Macrocyclic RAS inhibitors

Abstract

The present disclosure features macrocyclic compounds of Formula (1a) or (1b) capable of inhibiting the Ras protein, as well as pharmaceutical compositions and protein complexes thereof, and their use in the treatment of cancer.

Description

Background Technology

[0001] Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of those proteins. For example, cholesterol-lowering drugs known as statins bind to the active site of HMG-CoA reductase, preventing the enzyme from binding to its substrate. The fact that many such drug / target interactions are known may mislead some into believing that, given reasonable time, effort, and resources, small molecule regulators targeting most (if not all) proteins can be discovered. This is far from the truth. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules. (Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019)). The other 90% are currently considered refractory or intractable to the aforementioned small molecule drug discovery. These targets are often referred to as “undruggable.” These undruggable targets include a large number of medically significant human proteins that remain largely unexplored. Therefore, there is considerable interest in discovering new molecular patterns capable of modulating the function of such undruggable targets.

[0002] The literature has well-established that Ras proteins (K-Ras, H-Ras, and N-Ras) play a crucial role in various human cancers and are therefore suitable targets for anticancer therapies. In fact, mutations in Ras proteins explain approximately 30% of all cancers in the United States, many of which are fatal. Aberrant regulation of Ras proteins caused by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancers. For example, an activating mutation at codon 12 in Ras proteins functions by inhibiting both the GTPase-activated protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly biasing the population of Ras mutant proteins toward the "on" (GTP-bound) state (Ras (on)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing it to be activated even in low concentrations of this nucleotide. Mutations in Ras at codons 13 (e.g., G13C) and 61 (e.g., Q61K) also induce oncogenic activity in some cancers.

[0003] Despite extensive drug development efforts targeting Ras over the past few decades, the United States has only approved two agents targeting the K-Ras G12C mutant (sotorasib and adagrasib). Further efforts are needed to discover additional drugs for cancers driven by various Ras mutations. Summary of the Invention

[0004] This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytoplasmic chaperone (presenting protein) (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity three-component complex or conjugate between the Ras protein and the widely expressed cytoplasmic chaperone cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way in which the inhibitory effect on Ras is influenced by the compounds of the present invention and the complexes or conjugates they form is through the spatial closure of the interaction site between Ras and downstream effector molecules (such as RAF and PI3K), which are required for the propagation of oncogenic signals.

[0005] Therefore, in one aspect, this disclosure is characterized by a compound having the structure of formula Ia or formula Ib: Or its pharmaceutically acceptable salt, wherein: Q is a optionally substituted 7- to 12-membered bicyclic aryl, optionally substituted 7- to 12-membered bicyclic heteroaryl, or optionally substituted 7- to 12-membered bicyclic heterocyclic, wherein the first ring in Q is bonded to X, and the second ring in Q is bonded to A; X is a bond; a straight-chain C1-C3 alkylene group, optionally substituted by 1 to 3 substituents independently selected from fluorinated, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl groups; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, where "*" indicates that a portion of X is bonded to -C(R 7 (R) 8 )-; Y is -O-, -NH-, or -N(C1-C3 alkyl)-; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. L stands for connector; R 3 It is an optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclic group; R 10It is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group; R 8 It is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic; or R 7 and R 8 Together they form =CH2, optionally substituted C3-C6 cycloalkyl groups or 3 to 7-membered saturated heterocyclic groups; or R 8 With the ring atoms in Q, R 7 The bonded carbon atoms and X form 4- to 9-membered saturated or unsaturated heterocyclic groups fused to Q; R 6 It is hydrogen or -CH3; Each R 5 It is independently a halogen, an optionally substituted C1-C3 alkyl group, or an optionally substituted C1-C3 haloalkyl group; p is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0006] In one aspect, the invention is characterized by a compound having the structure of formula IIa or IIb: Or its pharmaceutically acceptable salt, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L stands for connector; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y5 It is CR x CH, CH2 or N; Y 6 It is CR z C(O), CH, CH2 or N; R x It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 13 and R 2 The atoms to which it is attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It does not exist; it is hydrogen; it is optionally substituted C1-C6 alkyl; it is optionally substituted C2-C6 alkenyl; it is optionally substituted C2-C6 alkynyl; it is optionally substituted 3- to 6-membered cycloalkyl; it is optionally substituted 3- to 7-membered heterocycloalkyl; it is optionally substituted 6-membered aryl; it is optionally substituted 5- or 6-membered heteroaryl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen; a C1-C4 alkyl group optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl; cyclopropyl; or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R 10a It is hydrogen or halogen; R 11It is hydrogen or an optional substituted C1-C3 alkyl group; R 21 It is hydrogen or an optional substituted C1-C3 alkyl group; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0007] In one aspect, the invention is characterized by a compound having the structure of formula IIa-1: , Formula IIa-1 Or its pharmaceutically acceptable salt, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L stands for connector; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CR x CH, CH2 or N; Y 6 It is CR z C(O), CH, CH2 or N; R x It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 13 and R 2 The atoms to which it is attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It does not exist; it is hydrogen; it is optionally substituted C1-C6 alkyl; it is optionally substituted C2-C6 alkenyl; it is optionally substituted C2-C6 alkynyl; it is optionally substituted 3- to 6-membered cycloalkyl; it is optionally substituted 3- to 7-membered heterocycloalkyl; it is optionally substituted 6-membered aryl; it is optionally substituted 5- or 6-membered heteroaryl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen; a C1-C4 alkyl group optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl; cyclopropyl; or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R8a It is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R 10a It is hydrogen or halogen; R 11 It is hydrogen or optionally substituted C1-C3 alkyl; and R 21 It is hydrogen or an optional substituted C1-C3 alkyl group.

[0008] In one aspect, the invention is characterized by a compound having the structure of formula IIIa or IIIb: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene. Y 8 yes , , , , , , or ; L stands for connector; R 13 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 10 It is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 7-membered heterocyclic alkyl; R 7 and R 8 Each is independently selected from F or CH3, or R 7 and R 8 It combines with the atoms it is attached to to form a 3-membered cycloalkyl group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C3 alkoxy, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 6-membered heterocycloalkyl. t is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 RL4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0009] In one aspect, the invention is characterized by a compound having the structure of formula IIIa-1: , Formula IIIa-1 Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene. Y 8 yes , , , , , , or ; L stands for connector; X 4 and X 5 Each can be independently CH2, CH(CH3) or NH; R 13 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 10 It is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 7-membered heterocyclic alkyl; R 7 and R 8 Each is independently selected from F or CH3, or R 7 and R 8 It combines with the atoms it is attached to to form a 3-membered cycloalkyl group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0010] In one aspect, the invention is characterized by a compound having the structure of formula IVa or IVb: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X 9 Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0011] In one aspect, the invention is characterized by a compound having the structure of formula Va or formula Vb: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X 9 Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0012] In one aspect, the invention is characterized by a compound having the structure of formula VIIa or VIIb: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; X 6 X 7 and X 8 Each is independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 10-membered heterocyclic alkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocycloalkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium; z is 0, 1, or 2; X 9 Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0013] In one aspect, the present invention is characterized by a compound having the structure of formula XI: , Formula XI Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene or optionally substituted C2-C4 alkenylene. W is an optionally substituted 3- to 10-membered heterocyclic alkyl group or an optionally substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 alkenyl, an optional substituted C1-C6 alkynyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl, or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they can form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen, and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted four-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen, and R 4 and R 6Together with the atoms to which they are attached, they form optionally substituted four-membered cycloalkyl groups; R 10 Yes - OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 and R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0014] In one aspect, the present invention is characterized by the compounds in Table 1 or pharmaceutically acceptable salts thereof.

[0015] Pharmaceutical compositions are also provided, the pharmaceutical compositions comprising a compound of any one of the foregoing aspects and embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0016] A method for treating cancer in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, a method is provided for treating a subject with Ras protein-related conditions, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0018] A method for inhibiting Ras protein in cells is further provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0019] In particular, it is contemplated that any limitations set forth with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0020] Definitions and Chemical Terms In this application, unless the context clearly indicates otherwise, (i) the term “a / an” means “one or more / a combination of”; (ii) the term “or” is used to mean “and / or” (unless explicitly indicated to mean only alternatives or alternatives mutually exclusive), although this disclosure supports the definition of only alternatives and “and / or”; (iii) the terms “comprising” and “including” should be understood to cover the listed components or steps presented alone or together with one or more other components or steps; and (iv) where scope is provided, endpoints are included.

[0021] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the means or method used to determine said value. In some embodiments, the term "about" refers to a range of values ​​(greater than or less than) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction of the stated value, unless otherwise stated or obvious from the context in its other form (e.g., where such numbers would exceed 100% of possible values).

[0022] As used in this article, when describing adjacent atoms, the term "adjacent" refers to divalent atoms directly connected by covalent bonds.

[0023] Whether explicitly mentioned or not, as used herein, “compounds of the present invention” and similar terms refer to the Ras inhibitors described herein, including compounds of formula I and its sub-formulas, such as the compounds in Table 1, as well as their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers), and tautomers.

[0024] The term "wildtype" refers to an entity that has the structure or activity found in nature in a "normal" state or background (as opposed to mutants, diseased, altered, etc.). Those skilled in the art will understand that wild-type genes and polypeptides typically exist in many different forms (e.g., alleles).

[0025] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomers (e.g., stereoisomers, geometric isomers, transisomers, tautomers) or isotopic forms (e.g., one or more atoms have been substituted with different isotopes of the atoms, such as hydrogen being replaced with deuterium). Unless otherwise indicated or clear from the context, the structures depicted are to be understood as individually or in combination representing any such isomer or isotopic form.

[0026] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are contemplated in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and can be isolated as mixtures of isomers or as separate isomeric forms.

[0027] In some embodiments, one or more compounds described herein may exist in different tautomer forms. As will be clear from the context, unless explicitly excluded, references to such compounds encompass all such tautomer forms. In some embodiments, the tautomer form arises from the exchange of a single bond with an adjacent double bond and the accompanying proton migration. In some embodiments, the tautomer form may be a proton-shift tautomer, which is an isoprotonated state having the same empirical formula and total charge as the reference form. Examples of portions having proton-shift tautomerism include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms, wherein the proton can occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomerism may be in equilibrium or spatially locked into one form by appropriate substitution. In some embodiments, the tautomerism is caused by acetal tautomerism.

[0028] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35S, 18 F, 36 Cl、 123 I and 125 I. Isotope-labeled compounds (e.g., those labeled with...) 3 H and 14 Those labeled with C can be used in the determination of the tissue distribution of compounds or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes can be useful due to their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In some embodiments, one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being... 13 C or 14 Carbon-enriched carbon substitution. Positron-emitting isotopes (such as...) 15 O、 13 N、 11 C and 18 F) It can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents by following procedures similar to those disclosed for the compounds of the present invention described herein.

[0029] Non-limiting examples of compounds of the present invention containing one or more deuterium-substituted moieties (wherein “R” at any position may be deuterium (D)) include: , and .

[0030] Other examples include, for example , , , , , and The deuteration of parts and similar parts, such as in compounds of formulas I, II, III, IV, V, and VI and their subforms. Furthermore, deuteration of any available position in part A of compounds of the formulas described herein is contemplated, such as... , , and Furthermore, deuterium substitution can also occur at the junction site in the compounds of the present invention, such as... Furthermore, deuterium substitution can also occur at the junction site in the compounds of the present invention, such as... .

[0031] Furthermore, deuterium substitution can also occur at the junction site in the compounds of the present invention, such as... and .

[0032] In another embodiment, silanization substitution is also envisioned, such as in the connector as follows: .

[0033] As is known in the art, many chemical entities can be in a variety of different solid forms, such as, for example, amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be in any such form, including use in any solid form. In some embodiments, the compounds described or depicted herein may be provided or used in hydrate or solvate form.

[0034] Substituents of the compounds disclosed herein are disclosed at various locations in this specification, either as groups or as ranges. This disclosure is specifically intended to include each individual combination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes multiple locations where substituents are disclosed as groups or as ranges, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., classes and subclasses) containing each individual combination of members at each location.

[0035] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). Characteristic "X" (e.g., alkyl) per seThis is not intended to imply optionality. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. Generally, regardless of whether the term "optionally" is preceding it, the term "substituted" means that one or more hydrogens of the specified moieties are replaced by suitable substituents (e.g., any of the substituents or groups described herein). Unless otherwise indicated, the "optionally substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl," the alkyl moieties, heteroaryl moieties, or both may be optionally substituted. The combinations of substituents contemplated in this disclosure are preferably those combinations that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions permitted for the preparation, testing, and, in some embodiments, recovery, purification, and use for one or more purposes disclosed herein.

[0036] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can be independently deuterium; halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which can be substituted by R°; -(CH2)0-4O(CH2)0-1Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2)0- 4O(CH2)O-1-pyridyl, which may be substituted with R°; 4 to 8-membered saturated or unsaturated heterocyclic alkyl groups (e.g., pyridyl); 3 to 8-membered saturated or unsaturated cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)O-4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4-C(O)-N(R o )2;-(CH2)0-4-C(O)-N(R o )-S(O)2-R o;-C(NCN)NR°2;-(CH2)0-4C(O)SR°;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR°;-SC (S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)0-4OC(O)NR°2; -C(O)N(OR °)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2O R°;-(CH2)0-4OS(O)2R°;-S(O)2NR°2;-(CH2)0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;- C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°; -SiR°3; -(C1-4 straight-chain or branched alkylene)ON(R°)2; or -(C1-4 straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6 Aliphatic groups, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5 to 6-membered heteroaryl ring) or 3 to 6-membered saturated, partially unsaturated rings or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or although defined above, two independently occurring R° together with one or more intermediary atoms form 3 to 12-membered saturated, partially unsaturated rings or aryl monocyclic or bicyclic rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the monocyclic or bicyclic ring may be substituted as defined below.

[0037] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R° and their interatoms) can be halogens, -(CH2)O-2R, or -(CH2)O-2R. ● -(halogenated R) ● -(CH2)O-2OH, -(CH2)O-2OR ● -(CH2)0-2CH(OR) ● )2;-O(halogenated R ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ●-(CH2)O-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● -(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C1-4 straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, when preceded by "halogenated", substituted only by one or more halogens, and independently selected from C1-4 aliphatic groups, -CH2Ph, -O(CH2)0-1Ph, or 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0038] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2))2-3O-or-S(C(R) * 2))2-3S-, where each independently occurring R * Selected from hydrogen, C1-6 aliphatic groups that may be substituted as defined below, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR * 2)2-3O-, where each independently occurring R * It is selected from hydrogen, C1-6 aliphatic groups that may be substituted as defined below, or unsubstituted 5- to 6-membered saturated, partially unsaturated rings or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0039] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, when preceded by "halogenated", substituted only by one or more halogens, and is independently a C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated ring or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, it can be hydrogen, a substituted C1-6 aliphatic group as defined below, a substituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring R groups. † Together with one or more intermediary atoms, it forms an unsubstituted 3 to 12-membered saturated, partially unsaturated ring or aryl monocyclic or bicyclic ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen or sulfur.

[0041] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ●It is unsubstituted or, when preceded by "halogenated", substituted only by one or more halogens, and is independently a C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R † Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0042] As used in this article, the term "acetyl" refers to the group -C(O)CH3.

[0043] As used herein, the term "alkoxy" refers to -O-Cl-C 20 Alkyl groups, wherein the alkoxy group is attached to the rest of the compound via an oxygen atom.

[0044] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., straight-chain); in some embodiments, the alkyl group is branched. Alkyl groups are exemplified by, but are not limited to, the following groups: methyl, ethyl, ... n-butyl -and iso-butyl -propyl, n-butyl -、 sec-butyl -、 iso-butyl -and tert-butyl -Butyl and neopentyl.

[0045] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, etc. The term "C" x -C y "alkylene" refers to an alkylene group having x to y carbons. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C...). 10 C2-C 20 C2-C6, C2-C 10 Or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted by one, two, three or four substituents as defined herein.

[0046] Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent straight-chain or branched group containing 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) and one or more carbon-carbon double bonds, and is exemplified by vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. Unless otherwise specified, as used herein, the term "alkenylene" refers to a divalent straight-chain or branched group containing 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) and one or more carbon-carbon double bonds.

[0047] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group containing 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) with a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0048] As used herein, the term "alkynyl sulfone" refers to a group comprising the following structure: , where R is any chemically feasible substituent described herein.

[0049] As used herein, the term "amino" signifies -N(R) † )2, for example -NH2 and -N(CH3)2.

[0050] As used herein, the term "aminoalkyl" refers to an alkyl moiety on one or more carbon atoms that is replaced by one or more amino moieties.

[0051] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to a parent molecule group via a side chain, an amino group, or an acid group (e.g., a side chain). As used herein, the term "amino acid" broadly refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, the amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxyl valine, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0052] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed from carbon atoms, wherein the ring attached to a side group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthryl, and anthracene. The aryl ring may be attached to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise specified, any one of the ring atoms may be optionally substituted.

[0053] As used herein, the term “C0” denotes a bond. For example, the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, and the group is also represented by -N(C(O)-H)-.

[0054] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to C3-C groups with optional substitutions in monovalent form. 12 A monocyclic, bicyclic, or tricyclic ring structure, wherein the ring structure can be a bridged ring, a fused ring, or a spirocyclic ring, wherein all rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indenyl, decahydronaphthyl, etc. The carbocyclic ring may be attached to its side group at any ring atom that produces a stable structure, and unless otherwise specified, any one of the ring atoms may be optionally substituted.

[0055] As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented as C=O.

[0056] As used herein, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH or its unprotonated counterpart.

[0057] As used herein, the term "cyano" refers to the -CN group.

[0058] As used herein, the term "cycloalkyl" means, unless otherwise specified, a monovalent saturated cyclic hydrocarbon group having three to eight cyclic carbons, including bridged, fused, or spirocyclic rings, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0059] As used herein, the term "cycloalkenyl" means, unless otherwise specified, a monovalent, non-aromatic, saturated cyclic hydrocarbon group having three to eight cyclic carbons and containing one or more carbon-carbon double bonds, including bridged, fused, or spirocyclic rings.

[0060] As used in this article, the term “diastereomer” means a stereoisomer that is not a mirror image of another and cannot be superimposed on another.

[0061] As used herein, the term "enantiomer" means each individual optically active form of the compound of the present invention having an optical purity of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of another enantiomer), preferably at least 90% and more preferably at least 98% or an enantiomer excess (as determined by methodological standards in the art).

[0062] The term "guanidinyl" refers to a group having the following structure: , where each R is independently any chemically feasible substituent described herein.

[0063] As used herein, the term "guanidinyl alkyl" refers to an alkyl moiety on one or more carbon atoms that is replaced by one or more guanidinyl moieties.

[0064] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one of the hydrogen atoms has been replaced by a halogen.

[0065] As used herein, the term "halogenated alkyl" refers to an alkyl moiety on one or more carbon atoms that is replaced by one or more identical or different halogen moieties.

[0066] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0067] As used herein, the term "heteroalkyl" refers to an "alkyl" group as defined herein, wherein at least one carbon atom has been replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the end of the group.

[0068] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4... n +2 π electrons and containing at least one cyclic heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the above heteroaryl rings is fused to one or more aryl or carbon rings, such as phenyl or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. The heteroaryl ring may be attached to its side groups at any ring atom that produces a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0069] As used herein, the term "heterocyclic alkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic system that may be a bridged, fused, or spirocyclic ring, wherein at least one ring is non-aromatic and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have zero to two double bonds, and six- and seven-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclic alkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclic alkyl" also refers to a heterocyclic compound having a bridged polycyclic structure in which one or more carbons or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as a quinine cycloyl group. The term "heterocyclic alkyl" includes bicyclic, tricyclic, and tetracyclic groups, wherein any of these heterocycles is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene, pyridine, or pyrrolidine rings. Examples of heterocyclic alkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthidine. Heterocyclic alkyl rings may be attached to their side groups at any ring atom that produces a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted.

[0070] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0071] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety that is substituted on one or more carbon atoms by one or more -OH moieties.

[0072] As used herein, the term "isomer" means any tautomer, stereoisomer, transisomer, enantiomer, or diastereomer of any compound of the present invention. It should be understood that the compounds of the present invention may have one or more chiral centers or double bonds, and thus exist in stereoisomers (such as double-bonded isomers, i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures described herein and therefore the compounds of the present invention include all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of the present invention can generally be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallizing the compound into a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomer or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0073] As used herein, the term "connector" refers to a divalent organic moiety that links a first portion (e.g., a portion of a macrocycle) to a second portion (e.g., a second portion of the same macrocycle). In some embodiments, the connector produces compounds capable of achieving an IC50 of 2 µM or less in the Ras-RAF destruction assay protocol provided herein. The purpose of this biochemical assay was to measure the ability of the test compound to induce the formation of a ternary complex between the nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex was disrupted by BRAF. RBD The binding of the construct suppresses Ras signaling through the RAF effector.

[0074] In an assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, unlabeled cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAF were added. RBD Compounds were combined in 384-well plates at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compounds were present in the wells in a 10-point, 3-fold dilution series starting at a final concentration of 30 μM. After incubation at 25 °C for 3 h, mixtures of anti-His Eu-W1024 and anti-GST allophycocyanin were added to the sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for another 1.5 h. TR-FRET signals were read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that induced disruption of the Ras:RAF complex were identified as those that induced a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0075] This assay can also be used to assess selectivity. In some embodiments, the compounds of the present invention are selective for one or more specific Ras mutants, but not for other Ras mutants or the wild type, compared to compounds known in the art. For example, compounds of formula Ia and its derivatives may be more selective for K-Ras G12C or K-Ras G13C than for the K-Ras wild type. For example, compounds of formula IIa-1 and IIa-2 may be more selective for K-Ras G12C, K-Ras G13C, K-Ras G12D, or K-Ras G12V than for the K-Ras wild type. For example, compounds of formula IIIa-1 and IIIa-2 may be more selective for K-Ras G12D or K-Ras G12V than for the K-Ras wild type. For example, compounds of formula IVa and its derivatives may be more selective for K-Ras G12C or K-Ras G13C than for the K-Ras wild type. For example, compounds of formula VIa and its derivatives may exhibit higher selectivity for K-Ras G12D than for the wild-type K-Ras. Similarly, compounds of formula VIIa and its derivatives may exhibit higher selectivity for K-Ras G12D than for the wild-type K-Ras.

[0076] Unbound by theory, the inventors hypothesize that the non-covalent interaction between "L" and chaperone proteins (such as cyclophilin A) may contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, as well as combinations thereof, may contribute to the ability of the compounds of this invention to form complexes and act as Ras inhibitors. The inventors also hypothesize that "L" also imparts structural rigidity to the compounds, which may optimize these non-covalent interactions, thereby contributing to the inhibition of Ras activity.

[0077] In some embodiments, the linker comprises 20 or fewer straight-chain atoms. In some embodiments, the linker comprises 15 or fewer straight-chain atoms. In some embodiments, the linker comprises 10 or fewer straight-chain atoms. In some embodiments, the linker has a molecular weight of less than 500 g / mol. In some embodiments, the linker has a molecular weight of less than 400 g / mol. In some embodiments, the linker has a molecular weight of less than 300 g / mol. In some embodiments, the linker has a molecular weight of less than 200 g / mol. In some embodiments, the linker has a molecular weight of less than 100 g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0078] As used herein, the "monovalent organic fraction" is less than 500 kDa. In some embodiments, the "monovalent organic fraction" is less than 400 kDa. In some embodiments, the "monovalent organic fraction" is less than 300 kDa. In some embodiments, the "monovalent organic fraction" is less than 200 kDa. In some embodiments, the "monovalent organic fraction" is less than 100 kDa. In some embodiments, the "monovalent organic fraction" is less than 50 kDa. In some embodiments, the "monovalent organic fraction" is less than 25 kDa. In some embodiments, the "monovalent organic fraction" is less than 20 kDa. In some embodiments, the "monovalent organic fraction" is less than 15 kDa. In some embodiments, the "monovalent organic fraction" is less than 10 kDa. In some embodiments, the "monovalent organic fraction" is less than 1 kDa. In some embodiments, the "monovalent organic fraction" is less than 500 g / mol. In some embodiments, the "monovalent organic fraction" ranges between 500 g / mol and 500 kDa.

[0079] As used herein, the term "stereoisomer" refers to all possible different isomers and conformations that a compound (such as any compound of the formula described herein) can have, specifically all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers, or conformations, including transisomeric isomers. Some compounds of the present invention may exist in different tautomer forms, and all tautomer forms are included within the scope of the present invention.

[0080] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0081] As used in this article, the term "thiocarbonyl" refers to the -C(S)- group.

[0082] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group directly attached to a carbon-carbon double bond.

[0083] As used herein, the term “vinyl sulfone” refers to a group containing a sulfonyl group directly linked to a carbon-carbon double bond.

[0084] As used herein, the term "acetylenolone" refers to a group comprising the following structure: , where R is any chemically feasible substituent described herein.

[0085] Those skilled in the art will understand from this disclosure that certain compounds described herein may be provided or used in any of a variety of forms, such as, for example, salt forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a specific form of that compound. In some embodiments, reference to a particular compound may refer to any form of the compound. In some embodiments, for example, a formulation of a single stereoisomer of the compound may be considered a form of the compound distinct from a racemic mixture of the compound; a particular salt of the compound may be considered a form distinct from another salt form of the compound; a formulation of a conformational isomer ((Z) or (E)) containing a double bond may be considered a form distinct from other conformational isomers ((E) or (Z)) containing a double bond; a formulation in which one or more atoms are isotopes distinct from those present in a reference formulation may be considered a distinct form. Detailed Implementation

[0086] compound This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytoplasmic chaperone (presenting protein) (e.g., cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity three-component complex or conjugate between the Ras protein and the widely expressed cytoplasmic chaperone cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way in which the inhibitory effect on Ras is influenced by the compounds of the invention and the complexes or conjugates they form is through the spatial closure of the interaction site between Ras and downstream effector molecules (such as RAF), which are required for the propagation of oncogenic signals.

[0087] Not bound by theory, the inventors hypothesize that covalent, non-covalent, or combined covalent and non-covalent interactions between the compounds of the present invention and Ras and chaperone proteins (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. In some embodiments, the compounds of the present invention form covalent adducts with the side chains of Ras proteins (e.g., the side chain of the histidine residue at position 61 of the mutant Ras protein). Covalent adducts may also be formed using other side chains of Ras. Furthermore, or alternatively, non-covalent interactions may play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors.

[0088] Therefore, the compounds of the present invention can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras, and mutants of them at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, Q61H, Q61K, Q61R, and Q61L, as well as other mutants described herein, or combinations thereof).

[0089] Methods for determining the formation of covalent adducts are known in the art. One method for determining the formation of covalent adducts is to perform a "crosslinking" determination, such as under these conditions.

[0090] Note – The following protocol describes a procedure for monitoring the cross-linking of K-Ras G12C (GMP-PNP) with the compounds of the present invention. This protocol can also be performed with other Ras proteins or nucleotides substituted. J. Pharmaceutical Sciences

[0091] The purpose of this biochemical assay was to measure the ability of the test compound to be covalently labeled with a nucleotide-loaded K-Ras isoform. The 5 µM stock solution of GMP-PNP-loaded K-Ras (1-169) G12C was diluted 10-fold in an assay buffer containing 12.5 mM HEPES (pH 7.4), 75 mM NaCl, 1 mM MgCl2, 1 mM BME (if studying cysteine ​​Ras mutants, such as K-Ras G12C or G13C), 5 µM cyclophilin A, and 2 µM of the test compound, to obtain a final concentration of 0.5 µM; the final sample volume was 100 µL.

[0092] The sample was incubated at 25°C for up to 24 hours, followed by quenching with 10 µL of 5% formic acid. The quenched sample was centrifuged at 15,000 rpm for 15 minutes in a benchtop centrifuge, and then 10 µL aliquots were injected into a reverse-phase C4 column and eluted to a mass spectrometer using an acetonitrile gradient added to the mobile phase. The raw data were analyzed using Waters MassLynx MS software, and the binding percentage was calculated based on the deconvolution of labeled and unlabeled K-Ras protein peaks.

[0093] Therefore, this paper provides compounds having the structure of formula Ia or formula Ib: Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is a optionally substituted 7- to 12-membered bicyclic aryl, optionally substituted 7- to 12-membered bicyclic heteroaryl, or optionally substituted 7- to 12-membered bicyclic heterocyclic, wherein the first ring in Q is bonded to X, and the second ring in Q is bonded to A; X is a bond; a straight-chain C1-C3 alkylene group, optionally substituted by 1 to 3 substituents independently selected from fluorinated, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl groups; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, where "*" indicates that a portion of X is bonded to -C(R 7 (R) 8 )-; Y is -O-, -NH-, or -N(C1-C3 alkyl)-; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. L stands for connector; R 3 It is an optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclic group; R 10 It is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group; R 8 It is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic; or R 7 and R 8 Together they form =CH2, optionally substituted C3-C6 cycloalkyl groups or 3 to 7-membered saturated heterocyclic groups; or R 8 With the ring atoms in Q, R 7 The bonded carbon atoms and X form 4- to 9-membered saturated or unsaturated heterocyclic groups fused to Q; R 6 It is hydrogen or -CH3; Each R 5 It is independently a halogen, an optionally substituted C1-C3 alkyl group, or an optionally substituted C1-C3 haloalkyl group; p is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0094] In some embodiments, the compound has the structure of formula Ia-1: Formula Ia-1 Or its pharmaceutically acceptable salts, enantiomers, stereoisomers or tautomers, wherein Q is a optionally substituted 7- to 12-membered bicyclic aryl, optionally substituted 7- to 12-membered bicyclic heteroaryl, or optionally substituted 7- to 12-membered bicyclic heterocyclic, wherein the first ring in Q is bonded to X, and the second ring in Q is bonded to A; X is a bond; a straight-chain C1-C3 alkylene group, optionally substituted by 1 to 3 substituents independently selected from fluorinated, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl groups; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2, where "*" indicates that a portion of X is bonded to -C(R 7 (R) 8 )-; Y is -O-, -NH-, or -N(C1-C3 alkyl)-; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. L stands for connector; R 3 It is an optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclic group. R 10 It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 hydroxyalkyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group; R 8 It is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic; or R 7 and R 8 Together they form =CH2, optionally substituted C3-C6 cycloalkyl groups or 3 to 7-membered saturated heterocyclic groups; or R 8 With the ring atoms in Q, R 7 The bonded carbon atoms, together with X, form 4 to 9 member saturated or unsaturated heterocyclic groups fused to Q; R 6 It is hydrogen or -CH3; Each R 5 It is independently a halogen, an optionally substituted C1-C3 alkyl group, or an optionally substituted C1-C3 haloalkyl group; and p is 0, 1, 2 or 3.

[0095] In some embodiments, the compound has the structure of formula Ia-2: Formula Ia-2, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0096] in: X is a bond, -O-, -CH2-, -CH(CH3)-, *-CH2-O-, or -CH2-CH2-, where "*" indicates that a portion of X is bonded to C(R). 4 (R) 5 ); Y is -O- or -NH-; L stands for connector; R 3 It is -C1-C4 alkyl, -(CH2)0-1-(C3-C6 cycloalkyl) or -C4-C6 cycloalkyl; R7 It is hydrogen, halogroup or C1-C3 alkyl; R 8 It is hydrogen, halogroup, -OH, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkylene, -O-C1-C3 alkyl, C1-C3 haloalkyl, -(CH2)0-1-C3-C6 cycloalkyl, C1-C3 cyanoalkyl, or -(CH2)0-1-aryl (benzyl), or R 7 and R 8 Together form = CH 2、 Or C3-C6 cycloalkyl, or R 8 It forms 5- to 7-membered saturated heterocyclic groups with the ring atoms in Q, the carbon atoms bonded to them, and X; Q is a bicyclic aryl, bicyclic heterocyclic, or bicyclic heterocyclic group, wherein: The first loop in Q is bonded to X, and the second loop in Q is bonded to Z; and Q is optionally substituted by one or more independently selected substituents selected from =O; -CN; halogen; -C1-C5 alkyl, optionally substituted by one or more independently selected halogroups, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -O-(C2-C3 ynyl), -(C3-C6 cycloalkyl) or 4- to 7-membered saturated heterocyclic groups; -O-(C1-C3 alkyl), optionally substituted by one or more independently selected halogroups; C2-C5 alkenyl Optionally substituted with one or more independently selected -CN or -OH groups; C2-C3 alkynyl; -S(O)2-C1-C3 alkyl; -(CH2)0-1-C3-C6 cycloalkyl, optionally substituted with one or more independently selected halogroups, =O, -CN, C1-C3 alkyl groups optionally substituted with -CN or -O-C1-C3 alkyl groups, -C(O)-saturated heterocyclic groups, -O-saturated heterocyclic groups, O-cycloalkyl groups, or -O-aryl groups; -(CH2)0-1-heteroaryl .... Multiple independently selected halogroups, -CN, C1-C3 alkyl groups optionally substituted with -CN or -O-C1-C3 alkyl groups, -C(O)-saturated heterocyclic groups, -O-saturated heterocyclic groups, O-cycloalkyl groups, or -O-aryl groups; -(CH2)0-1-heterocyclic groups, which are optionally substituted with one or more independently selected halogroups, =O, -CN, C1-C3 alkyl groups optionally substituted with -CN or -O-C1-C3 alkyl groups, -C(O)-saturated heterocyclic groups, -O-saturated heterocyclic groups, O-cycloalkyl groups, or -O-aryl groups. Substitution; -(CH2)O-1-aryl, optionally substituted with one or more independently selected halogroups, -CN, -C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclic, -O-saturated heterocyclic, O-cycloalkyl or -O-aryl; -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 imenyl=NO-(C1-C3 alkyl) optionally substituted with C3-C6 cycloalkyl; or Two substituents on the same or adjacent ring atoms of Q together form a 5- to 7-membered monocyclic or a 6- to 12-membered bicyclic, wherein the monocyclic or bicyclic is optionally substituted by one or more independently selected halogen groups, =O, -CN, C1-C3 alkyl or -O-C1-C3 alkyl; and fused to Q.

