主权项 |
1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 and R1′ are independently hydrogen or optionally substituted C1-6 aliphatic, or R1 and R1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring; R2a is —OH or —NHSO2R2; R2 is —N(R)2 or an optionally substituted group selected from C3-7 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 C1-6 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; R3 is a warhead -L-Y, wherein:
L is a bivalent C2-8 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 —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, 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 Re groups; and
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C1-6 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—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—; andZ is hydrogen or C1-6 aliphatic substituted with oxo, halogen, NO2, or CN; or R3 and R1 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 a warhead group -L-Y; or R3 and a ring formed by R1 and R1′ 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 a warhead group -L-Y; R4 is H, —NHC(O)R5, —NHC(O)OR6,or a natural or unnatural amino acid side-chain group;
each R5 is independently —N(R)2 or an optionally substituted group selected from C1-6 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; R6 is an optionally substituted group selected from C1-6 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 R7 is an optionally substituted group selected from C1-6 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 Rz is or R4 and Rz are taken together with their intervening atoms to form a saturated or unsaturated 16-22 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
wherein the 16-22 membered ring is optionally substituted with (Rm)p, wherein:
p is an integer from 1 to 6, inclusive;each occurrence of Rm is independently halogen, —ORo; —CN; —N(Ro)2; or an optionally substituted group selected from C1-6 aliphatic or C3-7 cycloalkyl; andeach Ro is independently optionally substituted C1-6 aliphatic; each occurrence of Ry is independently selected from halogen, —ORo, —CN, —NO2, —N(Ro)2, or optionally substituted C1-4 aliphatic; m is an integer from 0 to 4, inclusive; s is an integer from 0 to 4, inclusive; and t is an integer from 0 to 4, inclusive; wherein the sum of s and t is non-zero. |