —NHC(O)NHR 5 , —NHC(O)OR 6 , or
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;
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;
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; and
R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, C 3-7 cycloalkyl, 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.
2. The conjugate of claim 1 , wherein R 1 is n-propyl.
3. The conjugate of claim 1 , wherein R 1 is
4. The conjugate of claim 1 , wherein R 2 is cyclopropyl.
5. The conjugate of claim 1 , wherein R 4 is —NHC(O)OR 6 .
6. The conjugate of claim 1 , wherein R 5 is an optionally substituted 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
7. The conjugate of claim 6 , wherein R 5 is
8. The conjugate of claim 1 , wherein R 5 is an optionally substituted C 1-6 aliphatic group.
9. The conjugate of claim 8 , wherein R 5 is t-butyl.
10. The conjugate of claim 1 , wherein R 7 is an optionally substituted C 3-7 cycloalkyl group.
11. The conjugate of claim 10 , wherein R 7 is cyclohexyl.
12. The conjugate of claim 1 , wherein the linker is a bivalent group derived from the reaction of a warhead group —(CH 2 ) n -L-Y with the Cys159 of HCV protease, wherein:
n is an integer from 0 to 5, inclusive;
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; and
each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:
Q is a covalent bond or a bivalent C 1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and
Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
13. The conjugate according to claim 12 , wherein n is an integer from 1 to 5, inclusive.
14. The conjugate according to claim 12 , wherein:
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and
Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
15. The conjugate according to claim 14 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.
16. The conjugate according to claim 14 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—.
17. The conjugate according to claim 12 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)CH═CHCH 2 O—, —NRC(O)C(═CH 2 )CH 2 —, or —CH 2 NRC(O)CH═CH—; wherein the R group of L is H or optionally substituted C 1-6 aliphatic; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
18. The conjugate according to claim 17 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—.
19. The conjugate according to claim 12 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.