[0097] In some embodiments, the compound has the structure of formula Ia-3: Formula Ia-3, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0098] In some embodiments, the compound has the structure of formula (Ic): (Ic), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0099] In some embodiments, Q is a 5,6-bicyclic heterocyclic aryl, a 5,6-bicyclic heterocyclic aryl, a 6,6-bicyclic heterocyclic aryl, or a 6,6-bicyclic heterocyclic aryl; and wherein Q is optionally substituted. In some embodiments, Q is a 5,6-bicyclic heterocyclic aryl, wherein Q is optionally substituted. In some embodiments, Q is a 5,6-bicyclic heterocyclic aryl, wherein Q is optionally substituted. In some embodiments, Q is a 6,6-bicyclic heterocyclic aryl, wherein Q is optionally substituted.

[0100] In some implementations, Q is selected from the following groups: , , , , , , , , , , , , , , , and , in: Each of V1, V2, V3, and V4 is independently C, CH, CF, or N; R Q1 It is -S(O)2-R Q11 -C(O)-R Q11 -S(O)2-N(R) Q11 )R Q12 -C(O)-N(R) Q11 )R Q12 C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4- to 14-membered heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted; or R Q1 Together with the nitrogen atom to which it is attached and the adjacent ring atom, it forms an optionally substituted 4- to 8-membered ring, which may optionally be further fused to a 5- to 6-membered ring; R Q11 and R Q12 Each is independently C1-C 10 Alkyl, C3-C10 Cycloalkyl, 4- to 14-membered heterocyclic, aryl or heteroaryl, wherein R Q11 and R Q12 Each can be replaced at its own discretion; or R Q11 and R Q12 Together with the nitrogen atoms they are connected to, they form optionally substituted 4- to 8-membered rings, where R Q11 and R Q12 The rings formed together can be selectively fused to another 5- or 6-membered ring.

[0101] In some embodiments, Q is optionally substituted with 1 to 4 substituents, said substituents being independently selected from =O; halogroup; -OH; -CN; -C1-C5 alkyl, which is optionally substituted with one or more independently selected halogroups, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -OC(O)-N(C1-C3 alkyl)2, -O-(C2-C3 alkynyl), -(C3-C6 cycloalkyl), 5- to 6-membered heteroaryl groups optionally substituted with one or more C1-C3 alkyl groups, or 4- to 7-membered saturated heterocyclic groups; -O-(C1-C3 alkyl), which is optionally substituted with one or more C1-C3 alkyl groups. Optionally substituted with one or more independently selected halogen groups; -C2-C5 alkenyl, optionally substituted with one or more independently selected -CN or -OH; C2-C3 ynyl, optionally substituted with a heteroaryl group; -S(O)2-C1-C3 alkyl; -(CH2)0-1-C3-C6 cycloalkyl, optionally substituted with one or more independently selected halogen groups, =O, -CN, C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclic group, -O-saturated heterocyclic group, O-cycloalkyl or -O-aryl group; -(CH2)0-1-heteroaryl, optionally substituted with one or more independently selected halogen groups, =O, -CN, C1-C3 alkyl ...2-C5 alkenyl, optionally substituted with one or more independently selected halogen groups, =O, -CN, C1-C3 alkyl substituted with -CN or -O-C1-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 alkyl, -C2-C3 The substituted group is substituted by one or more independently selected halogen groups, =O, -CN, C1-C3 alkyl groups optionally substituted by -CN or -O-C1-C3 alkyl groups, -C(O)-saturated heterocyclic groups, -O-saturated heterocyclic groups, O-cycloalkyl groups, or -O-aryl groups; the .... The substituted halogen group, -CN, -C1-C3 alkyl group optionally substituted with -CN, -C(O)-O-C1-C3 alkyl group, -C1-C3 alkylene group -O-C1-C3 alkyl group, -O-C1-C3 alkyl group, NO2, -C(O)-saturated heterocyclic group, -CH2-saturated heterocyclic group, -O-saturated heterocyclic group, O-cycloalkyl or -O-aryl substituted group; -CH2-O-heteroaryl, -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkylene group =NO-(C1-C3 alkyl), which is optionally substituted with C3-C6 cycloalkyl; or The two substituents at Q together form a 5- to 7-membered monocyclic or a 6- to 12-membered bicyclic ring, wherein the monocyclic or bicyclic ring is optionally substituted by one or more independently selected halogen groups, =O, -CN, C1-C3 alkyl, or -O-C1-C3 alkyl groups; and fused to Q; and "**" represents the part of Q that is bonded to ring Z.

[0102] In some implementations, Q is In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... .

[0103] In some embodiments, Q is optionally substituted with 1 to 4 substituents, said substituents being independently selected from chloro, fluorinated, -CN, -CH3, -CF3, -CHF2, -CH2CH3, -CH2-CN, -(CH2)2-CN, -OCH3, -CH2-O-CH3, -(CH2)2-O-CH3, -CH2-O-CH2-CN, -CH(CN)-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -C(O)-CH3, -S(O)2CH3, -C(CH3)=NO-CH(CH3)2, -C(CH3)=NO-CH3, -C≡C-CH3, -C≡CH, -CH =CH-CN, -CH2-O-CH2-C≡CH, -C(CH3)(CN)CH2CN, -CH2-OC(O)-N(CH3)2, 1-(cyclopentyl)-1-cyanoethyl-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethyl-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoethyl-1-yl, 1,3-dimethoxy-2-cyanopropyl-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpiperidin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, (1-methylpyrazol-4-yl)cyano Methyl, 1-oxoindoline-5-yl, 1-oxoisoindoline-4-yl, 1-oxoisoindoline-6-yl, 2-(2-methoxyeth-1-yl)phenyl, 3-(1,1-dioxothiomorpholin-1-ylmethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxacyclopenten-4-yl, 2-chlorophenyl, 2-cyano-2-tetrahydrofuran-3-ylpropane, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-4-methoxybut-2-yl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2- Cyano-5-methoxyphenyl, 2-cyano-5-(methoxymethyl)phenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-bromophenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-(tetrahydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropyl-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-(methoxymethyl)phenyl, 2-nitrophenyl, 2-oxopyrrolidone-1-yl, 2-phenoxyphenyl, 3-(2-methoxyethyl-1-yl)phenyl, 3-methoxycarbonylphenyl, 3,5-Difluoro-4-(pyrrolidine-1-ylcarbonyl)phenyl, 3-cyano-2-methylprop-2-yl, 3-cyanomethylphenyl, 3-cyanopent-3-yl, 3-cyanophenyl, 3-hydroxy-2-methyl-2-yl, 3-hydroxy-3-methyl-1-yn-1-yl, 3-methoxy-2-methylbut-2-yl, 3-methoxyphenyl, 3-methoxymethyl-5-methylisoxazole -4-yl, 3-oxo-2-methylbut-2-yl, 3-(tetrahydropyran-4-yl)-2-cyanopropyl-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxacyclopenten-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol- 5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, morpholino-4-ylmethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyrazol-1-ylmethyl, pyridin-2-yl, pyridin-2-ylmethyl, pyridin-2-yloxymethyl, pyridin-3-yl, pyridin-3-yl-ethynyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyridin-4-yl-ethynyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyridin-4-yl, tetrahydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)eth-1-yl, tetrahydropyran-4-ylcyanomethyl or tetrahydropyran-4-yl, or, Two substituents attached to the same carbon atom together form =O, 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuran[2,3-b]pyridine-3,3-diyl, tetrahydropyridine-3,3-diyl, 6,7-dihydro-5H-cyclopentan[c]pyridine-6,6-diyl or tetrahydropyridine-4,4-diyl, or Two substituents attached to adjacent carbon atoms together form 4-cyanophenyl-1,2-diyl, 3-cyanophenyl-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexyl-1,2-diyl, 3-methoxyphenyl-1,2-diyl, phenyl-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentan-1,2-diyl, or pyridine-3,4-diyl.

[0104] In some implementations, Q is selected from the following groups: , , , , , , , , , , , , and , in: Each of V1, V2, V3, and V4 is independently CH, N, C(F), C(CH3), C(OH), C(OCH3), or C(CN); Each of V5, V6, and V7 is independently C(R) 17a (R) 17b ) or C(=O), where R 17a and R 17b Each is independently selected from hydrogen, halogroup, -C1-C3 alkyl, -C1-C3 haloalkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, and at most two of V5, V6 and V7 are C (=O); R NQ1 It is hydrogen, optionally substituted -S(O)2-R Q11 -C(O)-R Q11 -S(O)2-N(R) Q11 )R Q12 -C(O)-N(R) Q11 )R Q12 C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4- to 14-membered heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be substituted; Each R Q2 Independently hydrogen, CN, or optionally substituted -S(O)2-R Q11 -C(O)-R Q11 -S(O)2-N(R) Q11 )R Q12 -C(O)-N(R) Q11 )R Q12 C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4- to 14-membered heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted; or R NQ1 And an R Q2 Together with the atoms they are bonded to, they form optionally substituted 4- to 8-membered rings, where R NQ1 And an R Q2 The rings formed together can be selectively further fused into 5- to 6-membered rings; Each R Q3Independently hydrogen, CN, or optionally substituted -S(O)2-R Q11 -C(O)-R Q11 -S(O)2-N(R) Q11 )R Q12 -C(O)-N(R) Q11 )R Q12 C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-14 membered heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted, or Two R atoms bonded to the same atom Q3 Together they form =CH, =O, =S, or =NR V4 ;or Two R atoms bonded to the same atom Q3 Together with the atoms they are bonded to, they form optionally substituted 4- to 8-membered rings, wherein each R Q3 The rings formed together may be further fused into 5- to 6-membered rings; or R NQ1 And an R Q3 Together with the atoms they are bonded to, they form optionally substituted 4- to 8-membered rings, wherein R NQ1 and R Q3 The rings formed together can be selectively further fused into 5- to 6-membered rings; R Q11 and R Q12 Each is independently C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4- to 14-membered heterocyclic, aryl or heteroaryl, wherein R Q11 and R Q12 Each can be replaced at its own discretion; or R Q11 and R Q12 Together with the atoms they are attached to, they form optionally substituted 4- to 8-membered rings, wherein R Q11 and R Q12 The rings formed together may optionally fuse to another 5- or 6-membered ring; and "**" represents the part of Q that is bonded to ring Z.

[0105] In some implementations, Q is , , , , , or In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... .

[0106] In some implementations, Q is selected from the following groups: , , , , and In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... .

[0107] In some embodiments, the compound has the structure of formula (Id): (Id), or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

[0108] In some embodiments, the compound has the structure of formula (Ie): (Ie), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0109] In some embodiments, the compound has the structure of formula (Ig): (Ig), or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein Qa is a 4- to 9-membered saturated heterocyclic group.

[0110] In some embodiments, the compound has the structure of formula (Ij): (Ij), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0111] In some embodiments, the compound has the structure of formula (Ik): (Ik), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0112] In some embodiments, the compound has the structure of formula (Ik'): (Ik'), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0113] In some implementations, Q is selected from the following groups: , , , , , , , , , , , , , , , , and , in: "1" indicates a portion of Q bonded to X; and Q is further optionally replaced. In some implementations, Q is In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... .

[0114] In some implementations, Q is selected from the following groups: , , , , , , and , in: R is -CH2CH3, -CH2CH-OCH3, -CH2CHF2, -CH2-CN, CH2(CH3)2-CN, -C(CH3)2-CH2CN, -CH2CH2-CN, cyclohexyl, cyclobutyl, cyclopropyl, pyridin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, oxacyclobut-3-ylmethyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methoxymethylphenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-bromophenyl, 2-methoxyethyl-1-yl, 2-cyanopropyl-2-yl, 2-tetrahydropyran-4-ylethyl-1-yl, 3-cyanopent-3-yl, 2-cyano-4-methoxybutyl-2-yl, or R is , , , , , , , , , , or ; R 23 It is hydrogen or halogen, such as fluorinated groups; R 24It contains hydrogen, chloro groups, -CN, -CH3, -CH2CH3, -CHF2, -CF3, -CH2-CN, -CH(CN)-CH3, -C(CH3)2-CN, -C(CH2CH3)2-CN, -CH2-CH2-CN, -C(CH3)=NO-CH(CH3)2, -C(CH3)=NO-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -OCH3, -CH2-O-CH3, -C≡CH, -C≡C-CH3, -S(O)2CH3, and 1-(cyclopentyl)-1 -Cyanoethyl-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoethyl-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethyl-1-yl, 1,3-dimethoxy-2-cyanopropyl-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-ylcyanomethyl, 1-methylpiperidin-4-yl, 1-methylpyrazol-5-yl, 1-oxoindoline-5-yl, 1-oxoisoindoline-4-yl, 1 -Oxoisoindoline-6-yl, 2-(2-methoxyeth-1-yl)phenyl, 2-(methoxymethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxacyclopenten-4-yl, 2,3-dicyanopropyl-2-yl, 2-chlorophenyl, 2-cyano-3-(tetrahydropyran-4-yl)propyl-2-yl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-Cyano-5-methoxyphenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-(tetrahydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropyl-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-nitrophenyl, 2-oxopyrrolidone-1-yl, 2-phenoxyphenyl, 3-(1,1-dioxothiomorpholino-4-ylmethyl)phenyl, 3-(2-methoxyethyl-1-yl)phenyl, 3,5-Difluoro-4-(pyrrolidine-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropyl-2-yl, 3-cyanomethylphenyl, 3-cyanopent-3-yl, 3-cyanophenyl, 3-hydroxy-2-methylbut-2-yl, 3-hydroxy-3-methyl-but-1-yn-1-yl, 3-methoxy-2-methylbut-2-yl, 3-methoxymethyl-5-methylisoxazol-4-yl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 3-oxo-2-methylbut-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d] [1,3]dioxacyclopenten-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazolyl-2-yl, benzo[d]thiazolyl-4-yl, benzo[d]thiazolyl-5-yl, benzo[d]thiazolyl-6-yl, benzo[d]thiazolyl-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, N-methoxycyclopropanemethylammonium, phenyl, pyridin-2-ylmethyl, pyridin-3-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyran-4-yl or tetrahydropyran-4-ylcyanomethyl; R 27 It is hydrogen, -CH3, -CHF2, -CH2CH3, -CH2-O-CH3, -CH2CN, -CN, -CH2-O-CH2-CN, -C(O)-N(CH3)2, -C(O)-NH-CH3, -CH2-O-CH2-C≡CH, 2-methoxyphenyl, 3-methoxyphenyl, 2,2-difluorobenzo[d][1,3]dioxanepenten-4-yl, 2-cyanophenyl, 3-cyanophenyl, phenyl, 2-benzylmethyl ether, 2-(2-methoxyethyl)benzene, 2-(2-difluoromethoxyethyl)benzene, 2-(2-dimethylmethoxyethyl)benzene, pyridin-3-yl, pyridin-2-yl, pyridin-3-ylmethyl or tetrahydropyridin-4-yl, or R 24 and R 27 Together they form 4-cyanophenyl-1,2-diyl, 3-cyanophenyl-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexyl-1,2-diyl, 3-methoxyphenyl-1,2-diyl, phenyl-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentan-1,2-diyl or pyridine-3,4-diyl; R 28 It is hydrogen, -CH3, or -CH2-O-CH3; and R 29It is hydrogen, acetyl, CN, -CH2-CN, -CH2-CH2-CN, -CH2-O-CH3, -CH=CH-CN, -CH2-OC(O)-N(CH3)2, morpholino-4-ylmethyl, pyrazol-1-ylmethyl, pyridin-3-yl, pyridin-3-ylethynyl, pyridin-2-yloxymethyl, or 2-cyanopropyl-2-yl, or R 28 and R 29 Together they form 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuran[2,3-b]pyridin-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopentan[c]pyridin-6-yl, tetrahydropyran-4,4-diyl, or 4-methoxycyclohexane. In some embodiments, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... In some implementations, Q is... .

[0115] In some implementation schemes, R 3 It is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxybenzyl or tetrahydropyran-4-yl.

[0116] In one aspect, the invention is characterized by a compound having the structure of formula IIa or IIb: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L stands for connector; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CR x CH, CH2 or N; Y 6 It is CR z C(O), CH, CH2 or N; R x It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 13 and R 2 The atoms to which it is attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It does not exist; it is hydrogen; it is optionally substituted C1-C6 alkyl; it is optionally substituted C2-C6 alkenyl; it is optionally substituted C2-C6 alkynyl; it is optionally substituted 3- to 6-membered cycloalkyl; it is optionally substituted 3- to 7-membered heterocycloalkyl; it is optionally substituted 6-membered aryl; it is optionally substituted 5- or 6-membered heteroaryl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen; a C1-C4 alkyl group optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl; cyclopropyl; or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R8a It is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R 10a It is hydrogen or halogen; R 11 It is hydrogen or an optional substituted C1-C3 alkyl group; R 21 It is hydrogen or an optional substituted C1-C3 alkyl group; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0117] In one aspect, this disclosure is characterized by compounds of structural formula IIa-1: , Formula IIa-1 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L stands for connector; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CR x CH, CH2 or N; Y 6 It is CR z C(O), CH, CH2 or N; R x It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z It is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 13 and R 2 The atoms to which it is attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It does not exist; it is hydrogen; it is optionally substituted C1-C6 alkyl; it is optionally substituted C2-C6 alkenyl; it is optionally substituted C2-C6 alkynyl; it is optionally substituted 3- to 6-membered cycloalkyl; it is optionally substituted 3- to 7-membered heterocycloalkyl; it is optionally substituted 6-membered aryl; it is optionally substituted 5- or 6-membered heteroaryl. R 14 Does not exist, or R2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen; a C1-C4 alkyl group optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl; cyclopropyl; or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R 10a It is hydrogen or halogen; R 11 It is hydrogen or optionally substituted C1-C3 alkyl; and R 21 It is hydrogen or an optional substituted C1-C3 alkyl group.

[0118] In some embodiments, this disclosure is characterized by compounds of structural formula IIa-2: Formula IIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R)7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L stands for connector; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CH, CH2, CF, CHF, CF2, or N; Y 6 It is C(O), CH, CH2, CF, CHF, CF2, or N; R 13 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 13 and R 2 The atoms to which it is attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It does not exist; it is hydrogen; halogen; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; optionally substituted 3- to 6-membered cycloalkyl; optionally substituted 3- to 7-membered heterocycloalkyl; optionally substituted 6-membered aryl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted C1-C3 acyl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen; a C1-C4 alkyl group optionally substituted with halogen, cyano, hydroxyl or C1-C4 heteroalkyl; cyclopropyl; or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 heteroalkyl or optionally substituted C1-C3 alkyl; R 10a It is hydrogen or halogen; R 11 It is hydrogen or optionally substituted C1-C3 alkyl; and R 21 It is hydrogen or an optional substituted C1-C3 alkyl group.

[0119] In some embodiments, compounds having the structure of formula IIa-3 are provided herein: Formula IIa-3 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R).6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, acetyl ketone, haloacetal or acetyl sulfone; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CH, CH2, CF, CHF, CF2, or N; Y 6 It is C(O), CH, CH2, CF, CHF, CF2, or N; R 13 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 13 and R 2 The atoms to which it is attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2It does not exist; it is hydrogen; halogen; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; optionally substituted 3- to 6-membered cycloalkyl; optionally substituted 3- to 7-membered heterocycloalkyl; optionally substituted 6-membered aryl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted C1-C3 acyl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogroup, hydroxyl group, C1-C3 alkoxy group or C1-C3 alkyl group; R 10a It is hydrogen or a halide group; and R 11 It is hydrogen or C1-C3 alkyl.

[0120] In some embodiments, this disclosure is characterized by compounds of structural formula IIa-4: Formula IIa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R) 9 )-, where carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R).6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, acetyl ketone, haloacetal or acetyl sulfone; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 and Y 6 It can be CH, CF, or N independently; R 13 It is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl or optionally substituted C1-C3 acyl. R 14 Does not exist, or R 2 and R 14The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; R 10It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0121] In some embodiments of the compounds of the present invention, G is an optionally substituted C1-C4 heteroalkylene group.

[0122] In some embodiments, compounds having the structure of formula IIa-5 are provided: Formula IIa-5 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R) 9 )-, where carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; X 2 It is O or NH; X 3 It is N or CH; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 and Y 6 It can be CH, CF, or N independently; R 13 It is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl or optionally substituted C1-C3 acyl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0123] In some embodiments of the compounds of the present invention, X 2 It is NH. In some implementations, X 3 It is CH. In some implementations, R 11 It is hydrogen. In some implementations, R 11 It is a C1-C3 alkyl group. In some embodiments, R 11 It is a methyl group.

[0124] In some embodiments, the compounds of the present invention have the structure of formula IIa-6: Formula IIa-6 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 13 It is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0125] In some embodiments of the compounds of the present invention, X 1 It is an optionally substituted C1-C2 alkylene group. In some embodiments, X 1 It is methylene. In some embodiments, X 1 It is a methylene group substituted with a C1-C6 alkyl group or a halogen. In some embodiments, X 1 It is -CH(Br)-. In some implementations, X 1 It is -CH(CH3)-. In some implementations, R 5 It is hydrogen. In some implementations, R 5 It is a C1-C4 alkyl group optionally substituted with a halogen. In some embodiments, R 5 It is a methyl group. In some embodiments, Y... 4It is C. In some implementations, R 4 It is hydrogen. In some implementations, Y 5 It is CH. In some implementations, Y 5 It is CF. In some implementations, Y 6 It is CH. In some implementations, Y 6 It is CF. In some implementations, Y 1 It is C. In some implementations, Y 2 It is C. In some implementations, Y 3 It is N. In some implementations, R 3 It does not exist. In some implementations, Y 7 It is C. In some implementations, Y 4 It is C and R 15 It is F.

[0126] In some embodiments, the compounds of the present invention have the structure of formula IIa-7: Formula IIa-7 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 13 It is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 14 Does not exist, or R2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 5 It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0127] In some embodiments of the compounds of the present invention, R 6 It is hydrogen. In some implementations, R 2 It is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R2 is a fluoroalkyl group. In some embodiments, R... 2 It is an ethyl group. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is a C2-C6 ynyl group. In some embodiments, R2 is -CHC≡CH. In some embodiments, R2 is -CH2C≡CCH3. In some embodiments, R... 7 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 7 It is a C1-C3 alkyl group. In some embodiments, R 8 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 8 It is a C1-C3 alkyl group.

[0128] In some embodiments, the compounds of the present invention have the structure of formula IIa-8: Formula IIa-8 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 13 It is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. R 2It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl.

[0129] In some embodiments of the compounds of the present invention, R 13 It is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 6-membered cycloalkenyl, or an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 13 It is an optionally substituted 6-membered aryl, optionally substituted 6-membered cycloalkenyl, or optionally substituted 6-membered heteroaryl.

[0130] In some embodiments of the compounds of the present invention, R 13 yes , , , , , , , or or its stereoisomers (e.g., the reversible isomer). In some embodiments of the compounds of the present invention, R 13 yes or its stereoisomers (e.g., the reversible isomer). In some embodiments of the compounds of the present invention, R 13 yes In some implementations, R 13 yes or its stereoisomers. In some embodiments, R 13 yes .

[0131] In some embodiments, the compounds of the present invention have the structure of formula IIa-9: Formula IIa-9 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to -CH(R) 10 ()- carbon atom, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R)9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 2 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl. X e and X f Independently N, CH or CR 17 ;and R 12 It is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 6-membered heterocyclic alkylene.

[0132] R 17 It is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0133] In some embodiments of the compounds of the present invention, X e It is N and X f It is CH. In some implementations, X e It is CH and X f It is N.

[0134] In some embodiments of the compounds of the present invention, R 12 It is an optionally substituted C1-C6 heteroalkyl group. In some embodiments, R 12 yes , , , , , , or In some embodiments of the compounds of the present invention, R 12It is an optionally substituted C1-C6 heteroalkyl group. In some embodiments, R 12 yes .

[0135] In some embodiments, the compounds of the present invention have the structure of formula IIa-10: Formula IIa-10 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3- to 11-membered heterocyclic alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl. R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; X e Is it CH or CR? 17 ;and R 17 It is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0136] In some embodiments, the compounds of the present invention have the structure of formula IIa-11: Formula IIa-11 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3- to 11-membered heterocyclic alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl. R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl.

[0137] In some embodiments, the compounds of the present invention have the structure of formula II-VI: Formula II-VI Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bonded to -CH(R) 10 The carbon atom of )-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) or optionally substituted 5 to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’In which carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R 6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, acetyl ketone, haloacetal or acetyl sulfone; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CH, CH2, CF, CHF, CF2, or N; Y 6 It is C(O), CH, CH2, CF, CHF, CF2, or N; R 2It does not exist; it is hydrogen; halogen; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; optionally substituted 3- to 6-membered cycloalkyl; optionally substituted 3- to 7-membered heterocycloalkyl; optionally substituted 6-membered aryl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted C1-C3 acyl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5 It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogroup, hydroxyl group, C1-C3 alkoxy group or C1-C3 alkyl group; R 10a It is a hydrogen or halogroup; R 11 It is hydrogen or C1-C3 alkyl; R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl); and X e and X f It can be either N or CH on its own.

[0138] In some embodiments, the compounds of the present invention have the structure of formula II-VIa: Formula II-VIa Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g. phenyl or phenol) or optionally substituted 5 to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; R 2 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; X e and X f It can be either N or CH independently; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or C1-C3 alkyl.

[0139] In some embodiments of the compounds of the present invention, X e It is N and X f It is CH. In some implementations, X e It is CH and X f It is N.

[0140] In some embodiments, the compounds of the present invention have the structure of formula II-VIb: Formula II-VIb Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g. phenyl or phenol) or optionally substituted 5 to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; L is absent or a connector; and W is a crosslinking group, including vinyl ketones, vinyl sulfones, alkynyl ketones, or alkynyl sulfones. In some embodiments of the compounds of the present invention, A is an optionally substituted 6-membered arylene.

[0141] In some embodiments, the compounds of the present invention have the structure of formula II-VIc: Formula II-VIc Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein the dashed line indicates zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bonded to -CH(R) 10 The carbon atom of )-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) or optionally substituted 5 to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ In which carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group, an optionally substituted C1-C4 alkenyl group, an optionally substituted C1-C4 heteroalkylene group, or -C(O)O-CH(R). 6 )-, where C is bonded to -C(R) 7 R 8 )-、-C(O)NH-CH(R6 )-, where C is bonded to -C(R) 7 R 8 - Optionally substituted C1-C4 heteroalkylene or 3 to 8-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, including vinyl ketone, vinyl sulfone, acetyl ketone, haloacetal or acetyl sulfone; X 1 It is an optionally substituted C1-C2 alkylene group, NR, O, or S(O). q ; X 2 It is O or NH; X 3 It is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2. Each R ’ It is independently H or an optionally substituted C1-C4 alkyl group; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 It can be either C or N independently; Y 5 It is CH, CH2, CF, CHF, CF2, or N; Y 6 It is C(O), CH, CH2, CF, CHF, CF2, or N; R 2 It does not exist; it is hydrogen; halogen; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; optionally substituted 3- to 6-membered cycloalkyl; optionally substituted 3- to 7-membered heterocycloalkyl; optionally substituted 6-membered aryl; optionally substituted 5- or 6-membered heteroaryl; or optionally substituted C1-C3 acyl. R 14 Does not exist, or R 2 and R 14 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 15 It does not exist; it is hydrogen, halogen, cyano, or a methyl group optionally substituted with 1 to 3 halogens. R 5It is hydrogen, C1-C4 alkyl (optionally substituted with halogen, cyano, hydroxyl or C1-C4 alkoxy), cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atoms it is attached to to form C=CR 7’ R 8’ C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is a C1-C3 alkyl group, which is hydrogen, halogenated, or optionally substituted; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; or R 9 L and the atoms to which they are attached combine to form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R9’ It is hydrogen or an optionally substituted C1-C6 alkyl group; or R 9 and R 9’ It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogroup, hydroxyl group, C1-C3 alkoxy group or C1-C3 alkyl group; R 10a It is a hydrogen or halogroup; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0142] In some implementations, Z is -C(O)-.

[0143] In some embodiments, A is an optionally substituted C2-C4 alkylene group. In some embodiments, A is an optionally substituted C3 alkylene group. In some embodiments, A is: .

[0144] In some embodiments, A is an optionally substituted C2-C4 alkenyl group. In some embodiments, A is an optionally substituted C3 alkenyl group. In some embodiments, A is an optionally substituted C1-C4 heteroalkyl group. In some embodiments, A is an optionally substituted C2 heteroalkyl group. In some embodiments, A is: or .

[0145] In some implementations, A has the following structure: Where R 13 It is hydrogen, halogroup, hydroxyl group, amino group, optionally substituted C1-C6 alkyl group, or optionally substituted C1-C6 heteroalkyl group; and R 13a It is hydrogen or halogen. In some implementations, R 13 It is hydrogen. In some implementations, R 13 and R 13a Each is hydrogen. In some implementations, R 13 It is hydroxyl, methyl, fluorinated or difluoromethyl.

[0146] In some embodiments, A is an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, A is: .

[0147] In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl group. In some embodiments, A is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0148] In some embodiments, A is an optionally substituted C1-C4 heteroalkylene group. In some embodiments, A is: In some embodiments, A is an optionally substituted 3- to 6-membered heterocyclic alkyl group. In some embodiments, A is: , , , , , , , , , , , or In some implementations, A is... .

[0149] In some implementation schemes, R 9 It is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl. In some embodiments, R 9 yes: , , , , , , , , , , , , , , , , , , or In some implementations, R 9 yes: In some implementations, R 9 It is H, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl.

[0150] In some embodiments of the compounds of the present invention, B is an optionally substituted 6-membered arylene. In some embodiments, B is a 6-membered arylene. In some embodiments, B is: .

[0151] In some implementation schemes, R 13 yes In some implementations, R 13 yes .

[0152] In some implementation schemes, R 13 yes , Z 1 It is N or CH; m is 1 or 2; R 18 R 19 R 20 and R 25 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 18 and R 20 The atoms attached to them combine to form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups; or R 20 and R 25 The atoms attached to them combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 19 and R20 The atoms attached to them combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0153] In some implementation schemes, R 13 yes In some implementations, R 13 yes .

[0154] In some implementation schemes, R 18 It is a methyl group.

[0155] In some implementation schemes, R 13 yes or .

[0156] In some embodiments of the compounds of the present invention, R 7 It is a methyl group.

[0157] In some embodiments of the compounds of the present invention, R 8 It is a methyl group.

[0158] In some implementation schemes, R 21 It is hydrogen.

[0159] In some embodiments of the compounds of the present invention, B is -CHR. 9 - In some implementations, R 9 It is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, B is an optionally substituted 6-membered arylene. In some embodiments, B is absent.

[0160] In some implementations, L has the structure of formula L0: Formula L0 Where X 12 It is O, S, SO2, NH, CH2, C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkyneyl, and is attached to ring A; and E is a bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C6 alkenylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heteroalkylene, optionally substituted 5- to 12-membered arylene, or optionally substituted 5- to 12-membered heteroarylene.

[0161] In some embodiments of the compounds of the present invention, the connector has the structure of formula II-II: A 1 -(B1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Formula II-II Where A 1 It is the key between connector B; A 2 It is the key between A and the connector; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR. N ;R N It is hydrogen, and the C is optionally substituted. 1–4 Alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1- to C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D 1 It is an optional substitution of C1-C 10 Alkylene, optionally substituted C2-C 10 alkenyl, optionally substituted C2-C 10 Alynyl, optionally substituted 3- to 14-membered heterocyclic alkylene, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C 10 Polyethylene glycol or optionally substituted C1-C 10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A2 The chemical bonds. In some embodiments, the linker is acyclic. In some embodiments, the linker has a structure of formula II-IIa: Formula II-IIa Where X a It either does not exist or is N; R 14 It is absent, or is hydrogen or optionally substituted C1-C6 alkyl; and L 2 The presence of X is absent, is -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene. a R 14 or L 2 At least one of them. In some embodiments, the connector has the following structure: , , , , , , , , , , , , , , , , or In some implementations, the connector has the following structure: , , , , or In some implementations, L is... In some implementations, L is... .

[0162] In some embodiments, the joint is or includes an annular portion. In some embodiments, the joint has a structure of formula II-IIb: Formula II-IIb Where o is 0 or 1; R 15 It is hydrogen or an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 8-membered cycloalkylene, or an optionally substituted 3- to 8-membered heterocycloalkylene; X 4It does not exist, or is an optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroalkylene; and L 3 It does not exist, is -SO2-, is an optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0163] In some embodiments, the connector has a structure of formula II-IIb-1: Formula II-IIb-1 Where o is 0 or 1; R 15 It is hydrogen or an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 8-membered cycloalkylene, or an optionally substituted 3- to 8-membered heterocycloalkylene; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroalkylene; and L 3 It does not exist, is -SO2-, is an optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0164] In some implementations, the connector has the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0165] In some implementations, the connector has a structure of type II-IIc: Formula II-IIc Where R 15 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cyclohexene alkyl, or optionally substituted 3- to 8-membered heterocyclohexene alkyl; and R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Independently, it is hydrogen, halogroup, hydroxyl group, cyano group, amino group, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 alkoxy group, or R 15b and R 15d It combines with the carbon atoms to form optionally substituted 3 to 8-membered cycloalkylene groups or optionally substituted 3 to 8-membered heteroalkylene groups.

[0166] In some implementations, the connector has the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0167] In some implementations, the connector has the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , or .

[0168] In some implementations, the joint has a structure .

[0169] In some implementations, the joint has a structure .

[0170] In some implementations, the connector of Formula II is selected from the group consisting of: , and .

[0171] In one aspect, the invention is characterized by a compound having the structure of formula IIIa or IIIb: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y 8 yes , , , , , , or ; L stands for connector; R 13 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 10 It is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 7-membered heterocyclic alkyl; R 7 and R 8 Each is independently selected from F or CH3, or R 7 and R 8 It combines with the atoms it is attached to to form a 3-membered cycloalkyl group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C3 alkoxy, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 6-membered heterocycloalkyl. t is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0172] In one aspect, the invention is characterized by a compound having the structure of formula IIIa-1: , Formula IIIa-1 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y 8yes , , , , , , or ; L stands for connector; X 4 and X 5 Each can be independently CH2, CH(CH3) or NH; R 13 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 10 It is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 7-membered heterocyclic alkyl; R 7 and R 8 Each is independently selected from F or CH3, or R 7 and R 8 It combines with the atoms it is attached to to form a 3-membered cycloalkyl group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0173] In some embodiments, this disclosure is characterized by compounds of structural formula IIIa-2: Formula IIIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene; Y 8 yes , , , , , , or ; L stands for connector; X 4 and X 5 Each can be independently CH2, CH(CH3) or NH; R 13 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl. R 10 It is hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocyclic alkyl; and R 7 and R 8 Each is independently selected from F or CH3, or R 7 and R 8 It combines with the atoms it is attached to to form a 3-membered cycloalkyl group.

[0174] In some embodiments, the compound has the structure of formula IIIa-3: Formula IIIa-3 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene. Y 8 yes , , , , or ; R 13It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 6-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 10 It is hydrogen or optionally substituted C1-C6 heteroalkyl. In some embodiments, R 10 It is hydrogen.

[0175] In some implementation schemes, R 13 It is an optionally substituted 6- to 10-membered aryl group or an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, R 13 It is either a substituted phenyl or a substituted pyridine.

[0176] In some embodiments, A is an optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, A is an optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, or phenyl. In some embodiments, A is not an optionally substituted phenyl or benzimidazole. In some embodiments, A is not a hydroxyphenyl.

[0177] In some implementation schemes, Y 8 It is -NHC(O)- or -NHC(O)NH-.

[0178] In some embodiments, the compound has the structure of formula IIIa-4: Formula IIIa-4, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0179] In some embodiments, the compound has the structure of formula IIIa-5: Formula IIIa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0180] In some embodiments, the compound has the structure of formula IIIa-6: , Formula IIIa-6 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0181] In some embodiments, the compound has the structure of formula IIIa-7: Formula IIIa-7, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0182] In some embodiments, the compound has the structure of formula IIIa-8: , Formula IIIa-8 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0183] In some embodiments, the compound has the structure of formula IIIa-9: Formula IIIa-9, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is H. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0184] In some embodiments, the compound has the structure of formula IIIa-10: , Formula IIIa-10 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0185] In some embodiments, the compound has the structure of formula IIIa-11: , Formula IIIa-11 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0186] In some implementations (e.g., implementations of either Formula IIIa-10 or Formula IIIa-11), R 6 It is a methyl group.

[0187] In some embodiments, the compound has the structure of formula IIIa-12 or IIIa-13: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0188] In some embodiments, the compound has the structure of formula IIIa-a: Formula IIIa-a, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0189] In some embodiments, the compound has the structure of formula IIIa-a1: Formula IIIa-a1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0190] In some embodiments, the compound has the structure of formula IIIa-a2: , Formula IIIa-a2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0191] In some embodiments, the compound has the structure of formula IIIa-a3: Formula IIIa-a3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0192] In some embodiments, the compound has the structure of formula IIIa-a4: , Formula IIIa-a4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0193] In some embodiments, the compound has the structure of formula IIIa-a5: Formula IIIa-a5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0194] In some embodiments, the compound has the structure of formula IIIa-a6: , Formula IIIa-a6 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0195] In some embodiments, the compound has the structure of formula IIIa-a7: , Formula IIIa-a7 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0196] In some implementations (e.g., implementations of any one of formulas IIIa-a6 or IIIa-a7), R 6 It is a methyl group.

[0197] In some embodiments, the compound has the structure of formula IIIa-a8 or formula IIIa-a9: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0198] In some embodiments, the compound has the structure of formula III-IVa: Formula III-IVa, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0199] In some embodiments, the compound has the structure of formula III-IVa-1: Formula III-IVa-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0200] In some embodiments, the compound has the structure of formula III-IVa-2: Formula III-IVa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0201] In some embodiments, the compound has the structure of formula III-IVa-3: Formula III-IVa-3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0202] In some embodiments, the compound has the structure of formula III-IVa-4: Formula III-IVa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0203] In some embodiments, the compound has the structure of formula III-IVa-5: Formula III-IVa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0204] In some embodiments, the compound has the structure of formula III-IVa-6: Formula III-IVa-6 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0205] In some embodiments, the compound has the structure of formula III-IVa-7: Formula III-IVa-7 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0206] In some implementations (e.g., implementations of either Formula III-IVa-6 or Formula III-IVa-7), R 6 It is a methyl group.

[0207] In some embodiments, the compound has the structure of formula III-IVa-8 or III-IVa-9: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0208] In some implementation schemes, Y 8 It is -NHS(O)2- or -NHS(O)2NH-.

[0209] In some embodiments, the compound has the structure of formula III-Va: Formula III-Va, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0210] In some embodiments, the compound has the structure of formula III-Va-1: Formula III-Va-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0211] In some embodiments, the compound has the structure of formula III-Va-2: Formula III-Va-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0212] In some embodiments, the compound has the structure of formula III-Va-3: Formula III-Va-3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0213] In some embodiments, the compound has the structure of formula III-Va-4: Formula III-Va-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0214] In some embodiments, the compound has the structure of formula III-Va-5: Formula III-Va-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0215] In some embodiments, the compound has the structure of formula III-VIa: Formula III-VIa, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0216] In some embodiments, the compound has the structure of formula III-VIa-1: Formula III-VIa-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0217] In some embodiments, the compound has the structure of formula III-VIa-2: Formula III-VIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0218] In some embodiments, the compound has the structure of formula III-VIa-3: Formula III-Via-3 Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0219] In some embodiments, the compound has the structure of formula III-Via-4: Formula III-Via-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0220] In some embodiments, the compound has the structure of formula III-VIa-5: Formula III-VIa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0221] In some embodiments, the compound has the structure of formulas III-VIIa: Formulas III-VIIa, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 9 It is an H or C1-C6 alkyl group; and a is 0 or 1.

[0222] In some embodiments, the compound has the structure of formula III-VIIa-1: Formula III-VIIa-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0223] In some embodiments, the compound has the structure of formula III-VIIa-2: Formula III-VIIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0224] In some embodiments, the compound has the structure of formula III-VIIa-3: Formula III-VIIa-3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0225] In some embodiments, the compound has the structure of formula III-VIIa-4: Formula III-VIIa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0226] In some embodiments, the compound has the structure of formula III-VIIa-5: Formula III-VIIa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0227] In some implementation schemes (e.g., implementations of any one of formulas VIIa, VIIa-1, VIIa-2, VIIa-3, VIIa-4, or VIIa-5), R 9 It is a methyl group.

[0228] In some implementations, Y is -NHS(O)- or -NHS(O)NH-.

[0229] In some embodiments, the compound has the structure of formula III-VIIIa: Formula III-VIIIa, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0230] In some embodiments, the compound has the structure of formula III-VIIIa-1: Formula III-VIIIa-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0231] In some embodiments, the compound has the structure of formula III-VIIIa-2: Formula III-VIIIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0232] In some embodiments, the compound has the structure of formula III-VIIIa-3: Formula III-VIIIa-3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0233] In some embodiments, the compound has the structure of formula III-VIIIa-4: Formula III-VIIIa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0234] In some embodiments, the compound has the structure of formula III-VIIIa-5: Formula III-VIIIa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0235] In some embodiments, the compound has the structure of formula III-IXa: Formula III-IXa, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0236] In some embodiments, the compound has the structure of formula III-IXa-1: Formula III-IXa-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0237] In some embodiments, the compound has the structure of formula III-IXa-2: Formula III-IXa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0238] In some embodiments, the compound has the structure of formula III-IXa-3: Formula III-IXa-3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5 Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0239] In some embodiments, the compound has the structure of formula III-IXa-4: Formula III-IXa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0240] In some embodiments, the compound has the structure of formula III-IXa-5: Formula III-IXa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0241] In some embodiments, the compound has the structure of formula III-Xa: Formula III-Xa, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein a is 0 or 1.

[0242] In some embodiments, the compound has the structure of formula III-Xa-1: Formula III-Xa-1, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is N or CH; Each R 3 Independently selected from halogens, cyano groups, hydroxyl groups, optionally substituted amines, optionally substituted amide groups, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered cycloalkenyl groups, optionally substituted 3- to 11-membered heteroalkyl groups (e.g., optionally substituted 3- to 6-membered heteroalkyl groups), optionally substituted 6- to 10-membered aryl groups, or optionally substituted 5- to 10-membered heteroaryl groups; and n is an integer from 1 to 4.

[0243] In some embodiments, the compound has the structure of formula III-Xa-2: Formula III-Xa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0244] In some embodiments, the compound has the structure of formula III-Xa-3: Formula III-Xa-3, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 and R 5Each is independently selected from halogen, cyano, hydroxyl, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heteroalkyl (e.g., optionally substituted 3- to 6-membered heteroalkyl), optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl.

[0245] In some embodiments, the compound has the structure of formula III-Xa-4: Formula III-Xa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0246] In some embodiments, the compound has the structure of formula III-Xa-5: Formula III-Xa-5, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 3 It is N or CH; m is 1 or 2; R 6 R 7 R 8 and R 11 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 7 and R 11 The atoms to which it is attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups. In some embodiments, X 3 It is N. In some implementations, m is 1. In some implementations, R 11 It is hydrogen. In some implementations, X 3 It is N, m is 1, and R 11 It's H.

[0247] In some embodiments of any aspect described herein, a is 0. In some embodiments of any of the above aspects, a is 0.

[0248] In some implementations of any aspect described herein, R 2 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 2 Selected from -CH2CH3 or -CH2CF3.

[0249] In one aspect, the invention is characterized by a compound having the structure of formula IVa or IVb: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X 9 Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0250] In some embodiments, the compound has the structure of formula IVa-1 or IVb-1: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0251] In some embodiments, the compound has the structure of formula IVa-2: , Formula IVa-2 Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0252] In some embodiments, this disclosure is characterized by compounds of the structural formula IVa-3: , Formula IVa-3 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl.

[0253] In some embodiments, compounds having the structure of formula IVa-4 are provided herein: Formula IVa-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0254] In some embodiments of the compounds of the present invention, A is an optionally substituted thiazole, optionally substituted oxazole, optionally substituted morpholino, optionally substituted pyrrolidinyl, optionally substituted pyridinyl, optionally substituted azacyclobutyl, optionally substituted pyrazinyl, optionally substituted pyrimidine, optionally substituted piperidinyl, optionally substituted oxadiazole, optionally substituted thiadiazole, optionally substituted triazole, optionally substituted thiomorpholino, or optionally substituted phenyl.

[0255] In some embodiments, this disclosure is characterized by compounds of the structural formula IVa5: Formula IVa5 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0256] In some embodiments, compounds having the structure of formula IVa6 are provided: Formula IVa6, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 4 R 5 and R 6 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl; or R 4 and R 5 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 4 and R 6 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl.

[0257] In some embodiments, the compounds of the present invention have the structure of formula IVa7: Formula IVa7 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0258] In some embodiments, the compounds of the present invention have the structure of formula IVa8: Formula IVa8 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0259] In some embodiments, the compounds of the present invention have the structure of formula IVa9f: Formula IVa9 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0260] In some embodiments of the compounds of the present invention, R 2 yes: or .

[0261] In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 yes: .

[0262] In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted C1-C3 heteroalkyl group. In some embodiments, R 3 yes: .

[0263] In some embodiments of the compounds of the present invention, A is an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, A is: , , , , , , , , , , , or .

[0264] In some embodiments of the compounds of the present invention, A is an optionally substituted phenyl group. In some embodiments, A is: , , or .

[0265] In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocyclic alkyl group. In some embodiments, A is selected from the following structures or their stereoisomers: , , , , , , , or .

[0266] In some embodiments of the compounds of the present invention, the connector has the structure of formula IV-III: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Formula IV-III, Where A 1 It is the connector and CH(R) 3 The bond between ); A 2 It is the key between A and the connector; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR. N ; Each R N Independently hydrogen, optionally substituted C 1– C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1- to C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D 1 It is an optional substitution of C1-C 10 Alkylene, optionally substituted C2-C 10 alkenyl, optionally substituted C2-C 10 Alynyl, optionally substituted 3- to 14-membered heterocyclic alkylene, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C 10 Polyethylene glycol or optionally substituted C1-C 10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 )g -(B 2 ) h -Connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Chemical bonds.

[0267] In some embodiments of the compounds of the present invention, the connector is or comprises a ring-shaped portion. In some embodiments, the connector has the structure of formula IV-IIIa: Formula IV-IIIa, Where o is 0 or 1; R 7 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X 1 It does not exist, or is an optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene; Cy is an optionally substituted 3- to 8-membered cycloene alkyl group, an optionally substituted 3- to 12-membered heterocycloene alkyl group, an optionally substituted 6- to 10-membered arylene group, or an optionally substituted 5- to 10-membered heterocycloene alkyl group; and L 2 It does not exist, is -SO2-, -NH-, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted 3 to 6-membered heterocyclic alkylene.

[0268] In some embodiments, the connector is selected from the following substances or their stereoisomers: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0269] In some embodiments, the connector is selected from the following substances or their stereoisomers: , , , , , , , , , , , , , , , , , , , , , , , , or .

[0270] In some embodiments, the compounds of the present invention have the structure of formula IVa9: Formula IVa9, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein Cy 1 It is an optionally substituted spirocyclic 8- to 11-membered heterocyclic alkylene group or an optionally substituted 7- to 9-membered heterocyclic alkylene group; and Where W includes vinyl ketone or vinyl sulfone.

[0271] In some implementations, Cy 1 It is an optional substituted 10 to 11-membered heterocyclic alkyl group.

[0272] In some embodiments, the compounds of the present invention have the structure of formula IVa10: Formula IVa10, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is O, C(R) 11 2. NR 12 , S or SO2; r is 1 or 2; Each t is independently 0, 1, or 2; R 11 and R 12 Each is independently hydrogen, an optionally substituted C1-C4 alkyl group, an optionally substituted C2-C4 heteroalkyl group, or an optionally substituted 3- to 5-membered cycloalkyl group; and Each R 13 It is -CH3 on its own.

[0273] In some embodiments, the compounds of the present invention have the structure of formula IVa11: Formula IVa11, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is O, C(R) 11 2. NR 12 , S or SO2; r is 1 or 2; Each t is independently 0, 1, or 2; R 11 and R 12 Each is independently hydrogen, an optionally substituted C1-C4 alkyl group, an optionally substituted C2-C4 heteroalkyl group, an optionally substituted 3- to 6-membered heterocyclic alkyl group, or an optionally substituted 3- to 5-membered cycloalkyl group; and Each R 13 Independently -CH3, F, or two R atoms attached to the same atom 13The atoms they are attached to combine to form optionally substituted C3-C6 cycloalkyl groups, or two R atoms attached to the same atom. 13 The atoms attached to them combine to form optionally substituted 3- to 6-membered heterocyclic alkyl groups.

[0274] In some embodiments, the compounds of the present invention have the structure of formula IVa12: Formula IVa12 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0275] In some embodiments, the compounds of the present invention have the structure of formula IVa13: Formula IVa13 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0276] In some embodiments, the compounds of the present invention have the structure of formula IVa14: Formula IVa14 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0277] In some implementations, r is 1. In some implementations, r is 2. In some implementations, X 2 It is O. In some implementations, X 2 It is S. In some implementations, X 2 It is SO2.

[0278] In some implementation schemes, X 2 It is NR 12 In some implementations, R 12 Selected from the following substances or their stereoisomers: -CH3、 , , , , , , , , , Or -H.

[0279] In some implementation schemes, X 2 It is C(R) 11 2. In some implementations, each R 11 It is hydrogen.

[0280] In some embodiments, the compounds of the present invention have the structure of formula IVa15: Formula IVa15, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein Q 1 It is CH2, NR N Or O; Q 2 It is CO, NR N Or O; and Z is an optionally substituted 3- to 6-membered heterocyclic alkylene or an optionally substituted 5- to 10-membered heteroarylene; or Q 1 -Q 2 -Z is an optionally substituted 9- to 10-membered spirocyclic heterocyclic alkyl group.

[0281] In some embodiments, the compounds of the present invention have the structure of formula IVa16: Formula IVa16, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 14 It is a fluorinated group, hydrogen, or C1-C3 alkyl group; and u is 0 or 1.

[0282] In some implementation schemes, R 14 It is a fluorinated group and u is 1. In some embodiments, R 14 It is hydrogen and u is 0.

[0283] In some embodiments, the compounds of the present invention have the structure of formula IVa17: Formula IVa17 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0284] In some embodiments, the compounds of the present invention have the structure of formula IVa18: Formula IVa18 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0285] In one aspect, this disclosure is characterized by compounds of structural formula VIa-1: Formula VIa-1 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; W is a crosslinking group, including aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, oxazonium or glycal; X 6 It is CH2 or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, or optionally substituted 3- to 10-membered heterocyclic alkyl; and R 2 It is an optional substituted C1-C6 alkyl group.

[0286] In one aspect, the invention is characterized by a compound having the structure of formula Va or formula Vb: Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X 9 Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3 RL4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0287] In some embodiments, the compound has the structure of formula Va-1: , Formula Va-1 Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0288] In some embodiments, the compound has the structure of formula Va-2: , Va-2 Or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 3- to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heterocyclic arylene; L stands for connector; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted 3- to 10-membered heterocyclic alkyl or optionally substituted C1-C6 heteroalkyl. R 2 It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C3 heteroalkyl.

[0289] In some embodiments, the compounds of the present invention have the structure of formula V-Ia: Formula V-Ia Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0290] In some embodiments, the compounds of the present invention have the structure of formula V-II-1: Formula V-II-1 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0291] In some embodiments, the compounds of the present invention have the structure of formula V-II-2: Formula V-II-2, Or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, wherein R 6 R 7 and R 8 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl; or R 6 and R 7 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl; or R 6 and R 8 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl.

[0292] In some embodiments, the compounds of the present invention have the structure of formula V-II-3: Formula V-II-3 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0293] In some embodiments, the compounds of the present invention have the structure of formula V-II-4: Formula V-II-4 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein X 2 It is CH2 or O; and o is 1 or 2.

[0294] In some embodiments, the compound has the structure of formula VIa or formula VIb: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; W is a crosslinking group, including aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, oxazonium or enosylate; X 6 It is CH2 or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl or optionally substituted 3 to 10-membered heterocyclic alkyl; R 2 It is an optional substituted C1-C6 alkyl group; z is 0, 1, or 2; X 9 Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0295] In some embodiments, the compound has the structure of formula VIa-1: , Formula VIa-1 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; W is a crosslinking group, including aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, oxazonium or enosylate; X 6 It is CH2 or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl or optionally substituted 3 to 10-membered heterocyclic alkyl; R 2 It is an optional substituted C1-C6 alkyl group; Each R 33Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0296] In some embodiments, the compound has the structure of formula VIa-2: , Formula VIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; W is a crosslinking group, including aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boric acid, borate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, oxazonium or enosylate; X 6 It is CH2 or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, or optionally substituted 3- to 10-membered heterocyclic alkyl; and R 2 It is an optional substituted C1-C6 alkyl group.

[0297] In some embodiments of the compounds of the present invention, X 2 It is CH2. In some implementations, o is 1. In some implementations, o is 2.

[0298] In some embodiments of the compounds of the present invention, X 6 It is 0. In some implementations, 0 is 1. In some implementations, 0 is 2.

[0299] In some embodiments of the compounds of the present invention, R 2 yes: or .

[0300] In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 yes: .

[0301] In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted 3- to 6-membered cycloalkyl group. In some embodiments, R 3 yes: .

[0302] In some embodiments of the compounds of the present invention, A is an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, A is: or .

[0303] In some embodiments of the compounds of the present invention, A is an optionally substituted phenyl group. In some embodiments, A is: , , or .

[0304] In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocyclic alkyl group. In some embodiments, A is selected from the following structures or their stereoisomers: , , .

[0305] In some embodiments of the compounds of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X 1 It is CH2. In some implementations, X 6 It is O. In some implementations, m is 1, n is 1, and X is 1. 6 It is CH2. In some implementations, m is 1, n is 1, and X 6 It is O.

[0306] In some embodiments of the compounds of the present invention, m is 2. In some embodiments, X 6 It is CH2. In some implementations, n is 1. In some implementations, n is 0. In some implementations, m is 2, X 6 It is CH2, and n is 1. In some implementations, m is 2, and X 6 It is O. In some implementations, m is 2, X 6 It is O, and n is 1. In some implementations, m is 2, X 6 It is O, and n is 0.

[0307] In some embodiments of the compounds of the present invention, W comprises aziridine. In some embodiments, W comprises an optionally substituted cyclopropyl-aziridine moiety. In some embodiments, W is selected from the following structures or stereoisomers thereof: , , , , , , , , , , or .

[0308] In some embodiments of the compounds of the present invention, W includes epoxides. In some implementations, W is selected from the following structures or their stereoisomers: or .

[0309] In one aspect, the invention is characterized by a compound having the structure of formula VIIa or VIIb: Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; X 6 X 7 and X 8 Each is independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 10-membered heterocyclic alkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocycloalkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium; z is 0, 1, or 2; X 9Yes -NR L6 -, -C(O)- or -S(O)2-; R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atom, form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclic group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0310] In some embodiments, the compound has the structure of formula VIIa-1: , Formula VIIa-1 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; X 6 X 7 and X 8 Each is independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 10-membered heterocyclic alkyl. R 2 It is an optional substituted C1-C6 alkyl group; R 3It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocycloalkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0311] In some embodiments, this disclosure is characterized by compounds of structural formula VIIa-2: , Formula VIIa-2 Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. L stands for connector; X 6 X 7 and X 8 Each is independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 ynyl, optionally substituted C1-C6 heteroalkyl or optionally substituted 3 to 10-membered heterocyclic alkyl. R 2 It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocycloalkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium.

[0312] In some embodiments, the compounds of the present invention have the structures of formula VI-Ia, formula VI-Ib, and formula VI-Ic: Formula VI-Ia, Formula VI-Ib, Formula VI-Ic, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein each D represents a hydrogen with a deuterium isotope enrichment factor of at least 5.

[0313] In some embodiments, the compounds of the present invention have the structure of formula VI-II: .

[0314] Formula VI-II Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. R 2 It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocyclic alkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium.

[0315] In some embodiments, the compounds of the present invention have the structure of formula VI-V: .

[0316] Type VI-V Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. R 2 It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocyclic alkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium.

[0317] In some embodiments, the compounds of the present invention have the structure of formula VI-VI: .

[0318] Style VI-VI Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. R 2It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocyclic alkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium.

[0319] In some embodiments, the compounds of the present invention have the structures of formulas VI-VII: .

[0320] Formulas VI-VII Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 3 to 6-membered heterocyclic alkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 10-membered heterocyclic arylene. R 2 It is an optionally substituted C1-C6 alkyl group; and R 3 It is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocyclic alkyl. Furthermore, each hydrogen atom is independently and optionally isotopically enriched in deuterium.

[0321] In some embodiments, the compounds of the present invention have the structures of formula VI-Va, formula VI-Vb, and formula VI-Vc: Formula VI-Va, Formula VI-Vb, Formula VI-Vc Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein each D represents a hydrogen with a deuterium isotope enrichment factor of at least 5.

[0322] In some embodiments, the compounds of the present invention have the structures of formula VI-Vd, formula VI-Ve, and formula VI-Vf: Formula VI-Vd, Formula VI-Ve, Formula VI-Vf, Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein each D represents a hydrogen with a deuterium isotope enrichment factor of at least 5.

[0323] In one aspect, the present invention is characterized by a compound having the structure of formula XI: , Formula XI Or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C2-C4 alkylene or optionally substituted C2-C4 alkenylene. W is an optionally substituted 3- to 10-membered heterocyclic alkyl group or an optionally substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 alkenyl, an optional substituted C1-C6 alkynyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, an optional substituted 3- to 6-membered cycloalkenyl, an optional substituted 3- to 15-membered heterocycloalkyl, an optional substituted 6- to 10-membered aryl, or an optional substituted 5- to 10-membered heteroaryl. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they can form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen, and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted four-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen, and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted four-membered cycloalkyl groups; R 10 Yes - OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13Each is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 and R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t can be 0, 1, 2, or 3.

[0324] In some embodiments, A is an optionally substituted thiazol-diyl, optionally substituted oxazol-diyl, optionally substituted morpholine-diyl, optionally substituted pyrrolidine-diyl, optionally substituted piperidine-diyl, or optionally substituted phenylene. In some embodiments, A is an optionally substituted thiazol-diyl or optionally substituted morpholine-diyl. In some embodiments of the compounds of the present invention, A is an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, A is: or In some implementations, A is... .

[0325] In some embodiments of the compounds of the present invention, A is an optionally substituted phenylene. In some embodiments, A is: , , , or In some implementations, A is... .

[0326] In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocyclic alkylene group. In some embodiments, A is an optionally substituted 6-membered heterocyclic alkylene group. In some embodiments, A is selected from the following structures or their stereoisomers: , or In some implementations, A is selected from the following structures or their stereoisomers: , .

[0327] In some embodiments of the compounds of the present invention, R 1 It is hydrogen, optionally substituted 3- to 10-membered heterocyclic alkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments of the compounds of the present invention, R 1 It is hydrogen or optionally substituted 3- to 10-membered heterocyclic alkyl. In some embodiments of the compounds of the present invention, R 1 It is an optionally substituted 3- to 10-membered heterocyclic alkyl group. In some embodiments of the compounds of the present invention, R1 yes: , , or .

[0328] In some embodiments of the compounds of the present invention, R 1 yes: , or , where each D represents hydrogen with a deuterium isotope enrichment factor of at least 5.

[0329] In some embodiments of the compounds of the present invention, R 2 yes: or .

[0330] In some embodiments of the compounds of the present invention, R 2 yes: , , or , where each D represents hydrogen with a deuterium isotope enrichment factor of at least 5.

[0331] In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl. In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 yes: or In some implementations, R 3 yes: In some implementations, R 3 yes: , where each D represents hydrogen with a deuterium isotope enrichment factor of at least 5.

[0332] In some embodiments of the compounds of the present invention, R 3 It is an optionally substituted 3- to 6-membered cycloalkyl group. In some embodiments, R 3 yes: or In some implementations, R 3 yes: .

[0333] In some embodiments of the compounds of the present invention, R 2 yes: or ;R 3 yes or And A is , , or .

[0334] In some implementation schemes, R 2 yes or ;R 3 yes or And A is , or .

[0335] In some embodiments of the compounds of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X 1 It is CH2. In some implementations, X 2 It is CH2. In some implementations, X 3 It is CH2. In some implementations, m is 1, n is 1, and X 1 X 2 and X 3 Each of them is CH2.

[0336] In one aspect, the present invention is characterized by a compound having the structure of formula Ic: , Formula Ic Or its pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer, wherein: Q is a optionally substituted 7- to 12-membered bicyclic aryl, optionally substituted 7- to 12-membered bicyclic heteroaryl, or optionally substituted 7- to 12-membered bicyclic heterocyclic, wherein the first ring in Q is bonded to X, and the second ring in Q is bonded to A; X is a bond; a straight-chain C1-C3 alkylene group, optionally substituted by 1 to 3 substituents independently selected from fluorinated, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl groups; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, where "*" indicates that a portion of X is bonded to -C(R 7 (R) 8 )-; Y is -O-, -NH-, or -N(C1-C3 alkyl)-; A is an optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. L stands for connector; T is the second connector; R 3 It is an optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclic group; R 10 It is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl; R 7 It is a hydrogen, halogen, or optionally substituted C1-C3 alkyl group; R 8 It is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic; or R 7 and R 8 Together they form =CH2, optionally substituted C3-C6 cycloalkyl groups or 3 to 7-membered saturated heterocyclic groups; or R 8 With the ring atoms in Q, R 7 The bonded carbon atoms and X form 4- to 9-membered saturated or unsaturated heterocyclic groups fused to Q; R 6 It is hydrogen or -CH3; Each R 5 It is independently a halogen, an optionally substituted C1-C3 alkyl group, or an optionally substituted C1-C3 haloalkyl group; p is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 Yes -NR L6 -、-C(O)- or -S(O)2-; and R L1 R L2 R L3 R L4 R L4 R L5 and R L6Each of these elements is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, or optionally substituted C1-C6 heteroalkyl; or R L1 R L2 R L3 R L4 R L4 R L5 and R L6 Any two atoms connected to them, together with any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3 to 8-membered heterocyclic groups.

[0337] In some embodiments of any of the compounds described herein, T has the structure of formula XV: .

[0338] XV In some implementations of formula XV, z is 0.

[0339] In some embodiments of any of the compounds described herein, T has the structure of formula XVa: .

[0340] Formula XVa In some implementations, T has a structure .

[0341] In some implementations of formula XV, z is 1.

[0342] In some embodiments of any of the compounds described herein, T has the structure of formula XVb: Formula XVb In some embodiments of any of the compounds described herein, T has the structure of formula XVc: .

[0343] XVc In some embodiments of any of the compounds described herein, T has the structure of formula XVd: .

[0344] Formula XVd In some embodiments of any of the compounds described herein, T has the structure of formula XVe: .

[0345] XVe In some implementations of formula XV, z is 2.

[0346] In some embodiments of any of the compounds described herein, T has the structure of formula XVf: .

[0347] Formula XVf In some implementations, R L1 It is hydrogen. In some implementations, R L1 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R L1 It is methyl, ethyl, or trifluoromethyl. In some embodiments, R L1 It is an optionally substituted C1-C6 heteroalkyl group. In one embodiment, R L1 It is methoxy or ethoxy. In some embodiments, R L1 It is an optionally substituted C2-C6 ynyl group. In some embodiments, R L1 It is an acetylene group.

[0348] In some implementation schemes, R L2 It is hydrogen. In some implementations, R L2 It is a halogen. In some implementations, R L2 It is a fluorinated group.

[0349] In some implementation schemes, R L3 It is hydrogen. In some implementations, R L3 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R L3 It is a methyl group.

[0350] In some implementation schemes, R L4 It is hydrogen.

[0351] In some implementation schemes, R L1 and R L4 Combining them to form optionally substituted C4 cycloalkyl groups.

[0352] In some implementation schemes, R L1 and R L3 Combining them forms optionally substituted C4 cycloalkyl groups. In some embodiments, R L1 and R L3 Combining them to form optionally substituted C5 cycloalkyl groups.

[0353] In some implementations, two R L1 Combining them to form optionally substituted C3-C6 cycloalkyl groups.

[0354] In some implementation schemes, R L1 and R L2Combining them to form optionally substituted C3-C6 cycloalkyl groups.

[0355] In some implementations, T is: , , , , , , , , , , , , , , , , , , , , , , , or .

[0356] In some implementations, T is: , , , , , , , , , , , , , , , , , , , , , , or .

[0357] In some embodiments of any of the compounds described herein, T has the structure of formula XVI: XVI In some implementation schemes, X 9 Yes -NR L6 -

[0358] In some embodiments of any of the compounds described herein, T has the structure of formula XVIa: .

[0359] Formula XVIa In some embodiments of any of the compounds described herein, T has the structure of formula XVIb: .

[0360] Formula XVIb In some implementation schemes, R L6 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R L6 It is a methyl group.

[0361] In some implementation schemes, X 9 It is -C(O)-. In some implementations, X 9 It is -S(O)2-.

[0362] In some implementation schemes, R L5 It is hydrogen. In some implementations, R L5 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R L5 It is an optionally substituted C3-C8 cycloalkyl group. In some embodiments, the two Rs... L5 Combining them to form optionally substituted C3-C8 cycloalkyl groups.

[0363] In some embodiments of any of the compounds described herein, T is: , , , , , , , , , , , , , , or .

[0364] In some embodiments of any of the compounds described herein, T is: , , , , , or .

[0365] In some embodiments of any of the compounds described herein, T does not have the following structure: , , , , , , , , , or .

[0366] In some implementations, L has the structure of formula XIII: A 1 -(Z 1 ) f -(C 1 ) g -(Z 2 ) h -(D 1 )-(Z 3 ) i -(C 2 ) j -(Z 4 ) k –A 2 Formula XIII Where A 1 It is the key between the connector and the rest of the large ring; A 2 It is the key between A and the connector; Z 1 Z 2 Z 3 and Z 4 Each of these independently comprises an optionally substituted C1-C3 alkylene group, an optionally substituted C1-C3 heteroalkylene group, an optionally substituted C1-C2 alkenylene group, an optionally substituted 3- to 8-membered heterocyclic alkylene group, an optionally substituted 3- to 8-membered heterocyclic alkylene group, O, NR N Or crosslinking groups, including vinyl ketones, acetylacetones, vinyl sulfones, acetylacetonates, carbodiimides, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketones, boric acid, borate esters, N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoe-EEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R N It is hydrogen, and the C is optionally substituted. 1– C4 alkyl or optionally substituted 6-membered arylene; C 1 and C 2Each is independently carbonyl or O; f, g, h, i, j, and k are each independently 0 or 1; and D 1 It is an optionally substituted C1-C2 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkyneene, optionally substituted 3- to 8-membered heterocyclic alkylene, optionally substituted 3- to 8-membered heterocyclic alkylene, or optionally substituted C1-C3 heterocyclic alkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, or A 1 -(Z 1 ) f -(C 1 ) g -(Z 2 ) h -Connected to -(Z) 3 ) i -(C 2 ) j -(Z 4 ) k –A 2 Chemical bonds.

[0367] In some embodiments of the connector of formula XIII, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1.

[0368] In some implementations of the connector of type XIII, Z 1 It is NR N In some implementations, R N C is an optional substitute 1– C4 alkyl. In some embodiments, R N It is a methyl group.

[0369] In some implementations of the connector of type XIII, C 1 It is a carbonyl group.

[0370] In some implementations of the connector of type XIII, D 1 It is a 3- to 8-membered cycloalkylene group. In some embodiments, D 1 It is an optionally substituted C1-C2 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkyneene, or optionally substituted C1-C3 heteroalkylene. In some embodiments, D 1 It is an optional substituted 3 to 8-membered heterocyclic alkyl group.

[0371] In some implementations of the connector of type XIII, Z4 It is O. In some implementations, Z 4 It is an optionally substituted C1-C3 alkylene group. In some embodiments, Z 3 It is an optional substituted C1-C3 alkylene group.

[0372] In some implementations, L has the structure of formula VIII: Formula VIII Where X 5 It is O or CH2 and connected to ring A; and Z is an optionally substituted 3- to 6-membered heterocyclic alkylene, an optionally substituted C1-C6 alkylene, or an optionally substituted C1-C6 heterocyclic alkylene.

[0373] In some implementations of the connector of type XIII, X 5 It is O.

[0374] In some embodiments of the connector of formula VIII, Z is an optionally substituted 3- to 6-membered heterocyclic alkylene group. In some embodiments, Z is an optionally substituted 5-membered heterocyclic alkylene group. In some embodiments, Z is an optionally substituted pyrrolidine-diyl group.

[0375] In some implementations, L has the structure of formula VIIIa: Formula VIIIa Where X 9 It is NR, O, or CH2 and connected to ring A; X 10 It is CH or N; X 11 It is NR'', O, C(O), C(O)N(R''')2 or CH2; R'' is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R''', C(O)OR''', C(O)N(R''')2, S(O)R''', S(O)2R''' or S(O)2N(R''')2; Each R''' is independently hydrogen, an optionally substituted C1-C4 alkyl group, or an optionally substituted 3- to 6-membered heterocyclic alkyl group; R 30 and R 32 Independently hydrogen, optionally substituted C6-C 10 Aryl or optionally substituted C1-C6 alkylene groups; R 31 It is hydrogen, optionally substituted C6-C 10Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heteroalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene; and q and r are independently 0, 1, 2 or 3.

[0376] In some implementations, L has the structure of formula VIIIb: .

[0377] Formula VIIIb In some implementations, L has the structure of formula VIIIc: .

[0378] Formula VIIIc In some implementations, L has the structure of formula VIIId: .

[0379] Formula VIIId In some implementations, L has the structure of formula VIIIe: .

[0380] Formula VIIIe In some implementations, L has the structure of formula VIIIf: .

[0381] Equation VIIIf In some implementations, L has the structure of formula VIIIg: .

[0382] Formula VIIIg In some embodiments of the connector of formula VIIIa, the connector is: , , , or .

[0383] In some implementations, the connector has the following structure: Where R 37 It is hydrogen or a substituted C1-C4 alkyl group; R 38It is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3- to 7-membered heterocyclic alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted spirocyclic 8- to 11-membered heterocyclic alkylene; and q can be 0, 1, 2 or 3.

[0384] In some implementations, the connector has the following structure: Where R 38 It is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3- to 7-membered heterocyclic alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted spirocyclic 8- to 11-membered heterocyclic alkylene; and y and e are 1, 2 or 3 independently.

[0385] In some implementations, the connector has the structure of type XII: , Formula XII The O atom on the left is connected to ring A; R 35 It is NR 36 C(O)CH2N(R 36 )2 or optionally substituted 3 to 6-membered heterocyclic alkylene groups; and Each R 36 Independently, it is an optional substituted C1-C4 alkyl group.

[0386] In some implementations, the connector has a structure of type XIV: Formula XIV in X 5 It is O and connected to ring A; Each X 13 Independently, it is O or NR 34 ;and Each R 34 It is independently hydrogen or optionally substituted C1-C6 alkyl.

[0387] In some implementations, L has the structure of formula IX: Formula IX in B is an optionally substituted 3- to 6-membered heterocyclic alkyl group; R 22It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclic group, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C6-C 10 Aryl, , , or ; R 23 and R 24 Each is independently hydrogen or optionally substituted C1-C6 alkyl; R 25 It is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclic group; R 26 It is an optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 3- to 6-membered heterocyclic groups, optionally substituted 5- to 10-membered heteroaryl groups, or optionally substituted C6-C 10 Aryl; and R 27 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 ynyl, optionally substituted C2-C6 heteroynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclic groups, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted 3- to 10-membered heterocyclic alkenyl, optionally substituted C6-C 10 Aryl or optionally substituted 5 to 10-membered heteroaryl groups.

[0388] In some implementations, the connector of formula IX has the structure of formula X: Formula X In some implementations of the connector of type IX or X, R 22 yes In some implementations, R 27 It is an optionally substituted C1-C6 alkyl group. In some embodiments, R 27 It is an optionally substituted C2-C6 alkenyl group. In some embodiments, R 27 It is an optionally substituted C2-C6 ynyl group. In some embodiments, R 27 It is an optionally substituted C1-C6 heteroalkyl group. In some embodiments, R 27It is an optionally substituted C2-C6 heteroene group. In some embodiments, R 27 It is an optionally substituted C2-C6 heteroyne group. In some embodiments, R 27 It is an optional substitution of C3-C 10 Cycloalkenyl. In some embodiments, R 27 It is hydrogen. In some implementations, R 27 It is an optional substitution of C3-C 10 Cycloalkyl. In some embodiments, R 27 It is an optional substituted 3 to 10-membered heterocyclic group.

[0389] In some implementations of the connector of type IX or X, R 22 yes In some implementations, R 26 It is an optionally substituted 5- to 10-membered heteroaryl group. In some embodiments, R 26 It is an optional substituted 3 to 10-membered heterocyclic group.

[0390] In some implementations of the connector of type IX or X, R 22 It is an optional substituted 3- to 6-membered heterocyclic group.

[0391] In some embodiments of compounds of formula I, II, III, IV, IVa, IVb, IVc, V, or VI, A is an optionally substituted 3- to 6-membered heterocyclic alkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heterocyclic arylene. In some embodiments, A is an optionally substituted 6-membered arylene. In some embodiments, A is: , , , or .

[0392] In some implementation schemes, A is: .

[0393] In any embodiment herein, the compounds of the present invention may be modified with substituents found in any one or more of the following applications: WO 2024 / 060966, WO 2024 / 017859, WO 2024 / 008834, WO2024 / 008610, WO 2023 / 232776, WO 2023 / 208005, WO 2023 / 086341, WO 2023 / 025832, WO2023 / 015559, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684, which are incorporated herein by reference in their entirety.

[0394] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof.

[0395] Table 1: Some compounds of the present invention Pharmaceutical compositions are also provided, the pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0396] Conjugates of the compounds of the present invention or salts thereof are also provided, wherein the compounds of the present invention have a covalent warhead bonded to a monovalent organic moiety.

[0397] In some embodiments of the conjugates of the present invention, the monovalent organic portion is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, N-Ras G13C, K-Ras Q61H, H-Ras Q61H, N-Ras Q61H, N-Ras Q61K, or N-Ras Q61R.

[0398] The compounds of this invention are also applicable to antibody-drug conjugates and degradation agents.

[0399] A method of treating a subject with cancer is further provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, or multiple myeloma. In some embodiments, the cancer contains a Ras mutation, such as K-Ras Q61H, H-Ras Q61H, or N-Ras Q61H. Other Ras mutations are described herein.

[0400] Furthermore, a method for treating Ras protein-related conditions in subjects in need is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0401] A method for inhibiting Ras protein in cells is further provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras Q61H, H-Ras Q61H, or N-Ras Q61H. Other Ras proteins are described herein. The cells may be cancer cells, such as pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells, or squamous cell lung cancer cells. In some embodiments, the cells are pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, or multiple myeloma cells; other cancer types are described herein. The cells may be in vivo or in vitro.

[0402] Regarding the compounds of the present invention, one stereoisomer may exhibit better inhibition than another stereoisomer. For example, one transisomer may exhibit inhibition, while another transisomer may exhibit little or no inhibition.

[0403] In some embodiments, the methods or uses described herein also include administration of additional anticancer therapies. In some embodiments, the additional anticancer therapies are HER2 inhibitors, EGFR inhibitors, second Ras inhibitors, SHP2 inhibitors, SOS1 inhibitors, Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, mTORC1 inhibitors, BRAF inhibitors, PD-L1 inhibitors, PD-1 inhibitors, CDK4 / 6 inhibitors, or combinations thereof. In some embodiments, the additional anticancer therapies are SHP2 inhibitors. Other additional anticancer therapies are described herein.

[0404] Synthesis method The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0405] The compounds of the present invention (see, for example, the compounds in Table 1) can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following embodiments, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. As further examples, the synthetic methods described in WO 2020 / 132597, WO 2021 / 091982, WO 2021 / 091967, WO 2021 / 091956, WO 2022 / 060836, WO 2022 / 235864, WO 2022 / 235870, WO 2023 / 060253, and WO 2023 / 133543 can be used to prepare the compounds of the present invention, the disclosure of each of which is incorporated herein by reference. These methods include, but are not limited to, those described in the following embodiments.

[0406] Scheme 1. General Synthesis of Functionalized Bimacrocyclic Compounds Scheme 1 outlines the general synthesis of functionalized bimacrocyclic compounds. Appropriately substituted biaromatic intermediates (1) can be derived from appropriately substituted 3-(5-bromo-2-iodo-1-) H The intermediate (-indol-3-yl)-2,2-dimethylprop-1-ol and a suitably substituted methylpiperazine-containing arylboronic ester are prepared in one step by palladium-mediated coupling followed by ester hydrolysis. After macrocyclic lactone formation, deprotection with amine and phenol yields the macrocyclic ester (2).

[0407] Appropriately substituted 2-(toluenesulfonyloxymethyl)-3-(amido)cyclic amines (3) can be obtained by using peptide coupling reagents. O - Protected N -methyl- L -Valine (4) is prepared by coupling with a suitably substituted 2-(hydroxymethyl)-3-carboxylic acid ester cyclic amine, followed by toluenesulfonation of the alcohol and deprotection of the carboxylic acid.

[0408] The final functionalized bimacyclic compound can then be prepared by coupling the macrocyclic ester (1) with the peptide of intermediate (3) and then forming a macrocyclic ether in the presence of a base. Deprotection and coupling of the amine with a suitably substituted carboxylic acid (or other coupling partner) can produce the macrocyclic product (5).

[0409] Scheme 2. Substitution of macrocyclic ester intermediate (2) in general synthesis Alternatively, the macrocyclic ester intermediate (2) can be prepared as described in Scheme 2. In the presence of a palladium catalyst, a suitably substituted arylboronic ester (5) can be coupled with a suitably protected 3-(5-bromo-indole-3-yl)-2,2-dimethylprop-1-ol (6). This can be followed by indole iodination, alcohol deprotection, and ester hydrolysis. Subsequently, it is reacted with a methyl group ( S The iodinated macrocyclic intermediate (7) can be obtained by coupling with piperazine ester, ester hydrolysis, and macrocyclic lactone esterification. Coupling with a suitably substituted arylboronic ester (8) in the presence of a palladium catalyst and subsequent indole coupling yields the intermediate. N - Alkylation, followed by amine and phenol deprotection, yields intermediate (2).

[0410] Scheme 3. General Synthesis of Functionalized Amine Bimacrocyclic Compounds Scheme 3 outlines the general synthesis of functionalized bimacrocyclic compounds. Appropriately protected hydroxyalkyl amino acids can be coupled with peptide coupling reagents. O - Protected N -methyl- L -Valine (3) is coupled. Subsequently, the alcohol and carboxylic acid are deprotected to produce an appropriately substituted intermediate (7).

[0411] The protected amine bimacyclic intermediate can be prepared by peptide coupling of a macrocyclic ester intermediate (2) with a carboxylic acid (7), followed by the formation of a bimacyclic ether in the presence of a triphenylphosphine and an azodicarboxylic acid ester. Deprotection and coupling of the amine with a suitably substituted carboxylic acid (or other coupling coupler) yields a macrocyclic product (8).

[0412] Scheme 4. General Synthesis of Functionalized Amine Bimacrocyclic Compounds Scheme 4 outlines the general synthesis of functionalized bimacrocyclic compounds. In the presence of a palladium catalyst, a suitably substituted terminal alkyne (9) can be coupled with a suitably substituted bromoaryl iodide (10). The aryl alkyne intermediate (11) is then reduced, followed by amino acid synthesis. N - Deprotection, carboxylic acid deprotection, macrocyclization in the presence of peptide coupling reagents, ester hydrolysis, and peptide-methylation ( S The macrocyclic intermediate (12) can be obtained by coupling with 3-(5-boronico-indol-3-yl)-2,2-dimethylprop-1-ol via palladium-mediated coupling, macrocyclic lactone formation, deprotection of the amine, and coupling of the amine with a suitable substituted carboxylic acid (or other coupling spouse) to give the functionalized bicyclic compound (13).

[0413] Scheme 5. General Synthesis of Functionalized Amine Bimacrocyclic Compounds Scheme 5 outlines the general synthesis of functionalized bimacrocyclic compounds. In the presence of a base and a chiral auxiliary, a suitably substituted 2-bromo-4-bromomethyl-5-vinyl 5-membered heteroaryl hydrocarbon (14) can react with ethyl 2-((diphenylethylene)amino)acetate. The amide is then coupled with a suitably substituted 2-(vinyl)-3-(amido)cycloamine (15), followed by olefin metathesis, ester hydrolysis, and reaction with a methyl group (…). S The amide coupling reaction of )-piperazine ester can yield macrocyclic compound (16).

[0414] Functionalized amine bicyclic compounds (17) can then be obtained by palladium-mediated coupling with appropriately substituted 3-(5-boronico-indol-3-yl)-2,2-dimethylprop-1-ol, methyl ester hydrolysis, macrocyclic lactone formation, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling spouse).

[0415] Scheme 6. General Synthesis of Functionalized Amine Bimacrocyclic Compounds Scheme 6 outlines the general synthesis of functionalized bimacrocyclic compounds. Appropriately substituted bromoaromatic iodides (10) can be coupled with vinyl borate esters in the presence of a palladium catalyst. The vinyl ethers are then hydrolyzed in the presence of an acid to yield an aldehyde (18).

[0416] In the presence of acid and reducing agent, appropriate N -functionalization O- The protected amino acid (19) can be coupled with the aldehyde (18). Subsequently, in the presence of an amide coupling agent, deprotection of the carboxylic acid and... O - Protected N -methyl- L The coupling of valine (3) was followed by deprotection with carboxylate and amine, and then cyclization in the presence of a peptide coupling reagent to obtain the macrocyclic intermediate (20).

[0417] Then, the intermediate (20) can be coupled with a suitably substituted 3-(5-boronico-indol-3-yl)-2,2-dimethylprop-1-ol via palladium-mediated coupling, followed by ester hydrolysis to prepare a suitably substituted biaromatic intermediate (21) in two steps. Subsequently, the intermediate is coupled with a methyl group via a peptide coupling reagent. S The coupling of )-piperazine ester, followed by ester hydrolysis and macrocyclic esterification, yields a functionalized amine bimacrocyclic compound (22).

[0418] Scheme 7. General Synthesis of Functionalized Bimacrocyclic Compounds Scheme 7 outlines the general synthesis of functionalized bimacrocyclic compounds. Appropriately substituted biaromatic intermediates (1) can be derived from appropriately substituted 3-(5-bromo-2-iodo-1-) H The intermediate (-indol-3-yl)-2,2-dimethylprop-1-ol and a suitably substituted methylpiperazine-containing arylboronic ester are prepared in one step by palladium-mediated coupling followed by ester hydrolysis. After macrocycl...

Claims

1. A compound selected from Formula la, Formula lb, Formula Ila, Formula lib, Formula Ila-1, Formula Ilia, Formula Illb, Formula Ilia-1, Formula IVa, Formula IVb, Formula Va, Formula Vb, Formula Via, Formula VIb, Formula VIIa, Formula VIIb, or Formula XI, or a pharmaceutically acceptable salt thereof, wherein Formula la has the following structure: Formula la or a pharmaceutically acceptable salt thereof, wherein: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; Y is -0-, -NH-, or -N(Ci-C3alkyl)-; A is an optionally substituted C2-C4alkylene, an optionally substituted Ci-C4heteroalkylene, or an optionally substituted C2-C4alkenylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; p is 0, 1, 2, or 3; and z is 0, 1, or 2; wherein Formula lb has the following structure: Formula lb or a pharmaceutically acceptable salt thereof, wherein: Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; Y is -0-, -NH-, or -N(Ci-C3alkyl)-; A is an optionally substituted C2-C4alkylene, an optionally substituted Ci-C4heteroalkylene, or an optionally substituted C2-C4alkenylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; p is 0, 1, 2, or 3; and z is 0, 1, or 2; wherein Formula Ila has the following structure: Formula Ila or a pharmaceutically acceptable salt thereof, wherein a dashed line represents zero, one, two, three, or four non-adjacent double bonds; A is an optionally substituted C2-C4alkylene, an optionally substituted Ci-C4heteroalkylene, an optionally substituted C2-C4alkenylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted Ci-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, C(0)R', C(0)0R', C(0)N(R')2, S(0)R', S(0)2R', or S(0)2N(R')2; and z is 0, 1, or 2; wherein Formula lib has the following structure: Formula lib or a pharmaceutically acceptable salt thereof, wherein a dashed line represents zero, one, two, three, or four non-adjacent double bonds; ​ ， ​ ​ ​ X is a bond; straight chain C1-C3 alkylene, optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; -CH2-O-; -CH2-S(O)0-2-; -O-CH2-; or -CH2-S(O)0-2-, wherein "*" indicates the portion of X that is bonded to -C(R 7 )(R 8 )-; ​ ​ ​ R 3 is optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C6aryl, or optionally substituted 3- to 7-membered heterocyclyl; R 10 is hydrogen, halogen, optionally substituted C1-C3alkyl, or C1-C3optionally substituted heteroalkyl; R 7 is hydrogen, halogen or optionally substituted C1-C3alkyl; R 8 It is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic; or R 7 and R 8 together form =CH2, optionally substituted C3-C6cycloalkyl or 3- to 7-membered saturated heterocyclyl; or R 8 with the ring atoms in Q, R 7 the carbon atom to which R is bound and X form a 4- to 9-membered saturated or unsaturated heterocyclyl fused to Q; R 6 is hydrogen or -CH3; Each R 5 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, or an optionally substituted C1-C3 haloalkyl group; ​ ​ X 9 is -NR L6 -, -C(O)- or -S(O)2-; and R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; ​ ， ​ ​ ​ X is a bond; straight chain C1-C3 alkylene, optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; -CH2-O-; -CH2-S(O)0-2-; -O-CH2-; or -CH2-S(O)0-2, wherein "*" indicates the portion of X that is bonded to -C(R 7 )(R 8 )-; ​ ​ ​ R 3 is optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C6aryl, or optionally substituted 3- to 7-membered heterocyclyl; R 10 is hydrogen, halogen, optionally substituted C1-C3alkyl, or C1-C3optionally substituted heteroalkyl; R 7 is hydrogen, halogen or optionally substituted C1-C3alkyl; R 8 It is hydrogen, halogen, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C6-C 10 Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclic; or R 7 and R 8 together form =CH2, optionally substituted C3-C6cycloalkyl or 3- to 7-membered saturated heterocyclyl; or R 8 with the ring atoms in Q, R 7 the carbon atom to which it is bound and X form a 4- to 9-membered saturated or unsaturated heterocyclyl fused to Q; R 6 is hydrogen or -CH3; Each R 5 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, or an optionally substituted C1-C3 haloalkyl group; ​ ​ X 9 is -NR L6 -, -C(O)- or -S(O)2-; and R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; ​ ， ​ ​ ​ B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is optionally substituted C1-C4alkylene, optionally substituted C1-C4alkenylene, optionally substituted C1-C4heteroalkylene, -C(0)0-CH(R 6 )-, wherein the C is bound to -C(R 7 R 8 )-, -C(0)NH-CH(R 6 )-, wherein the C is bound to -C(R 7 R 8 )-, optionally substituted C1-C4heteroalkylene, or 3- to 8-membered heteroarylene; ​ X 3 is N or CH; ​ ​ Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 , Y 3 , Y 4 and Y 7 are independently C or N; Y 5 is CR x , CH, CH2or N; Y 6 is CR z , C(O), CH, CH2, or N; R x is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13 is cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R 13 and R 2 , in combination with the atom to which it is attached, forms an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 14 is absent, or R 2 and R 14 , in combination with the atom to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 15 is absent, hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen; C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4heteroalkyl; cyclopropyl; or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3alkyl, or R 6 and R 7 in combination with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3heteroalkyl, optionally substituted C1-C3alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 in combination with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a is independently hydrogen, halogen, optionally substituted C1-C3alkyl, or combines with the carbon to which it is attached to form a carbonyl group; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ and the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R 9 and L, taken in combination with the atom to which it is attached, forms an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6alkyl; or R 9 and R 9’ , in combination with the atom to which they are attached, form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3heteroalkyl, or optionally substituted C1-C3alkyl; R 10a is hydrogen or halogen; R 11 is hydrogen or optionally substituted C1-C3alkyl; R 21 is hydrogen or optionally substituted C1-C3alkyl; ​ X 9 is -NR L6 -, -C(O)- or -S(O)2-; and R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; ​ ， ​ ​ A is optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene, optionally substituted C2-C4alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is optionally substituted C1-C4alkylene, optionally substituted C1-C4alkenylene, optionally substituted C1-C4heteroalkylene, -C(0)0-CH(R 6 )-, wherein the C is bound to -C(R 7 R 8 )-, -C(0)NH-CH(R 6 )-, wherein the C is bound to -C(R 7 R 8 )-, optionally substituted C1-C4heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X 3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 , Y 3 , Y 4 and Y 7 are independently C or N; Y 5 is CR x , CH, CH2or N; Y 6 is CR z , C(O), CH, CH2, or N; R x is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13 is cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R 13 and R 2 , in combination with the atom to which it is attached, forms an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 14 is absent, or R 2 and R 14 , in combination with the atom to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 15 is absent, hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen; C1-C4 alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4 heteroalkyl; cyclopropyl; or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3alkyl, or R 6 and R 7 in combination with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3heteroalkyl, optionally substituted C1-C3alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 in combination with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a is independently hydrogen, halogen, optionally substituted C1-C3alkyl, or combines with the carbon to which it is attached to form a carbonyl group; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ in combination with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R 9 and L, in combination with the atom to which it is attached, forms an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6alkyl; or R 9 and R 9’ , in combination with the atom to which they are attached, form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3heteroalkyl, or optionally substituted C1-C3alkyl; R 10a is hydrogen or halogen; R 11 is hydrogen or optionally substituted C1-C3alkyl; R 21 is hydrogen or optionally substituted C1-C3alkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; and R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; wherein Formula IIa-1 has the following structure: ， Formula IIa-1 or a pharmaceutically acceptable salt thereof, wherein the dotted line represents zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene, optionally substituted C2-C4alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9’ or >CR 9 R 9’ The carbon is bonded to -N(R) 11 C(O)- carbonyl carbon, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heteroalkylene, optionally substituted 6-membered arylene or optionally substituted 5 to 6-membered heteroarylene; G is optionally substituted C1-C4alkylene, optionally substituted C1-C4alkenylene, optionally substituted C1-C4heteroalkylene, -C(0)0-CH(R 6 )-, wherein the C is bound to -C(R 7 R 8 )-, -C(0)NH-CH(R 6 )-, wherein the C is bound to -C(R 7 R 8 )-, optionally substituted C1-C4heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X 1 is optionally substituted C1-C2alkylene, NR, O, or S(O) q ; X 2 is O or NH; X 3 is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4alkyl, optionally substituted C2-C4alkenyl, optionally substituted C2-C4alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; Each R ’ It is independently hydrogen or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 , Y 3 , Y 4 and Y 7 are independently C or N; Y 5 is CR x , CH, CH2or N; Y 6 is CR z , C(O), CH, CH2, or N; R x is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R z is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; R 13 is cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R 13 and R 2 , in combination with the atom to which it is attached, forms an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6- membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6- membered heteroaryl; R 14 is absent, or R 2 and R 14 , in combination with the atom to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 15 is absent, hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen; C1-C4alkyl optionally substituted with halogen, cyano, hydroxyl, or C1-C4heteroalkyl; cyclopropyl; or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3alkyl, or R 6 and R 7 in combination with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3heteroalkyl, optionally substituted C1-C3alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 in combination with the carbon atom to which they are attached form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a is independently hydrogen, halogen, optionally substituted C1-C3alkyl, or combine with the carbon to which they are attached to form a carbonyl group; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ in combination with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R 9 and L, in combination with the atom to which it is attached, forms an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6alkyl; or R 9 and R 9’ , in combination with the atom to which they are attached, form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 is hydrogen, halogen, hydroxyl, optionally substituted C1-C3heteroalkyl, or optionally substituted C1-C3alkyl; R 10a is hydrogen or halogen; R 11 is hydrogen or optionally substituted C1-C3alkyl; and R 21 is hydrogen or optionally substituted C1-C3alkyl; wherein Formula IIIa has the following structure: ， Formula IIIa or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene, or optionally substituted C2-C4alkenylene; Y 8 is , , , , , , or ; L is a linker; R 13 is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 10 is hydrogen, hydroxyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C3alkyl, optionally substituted C1-C6heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7 and R 8 are each independently selected from F or CH3, or R 7 and R 8 in combination with the atom to which they are attached form a 3-membered cycloalkyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C3 alkoxy, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 6-membered heterocycloalkyl. t is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; and R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; wherein Formula IIIb has the following structure: ， Formula IIIb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene, or optionally substituted C2-C4alkenylene; Y 8 is , , , , , , or ; L is a linker; R 13 is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 10 is hydrogen, hydroxyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C3alkyl, optionally substituted C1-C6heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7 and R 8 are each independently selected from F or CH3, or R 7 and R 8 form, together with the atom to which they are attached, a 3-membered cycloalkyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C3 alkoxy, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 6-membered heterocycloalkyl. t is 0, 1, 2, or 3; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; and R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; wherein Formula IIIa-1 has the following structure: ， Formula IIIa-1 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene, or optionally substituted C2-C4alkenylene; Y 8 is , , , , , , or ; L is a linker; X 4 and X 5 each independently is CH2, CH(CH3) or NH; R 13 is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 10 is hydrogen, hydroxyl, optionally substituted C1-C6alkoxy, optionally substituted C1-C3alkyl, optionally substituted C1-C6heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R 7 and R 8 are each independently selected from F or CH3, or R 7 and R 8 form, together with the atom to which they are attached, a 3-membered cycloalkyl group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula IVa has the following structure: ， Formula IVa or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6heteroalkyl; R 2 is optionally substituted C1-C6alkyl; R 3 is optionally substituted C1-C6alkyl or optionally substituted C1-C3heteroalkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula IVb has the following structure: ， Formula IVb or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6heteroalkyl; R 2 is optionally substituted C1-C6alkyl; R 3 is optionally substituted C1-C6alkyl or optionally substituted C1-C3heteroalkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula Va has the following structure: ， Formula Va or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6heteroalkyl; R 2 is optionally substituted C1-C6alkyl; R 3 is optionally substituted C1-C6alkyl or optionally substituted C1-C3heteroalkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula Vb has the following structure: ， Formula Vb or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6heteroalkyl; R 2 is optionally substituted C1-C6alkyl; R 3 is optionally substituted C1-C6alkyl or optionally substituted C1-C3heteroalkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atom(s) to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula Via has the following structure: ， Formula Via or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boronic acid, boronic ester, N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium or glycal; X 6 is CH2or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R 2 is optionally substituted C1-C6alkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula VIb has the following structure: ， Formula VIb or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, trifluoromethyl ketone, boronic acid, boronic ester, N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium or glycal; X 6 is CH2or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R 2 is optionally substituted C1-C6alkyl; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3; wherein Formula Vila has the following structure: ， Formula Vila or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; X 6 , X 7 and X 8 are each independently selected from CH2, CHF, CF2, C=0 or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted C1-C6heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R 2 is optionally substituted C1-C6alkyl; R 3 is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally isotopically enriched with deuterium; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atoms to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3. wherein Formula VIIb has the following structure: ， Formula VIIb or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L is a linker; X 6 , X 7 and X 8 are each independently selected from CH2, CHF, CF2, C=0 or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted C1-C6heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R 2 is optionally substituted C1-C6alkyl; R 3 is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally isotopically enriched with deuterium; z is 0, 1, or 2; X 9 is -NR L6 -, -C(O)- or -S(O)2-; R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 are each independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 , together with the atom(s) to which they are attached and any intervening atoms, form an optionally substituted C3-C8cycloalkyl or 3- to 8-membered heterocyclyl; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3. wherein Formula XI has the following structure: ， Formula XI or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, an optionally substituted 5- to 6-membered heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene; W is an optionally substituted 3- to 10-membered heterocycloalkyl or an optionally substituted 3- to 10-membered cycloalkyl; X 4 is CH2or NH; R 1 is optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6alkynyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they can form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 , R 5 , R 6 , and R 7 are each hydrogen; or R 4 and R 6 are hydrogen and R 5 and R 7 , together with the atoms to which they are attached, combine to form an optionally substituted four-membered cycloalkyl; or R 5 and R 7 are hydrogen and R 4 and R 6 , together with the atoms to which they are attached, combine to form an optionally substituted four-membered cycloalkyl; R 10 is -OR 11 or -NR 12 R 13 ; R 11 , R 12 , and R 13 are each independently optionally substituted Ci-C6alkyl, optionally substituted Ci-C6heteroalkyl, or R 12 and R 13 in combination form an optionally substituted 3- to 10-membered heterocycloalkyl group; Each R 33 Independently, it is a halogen, an optionally substituted C1-C3 alkyl group, an optionally substituted C1-C3 alkoxy group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkyl group; and t is 0, 1, 2, or 3.

2. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3.

5. A method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3.

6. A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3.

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