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 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 3 is a warhead group -L-Y, and -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 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or
(ix) a partially unsaturated 5-6 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 5-6 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, 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, or:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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.
2. A compound 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—, —(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 3 is a warhead group -L-Y, and -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 —, —CO(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 5-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 5-6 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 5-6 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 0-3 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 5-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(viii) a partially unsaturated 5-6 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 5-6 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 0-3 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, 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, or:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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.
3. A compound 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 3 is a warhead group -L-Y, and -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 0-3 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 5-6 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 5-6 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 5-6 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 0-3 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, 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, or:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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.
4. 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.
5. 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 .
6. 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 a warhead group -L-Y, 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 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
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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 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;
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.
7. The compound according to claim 6 , 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 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)—.
8. The compound according to claim 6 , 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)—.
9. The compound according to claim 6 , 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.
10. The compound according to claim 9 , 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—.
11. The compound according to claim 6 , 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 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 functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.
12. 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 a warhead group -L-Y, wherein:
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)—, —O—, —N(R)—, —C(O)—, —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 selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, 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; or
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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′ an d 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 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;
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.
13. The compound according to claim 12 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
14. The compound according to claim 13 , 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—.
15. 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 a warhead group -L-Y, wherein:
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 C 1-6 aliphatic 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 selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, 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; or
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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 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;
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.
16. The compound according to claim 15 , wherein Y is C 1-6 aliphatic substituted with oxo, halogen, NO 2 , or CN.
17. 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 a warhead group -L-Y; 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 —, or —SO 2 NH—; and
Y is selected from the following:
(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
(vi)
(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 5-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or
(x)
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)
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or
(xiv)
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 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, 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; or
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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 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;
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.
18. The compound according to claim 17 , wherein L is a covalent bond.
19. The compound according to any one of claims 1 - 3 , 6 or 17 , wherein Y is selected from:
wherein each R e is independently selected from halogen.
20. The compound according to any one of claim 1 - 3 , 6 , or 17 , wherein R 3 is selected from:
wherein each R e is independently a suitable leaving group, halogen, NO 2 , CN, or oxo.
21. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
23. The composition according to claim 22 , in combination with an additional therapeutic agent.
24. The composition according to claim 23 , wherein the additional therapeutic agent is an antiviral agent.
25. A covalent adduct formed by reacting a compound of claim 1 with HCV protease.
26. The covalent adduct of claim 25 , wherein the adduct is formed via a covalent bond between substituent R 3 and a cysteine sulfhydryl group of HCV protease, which cysteine is Cys159 of HCV protease or is at an equivalent position to Cys159 of the HCV protease subtype 1b polypeptide chain.
27. The covalent adduct of claim 25 , 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.
28. 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 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 a warhead group -L-Y; wherein
L is a covalent bond, —C(O)—, —N(R)C(O)—, —CH 2 —, —NH—, —NHCH 2 —, —NHC(O)—, —CH 2 NH—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and
Y is selected from the following:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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 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;
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.
29. 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 a warhead group selected from:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group;
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 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;
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.
30. The compound according to claim 17 , 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;
R 3 is the warhead group -L-Y;
or:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted saturated or unsaturated 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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.
31. The compound according to claim 17 , wherein said compound is of formula VIII-a or VIII-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 3 is the warhead group -L-Y, or:
R 3 and R 1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y; or
R 3 and a ring formed by R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
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.