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:
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 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 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 3 is a warhead group;
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 compound according to claim 1 , wherein the compound is of formula II-a:
or a pharmaceutically acceptable salt thereof.
3 . The compound according to claim 1 , wherein the compound is of formula II-b:
or a pharmaceutically acceptable salt thereof.
4 . The compound according to claim 2 , wherein the compound is of formula III-a:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is an optionally substituted group selected from C 1-6 aliphatic or C 3-7 cycloalkyl.
5 . The compound according to claim 3 , wherein the compound is of formula III-b:
or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 2 , wherein the compound is of formula IV-a:
or a pharmaceutically acceptable salt thereof.
7 . The compound according to claim 3 , wherein the compound is of formula IV-b:
or a pharmaceutically acceptable salt thereof.
8 . The compound according to claim 2 , wherein the compound is of formula V-a:
or a pharmaceutically acceptable salt thereof.
9 . The compound according to claim 3 , wherein the compound is of formula V-b:
or a pharmaceutically acceptable salt thereof.
10 . The compound according to claim 6 , wherein the compound is of formula IV-a-1 or IV-a-2:
11 . The compound according to claim 7 , wherein the compound is of formula IV-b-1 or IV-b-2:
12 . The compound according to claim 8 , wherein the compound is of formula V-a-1 or V-a-2:
13 . The compound according to claim 9 , wherein the compound is of formula V-b-1 or V-b-2:
14 . The compound of any one of claim 1 , 2 , 4 , 6 , 8 , 10 or 12 , wherein R 1 is n-propyl.
15 . The compound of any one of claim 1 , 3 , 5 , 7 , 9 , 11 , or 13 , wherein R 1 is
16 . The compound of any one of claim 1 , 2 , 4 , 6 , 8 , 10 or 12 , wherein R 2 is cyclopropyl.
17 . The compound of claim 1 , wherein R 4 is —NHC(O)OR 6 .
18 . The compound of any one of claim 1 , 2 , 4 , 6 , 8 , 10 or 12 , wherein R 5 is an optionally substituted 5-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
19 . The compound of claim 18 , wherein R 5 is
20 . The compound of any one of claim 1 , 3 , 5 , 7 , 9 , 11 , or 13 , wherein R 5 is an optionally substituted C 1-6 aliphatic group.
21 . The compound of claim 20 , wherein R 5 is t-butyl.
22 . The compound of any one of claim 1 , 2 , 4 , 6 , 8 , 10 or 12 , wherein R 7 is an optionally substituted C 3-7 cycloalkyl group.
23 . The compound of claim 22 , wherein R 7 is cyclohexyl.
24 . The compound according to claim 1 , wherein R 3 is —(CH 2 ) n -L-Y, 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.
25 . The compound according to claim 24 , wherein n is an integer from 1 to 5, inclusive.
26 . The compound according to claim 24 , 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 or two additional methylene units of L are optionally and independently 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.
27 . The compound according to claim 26 , 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 or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.
28 . The compound according to claims 26 , 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)—.
29 . The compound according to claim 24 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)(C═N 2 )—, —NRC(O)(C═N 2 )C(O)—, —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 —, —CH 2 NRC(O)—, —CH 2 NRC(O)CH═CH—, —CH 2 CH 2 NRC(O)—, or —CH 2 NRC(O)cyclopropylene-; wherein R 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.
30 . The compound according to claim 29 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —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 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-.
31 . The compound according to claim 24 , 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 or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.
32 . The compound according to claim 1 , wherein R 3 is —(CH 2 ) n -L-Y, 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 triple 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)—, or —C(O)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.
33 . The compound according to claim 32 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
34 . The compound according to claim 33 , wherein L is —C≡C—, —C≡CCH 2 N(isopropyl)-, —NHC(O)C≡CCH 2 CH 2 —, —CH 2 —C≡C—CH 2 —, —C≡CCH 2 O—, —CH 2 C(O)C≡C—, —C(O)C≡C—, or —CH 2 OC(═O)C≡C—.
35 . The compound according to claim 1 , wherein R 3 is —(CH 2 ) n -L-Y, wherein:
n is an integer from 0 to 5, inclusive;
L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)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.
36 . The compound according to claim 35 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
37 . The compound according to claim 1 , wherein R 3 is —(CH 2 ) n -L-Y, wherein:
n is an integer from 0 to 5, inclusive;
L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and
Y is selected from the following (i) through (xvii):
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN;
(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or
(vi)
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(x)
wherein each R e is as defined above and described herein; or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(xii)
wherein each R and R e is as defined above and described herein; or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or
(xiv)
wherein each R e is as defined above and described herein; or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or
(xvi)
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups;
wherein:
each 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;
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.
38 . The compound according to claim 37 , wherein L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—.
39 . The compound according to claim 38 , wherein L is a covalent bond.
40 . The compound according to any of claims 37 , 38 , and 39 , wherein Y is selected from:
wherein each R e is independently selected from halogen.
41 . The compound according to claim 1 , wherein R 3 is selected from:
wherein each R e is independently a suitable leaving group, NO 2 , CN, or oxo.
42 . A compound selected from the group consisting of:
43 . A composition comprising a compound according to any one of claims 1 through 42 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
44 . The composition according to claim 43 , in combination with an additional therapeutic agent.
45 . The composition according to claim 44 , wherein the additional therapeutic agent is an antiviral agent.
46 . 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 any of claims 1 through 42 or a composition according to claim 43 .
47 . A method for inhibiting HCV protease, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound according to any of claims 1 through 42 or a composition according to claim 43 .
48 . The method according to either of claim 46 or 47 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly.
49 . The method according to any one of claim 46 , 47 , or 48 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys159.
50 . The method according to any one of claim 46 , 47 , or 48 , wherein the HCV protease, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys16.
51 . A method for treating an HCV protease-mediated disorder in a patient, comprising the step of administering to said patient a compound according to any of claims 1 through 42 or a composition according to claim 43 .
52 . The method of claim 51 , wherein the step of administering occurs once daily.
53 . The method according to claim 51 , wherein the disorder is hepatitis C.
54 . A method of treating an HCV protease-mediated disorder in a patient comprising the step of irreversibly inhibiting HCV protease by covalently modifying Cys159 of HCV protease.
55 . A method of treating an HCV protease-mediated disorder in a patient comprising the step of irreversibly inhibiting HCV protease by covalently modifying Cys16 of HCV protease.
56 . A conjugate of the formula Cys159-modifier-inhibitor moiety, wherein the Cys159 is Cys159 of HCV protease.
57 . A conjugate of the formula Cys16-modifier-inhibitor moiety, wherein the Cys16 is Cys16 of HCV protease.
58 . The conjugate of claim 56 or 57 , 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.