HCV protease inhibitors and uses thereof
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
1. A covalent adduct of the formula: Cys159-linker-inhibitor moiety,
wherein:
the Cys159 is Cys159 of HCV protease;
the inhibitor moiety is a moiety that selectively binds HCV protease;
the linker is a bivalent group resulting from the reaction of Cys159 of HCV protease with a -L-Y warhead group, wherein -L-Y is selected from the following:
(a) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by a functional group selected from —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, or —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(b) 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 a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group, 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; or
(c) 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 a functional group selected from —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the functional group, 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; or
(h) 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 a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group, 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; or
(i) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two 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—, and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(k) 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—; and Y is C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN; or
(l) L is a covalent bond and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; 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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(m) L is —C(O)— and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(o) L is a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; 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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(p) 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 —, or —SO 2 NH—; and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; 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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium, or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN, wherein:
Q is a bivalent C 2-6 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—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and
each Z is independently hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN.
2. The covalent adduct according to claim 1 , 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(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—; and
Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
3. The covalent adduct according to claim 1 , 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)—.
4. The covalent adduct according to claim 2 , 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)—.
5. The covalent adduct according to claim 1 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —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.
6. The covalent adduct according to claim 5 wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—.
7. The covalent adduct according to claim 1 , 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 —C(O)—.
8. The covalent adduct according to claim 1 , wherein -L-Y is selected from the group consisting of:
wherein each R e is independently a suitable leaving group, halogen, NO 2 , CN, or oxo.
9. A covalent adduct of the formula: Cys159-linker-inhibitor moiety,
wherein:
the Cys159 is Cys159 of HCV protease;
the inhibitor moiety is a moiety that selectively binds HCV protease;
the linker is a bivalent group resulting from the reaction of Cys159 of HCV protease with a -L-Y warhead group, wherein -L-Y is selected from the group consisting of:
10. A covalent adduct of the formula: Cys16-linker-inhibitor moiety,
wherein:
the Cys16 is Cys16 of HCV protease;
the inhibitor moiety is a moiety that selectively binds HCV protease;
the linker is a bivalent group resulting from the reaction of Cys16 of HCV protease with a L-Y warhead group, wherein -L-Y is selected from the following:
(a) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by a functional group selected from —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, or —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(b) 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 a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group, 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; or
(c) 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 a functional group selected from —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the functional group, 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; or
(h) 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 a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO 2 — functional group, 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; or
(i) L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two 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—, and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN; or
(k) 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—; and Y is C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN; or
(l) L is a covalent bond and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; 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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(m) L is —C(O)— and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN; or
(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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(o) L is a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; 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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
(p) 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 —, or —SO 2 NH—; and Y is selected from:
(i) —CH 2 F, —CH 2 Cl, —CH 2 CN, or —CH 2 NO 2 ; or
(ii) C 2-6 alkenyl substituted with oxo, NO 2 , or CN, and optionally substituted with halogen; 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 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; 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
(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
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; 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
(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;
each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium, or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN, wherein:
Q is a bivalent C 2-6 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—, —SO 2 —, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO 2 —, or —SO 2 N(R)—; and
each Z is independently hydrogen or C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN.
11. The conjugate according to claim 10 , 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(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one additional methylene unit of L is optionally replaced by —C(O)—; and
Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
12. The covalent adduct according to claim 10 , 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)—.
13. The covalent adduct according to claim 11 , 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)—.
14. The covalent adduct according to claim 10 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —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.
15. The covalent adduct according to claim 14 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—.
16. The covalent adduct according to claim 10 , 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 —C(O)—.
17. The covalent adduct according to claim 10 , wherein -L-Y is selected from the group consisting of:
wherein each R e is independently a suitable leaving group, halogen, NO 2 , CN, or oxo.
18. A covalent adduct of the formula: Cys16-linker-inhibitor moiety,
wherein:
the Cys16 is Cys16 of HCV protease;
the inhibitor moiety is a moiety that selectively binds HCV protease;
the linker is a bivalent group resulting from the reaction of Cys16 of HCV protease with a -L-Y warhead group, wherein -L-Y is selected from the group consisting of: