Macrocyclic RAS inhibitors

Abstract

This disclosure features macrocyclic compounds of formula (Ia) or (Ib) that can inhibit the Ras protein, as well as pharmaceutical compositions and protein conjugates thereof, and their use in the treatment of cancer. JPEG2026515697000484.jpg60165

Description

[Background technology]

[0001] The vast majority of small molecule drugs act by binding to functionally important pockets on target proteins, thereby regulating the activity of those proteins. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from engaging with its substrate. The fact that many such drug / target interaction pairs are known can be misleading to some extent, leading people to believe that, given a reasonable amount of time, effort, and resources, it is possible to discover small molecule modulators for most, if not all, proteins. This is far from the truth. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules. Non-patent document 1. The other 90% are currently considered refractory or refractory to the small molecule drug discovery described above. Such targets are commonly referred to as "undrug-dealable." These undrug-dealable targets represent a vast and untapped reservoir of clinically important human proteins. Therefore, there is considerable interest in discovering novel molecular modalities that can control the function of these undrug-dealable targets.

[0002] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play essential roles in various human cancers and are therefore appropriate targets for anticancer therapy. In fact, mutations in the Ras protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the Ras protein due to mutation activation, overexpression, or upstream activation is common in human tumors, and mutation activation in Ras is frequently found in human cancers. For example, activation of a mutation at codon 12 in the Ras protein functions by inhibiting both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly distorting the population of Ras mutant proteins into an "on" (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. In particular, Ras exhibits picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations in codon 13 of Ras (e.g., G13C) and codon 61 (e.g., Q61K) also contribute to oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts against Ras over the past several decades, only two drugs targeting the K-Ras G12C variant (sotrasib and adaglasib) have been approved in the United States. Further efforts are needed to identify additional drugs for cancers promoted by various Ras mutations. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Bojadzic and Buchwald,Curr Top Med Chem 18:674-699(2019) [Overview of the project]

[0005] Ras inhibitors are provided herein. The approach described herein requires the formation of a high-affinity triplicate or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., Ras) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the Ras inhibitors described herein include a novel binding pocket cytosol in Ras, which drives the formation of a high-affinity triplicate or conjugate between the Ras protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). While not theoretically bound, one way in which the inhibitory effect on Ras is affected by the compounds and complexes or conjugates of the present invention is the formation of steric occlusion of the interaction site between Ras and downstream effector molecules such as RAF and PI3K, which the inventors believe is necessary for the growth of oncogenic signals.

[0006] Therefore, in certain embodiments, this disclosure relates to compounds having the structure of formula Ia or formula Ib:

[0007] [ka]

[0008] or characterized by a pharmaceutically acceptable salt thereof (in the formula, Q is an optionally substituted 7-12 membered bicyclic arylene, an optionally substituted 7-12 membered bicyclic heteroarylene, or an optionally substituted 7-12 membered bicyclic heterocyclene, where the first ring in Q is bonded to X and the second ring in Q is bonded to A, where X is a linear C1-C3 alkylene, -O-, -S(O)O-2-, *-CH2-O-, *-CH2-S(O)O-2-, *-O-CH2-, or *-CH2-S(O)O-2-, where "*" is -C(R 7 )(R 8 ) represents the part of X that is joined to ), Y is -O-, -NH-, or -N(C1-C3 alkyl)-, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, or an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. L is a linker, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, optionally substituted C6 aryl groups, or optionally substituted 3-7 member heterocyclines. R 10 is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl, R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, R 8 This includes hydrogen, halogens, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and optionally substituted C6-C 10Aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl, or R 7 and R 8 together form =CH2, optionally substituted C3-C6 cycloalkyl, or 3- to 7-membered saturated heterocyclyl, or R 8 and the ring atoms in Q, R 7 the carbon atom to which is attached, and X forms a 4- to 9-membered saturated or unsaturated heterocyclyl fused to Q, R 6 is hydrogen or -CH3, each R 5 is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl, p is 0, 1, 2, or 3, 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 each is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 and R L6 any two of which together with the atoms to which they are attached and any intervening atoms form optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocyclyl).

[0009] In one aspect, the invention provides a compound having a structure of formula IIa or formula IIb:

[0010] [ka]

[0011] or characterized by a pharmaceutically acceptable salt thereof (wherein the formula, the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. B does not exist, or -CH(R 9 )-,>C=CR 9 R 9’ Or >CR 9 R 9’ (The carbon in question is -N(R 11 (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L is a linker, X 3 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 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 ’ These are independently hydrogen, or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 CR x , CH, CH2, or N, Y 6 CR z , C(O), CH, CH2, or N, R x These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R z These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R 13 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 13 and R 2 These, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 2It is either absent, or hydrogen, 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, or optionally substituted 5 or 6-membered heteroaryl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 These are C1-C4 alkyl, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 heteroalkyl groups. R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’, forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halogens, optionally substituted C1-C3 alkyl groups, or together with the carbon to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl, R 10a is hydrogen or halogen, R 11 is hydrogen or optionally substituted C1-C3 alkyl, R 21 is hydrogen or optionally substituted C1-C3 alkyl, 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 each is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 、R L2 、R L3 、R L4 、R L4 、R L5 、and R L6 any two of which, together with the atoms to which they are attached and any intervening atoms, form optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocyclyl).

[0012] In one embodiment, the present invention features a compound having the structure of formula IIa-1:

[0013]

Chemical formula

[0014] or a pharmaceutically acceptable salt thereof (wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. B does not exist, or -CH(R 9 )-,>C=CR 9 R 9’ Or >CR 9 R 9’ (The carbon in question is -N(R 11 (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L is a linker, X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, 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-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 ’ These are independently hydrogen, or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 CR x , CH, CH2, or N, Y 6 CR z , C(O), CH, CH2, or N, R x These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R z These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R 13 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 13 and R 2 These, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 2It is either absent, or hydrogen, 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, or optionally substituted 5 or 6-membered heteroaryl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 These are C1-C4 alkyl, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 heteroalkyl groups. R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’, forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halogens, optionally substituted C1-C3 alkyl groups, or together with the carbon to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10This is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl. R 10a is hydrogen or halogen, R 11 is hydrogen, or optionally substituted C1-C3 alkyl, R 21 (wherein this is hydrogen, or optionally substituted C1-C3 alkyl).

[0015] In one embodiment, the present invention relates to a compound having the structure of formula IIIa or formula IIIb:

[0016] [ka]

[0017] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene, or an optionally substituted C2-C4 alkenylene, and Y 8 teeth,

[0018] [ka]

[0019] And, L is a linker, R 13 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-15 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. R 2These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R 10 These are hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. R 7 and R 8 Each of these is independently selected from F or CH3, or R 7 and R 8 These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6Any two of these atoms, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycline.

[0020] In one embodiment, the present invention relates to a compound having the structure of formula IIIa-1:

[0021] [ka]

[0022] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene, or an optionally substituted C2-C4 alkenylene) Y 8 teeth,

[0023] [ka]

[0024] And, L is a linker, X 4 and X 5 Each of these is independently CH2, CH(CH3), or NH. R 13 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-15 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. R 2These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R 10 These are hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. R 7 and R 8 Each of these is independently selected from F or CH3, or R 7 and R 8 These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0025] In one embodiment, the present invention relates to a compound having the structure of formula IVa or formula IVb:

[0026] [ka]

[0027] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, R 1This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0028] In one embodiment, the present invention relates to a compound having the structure of formula Va or formula Vb:

[0029] [ka]

[0030] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0031] In some embodiments, the present invention relates to compounds having the structure of formula VIIa or formula VIIb:

[0032] [ka]

[0033] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, X 6 , X 7 , and X 8 Each of these is independently selected from CH2, CHF, CF2, C=O, or O. m is either 1 or 2. n is either 0 or 1. R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted heterocycloalkyl. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0034] In one embodiment, the present invention relates to a compound having the structure of formula XI:

[0035] [ka]

[0036] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene) W is an optionally substituted 3-10 member heterocycloalkyl group, or an optionally substituted 3-10 member cycloalkyl group. X 4 It is CH2 or NH, R 1 These are optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkenyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-15 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, and R 3 It is hydrogen, or R 2 and R 3 These, together with the atoms to which they are bonded, form optionally substituted 8-14 member heterocycloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of them is either hydrogen or R 4 and R 6 is hydrogen, and R 5 and R 7 These, together with the atoms to which they are bonded, form an optionally substituted four-membered cycloalkyl group, or R5 and R 7 is hydrogen, and R 4 and R 6 These, together with the atoms to which they are bonded, form optionally substituted four-membered cycloalkyl groups. R 10 is -OR 11 or -NR 12 R 13 And, R 11 , R 12 , and R 13 Each of these is independently either an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, or R 12 and R 13 They combine to form optionally substituted 3-10 member heterocycloalkyl groups. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0037] In some embodiments, the present invention is characterized by the compounds listed in Table 1 or pharmaceutically acceptable salts thereof. Furthermore, pharmaceutical compositions are also provided that include a compound of any of the above embodiments and embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0038] A method for performing cancer treatment on a subject requiring such treatment is also provided, comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, a method is also provided for carrying out treatment in a subject requiring treatment for a Ras protein-related disorder, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0040] A method for inhibiting the Ras protein in cells is further provided, comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0041] Any limitations considered in relation to one embodiment of the present invention are specifically intended to be applicable to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention can be used in any manner of the present invention, and any compound or composition of the present invention can be produced or utilized using any manner of the present invention.

[0042] Definitions and Chemical Terms In this application, unless otherwise clearly indicated by context, (i) the term “one (a)” means “one or more”; (ii) is used to mean “and / or” unless it is explicitly indicated that it means only alternative expressions or that such alternative expressions are mutually exclusive, however this disclosure supports the definitions that refer only to alternative expressions and to “and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or processes, whether presented by themselves or together with one or more additional components or processes; and (iv) where a scope is indicated, it includes endpoints.

[0043] As used herein, the term “approximately” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. In certain embodiments, unless otherwise specified or otherwise evident from the context (for example, if such a number may exceed 100% of the possible values), the term “approximately” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) the stated value.

[0044] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms directly bonded by a covalent bond. As used herein, “compounds of the present invention” and similar terms mean, whether expressly stated or not, the compounds of formula I and its subformulas, e.g., the compounds of Table 1, in addition to their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers, as described herein.

[0045] The term "wild-type" refers to an entity with a structure or activity that is found in a "normal" state or context in nature (as opposed to mutants, diseases, modified forms, etc.). Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0046] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., one or more atoms are substituted with different isotopes, such as deuterium-substituted hydrogen). Unless otherwise specified or made clear from the context, the described structures can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0047] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, including enantiomers and diastereomers, are intended. Compounds of this disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active forms or in racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also exist among the compounds described herein, and all such stable isomers are intended in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and may be isolated as mixtures of isomers or as separated isomers.

[0048] In some embodiments, one or more compounds described herein may exist in different tautomerized forms. As will be apparent from the context, unless explicitly excluded, references to such compounds encompass all such tautomerized forms. In some embodiments, the tautomerized form arises from the exchange of a single bond with an adjacent double bond and the accompanying transfer of protons. In certain embodiments, the tautomerized form may be a prototropic tautomer, which is a protonated state of an isomer having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. In some embodiments, the tautomers can be in equilibrium or sterically fixed to one form by appropriate substitution. In certain embodiments, the tautomers arise from acetal interconversion.

[0049] Unless otherwise specified, the structures described herein also mean that they include different compounds only in the presence of one or more isotopic enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Isotope-labeled compounds (e.g., 3 H and 14 Compounds labeled with 1C may be useful in compound or substrate tissue partitioning assays. Tritium labeling (i.e., 3 H), and carbon-14 (i.e., 14 C) Isotopes can be useful due to their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e., 2 Substitution with H, etc., can lead to increased metabolic stability, resulting in certain therapeutic benefits (e.g., longer in vivo half-life or reduced dosage). In some embodiments, one or more hydrogen atoms are 2 H or 3 Replaced by H, or one or more carbon atoms 13 C or 14 It is replaced by carbon-enriched carbon. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as 14F are useful in positron emission tomography (PET) studies to test substrate receptor 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 unlabeled reagents with isotopically labeled reagents, following a procedure similar to the procedure disclosed for the compounds of the present invention as described herein.

[0050] Non-limiting examples of portions of the compound of the present invention that may contain one or more deuterium substitutions (where any position "R" may also be deuterium (D)) are:

[0051] [ka]

[0052] There is. Additional examples include, for example, compounds of formulas I, II, III, IV, V, and VI, and their subformulas.

[0053] [ka]

[0054] This includes deuteration of parts such as and similar parts. Furthermore, deuteration of any available position in any A part of the compounds of the formulas described herein is also considered, for example,

[0055] [ka]

[0056] Furthermore, deuterium substitution also affects the linker moiety in the compounds of the present invention, for example,

[0057] [ka]

[0058] This can occur in the following locations. Furthermore, deuterium substitution can also occur in the linker moiety of the compounds of the present invention, for example,

[0059] [ka]

[0060] This can occur in [location]. Furthermore, deuterium substitution also affects the linker moiety in the compounds of the present invention, for example,

[0061] [ka]

[0062] This can occur in [location]. In further embodiments, silylation substitutions, such as those in linkers as shown below, are also considered.

[0063] [ka]

[0064] As is known from the prior art, many chemical substances can exist in various different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or explained herein can be provided or used in hydrate or solvate form.

[0065] In various parts of this specification, substituents of the compounds of this disclosure are disclosed in groups or ranges. This disclosure is specifically intended to include each individual partial combination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions in which substituents are disclosed in groups or ranges, this disclosure is intended to include individual compounds and groups of compounds (e.g., genus and sub-genus) including each and all individual member subcombinations at each position, unless otherwise specified.

[0066] 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”). It is not intended to mean that feature “X” (e.g., alkyl) itself is optional. As described herein, a particular compound of interest may contain one or more “optionally substituted” moieties. Generally, “substituted” means that one or more hydrogens of a given moiety are replaced by a suitable substituent, e.g., any substituent or group described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each of its substitutable positions, and if two or more positions of any given structure can be replaced by two or more substituents selected from a particular group, the substituents are either the same at all positions or different at all positions. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl”, the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The substituent combinations conceivable in this disclosure preferably result in the formation of stable or chemically suitable compounds. The term “stable,” as used herein, means a compound that remains substantially unchanged when subjected to conditions anticipating production, detection, and, in certain embodiments, recovery, purification, and use for one or more purposes disclosed herein.

[0067] Suitable monovalent substituents on the replaceable carbon atoms of the "optionally substituted" group are, independently, deuterium, halogen, and -(CH2)O-4R ° ,-(CH2)0-4OR ° -O(CH2)O-4Ro, -O-(CH2)0-4C(O)OR°, -(CH2)0-4CH(OR ° )2, -(CH2)0-4SR °-(CH2)O-4Ph (may be substituted with R°), -(CH2)O-4O(CH2)O-1Ph (may be substituted with R°), -CH=CHPh (may be substituted with R°), -(CH2)O-4O(CH2)O-1-pyridyl (may be substituted with R°), 4-8 member saturated or unsaturated heterocycloalkyl (e.g., pyridyl), 3-8 member saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2)O-4N(R ° )2, -(CH2)0-4N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2)0-4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2)0-4N(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)O-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)2OR°;-(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 linear or branched alkylene)ON(R°)2; or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° may be substituted as defined below, independently of hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl ring), or nitrogen, oxygen, or sulfur The R° may be a 3-6 member saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from the above, or, notwithstanding the above definition, two independently existing R° may, together with the intervening atom(s), form a 3-12 member saturated ring, partially unsaturated ring, or aryl mono-ring or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and these may be substituted as defined below.

[0068] A suitable monovalent substituent on R (or a ring formed by two independent Rs together with the atoms in between) is independently a halogen, -(CH2)O-2R ● ,-(HaroR ● ), -(CH2)O-2OH, -(CH2)O-2OR● ,-(CH2)0-2CH(OR ● )2, -O(HaroR ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● ,-(CH2)0-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● ,-(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C1-4 straight or branched alkylene)C(O)OR ● , or -SSR ● (In the formula, each R ● It may be unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, and independently selected from C1-C4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.) Preferred divalent substituents on the saturated carbon atom of R° include =O and =S.

[0069] Preferred divalent substituents on the saturated carbon atom of the "optionally substituted" group include: =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- are listed, and in the formula, R exists independently in each case. *The group is selected from unsubstituted 5-6 membered, saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from hydrogen, C1-6 aliphatic which can be substituted as defined below, or nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to a substituted carbon adjacent to the "optionally substituted" group is -O(CR * 2) 2-3O- is an example (where each independent R * (These are selected from hydrogen, C1-6 aliphatic atoms which can be substituted as defined below, or from unsubstituted, 5-6 membered, saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.)

[0070] R * Preferred substituents on the aliphatic group are halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, and is independently a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or nitrogen, oxygen, or sulfur.

[0071] A suitable substituent on the substitutable nitrogen of the "optionally substituted" group is -R † , including, -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 † ;In the formula, each R † R may be an unsubstituted 3-6 member saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from hydrogen, C1-6 aliphatic (which may be substituted as defined below), unsubstituted -OPh, or nitrogen, oxygen, or sulfur, or two independently present R † These, together with the intervening atom(s), form an unsubstituted 3- to 12-membered saturated ring, a partially unsaturated ring, or an aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0072] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2 (wherein each R ● It is either unsubstituted, or, if preceded by "halo", substituted by only one or more halogens, independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 (Ph, or selected from 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 include =O and =S.

[0073] As used herein, the term "acetyl" means the group -C(O)CH3. As used herein, the term "alkoxy" means -O-C1-C 20Alkyl group refers to an alkyl group, where the alkoxy group is bonded to the rest of the compound via an oxygen atom.

[0074] As used herein, the term “alkyl” refers to a saturated, linear 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., linear), and in some embodiments, the alkyl group is branched. Alkyl groups are exemplified by, but are not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0075] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a saturated hydrocarbon, either linear or branched, by removing two hydrogen atoms, exemplified by methylene, ethylene, isopropylene, and the like. x -C y The term "alkylene" refers to an alkylene group having x to y carbon atoms. 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 with one, two, three, or four substituents as defined herein.

[0076] As used herein, the term “alkenyl” refers to a monovalent, linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds, unless otherwise specified, and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. As used herein, the term “alkenylene” refers to a divalent, linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds, unless otherwise specified.

[0077] As used herein, the term "alkynyl" refers to a monovalent, linear or branched group consisting of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbon atoms) containing a carbon-carbon triple bond, exemplified by ethynyl and 1-propynyl.

[0078] As used herein, the term "alkynyl sulfone" refers to a structure

[0079] [ka]

[0080] (wherein R is any chemically suitable substituent as described herein.) represents a group containing As used herein, the term "amino" means -N(R † )2, for example, represents -NH2 and -N(CH3)2.

[0081] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more amino moieties. As used herein, the term “amino acid” refers to a molecule having a side chain, an amino group, and an acidic group (e.g., -CO2H or -SO3H), and an amino acid is bonded to a parent molecule by a side chain, an amino group, or an acidic group (e.g., a side chain). As used herein, the term “amino acid” in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by the formation of 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, and in some embodiments, the amino acid is an L-amino acid. “Standard amino acid” means any of the 20 standard L-amino acids commonly found in naturally occurring peptides. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolicine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0082] As used herein, the term “aryl” refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein the ring bonded to the pendant group is aromatic. Examples of aryl groups include phenyl, naphthyl, phenantrenyl, and anthracenyl. The aryl ring may be bonded to its pendant group by any heteroatom or carbocyclic atom that results in a stable structure, and unless otherwise specified, any of the ring atoms may be optionally substituted.

[0083] As used herein, the term "C0" represents a bond. For example, part of the term -N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0084] As used herein, the terms "carbocyclic" and "carbocyclyl" refer to a monovalent C3-C3 compound with optional substitution. 12 This refers to monocyclic, bicyclic, or tricyclic structures, which may be bridged, condensed, or spirocyclic, where all rings are formed of carbon atoms and at least one ring is non-aromatic. Examples of carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups include cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, and dekalinyl. A carbocyclic ring can be bonded to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms may be substituted.

[0085] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O. As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the corresponding aprotonated group.

[0086] As used herein, the term "cyano" refers to the -CN group. As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, may be crosslinked, condensed, or a spirocyclic group having 3 to 8 ring carbons, exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0087] As used herein, the term "cycloalkenyl" means a monovalent, non-aromatic, saturated cyclic hydrocarbon group, which, unless otherwise specified, may be bridged, condensed, or a spirocyclic group having 3 to 8 ring carbons and containing one or more carbon-carbon double bonds.

[0088] As used herein, the term “diastereomer” means stereoisomers that are not mirror images of each other and cannot be superimposed on each other. As used herein, “enantiomer” means each individual optically active form of the compound of the present invention having at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98% optical purity or enantiomer excess (measured by methods standard in the art).

[0089] The term "guanidyl" refers to the structure

[0090] [ka]

[0091] (wherein each R independently represents any chemically suitable substituent as described herein.) As used herein, the term "guanidinoalkylalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more guanidyl moieties.

[0092] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen atom is substituted with a halogen. As used herein, the term "haloalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more identical or different halogen moieties.

[0093] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine. As used herein, the term “heteroalkyl” refers to an “alkyl” group (as defined herein) in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the ends of the group.

[0094] As used herein, the term “heteroaryl” refers to a monovalent, monocyclic or polycyclic cyclic structure containing at least one complete aromatic ring. That is, these contain 4n+2 π electrons within the monocyclic or polycyclic ring system and at least one ring heteroatom selected from N, O, or S within 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) carbon atoms. The term “heteroaryl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings, such as a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindylol. The heteroaryl ring can be bonded to its pendant group at any ring atom that provides a stable structure, and unless otherwise specified, any of the ring atoms may be substituted. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0095] As used herein, the term “heterocycloalkyl” refers to a monovalent, monocyclic, bicyclic, or polycyclic ring system, which may be bridged, condensed, or spirocyclic, in which at least one ring is non-aromatic, and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six- and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl 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) carbon atoms. The term “heterocycloalkyl” also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbons or heteroatoms bridge two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, pyridine ring, or pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthilidinyl. Heterocycloalkyl rings can be bonded to their pendant group at any ring atom that results in a stable structure, and any of the ring atoms may be optionally substituted unless otherwise specified.

[0096] As used herein, the term "hydroxy" refers to the -OH group. As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0097] As used herein, the term “isomer” means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention. Compounds of the present invention may have one or more chiral centers or double bonds and are therefore recognized to exist as stereoisomers, e.g., double bond 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 illustrated herein, i.e., compounds of the present invention, are recognized as having all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereoisomerically pure forms) and enantiomers. The present invention encompasses both enantiomers and mixtures of stereoisomers, such as racemic compounds. Mixtures of enantiomers and stereoisomers of the compounds of the present invention can typically be separated into their constituent enantiomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0098] As used herein, the term “linker” refers to a divalent organic moiety that links a first part (e.g., a part of a macroring) to a second part (e.g., a second part of the same macroring). In some embodiments, the linker results in a compound capable of achieving an IC50 of 2 μM or less in the Ras-RAF disruption assay protocol provided herein.

[0099] The purpose of this biochemical assay is to measure the ability of the test compound to facilitate the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclophyllin A, and the resulting ternary complex is BRAF. RBD It disrupts binding to constructs and inhibits Ras signaling via RAF effectors.

[0100] 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, untagged cyclophyllin A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAF were tested. RBD These compounds were combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compounds were present in the plate wells as a 10-point 3-fold dilution series, starting at a final concentration of 30 μM. After incubation at 25°C for 3 hours, the mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for a further 1.5 hours. The TR-FRET signal was read using a microplate reader (excitation 320 nm, fluorescence 665 / 615 nm). Compounds that promote the disruption of the Ras:RAF complex were identified as those that induced a decrease in the TR-FRET ratio compared to the DMSO control well.

[0101] This assay can also be used to evaluate selectivity. In some embodiments, the compounds of the present invention are more selective to one or more specific Ras variants than other Ras variants or wild types compared to those known in the art. For example, compounds of formula Ia and its subformulas may be more selective to K-Ras G12C or K-Ras G13C compared to K-Ras wild type. For example, compounds of formula IIa-1 and formula IIa-2 may be more selective to K-Ras G12C, K-Ras G13C, K-Ras G12D, or K-Ras G12V compared to K-Ras wild type. For example, compounds of formula IIIa-1 and formula IIIa-2 may be more selective to K-Ras G12D or K-Ras G12V compared to K-Ras wild type. For example, compounds of formula IVa and its subformulas may be more selective to K-Ras G12C or K-Ras G13C compared to K-Ras wild type. For example, compounds of formula VIa and its subformula may be more selective for K-Ras G12D compared to K-Ras wild-type. For example, compounds of formula VIIa and its subformula may be more selective for K-Ras G12D compared to K-Ras wild-type.

[0102] While not bound by theory, the inventors hypothesize that non-covalent interactions between "L" and chaperone proteins (e.g., cyclophyllin 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 the present invention to form complexes and act as RAS inhibitors. The inventors also hypothesize that "L" may impart structural rigidity to the compounds, thereby optimizing these non-covalent interactions and ultimately contributing to the inhibition of Ras activity.

[0103] In some embodiments, the linker contains 20 or fewer linear atoms. In some embodiments, the linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear 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.

[0104] As used herein, the "monovalent organic moiety" is less than 500 kDa. In some embodiments, the "monovalent organic moiety" is less than 400 kDa. In some embodiments, the "monovalent organic moiety" is less than 300 kDa. In some embodiments, the "monovalent organic moiety" is less than 200 kDa. In some embodiments, the "monovalent organic moiety" is less than 100 kDa. In some embodiments, the "monovalent organic moiety" is less than 50 kDa. In some embodiments, the "monovalent organic moiety" is less than 25 kDa. In some embodiments, the "monovalent organic moiety" is less than 20 kDa. In some embodiments, the "monovalent organic moiety" is less than 15 kDa. In some embodiments, the "monovalent organic moiety" is less than 10 kDa. In some embodiments, the "monovalent organic moiety" is less than 1 kDa. In some embodiments, the "monovalent organic moiety" is less than 500 g / mol. In some embodiments, the "monovalent organic moiety" is in the range of 500 g / mol to 500 kDa.

[0105] As used herein, the term “stereoisomer” means all possible different isomeric and structural forms that a compound may have (e.g., any compound of any formula described herein), in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, including atropisomers, all diastereomers, enantiomers, or conformational isomers. Some of the compounds of the present invention may exist in different tautomers, all of which are included in the scope of the present invention.

[0106] As used herein, the term "sulfonyl" refers to the -S(O)2- group. As used herein, the term "thiocarbonyl" means a -C(S)- group. As used herein, the term "vinyl ketone" means a group containing a carbonyl group directly bonded to a carbon-carbon double bond.

[0107] As used herein, the term "vinyl sulfone" means a group containing a sulfonyl group directly bonded to a carbon-carbon double bond. As used herein, the term "inon" means structure

[0108] [ka]

[0109] (wherein R is any chemically suitable substituent as described herein.) represents a group containing Those skilled in the art reading this disclosure will understand that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salts, protected forms, prodrugs, esters, isomers (e.g., optical or structural isomers), and isotopic forms. In some embodiments, reference to a particular compound may relate to a particular form of that compound. In some embodiments, reference to a particular compound may relate to that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing a structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing other structural isomers of the double bond ((E) or (Z)); and a preparation in which one or more atoms are isotopes different from those present in the reference preparation may be considered a different form. [Modes for carrying out the invention]

[0110] compound Ras inhibitors are provided herein. The approach described herein requires the formation of a high-affinity triplicate or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., Ras) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the Ras inhibitors described herein include a novel binding pocket cytosol in Ras, which drives the formation of a high-affinity triplicate or conjugate between the Ras protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). While not theoretically bound, the inventors believe that one way in which the inhibitory effect on Ras is affected by the compounds and complexes or conjugates of the present invention is the formation of steric occlusion of the interaction site between Ras and downstream effector molecules such as RAFs, which is necessary for the growth of oncogenic signals.

[0111] While not bound by theory, the inventors hypothesize that covalent, non-covalent, or combination-of-covalent interactions between the compounds of the present invention and Ras and chaperone proteins (e.g., cyclophyllin A) may contribute to the inhibition of Ras activity. In some embodiments, the compounds of the present invention form covalent adducts with side chains of the Ras protein (e.g., the histidine side chain at position 61 of a mutant Ras protein). Covalent adducts may also be formed with other side chains of Ras. Furthermore, or alternatively, non-covalent interactions may be at play: 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.

[0112] Therefore, various Ras proteins can be inhibited by the compounds of the present invention (for example, K-Ras, N-Ras, H-Ras at positions 12, 13, and 61, and their variants, e.g., G12C, G12D, G12V, G12S, G13C, G13D, Q61H, Q61K, Q61R, and Q61L, as well as others described herein, or combinations thereof).

[0113] Methods for measuring covalent adduct formation are known in the art. One method for measuring covalent adduct formation is to perform a "crosslinking" assay under these conditions. Note - The following protocol describes the procedure for monitoring the crosslinking of K-Ras G12C (GMP-PNP) to the compound of the present invention. This protocol can also be performed by substituting other Ras proteins or nucleotides.

[0114] The purpose of this biochemical assay is to measure the ability of the test compound to covalently label nucleotide-loaded K-Ras isoforms. In an assay buffer containing 12.5 mM HEPES (pH 7.4), the stock solution of 75 mM NaCl, 1 mM MgCl2, 1 mM BME (e.g., K-Ras G12C or G13C when testing cysteine ​​Ras variants), 5 μM cyclophyllin A, 2 μM test compound, and 5 μM GMP-PNP-loaded K-Ras(1-169) G12C is diluted 10-fold to obtain a final concentration of 0.5 μM. The final sample volume is 100 μL.

[0115] The sample is incubated at 25°C for up to 24 hours, then quenched by adding 10 μL of 5% formic acid. The quenched sample is centrifuged in a benchtop centrifuge at 15,000 rpm for 15 minutes, and then 10 μL of aliquots are injected into a reversed-phase C4 column and eluted into a mass spectrometer while increasing the acetonitrile gradient in the mobile phase. Raw data can be analyzed using Waters MassLynx MS software, and binding ratios are calculated from the reverse-convoluted protein peaks for labeled and unlabeled K-Ras.

[0116] Therefore, in this specification, compounds having the structure of formula Ia or formula Ib:

[0117] [ka]

[0118] Alternatively, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof are provided (in the formula, Q is an optionally substituted 7-12 membered bicyclic arylene, an optionally substituted 7-12 membered bicyclic heteroarylene, or an optionally substituted 7-12 membered bicyclic heterocyclene, where the first ring in Q is bonded to X and the second ring in Q is bonded to A, where X is a linear C1-C3 alkylene, -O-, -S(O)O-2-, *-CH2-O-, *-CH2-S(O)O-2-, *-O-CH2-, or *-CH2-S(O)O-2-, where "*" is -C(R 7 )(R 8 ) represents the part of X that is joined to ), Y is -O-, -NH-, or -N(C1-C3 alkyl)-, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, or an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. L is a linker, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, optionally substituted C6 aryl groups, or optionally substituted 3-7 member heterocyclines. R 10 is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl, R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, R 8 This includes hydrogen, halogens, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and optionally substituted C6-C 10 It is an aryl, an optionally substituted 4-8 member heteroaryl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 3-7 member heterocycline, or R 7 and R 8 Together, they form =CH2, optionally substituted C3-C6 cycloalkyl groups, or 3-7 member saturated heterocyclines, or R 8 and the ring atoms in Q, R 7 The carbon atoms bonded to Q, as well as X, form a 4- to 9-membered saturated or unsaturated heterocycline condensed with Q, and R 6 is hydrogen or -CH3, Each R 5 These are independently halogens, optionally substituted C1-C3 alkyls, or optionally substituted C1-C3 haloalkyls. p is 0, 1, 2, or 3. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of these atoms, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycline.

[0119] In some embodiments, the compound is given by formula Ia-1:

[0120] [ka]

[0121] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (in the formula, Q is an optionally substituted 7-12 membered bicyclic arylene, an optionally substituted 7-12 membered bicyclic heteroarylene, or an optionally substituted 7-12 membered bicyclic heterocyclene, where the first ring in Q is bonded to X and the second ring in Q is bonded to A, where X is a linear C1-C3 alkylene, -O-, -S(O)O-2-, *-CH2-O-, *-CH2-S(O)O-2-, *-O-CH2-, or *-CH2-S(O)O-2-, where "*" is -C(R 7 )(R 8 ) represents the part of X that is joined to ), Y is -O-, -NH-, or -N(C1-C3 alkyl)-, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, or an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. L is a linker, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, optionally substituted C6 aryl groups, or optionally substituted 3-7 member heterocyclines. R 10 This is hydrogen, a halogen, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C3 heteroalkyl, or an optionally substituted C1-C3 hydroxyalkyl.

[0122] R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, R 8 This includes hydrogen, halogens, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and optionally substituted C6-C10 It is an aryl, an optionally substituted 4-8 member heteroaryl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 3-7 member heterocycline, or R 7 and R 8 They combine to form =CH2, optionally substituted C3-C6 cycloalkyl groups, or 3-7 member saturated heterocyclines, or, R 8 R is a ring atom in Q. 7 Together with the carbon atom to which it is bonded, and X, it forms a 4- to 9-membered saturated or unsaturated heterocycline condensed with Q, R 6 is hydrogen or -CH3, Each R 5 These are independently halogens, optionally substituted C1-C3 alkyls, or optionally substituted C1-C3 haloalkyls. p is 0, 1, 2, or 3.

[0123] In some embodiments, the compound is given by formula Ia-2:

[0124] [ka]

[0125] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X is a bond, -O-, -CH2-, -CH(CH3)-, *-CH2-O-, or -CH2-CH2-, where "*" is C(R 4 )(R 5 This represents the part of X that is joined to ), Y, -O- or -NH-, L is a linker, R 3 These are -C1-C4 alkyl, -(CH2)0-1-(C3-C6 cycloalkyl), or -C4-C6 cycloalkyl. R 7 is hydrogen, halo, or C1-C3 alkyl, R 8is hydrogen, halo, -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, =CH 2、 Alternatively, they form a C3-C6 cycloalkyl group, or R 8 Q, together with the ring atom of Q, the carbon atom to which it is bonded, and X, forms a 5-7 member saturated heterocycline. Q is a bicyclic arylene, a bicyclic heteroarylene, or a bicyclic heterocycline, where the first ring in Q is bonded to X and the second ring in Q is bonded to Z, and Q is a -C1-C5 alkyl optionally substituted with =O, -CN, halogen, one or more independently selected halos, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -O-(C2-C3 alkynyl), -(C3-C6 cycloalkyl), or 4-7 member saturated heterocyclyl, one or more independently -O-(C1-C3 alkyl) optionally substituted with a selected halo, C2-C5 alkenyl, C2-C3 alkynyl, -S(O)2-C1-C3 alkyl, C1-C3 alkyl optionally substituted with one or more independently selected -CN or -OH, -S(O)2-C1-C3 alkyl, -C(CH2)O- saturated heterocyclyl, -O- saturated heterocyclyl, O-cycloalkyl, or -O-aryl optionally substituted with -(CH2)O- 1-C3-C6 cycloalkyl, one or more independently selected halos, C1-C3 alkyl optionally substituted with -CN, -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -(CH2)0-1-heteroaryl optionally substituted with -O-aryl, one or more independently selected halos, =O, C1-C3 alkyl optionally substituted with -CN, -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O- -(CH2)0-1-heterocyclyl optionally substituted with saturated heterocyclyl, O-cycloalkyl, or -O-aryl, one or more independently selected halos, -CN, -C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, -(CH2)0-1-aryl optionally substituted with O-cycloalkyl, or -O-aryl, -C(O)-NH-(C1-C3 alkyl), -C(O)-N(C1-C3 alkyl)2,It is optionally substituted with one or more independently selected substituents from C2-C3 alkenylene=NO-(C1-C3 alkyl) which are optionally substituted with C3-C6 cycloalkyl groups, or Two substituents on the same or adjacent ring atoms of Q combine to form a 5- to 7-membered monocyclic ring, or a 6- to 12-membered bicyclic ring optionally substituted with one or more independently selected halos, =O, -CN, C1-C3 alkyl, or -O-C1-C3 alkyl, which are then condensed onto Q.

[0126] In some embodiments, the compound is given by formula Ia-3:

[0127] [ka]

[0128] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is of formula (Ic):

[0129] [ka]

[0130] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, Q is a 5,6 bicyclic heteroarylene, a 5,6 bicyclic heterocyclene, a 6,6 bicyclic heteroarylene, or a 6,6 bicyclic heterocyclene, where Q can be optionally substituted. In some embodiments, Q is a 5,6 bicyclic heteroarylene, where Q can be optionally substituted. In some embodiments, Q is a 5,6 bicyclic heterocyclene, where Q can be optionally substituted. In some embodiments, Q is a 6,6 bicyclic heteroarylene, where Q can be optionally substituted. In some embodiments, Q is a 6,6 bicyclic heterocyclene, where Q can be optionally substituted.

[0131] In some embodiments, Q is

[0132] [ka]

[0133] Selected from the group consisting of, In the formula, each of V1, V2, V3, and V4 is independently C, CH, CF, or N, and R Q1 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 The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted or R Q1 It, together with the nitrogen atom to which it is bonded and adjacent ring atoms, forms an optionally substituted 4-8 membered ring, which can optionally be further condensed into a 5-6 membered ring. R Q11 and R Q12 Each of these is independently C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-14 member heterocyclyl, aryl, or heteroaryl, R Q11 and R Q12 Each of these can be arbitrarily substituted, or R Q11 and R Q12 Together with the nitrogen atom to which they are bonded, they form an arbitrarily substituted 4-8 membered ring, where R Q11 and R Q12 The ring formed by combining these elements can be arbitrarily condensed into another 5-6 member ring.

[0134] In some embodiments, Q is =O, halo, -OH, -CN, one or more independently selected halo, 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), a 5-6 member heteroaryl optionally substituted with one or more C1-C3 alkyls, or a -C1-C5 alkyl optionally substituted with a 4-7 member saturated heterocyclyl, or a -O-(C1-C3 alkyl) optionally substituted with one or more independently selected halos, 1 -C2-C5 alkenyls optionally substituted with one or more independently selected -CN or -OH groups, -C2-C3 alkynyls optionally substituted with heteroaryl groups, -S(O)2-C1-C3 alkyl groups, one or more independently selected halos, =O groups, -CN groups, -CN groups, or -O-C1-C3 alkyl groups optionally substituted with -O-C1-C3 alkyl groups, -C(O)-saturated heterocyclyl groups, -O-saturated heterocyclyl groups, O-cycloalkyl groups, or -(CH2)0-1-C3-C6 cycloalkyl groups optionally substituted with -O-aryl groups, one or more independently selected halos, -CN groups -(CH2)0-1-heteroaryl, optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl, one or more independently selected halos, -O, -CN, -CN or -O-C1-C3 alkyl, optionally substituted with -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl Lyl, one or more independently selected halo, -CN, -CN, -C(O)-O-C1-C3 alkyl, -C1-C3 alkylene, -O-C1-C3 alkyl, -C1-C3 alkyl, optionally substituted with NO2, -C(O)-saturated heterocyclyl, -CH2-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or optionally substituted with -O-aryl -(CH2)O-1-aryl, -CH2-O-heteroaryl, -C(O)-NH-(C1-C3 alkyl), -C(O)-N(C1-C3 alkyl)2,The C2-C3 alkenylene=NO-(C1-C3 alkyl) which is optionally substituted with a C3-C6 cycloalkyl group is optionally further substituted with 1 to 4 substituents independently selected from the C3-C6 cycloalkyl group, or, The two substituents on Q combine to form a 5-7 membered monocyclic ring, or a 6-12 membered bicyclic ring optionally substituted with one or more independently selected halos, =O, -CN, C1-C3 alkyl, or -O-C1-C3 alkyl, which are then condensed onto Q. "**" represents the part of Q that is bonded to ring Z.

[0135] In some embodiments, Q is

[0136] [ka]

[0137] In some embodiments, Q is

[0138] [ka]

[0139] In some embodiments, Q is

[0140] [ka]

[0141] In some embodiments, Q is

[0142] [ka]

[0143] In some embodiments, Q is

[0144] [ka]

[0145] In some embodiments, Q is

[0146] [ka]

[0147] In some embodiments, Q is

[0148] [ka]

[0149] In some embodiments, Q is

[0150] [ka]

[0151] In some embodiments, Q is

[0152] [ka]

[0153] In some embodiments, Q is

[0154] [ka]

[0155] In some embodiments, Q is

[0156] [ka]

[0157] In some embodiments, Q is

[0158] [ka]

[0159] In some embodiments, Q is

[0160] [ka]

[0161] In some embodiments, Q is

[0162] [ka]

[0163] In some embodiments, Q is

[0164] [ka]

[0165] In some embodiments, Q is

[0166] [ka]

[0167] In some embodiments, Q is

[0168] [ka]

[0169] That is the case. In some embodiments, Q is chloro, fluoro, -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-cyanoethane-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethane-1-yl, 1-(tetrahydropyra (1-4-yl)-1-cyanoethane-1-yl, 1,3-dimethoxy-2-cyanopropane-2-yl, 1,4-dimethylpyrazole-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridine-4-yl, 1-methylpiperidine-4-yl, 1-methylpyrazole-3-yl, 1-methylpyrazole-5-yl, (1-methylpyrazole-4-yl)cyanomethyl, 1-oxoindoline-5-yl, 1-oxoisoindoline-4-yl, 1-oxoisoindoline-6-yl, 2-(2-methoxyethane-1-yl)phenyl, 3-(1,1-dioxothiomorpholin-1-ylmethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluorobenzo[d][1,3] Dioxol-4-yl, 2-chlorophenyl, 2-cyano-2-tetrahydrofuran-3-ylpropanyl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-4-methoxybutan-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-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl 2-Methoxyphenyl, 2-Methoxycarbonylphenyl, 2-(Methoxymethyl)phenyl, 2-Nitrophenyl, 2-Oxopyrrolidine-1-yl, 2-Phenoxyphenyl, 3-(2-Methoxyethane-1-yl)phenyl, 3-Methoxycarbonylphenyl, 3,5-Difluoro-4-(Pyrrolidine-1-ylcarbonyl)phenyl, 3-Cyano-2-methylpropane-2-yl, 3-Cyanomethylphenyl, 3-Cyanopentan-3-yl, 3-Cyanophenyl , 3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methylbuto-1-in-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxyphenyl, 3-methoxymethyl-5-methylisoxazole-4-yl, 3-oxo-2-methylbutan-2-yl, 3-(tetrahydropyran-4-yl)-2-cyanopropane-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3] Dioxol-4-yl, benzo[d]oxazole-7-yl, benzo[d]thiazole-2-yl, benzo[d]thiazole-4-yl, benzo[d]thiazole-5-yl, benzo[d]thiazole-6-yl, benzo[d]thiazole-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, morpholine-4-ylmethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyrazole-1-ylmethyl, pyridine-2-yl, pyridine-2-ylmethyl, pyr It may be further optionally substituted with 1 to 4 substituents independently selected from din-2-yloxymethyl, pyridine-3-yl, pyridine-3-ylethynyl, pyridine-3-ylmethyl, pyridine-4-ylmethyl, pyridine-4-ylethynyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyridine-4-yl, tetrahydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethane-1-yl, tetrahydropyran-4-ylcyanomethyl, or tetrahydropyran-4-yl, or, Two substituents bonded to the same carbon atom combine to form =O, 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydroflu[2,3-b]pyridine-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridine-6,6-diyl, or tetrahydropyran-4,4-diyl, or Two substituents bonded to adjacent carbon atoms combine to form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexane-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentane-1,2-diyl, or pyridine-3,4-diyl.

[0170] In some embodiments, Q is

[0171] [ka]

[0172] Selected from the group consisting of, During the ceremony, Each of V1, V2, V3, and V4 is independently CH, N, C(F), C(CH3), C(OH), C(OCH3), or C(CN). V5, V6, and V7 are each independent of C(R 17a )(R 17b ), or C(=O), where R 17a and R 17b Each of them is independently selected from hydrogen, halo, -C1-C3 alkyl, -C1-C3 haloalkyl, -O-C1-C3 alkyl, and -O-C1-C3 haloalkyl, and two or fewer of V5, V6, and V7 are C (=O), R NQ1 This 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 The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds are optionally substituted. Each R Q2 These are independently hydrogen, CN, and 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 10A cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted, or R NQ1 and one R Q2 These, together with the atoms to which they are bonded, form an arbitrarily substituted 4-8 membered ring, where R NQ1 and one R Q2 The ring formed by combining them can be optionally further condensed into a 5-6 member ring. Each R Q3 These are independently hydrogen, CN, and 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 A cycloalkyl, 4- to 14-membered heterocyclyl, aryl, or heteroaryl group, where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted or bonded to the same atom. Q3 These combine to form =CH, =O, =S, or =NR V4 To form, or Two R atoms bonded to the same atom Q3 These, together with the atoms to which they are bonded, form an arbitrarily substituted 4-8 membered ring, where each R Q3 The ring formed by combining them can be optionally further condensed into a 5-6 member ring, or R NQ1 and one R Q3 These, together with the atoms to which they are bonded, form an arbitrarily substituted 4-8 membered ring, where R NQ1 and R Q3 The ring formed by combining them can be optionally further condensed into a 5-6 member ring. R Q11 and R Q12 Each of these is independently C1-C 10Alkyl, C3-C 10 Cycloalkyl, 4-14 member heterocyclyl, aryl, or heteroaryl, R Q11 and R Q12 Each of these can be arbitrarily substituted, or R Q11 and R Q12 These, together with the atoms to which they are bonded, form an arbitrarily substituted 4-8 membered ring, where R Q11 and R Q12 The ring formed by combining them can be optionally condensed into another 5-6 member ring. "**" represents the part of Q that is bonded to ring Z.

[0173] In some embodiments, Q is

[0174] [ka]

[0175] In some embodiments, Q is

[0176] [ka]

[0177] In some embodiments, Q is

[0178] [ka]

[0179] In some embodiments, Q is

[0180] [ka]

[0181] In some embodiments, Q is

[0182] [ka]

[0183] In some embodiments, Q is

[0184] [ka]

[0185] In some embodiments, Q is

[0186] [ka]

[0187] In some embodiments, Q is

[0188] [ka]

[0189] In some embodiments, Q is

[0190] [ka]

[0191] In some embodiments, Q is

[0192] [ka]

[0193] In some embodiments, Q is

[0194] [ka]

[0195] In some embodiments, Q is

[0196] [ka]

[0197] In some embodiments, Q is

[0198] [ka]

[0199] In some embodiments, Q is

[0200] [ka]

[0201] In some embodiments, Q is

[0202] [ka]

[0203] That is the case. In some embodiments, Q is

[0204] [ka]

[0205] It is selected from the group consisting of the following. In some embodiments, Q is

[0206] [ka]

[0207] In some embodiments, Q is

[0208] [ka]

[0209] In some embodiments, Q is

[0210] [ka]

[0211] In some embodiments, Q is

[0212] [ka]

[0213] In some embodiments, Q is

[0214] [ka]

[0215] In some embodiments, Q is

[0216] [ka]

[0217] That is the case. In some embodiments, the compound is of formula (Id):

[0218] [ka]

[0219] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is of formula (Ie):

[0220] [ka]

[0221] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is of formula (Ig):

[0222] [ka]

[0223] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, where Q a It is a 4- to 9-membered saturated heterocycline. In some embodiments, the compound is of formula (Ij):

[0224] [ka]

[0225] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is of formula (Ik):

[0226] [ka]

[0227] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is of formula (Ik'):

[0228] [ka]

[0229] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, Q is

[0230] [ka]

[0231] Selected from the group consisting of, In the formula, "1" represents the part of Q that is bound to X, and Q can be further optionally substituted. In some embodiments, Q is

[0232] [ka]

[0233] In some embodiments, Q is

[0234] [ka]

[0235] In some embodiments, Q is

[0236] [ka]

[0237] In some embodiments, Q is

[0238] [ka]

[0239] That is the case. In some embodiments, Q is

[0240] [ka]

[0241] In some embodiments, Q is

[0242] [ka]

[0243] In some embodiments, Q is

[0244] [ka]

[0245] In some embodiments, Q is

[0246] [ka]

[0247] In some embodiments, Q is

[0248] [ka]

[0249] In some embodiments, Q is

[0250] [ka]

[0251] In some embodiments, Q is

[0252] [ka]

[0253] In some embodiments, Q is

[0254] [ka]

[0255] In some embodiments, Q is. In some embodiments, Q is

[0256] [ka]

[0257] In some embodiments, Q is

[0258] [ka]

[0259] In some embodiments, Q is

[0260] [ka]

[0261] In some embodiments, Q is

[0262] [ka]

[0263] In some embodiments, Q is

[0264] [ka]

[0265] In some embodiments, Q is

[0266] [ka]

[0267] In some embodiments, Q is

[0268] [ka]

[0269] In some embodiments, Q is

[0270] [ka]

[0271] That is the case. In some embodiments, Q is

[0272] [ka]

[0273] Selected from the group consisting of, During the ceremony, R is -CH2CH3, -CH2CH-OCH3, -CH2CHF2, -CH2-CN, CH2(CH3)2-CN, -C(CH3)2-CH2CN, -CH2CH2-CN, cyclohexyl, cyclobutyl, cyclopropyl, pyridine-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, oxetane-3-ylmethyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-methoxymethylphenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-bromophenyl, 2-methoxyethane-1-yl, 2-cyanopropane-2-yl, 2-tetrahydropyran-4-ylethane-1-yl, 3-cyanopentan-3-yl, 2-cyano-4-methoxybutan-2-yl, or R is

[0274] [ka]

[0275] And, R 23 is hydrogen or halogen, for example, fluorocarbon. R 24is hydrogen, chloro, -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-CH 3,-OCH3,-CH2-O-CH3,-C≡CH,-C≡C-CH3,-S(O)2CH3,1-(cyclopentyl)-1-cyanoethane-1-yl,1-(tetrahydropyran-4-yl)-1-cyanoethane-1-yl,1-(tetrahydrofuran-3-yl)-1-cyanoethane-1-yl,1,3-dimethoxy-2-cyanopropane-2 -yl, 1,4-dimethylpyrazole-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocyclopentyl, 1-methyl-1,2,3,6-tetrahydropyridine-4-yl, 1-methylpyrazole-3-yl, 1-methylpyrazole-4-ylcyanomethyl, 1-methylpiperidine-4-yl, 1-methylpyrazole-5-yl, 1-oxoindorin-5-yl, 1-oxoisoindorin-4-yl, 1-oxoisoindorin-6-yl, 2-(2-methoxyethane-1-yl)phenyl, 2-(methoxymethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2,3-Dicyanopropan-2-yl, 2-chlorophenyl, 2-cyano-3-(tetrahydropyran-4-yl)propan-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-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-Nitrophenyl, 2-Oxopyrrolidine-1-yl, 2-Phenoxyphenyl, 3-(1,1-Dioxothiomorpholin-4-ylmethyl)phenyl, 3-(2-Methoxyethane-1-yl)phenyl, 3,5-Difluoro-4-(Pyrrolidine-1-ylcarbonyl)phenyl, 3-Cyano-2-methylpropane-2-yl, 3-Cyanomethylphenyl, 3-Cyanopentan-3-yl, 3-Cyanophenyl, 3-Hyd Roxy-2-methylbutan-2-yl, 3-hydroxy-3-methylbuto-1-in-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxymethyl-5-methylisoxazole-4-yl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 3-oxo-2-methylbutan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3] Dioxol-4-yl, benzo[d]oxazole-7-yl, benzo[d]thiazole-2-yl, benzo[d]thiazole-4-yl, benzo[d]thiazole-5-yl, benzo[d]thiazole-6-yl, benzo[d]thiazole-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyridine-2-ylmethyl, pyridine-3-yl, pyridine-3-ylmethyl, pyridine-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyran-4-yl, or tetrahydropyran-4-ylcyanomethyl, R 27 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]dioxol-4-yl, 2-cyanophenyl, 3-cyanophenyl, phenyl, 2-benzylmethyl ether, 2-(2-methoxyethyl)benzene, 2-(2-difluoromethoxyethyl)benzene, 2-(2-dimethylmethoxyethyl)benzene, pyridine-3-yl, pyridine-2-yl, pyridine-3-ylmethyl, or tetrahydropyridine-4-yl, or R 24 and R 27 These combine to form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexane-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentane-1,2-diyl, or pyridine-3,4-diyl. R 28 is hydrogen, -CH3, or -CH2-O-CH3, R 29is hydrogen, acetyl, CN, -CH2-CN, -CH2-CH2-CN, -CH2-O-CH3, -CH=CH-CN, -CH2-OC(O)-N(CH3)2, morpholine-4-ylmethyl, pyrazole-1-ylmethyl, pyridine-3-yl, pyridine-3-ylethynyl, pyridine-2-yloxymethyl, or 2-cyanopropane-2-yl, or R 28 and R 29 These combine to form 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofluoro[2,3-b]pyridine-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridine-6-yl, tetrahydropyran-4,4-diyl, or 4-methoxycyclohexane. In some embodiments, Q is

[0276] [ka]

[0277] In some embodiments, Q is

[0278] [ka]

[0279] In some embodiments, Q is

[0280] [ka]

[0281] In some embodiments, Q is

[0282] [ka]

[0283] In some embodiments, Q is

[0284] [ka]

[0285] In some embodiments, Q is

[0286] [ka]

[0287] In some embodiments, Q is

[0288] [ka]

[0289] In some embodiments, Q is

[0290] [ka]

[0291] That is the case. In some embodiments, R 3 These are -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.

[0292] In one embodiment, the present invention relates to a compound having the structure of formula IIa or formula IIb:

[0293] [ka]

[0294] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein the formula, dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. B does not exist, or -CH(R 9 )-,>C=CR 9 R 9’ Or >CR 9 R 9’ (The carbon in question is -N(R 11 (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L is a linker, X 3 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 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’ These are independently hydrogen, or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 CR x , CH, CH2, or N, Y 6 CR z , C(O), CH, CH2, or N, R x These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R z These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R 13 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 13 and R 2 These, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 2 It is either absent, or hydrogen, 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, or optionally substituted 5 or 6-membered heteroaryl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 These are C1-C4 alkyl, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 heteroalkyl groups. R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8aThese are independently hydrogen, halogens, optionally substituted C1-C3 alkyl groups, or together with the carbon to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10 This is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl. R 10a is hydrogen or halogen, R 11is hydrogen, or optionally substituted C1-C3 alkyl, R 21 is hydrogen, or optionally substituted C1-C3 alkyl, z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of these atoms, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycline.

[0295] In some embodiments, this disclosure relates to the compound of structural formula IIa-1:

[0296] [ka]

[0297] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein the formula, dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. B does not exist, or -CH(R 9 )-,>C=CR 9 R 9’ Or >CR 9 R 9’ (The carbon in question is -N(R 11 (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L is a linker, X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, 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-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 ’ These are independently hydrogen, or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 CR x , CH, CH2, or N, Y 6 CR z , C(O), CH, CH2, or N, R x These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R z These are hydrogen, halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R 13 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 13 and R 2 These, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 2It is either absent, or hydrogen, 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, or optionally substituted 5 or 6-membered heteroaryl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 These are C1-C4 alkyl, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 heteroalkyl groups. R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’, forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halogens, optionally substituted C1-C3 alkyl groups, or together with the carbon to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10This is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl. R 10a is hydrogen or halogen, R 11 is hydrogen, or optionally substituted C1-C3 alkyl, R 21 (wherein this is hydrogen, or optionally substituted C1-C3 alkyl).

[0298] In some embodiments, the present disclosure relates to the compound of structural formula IIa-2:

[0299] [ka]

[0300] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein the formula, dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. B does not exist, or -CH(R 9 )-,>C=CR 9 R 9’ Or >CR 9 R 9’ (The carbon in question is -N(R 11 (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L is a linker, X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, 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-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 ’ These are independently hydrogen, or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 is CH, CH2, CF, CHF, CF2, or N. Y 6 is C(O), CH, CH2, CF, CHF, CF2, or N. R 13This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 13 and R 2 These, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 2 It is either absent, or hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, or optionally substituted C1-C3 acyl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 These are C1-C4 alkyl, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 heteroalkyl groups. R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halogens, optionally substituted C1-C3 alkyl groups, or together with the carbon to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10 This is hydrogen, halogen, hydroxyl, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl. R 10a is hydrogen or halogen, R 11 is hydrogen, or optionally substituted C1-C3 alkyl, R 21 (wherein this is hydrogen, or optionally substituted C1-C3 alkyl).

[0301] In some embodiments, the following compounds having the structure of formula IIa-3 are used herein:

[0302] [ka]

[0303] Alternatively, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof are provided (wherein the formula, the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds). A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10)- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-10 member heteroarylene, B is -CH(R 9 )-or>C=CR 9 R 9’ (Carbon is -N(R) 11 These are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes. G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, haloacetals, or alkynyl sulfones. X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, 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-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’ These are independently H or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 is CH, CH2, CF, CHF, CF2, or N. Y 6 is C(O), CH, CH2, CF, CHF, CF2, or N. R 13 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 13 and R 2 These, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 2 It is either absent, or hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, or optionally substituted C1-C3 acyl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R5 This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0304] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, optionally substituted C1-C3 alkyl groups, or together with the carbons to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 This 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 heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is a hydrogen- or optionally substituted C1-C6 alkyl group, R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, R 11 (These are hydrogen or C1-C3 alkyl groups).

[0305] In some embodiments, the present disclosure relates to the compound of structural formula IIa-4:

[0306] [ka]

[0307] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein the formula, dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-6 member heteroarylene, B is -CH(R 9 )-(Carbon is -N(R 11 These are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes. G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, haloacetals, or alkynyl sulfones. X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, 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-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 ’ These are independently H or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 and Y 6 These are independently CH, CF, or N. R 13 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-7 member heterocycloalkyls, optionally substituted 6 member aryls, optionally substituted 5 or 6 member heteroaryls, or optionally substituted C1-C3 acyls. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0308] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 10 These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl, R 11 (These are hydrogen or C1-C3 alkyl groups).

[0309] In some embodiments of the compounds of the present invention, G is an optionally substituted C1-C4 heteroalkylene. In some embodiments, compounds having the structure of formula IIa-5:

[0310] [ka]

[0311] Alternatively, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof are provided (wherein the formula, the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds). A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-6 member heteroarylene, B is -CH(R 9 )-(Carbon is -N(R 11 These are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes. L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, or alkynyl sulfones. X 2 is O or NH, X 3 is N or CH, 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 ’ These are independently H or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 and Y 6 These are independently CH, CF, or N. R 13 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-7 member heterocycloalkyls, optionally substituted 6 member aryls, optionally substituted 5 or 6 member heteroaryls, or optionally substituted C1-C3 acyls. R 14 It does not exist, or R 2 and R 14These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0312] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 10 These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl, R 11 (These are hydrogen or C1-C3 alkyl groups).

[0313] In some embodiments of the present invention, X 2 is NH. In some embodiments, X 3 is CH. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a C1-C3 alkyl group. In some embodiments, R 11 It is methyl.

[0314] In some embodiments, the compounds of the present invention are of formula IIa-6:

[0315] [ka]

[0316] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein the formula, dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds, and A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R) 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-6 member heteroarylene, B is -CH(R 9 )-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, or alkynyl sulfones. 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 ’ These are independently H or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 and Y 6 They are independently CH or N, R 13These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are hydrogen, halogens, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-7 member heterocycloalkyls, optionally substituted 6 member aryls, and optionally substituted 5 or 6 member heteroaryls. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0317] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8is hydrogen, halogen, hydroxy, 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 together with the carbon atom to which they are attached 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’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, 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’ together with the carbon atom to which they are attached form optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl).

[0318] In some embodiments of the compounds of the present invention, X 1 is optionally substituted C1-C2 alkylene. In some embodiments, X 1 is methylene. In some embodiments, X 1 is methylene substituted with a C1-C6 alkyl group or a halogen. In some embodiments, X 1 is -CH(Br)-. In some embodiments, X 1 is -CH(CH3)-. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C4 alkyl optionally substituted with a halogen. In some embodiments, R 5 is methyl. In some embodiments, Y 4 is C. In some embodiments, R 4 is hydrogen. In some embodiments, Y 5 is CH. In some embodiments, Y 5 is CF. In some embodiments, Y 6 is CH. In some embodiments, Y 6 is CF. In some embodiments, Y 1 is C. In some embodiments, Y 2 is C. In some embodiments, Y 3 is N. In some embodiments, R 3 is absent. In some embodiments, Y 7 is C. In some embodiments, Y 4 is C and R 15 is F.

[0319] In some embodiments, the compounds of the present invention are of formula IIa-7:

[0320]

Chemical formula

[0321] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-6 member heteroarylene, B is -CH(R 9 )-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, or alkynyl sulfones. R 13 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are 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, and optionally substituted 5 or 6-membered heteroaryl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 5This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0322] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 10 (These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.)

[0323] In some embodiments of the compounds of the present invention, R 6 is hydrogen. In some embodiments, R 2 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-6 member heterocycloalkyl. In some embodiments, R 2 R is an optionally substituted C1-C6 alkyl group. In some embodiments, R2 is a fluoroalkyl group. In some embodiments, R 2 R is ethyl. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is -CHC≡CH. In some embodiments, R2 is -CH2C≡CCH3. In some embodiments, R 7 is an optionally substituted C1-C3 alkyl group. In some embodiments, R 7 is a C1-C3 alkyl group. In some embodiments, R 8 is an optionally substituted C1-C3 alkyl group. In some embodiments, R 8 It is a C1-C3 alkyl group.

[0324] In some embodiments, the compounds of the present invention are of formula IIa-8:

[0325] [ka]

[0326] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-6 member heteroarylene, B is -CH(R 9 )-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, or alkynyl sulfones. R 13 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 membered cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 (These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, or optionally substituted 3- to 7-membered heterocycloalkyl groups.)

[0327] In some embodiments of the compounds of the present invention, R 13 R is an optionally substituted 6-10 member aryl, an optionally substituted 3-6 member cycloalkenyl, or an optionally substituted 5-10 member heteroaryl. In some embodiments, R 13 This is an optionally substituted six-membered aryl, an optionally substituted six-membered cycloalkenyl, or an optionally substituted six-membered heteroaryl.

[0328] In some embodiments of the compounds of the present invention, R 13 teeth,

[0329] [ka]

[0330] or its stereoisomer (e.g., atropisomer). In some embodiments of the compounds of the present invention, R 13 teeth,

[0331] [ka]

[0332] or its stereoisomer (e.g., atropisomer). In some embodiments of the compounds of the present invention, R 13 teeth,

[0333] [ka]

[0334] In some embodiments, R 13 teeth,

[0335] [ka]

[0336] or its stereoisomer. 13 teeth,

[0337]

Chem.

[0338] is. In some embodiments, the compound of the present invention has the formula IIa-9:

[0339]

Chem.

[0340] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (A is -N(H or CH3)C(O)-(CH2)-(the amino nitrogen is bonded to the carbon atom of -CH(R 10 )), optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-6 member heteroarylene, B is -CH(R 9 ))-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or 5-6 member heteroarylene, L is absent or is a linker, W is a crosslinking group including vinyl ketone, vinyl sulfone, enone, or alkynyl sulfone, R 2 is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3-6 member cycloalkyl, R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, R 9These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. X e and X f These are independently N, CH, or CR 17 And, R 12 This is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, or an optionally substituted 3- to 6-membered heterocycloalkylene.

[0341] R 17 (These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-6 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups.)

[0342] In some embodiments of the present invention, X e is N, and X f is CH. In some embodiments, X e CH is X f It is N. In some embodiments of the compounds of the present invention, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth,

[0343] [ka]

[0344] In some embodiments of the compounds of the present invention, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth,

[0345] [ka]

[0346] That is the case. In some embodiments, the compounds of the present invention are of formula IIa-10:

[0347] [ka]

[0348] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-6 member heteroarylene) B is -CH(R 9 )-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L either does not exist or is a linker. 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 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 membered cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. X e CH, or CR 17 And, R 17 (These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-6 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups.)

[0349] In some embodiments, the compounds of the present invention are of formula IIa-11:

[0350] [ka]

[0351] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-6 member heteroarylene) B is -CH(R 9 )-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L either does not exist or is a linker. 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 3-11 member heterocycloalkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 membered cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 (These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, or optionally substituted 3- to 7-membered heterocycloalkyl groups.)

[0352] In some embodiments, the compounds of the present invention are of formula II-VI:

[0353] [ka]

[0354] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein the formula, the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene (e.g., phenyl or phenol), or optionally substituted 5-10 member heteroarylene, B does not exist, or -CH(R 9 )-,>C=CR9 R 9’ , or >CR 9 R 9’ (Carbon is -N(R 11 These are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes. G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, haloacetals, or alkynyl sulfones. X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, 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-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 ’ These are independently H or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y3 , Y 4 , and Y 7 These are independently C or N, Y 5 is CH, CH2, CF, CHF, CF2, or N. Y 6 is C(O), CH, CH2, CF, CHF, CF2, or N. R 2 It is either absent, or hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, or optionally substituted C1-C3 acyl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R 5 This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0355] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, optionally substituted C1-C3 alkyl groups, or together with the carbons to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 21 is hydrogen or a C1-C3 alkyl group (e.g., methyl), X e and X f (These are independently N or CH).

[0356] In some embodiments, the compounds of the present invention are of formula II-VIa:

[0357] [ka]

[0358] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene (e.g., phenyl or phenol), or an optionally substituted 5-6 member heteroarylene) B is -CH(R 9)-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, or alkynyl sulfones. X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O) q And, X 2 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 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 ’ These are independently H or optionally substituted C1-C4 alkyl groups. R 2 These are C1-C6 alkyl, C1-C6 fluoroalkyl, or 3-6 membered cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. X e and X f These are independently N or CH, R 11 is hydrogen or C1-C3 alkyl, R 21 (These are hydrogen or C1-C3 alkyl groups).

[0359] In some embodiments of the present invention, X e is N, and X f is CH. In some embodiments, X e CH is X f It is N. In some embodiments, the compounds of the present invention are of formula II-VIb:

[0360] [ka]

[0361] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene (e.g., phenyl or phenol), or an optionally substituted 5-6 member heteroarylene) B is -CH(R 9 )-(the carbon is bonded to the carbonyl carbon of -NHC(O)-), optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, R 9 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, or alkynyl sulfones.

[0362] In some embodiments of the compounds of the present invention, A is an optionally substituted six-membered arylene. In some embodiments, the compounds of the present invention are of formula II-VIc:

[0363] [ka]

[0364] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein the formula, the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH3)C(O)-(CH2)-(amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene (e.g., phenyl or phenol), or optionally substituted 5-10 member heteroarylene, B does not exist, or -CH(R 9 )-,>C=CR 9 R 9’ , or >CR 9 R 9’ (Carbon is -N(R 11 These are optionally substituted 3- to 6-membered cycloalkylenes (bonded to the carbonyl carbon of C(O)-), optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes. G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-(C is -C(R 7 R 8 )-bonded),-C(O)NH-CH(R 6 )-(C is -C(R 7 R 8 (-bound), optionally substituted C1-C4 heteroalkylene, or 3-8 member heteroarylene, L either does not exist or is a linker. W is a crosslinking group containing vinyl ketones, vinyl sulfones, inones, haloacetals, or alkynyl sulfones. X 1 This is an optionally substituted C1-C2 alkylene, NR, O, or S(O)q And, 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-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 ’ These are independently H or optionally substituted C1-C4 alkyl groups. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 These are independently C or N, Y 5 is CH, CH2, CF, CHF, CF2, or N. Y 6 is C(O), CH, CH2, CF, CHF, CF2, or N. R 2 It is either absent, or hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, or optionally substituted C1-C3 acyl. R 14 It does not exist, or R 2 and R 14 These, together with the atoms to which they are bonded, form optionally substituted 3-8 member cycloalkyl or optionally substituted 3-14 member heterocycloalkyl groups. R 15 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1-3 halogens. R5 This is a C1-C4 alkyl, cyclopropyl, or cyclobutyl compound optionally substituted with hydrogen, halogen, cyano, hydroxy, or C1-C4 alkoxy.

[0365] R 6 is hydrogen or methyl, and R 7 is either hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R 8 This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 Together with the carbon atoms to which they are bonded, C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, optionally substituted C1-C3 alkyl groups, or together with the carbons to which they are bonded, they form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’This 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 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L, together with the atoms to which they are bonded, form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is either hydrogen, or an optionally substituted C1-C6 alkyl, or R 9 and R 9’ These, together with the atoms to which they are bonded, form a 3-6 member cycloalkyl or 3-6 member heterocycloalkyl group. R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 21 (These are hydrogen or a C1-C3 alkyl group (e.g., methyl)).

[0366] In some embodiments, Z is -C(O)-. In some embodiments, A is an optionally substituted C2-C4 alkylene. In some embodiments, A is an optionally substituted C3 alkylene. In some embodiments, A is

[0367] [ka]

[0368] That is the case. In some embodiments, A is an optionally substituted C2-C4 alkenylene. In some embodiments, A is an optionally substituted C3 alkenylene. In some embodiments, A is an optionally substituted C1-C4 heteroalkylene. In some embodiments, A is an optionally substituted C2 heteroalkylene. In some embodiments, A is

[0369] [ka]

[0370] That is the case. In some embodiments, A is structure

[0371] [ka]

[0372] It has, in the formula, R 13 R is hydrogen, halo, hydroxy, amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, 13a is hydrogen or halogen. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 and R 13a These are hydrogen atoms, respectively. In some embodiments, R 13 These are hydroxy, methyl, fluoro, or difluoromethyl compounds.

[0373] In some embodiments, A is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is

[0374] [ka]

[0375] That is the case. In some embodiments, A is an optionally substituted 5-6 member heteroarylene. In some embodiments, A is

[0376] [ka]

[0377] That is the case. In some embodiments, A is an optionally substituted C1-C4 heteroalkylene. In some embodiments, A is

[0378] [ka]

[0379] In some embodiments, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is

[0380] [ka]

[0381] In some embodiments, A is

[0382] [ka]

[0383] That is the case. In some embodiments, R 9is 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 heterocycloalkyl. In some embodiments, R 9 teeth,

[0384] [ka]

[0385] In some embodiments, R 9 teeth,

[0386] [ka]

[0387] In some embodiments, R 9 This is H, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0388] 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

[0389] [ka]

[0390] That is the case. In some embodiments, R 13 teeth,

[0391] [ka]

[0392] In some embodiments, R13 teeth,

[0393] [ka]

[0394] That is the case. In some embodiments, R 13 teeth,

[0395] [ka]

[0396] That is (In the formula, Z 1 is N or CH, m is either 1 or 2. R 18 , R 19 , R 20 , and R 25 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 18 and R 20 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 20 and R 25 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or R 19 and R 20 These atoms, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups.

[0397] In some embodiments, R 13 teeth,

[0398] [ka]

[0399] In some embodiments, R 13 teeth,

[0400] [ka]

[0401] That is the case. In some embodiments, R 18 It is methyl. In some embodiments, R 13 teeth,

[0402] [ka]

[0403] That is the case. In some embodiments of the compounds of the present invention, R 7 It is methyl. In some embodiments of the compounds of the present invention, R 8 It is methyl.

[0404] In some embodiments, R 21 It is hydrogen. In some embodiments of the compounds of the present invention, B is -CHR 9 - In some embodiments, R 9 B 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.

[0405] In some embodiments, L has the structure of formula L0:

[0406] [ka]

[0407] (wherein X 12 is O, S, SO2, NH, CH2, C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, and is bonded to ring A. E is a bond, an optionally substituted C1-C6 alkylene, an optionally substituted C1-C6 heteroalkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 5- to 12-membered arylene, or an optionally substituted 5- to 12-membered heteroarylene.

[0408] In some embodiments of the compounds of the present invention, the linker has the structure of formula II-II: 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 II-II (In the formula, A 1 This is the bond between the linker and B, and A 2 This is the connection between A and the linker, and B 1 B 2 B 3 , and B 4 These are, independently, an arbitrarily substituted C1-C2 alkylene, an arbitrarily substituted C1-C3 heteroalkylene, O, S, and NR. N Selected from, R Nis hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C1-C7 heteroalkyl, C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, and f, g, h, i, j, and k are each independently 0 or 1, D 1 This is an arbitrarily substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylene, optionally substituted 3-14 member heterocycloalkylene, optionally substituted 5-10 member heteroarylene, optionally substituted 3-8 member cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C2-C 10 Polyethylene glycolen, or optionally substituted C1-C 10 Heteroalkylene, or A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -to-(B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 (A chemical bond that connects to a structure). In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of formula II-IIa:

[0409] [ka]

[0410] (wherein X a It does not exist, or it is N. R 14It is either absent, or a hydrogen atom, or an optionally substituted C1-C6 alkyl group. L 2 It does not exist, or it is -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene, X a , R 14 , or L 2 (At least one of these exists). In some embodiments, the linker has the following structure:

[0411] [ka]

[0412] In some embodiments, the linker has the following structure:

[0413] [ka]

[0414] In some embodiments, L is

[0415] [ka]

[0416] In some embodiments, L is

[0417] [ka]

[0418] That is the case. In some embodiments, the linker is a ring portion or includes one. In some embodiments, the linker has the structure of formula II-IIb:

[0419] [ka]

[0420] (where o is 0 or 1, R 15 This is hydrogen, or optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkylene, or optionally substituted 3-8 membered heterocycloalkylene. X 4 It is either absent, or 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 heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene. L 3 (either does not exist, or is -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene).

[0421] In some embodiments, the linker has the structure of formula II-IIb-1:

[0422] [ka]

[0423] (where o is 0 or 1, R 15 This is hydrogen, or optionally substituted C1-C6 alkyl, optionally substituted 3-8 membered cycloalkylene, or optionally substituted 3-8 membered heterocycloalkylene. Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene. L 3 (either does not exist, or is -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene).

[0424] In some embodiments, the linker has the following structure:

[0425] [ka]

[0426] [ka]

[0427] [ka]

[0428] In some embodiments, the linker has the structure of formula II-IIc:

[0429] [ka]

[0430] (wherein R 15 These are hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered cycloalkylene groups, or optionally substituted 3-8 membered heterocycloalkylene groups. R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , and R 15g R is independently hydrogen, halo, hydroxy, cyano, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 15b and R 15d These, together with the carbon atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkylenes, or optionally substituted 3- to 8-membered heterocycloalkylenes.

[0431] In some embodiments, the linker has the following structure:

[0432] [ka]

[0433] In some embodiments, the linker has the following structure:

[0434] [ka]

[0435] [ka]

[0436] [ka]

[0437] [ka]

[0438] In some embodiments, the linker is structure

[0439] [ka]

[0440] It holds. In some embodiments, the linker is structure

[0441] [ka]

[0442] It holds. In some embodiments, the linker of formula II is,

[0443] [ka]

[0444] It is selected from the group consisting of the following. In one embodiment, the present invention relates to a compound having the structure of formula IIIa or formula IIIb:

[0445] [ka]

[0446] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene, or an optionally substituted C2-C4 alkenylene) Y 8 teeth,

[0447] [ka]

[0448] And, L is a linker, R 13 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-15 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. R 2 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R10 These are hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. R 7 and R 8 Each of these is independently selected from F or CH3, or R 7 and R 8 These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of these atoms, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycline.

[0449] In one embodiment, the present invention relates to a compound having the structure of formula IIIa-1:

[0450] [ka]

[0451] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene, or an optionally substituted C2-C4 alkenylene) Y 8 teeth,

[0452] [ka]

[0453] And, L is a linker, X 4 and X 5 Each of these is independently CH2, CH(CH3), or NH. R 13 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-15 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. R 2 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R 10These are hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. R 7 and R 8 Each of these is independently selected from F or CH3, or R 7 and R 8 These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0454] In some embodiments, the present disclosure relates to the compound of structural formula IIIa-2:

[0455] [ka]

[0456] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene, or an optionally substituted C2-C4 alkenylene) Y 8 teeth,

[0457] [ka]

[0458] And, L is a linker, X4 and X 5 Each of these is independently CH2, CH(CH3), or NH. R 13 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-15 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. R 2 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R 10 These are hydrogen, hydroxyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. R 7 and R 8 Each of these is independently selected from F or CH3, or R 7 and R 8 (These atoms, together with the atoms they are bonded to, form a three-membered cycloalkyl group.)

[0459] In some embodiments, the compound is formula IIIa-3:

[0460] [ka]

[0461] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-6 member heteroarylene) Y 8 teeth,

[0462] [ka]

[0463] And, R 13 These are optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-6 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. R 2 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, and optionally substituted 5 or 6 member heteroaryl. R 10 (wherein is hydrogen, or optionally substituted C1-C6 heteroalkyl). In some embodiments, R 10 It is hydrogen.

[0464] In some embodiments, R 13 is an optionally substituted 6-10 member aryl or an optionally substituted 5-10 member heteroaryl. In some embodiments, R 13 This is an optionally substituted phenyl or an optionally substituted pyridine.

[0465] In some embodiments, A is an optionally substituted thiazole, an optionally substituted triazole, an optionally substituted morpholino, an optionally substituted piperidinyl, an optionally substituted pyridine, or an optionally substituted phenyl. In some embodiments, A is an optionally substituted thiazole, an optionally substituted triazole, an optionally substituted morpholino, or a phenyl. In some embodiments, A is not an optionally substituted phenyl or benzimidazole. In some embodiments, A is not a hydroxyphenyl.

[0466] In some embodiments, Y 8 It is -NHC(O)- or -NHC(O)NH-. In some embodiments, the compound is formula IIIa-4:

[0467] [ka]

[0468] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is formula IIIa-5:

[0469] [ka]

[0470] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0471] In some embodiments, the compound is formula IIIa-6:

[0472] [ka]

[0473] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula IIIa-7:

[0474] [ka]

[0475] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0476] In some embodiments, the compound is formula IIIa-8:

[0477] [ka]

[0478] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula IIIa-9:

[0479] [ka]

[0480] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11(These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is H. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0481] In some embodiments, the compound is formula IIIa-10:

[0482] [ka]

[0483] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula IIIa-11:

[0484] [ka]

[0485] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments (for example, one of formulas IIIa-10 or IIIa-11), R 6 It is methyl.

[0486] In some embodiments, the compound is formula IIIa-12 or formula IIIa-13:

[0487] [ka]

[0488] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is of formula IIIa-a:

[0489] [ka]

[0490] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is given by formula IIIa-a1:

[0491] [ka]

[0492] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0493] In some embodiments, the compound is formula IIIa-a2:

[0494] [ka]

[0495] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula IIIa-a3:

[0496] [ka]

[0497] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0498] In some embodiments, the compound is formula IIIa-a4:

[0499] [ka]

[0500] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula IIIa-a5:

[0501] [ka]

[0502] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0503] In some embodiments, the compound is formula IIIa-a6:

[0504] [ka]

[0505] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula IIIa-a7:

[0506] [ka]

[0507] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments (for example, one of formulas IIIa-a6 or IIIa-a7), R 6 It is methyl.

[0508] In some embodiments, the compound is formula IIIa-a8 or formula IIIa-a9:

[0509] [ka]

[0510] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-IVa:

[0511] [ka]

[0512] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is formula III-IVa-1:

[0513] [ka]

[0514] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0515] In some embodiments, the compound is formula III-IVa-2:

[0516] [ka]

[0517] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-Iva-3:

[0518] [ka]

[0519] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0520] In some embodiments, the compound is formula III-IVa-4:

[0521] [ka]

[0522] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-IVa-5:

[0523] [ka]

[0524] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0525] In some embodiments, the compound is formula III-IVa-6:

[0526] [ka]

[0527] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-IVa-7:

[0528] [ka]

[0529] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments (for example, one of formulas III-IVa-6 or III-IVa-7), R 6 It is methyl.

[0530] In some embodiments, the compound is formula III-IVa-8 or formula III-IVa-9:

[0531] [ka]

[0532] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, Y 8 This is -NHS(O)2- or -NHS(O)2NH-.

[0533] In some embodiments, the compound is represented by formula III-Va:

[0534] [ka]

[0535] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is represented by formula III-Va-1:

[0536] [ka]

[0537] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0538] In some embodiments, the compound is represented by formula III-Va-2:

[0539] [ka]

[0540] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is represented by formula III-Va-3:

[0541] [ka]

[0542] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0543] In some embodiments, the compound is represented by formula III-Va-4:

[0544] [ka]

[0545] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is represented by formula III-Va-5:

[0546] [ka]

[0547] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11(These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0548] In some embodiments, the compound is represented by formula III-VIa:

[0549] [ka]

[0550] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is represented by formula III-VIa-1:

[0551] [ka]

[0552] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0553] In some embodiments, the compound is represented by formula III-VIa-2:

[0554] [ka]

[0555] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-VIa-3:

[0556] [ka]

[0557] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0558] In some embodiments, the compound is represented by formula III-Via-4:

[0559] [ka]

[0560] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-VIa-5:

[0561] [ka]

[0562] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0563] In some embodiments, the compound is represented by formula III-VIIa:

[0564] [ka]

[0565] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 9 is H or C1-C6 alkyl, a is either 0 or 1.

[0566] In some embodiments, the compound is represented by formula III-VIIa-1:

[0567] [ka]

[0568] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0569] In some embodiments, the compound is represented by formula III-VIIa-2:

[0570] [ka]

[0571] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-VIIa-3:

[0572] [ka]

[0573] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0574] In some embodiments, the compound is formula III-VIIa-4:

[0575] [ka]

[0576] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-VIIa-5:

[0577] [ka]

[0578] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0579] In some embodiments (for example, any one of formulas VIIa, VIIa-1, VIIa-2, VIIa-3, VIIa-4, or VIIa-5), R 9 It is methyl.

[0580] In some embodiments, Y is -NHS(O)- or -NHS(O)NH-. In some embodiments, the compound is represented by formula III-VIIIa:

[0581] [ka]

[0582] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is represented by formula III-VIIIa-1:

[0583] [ka]

[0584] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0585] In some embodiments, the compound is represented by formula III-VIIIa-2:

[0586] [ka]

[0587] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is represented by formula III-VIIIa-3:

[0588] [ka]

[0589] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0590] In some embodiments, the compound is represented by formula III-VIIIa-4:

[0591] [ka]

[0592] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is represented by formula III-VIIIa-5:

[0593] [ka]

[0594] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0595] In some embodiments, the compound is given by formula III-IXa:

[0596] [ka]

[0597] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is represented by formula III-IXa-1:

[0598] [ka]

[0599] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0600] In some embodiments, the compound is formula III-IXa-2:

[0601] [ka]

[0602] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-IXa-3:

[0603] [ka]

[0604] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5 Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0605] In some embodiments, the compound is formula III-IXa-4:

[0606] [ka]

[0607] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-IXa-5:

[0608] [ka]

[0609] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0610] In some embodiments, the compound is given by formula III-Xa:

[0611] [ka]

[0612] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein a is 0 or 1). In some embodiments, the compound is given by formula III-Xa-1:

[0613] [ka]

[0614] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is N or CH, Each R 3 These are independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. n is an integer between 1 and 4.

[0615] In some embodiments, the compound is given by formula III-Xa-2:

[0616] [ka]

[0617] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is given by formula III-Xa-3:

[0618] [ka]

[0619] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 4 and R 5Each of these is independently selected from halogens, cyanos, hydroxyls, optionally substituted amines, optionally substituted amides, optionally substituted C1-C6 alkyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-11 member heterocycloalkyls (e.g., optionally substituted 3-6 member heterocycloalkyls), optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls).

[0620] In some embodiments, the compound is formula III-Xa-4:

[0621] [ka]

[0622] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound is formula III-Xa-5:

[0623] [ka]

[0624] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 3 is N or CH, and m is 1 or 2. R 6 , R 7 , R 8 , and R 11 Each of these is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered heterocycloalkyl groups, or, R 7 and R 11 (These, together with the atoms to which they are bonded, form optionally substituted 4- to 8-membered heterocycloalkyl groups). In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, R 11 H is H.

[0625] In some embodiments of any part described herein, a is 0. In any of the embodiments described above, a is 0. In some embodiments of any part described herein, R 2 is an optionally substituted C1-C6 alkyl group. In some embodiments, R 2 The channel is selected from -CH2CH3 or -CH2CF3.

[0626] In one embodiment, the present invention relates to a compound having the structure of formula IVa or formula IVb:

[0627] [ka]

[0628] or characterized by a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0629] In some embodiments, the compound is of formula IVa-1 or formula IVb-1:

[0630] [ka]

[0631] or having the structure of a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and RL6 Any two of these atoms, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycline.

[0632] In some embodiments, the compound is of formula IVa-2:

[0633] [ka]

[0634] or having the structure of a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0635] In some embodiments, the present disclosure relates to the compound of structural formula IVa-3:

[0636] [ka]

[0637] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 (These are optionally substituted C1-C6 alkyl groups, or optionally substituted C1-C3 heteroalkyl groups.)

[0638] In some embodiments, compounds having the structure of formula IVa-4 are used herein:

[0639] [ka]

[0640] Alternatively, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof are provided. 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 pyridyl, optionally substituted azetidinyl, 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.

[0641] In some embodiments, the present disclosure relates to the compound of structural formula IVa5:

[0642] [ka]

[0643] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof. In some embodiments, compounds having the structure of formula IVa6:

[0644] [ka]

[0645] Alternatively, pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof are provided (wherein R 4 , R 5 , and R 6 Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl, or R 4 and R 5 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 4 and R 6 These atoms, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups.

[0646] In some embodiments, the compound of the present invention is of formula IVa7:

[0647] [ka]

[0648] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound of the present invention is of formula IVa8:

[0649] [ka]

[0650] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound of the present invention is of formula IVa9f:

[0651] [ka]

[0652] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments of the compounds of the present invention, R 2 teeth,

[0653] [ka]

[0654] That is the case. In some embodiments of the compounds of the present invention, R 3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 teeth,

[0655] [ka]

[0656] That is the case. In some embodiments of the compounds of the present invention, R3 is an optionally substituted C1-C3 heteroalkyl. In some embodiments, R 3 teeth,

[0657] [ka]

[0658] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is

[0659] [ka]

[0660] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted phenyl. In some embodiments, A is

[0661] [ka]

[0662] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is selected from the following or their stereoisomers:

[0663] [ka]

[0664] In some embodiments of the compounds of the present invention, the linker 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 (In the formula, A 1 The linker and CH(R 3 It is a union between and A 2 This is the connection between A and the linker, and B 1 B 2 B 3 , and B 4 These are, independently, an arbitrarily substituted C1-C2 alkylene, an arbitrarily substituted C1-C3 heteroalkylene, O, S, and NR. N Selected from, each R N These are independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C1-C7 heteroalkyl, C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, and f, g, h, i, j, and k are each independently 0 or 1, D 1 This is an arbitrarily substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylene, optionally substituted 3-14 member heterocycloalkylene, optionally substituted 5-10 member heteroarylene, optionally substituted 3-8 member cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C2-C 10 Polyethylene glycolen, or optionally substituted C1-C 10 Heteroalkylene, or A 1 -( B 1 ) f -(C 1 ) g-( B 2 ) h -to-(B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 (A chemical bond that connects two things together.)

[0665] In some embodiments of the compounds of the present invention, the linker is a cyclic portion or includes a cyclic portion. In some embodiments, the linker has the structure of formula IV-IIIa:

[0666] [ka]

[0667] (where o is 0 or 1, R 7 These are hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered cycloalkylene groups, or optionally substituted 3-8 membered heterocycloalkylene groups. X 1 It is either absent, or optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene. Cy is an optionally substituted 3-8 member cycloalkylene, an optionally substituted 3-12 member heterocycloalkylene, an optionally substituted 6-10 member arylene, or an optionally substituted 5-10 member heteroarylene. L 2 (Neither exists, or is -SO2-, -NH-, an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 heteroalkylene, or an optionally substituted 3- to 6-membered heterocycloalkylene).

[0668] In some embodiments, the linker is selected from the following or their stereoisomers:

[0669] [ka]

[0670] [ka]

[0671] [ka]

[0672] In some embodiments, the linker is selected from the following or their stereoisomers:

[0673] [ka]

[0674] [ka]

[0675] In some embodiments, the compound of the present invention is of formula IVa9:

[0676] [ka]

[0677] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein Cy 1 These are optionally substituted spirocyclic 8-11 member heterocycloalkylenes, or optionally substituted bicyclic 7-9 member heterocycloalkylenes. (W contains vinyl ketones or vinyl sulfones).

[0678] In some embodiments, Cy 1 These are arbitrarily substituted spirocyclic 10-11 member heterocycloalkylenes. In some embodiments, the compound of the present invention is of formula IVa10:

[0679] [ka]

[0680] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 O, C(R 11 )2, NR 12 , S, or SO2, r is either 1 or 2. Each t is independently 0, 1, or 2. R 11 and R 12 Each of these is independently hydrogen, an optionally substituted C1-C4 alkyl, an optionally substituted C2-C4 heteroalkyl, or an optionally substituted 3- to 5-membered cycloalkyl. Each R 13 (It is independently -CH3).

[0681] In some embodiments, the compound of the present invention is of formula IVa11:

[0682] [ka]

[0683] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 O, C(R 11 )2, NR 12 , S, or SO2, r is either 1 or 2. Each t is independently 0, 1, or 2. R 11 and R 12 Each of these is independently hydrogen, an optionally substituted C1-C4 alkyl, an optionally substituted C2-C4 heteroalkyl, an optionally substituted 3-6 member heterocycloalkyl, or an optionally substituted 3-5 member cycloalkyl. Each R 13It is either independently -CH3,F or two R atoms bonded to the same atom. 13 These, together with the atom to which they are bonded, form an optionally substituted C3-C6 cycloalkyl group, or two R groups bonded to the same atom. 13 These atoms, together with the atoms to which they are bonded, form optionally substituted 3- to 6-membered heterocycloalkyl groups.

[0684] In some embodiments, the compound of the present invention is of formula IVa12:

[0685] [ka]

[0686] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound of the present invention is of formula IVa13:

[0687] [ka]

[0688] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound of the present invention is of formula IVa14:

[0689] [ka]

[0690] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, X 2 In some embodiments, X 2 is S. In some embodiments, X2 It is SO2.

[0691] In some embodiments, X 2 , NR 12 In some embodiments, R 12 The following, or their stereoisomers, are selected: -CH3,

[0692] [ka]

[0693] Or -H. In some embodiments, X 2 C(R 11 )2. In some embodiments, each R 11 It is hydrogen.

[0694] In some embodiments, the compound of the present invention is of formula IVa15:

[0695] [ka]

[0696] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein Q 1 CH2, NR N , or O, Q 2 CO, NR N , or O, Z is an optionally substituted 3-6 member heterocycloalkylene, or an optionally substituted 5-10 member heteroarylene, or Q 1 -Q 2 -Z is an arbitrarily substituted 9- to 10-membered spirocyclic heterocycloalkylene.

[0697] In some embodiments, the compound of the present invention is of formula IVa16:

[0698] [ka]

[0699] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 14 These are fluoro, hydrogen, or C1-C3 alkyl groups. (u is either 0 or 1).

[0700] In some embodiments, R 14 is fluoro, and u is 1. In some embodiments, R 14 is hydrogen, and u is 0. In some embodiments, the compound of the present invention is of formula IVa17:

[0701] [ka]

[0702] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compound of the present invention is of formula IVa18:

[0703] [ka]

[0704] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, this disclosure relates to the compound of structural formula VIa-1:

[0705] [ka]

[0706] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, L is a linker, W is a crosslinking group including aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycal, X 6 is CH2 or O, m is 1 or 2, n is 0 or 1, R 1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl, R 2 is optionally substituted C1-C6 alkyl).

[0707] In one aspect, the present invention relates to a compound having a structure of formula Va or formula Vb:

[0708]

Chemical formula

[0709] or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, L is a linker, R 1This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0710] In some embodiments, the compound is given by formula Va-1:

[0711] [ka]

[0712] or having the structure of a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C3 heteroalkyl group. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0713] In some embodiments, the compound is given by formula Va-2:

[0714] [ka]

[0715] or having the structure of a pharmaceutically acceptable salt thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 (These are optionally substituted C1-C6 alkyl groups, or optionally substituted C1-C3 heteroalkyl groups.)

[0716] In some embodiments, the compound of the present invention is of formula V-Ia:

[0717] [ka]

[0718] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compounds of the present invention are of formula V-II-1:

[0719] [ka]

[0720] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compounds of the present invention are of formula V-II-2:

[0721] [ka]

[0722] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein R 6 , R 7 , and R 8Each of these can be independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl, or R 6 and R 7 These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 8-membered heterocycloalkyl, or R 6 and R 8 These atoms, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 8-membered heterocycloalkyl groups.

[0723] In some embodiments, the compounds of the present invention are of formula V-II-3:

[0724] [ka]

[0725] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. In some embodiments, the compounds of the present invention are of formula V-II-4:

[0726] [ka]

[0727] or having a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer structure thereof (wherein X 2 is CH2 or O, (o is either 1 or 2).

[0728] In some embodiments, the compound is of formula VIA or formula VIB:

[0729] [ka]

[0730] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, W is a crosslinking group containing aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycal. X 6 is CH2 or O, m is either 1 or 2. n is either 0 or 1. R 1 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 is an optionally substituted C1-C6 alkyl group, z is 0, 1, or 2. X 9 -NR L6 -, -C(O)-, or -S(O)2-, R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6Each of these is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0731] In some embodiments, the compound is given by formula VIA-1:

[0732] [ka]

[0733] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, W is a crosslinking group containing aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycal. X 6 is CH2 or O, m is either 1 or 2. n is either 0 or 1. R 1 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 is an optionally substituted C1-C6 alkyl group, Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0734] In some embodiments, the compound is given by formula VIa-2:

[0735] [ka]

[0736] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, W is a crosslinking group containing aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycal. X 6 is CH2 or O, m is either 1 or 2. n is either 0 or 1. R 1 These are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 (wherein it is an arbitrarily substituted C1-C6 alkyl group).

[0737] In some embodiments of the present invention, X 2 is CH2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments of the present invention, X 6 is O. In some embodiments, o is 1. In some embodiments, o is 2.

[0738] In some embodiments of the compounds of the present invention, R 2 teeth,

[0739] [ka]

[0740] That is the case. In some embodiments of the compounds of the present invention, R 3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 teeth,

[0741] [ka]

[0742] That is the case. In some embodiments of the compounds of the present invention, R 3 R is an optionally substituted 3- to 6-membered cycloalkyl group. In some embodiments, R 3 teeth,

[0743] [ka]

[0744] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is

[0745] [ka]

[0746] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted phenyl. In some embodiments, A is

[0747] [ka]

[0748] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is selected from the following or their stereoisomers:

[0749] [ka]

[0750] In some embodiments of the compounds of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X 1 This is CH2. In some embodiments, X 6 is O. In some embodiments, m is 1, n is 1, and X 6 is CH2. In some embodiments, m is 1, n is 1, and X 6 It is O.

[0751] In some embodiments of the compounds of the present invention, m is 2. 6 is CH2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 2 and X 6 is CH2 and n is 1. In some embodiments, m is 2 and X 6 is O. In some embodiments, m is 2 and X 6 In some embodiments, m is 2 and X 6 The value of n is O, and n is 0.

[0752] In some embodiments of the compounds of the present invention, W comprises an aziridine. In some embodiments, W comprises an optionally substituted cyclopropyl-aziridinyl moiety. In some embodiments, W is selected from the following or their stereoisomers:

[0753] [ka]

[0754] In some embodiments of the compounds of the present invention, W comprises an epoxide. In some embodiments, W is selected from the following or their stereoisomers:

[0755] [ka]

[0756] In some embodiments, the present invention relates to compounds having the structure of formula VIIa or formula VIIb:

[0757] [ka]

[0758] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, X 6 , X 7 , and X 8 Each of these is independently selected from CH2, CHF, CF2, C=O, or O. m is either 1 or 2. n is either 0 or 1. R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted heterocycloalkyl. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium. z is 0, 1, or 2. X 9 -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 is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of them, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3-8 membered heterocycline. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0759] In some embodiments, the compound is given by formula VIIa-1:

[0760] [ka]

[0761] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) L is a linker, X 6 , X 7 , and X 8 Each of these is independently selected from CH2, CHF, CF2, C=O, or O. m is either 1 or 2. n is either 0 or 1. R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted heterocycloalkyl. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0762] In some embodiments, the present disclosure relates to the compound of structural formula VIIa-2:

[0763] [ka]

[0764] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene, L is a linker, X 6 , X 7 , and X 8 Each of these is independently selected from CH2, CHF, CF2, C=O, or O. m is either 1 or 2. n is either 0 or 1. R 1 This is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3-10 member heterocycloalkyl. R 2 is an optionally substituted C1-C6 alkyl group, R 3 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted heterocycloalkyl. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium.

[0765] In some embodiments, the compounds of the present invention are of formula VI-Ia, formula VI-Ib, and formula VI-Ic:

[0766] [ka]

[0767] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein each D represents hydrogen having an isotopic enrichment factor of at least 5 for deuterium).

[0768] In some embodiments, the compounds of the present invention are of formula VI-II:

[0769] [ka]

[0770] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) R 2 is an optionally substituted C1-C6 alkyl group, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted heterocycloalkyl groups. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium.

[0771] In some embodiments, the compounds of the present invention are of formula VI-V:

[0772] [ka]

[0773] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) R 2 is an optionally substituted C1-C6 alkyl group, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted heterocycloalkyl groups. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium.

[0774] In some embodiments, the compounds of the present invention are of formula VI-VI:

[0775] [ka]

[0776] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) R 2 is an optionally substituted C1-C6 alkyl group, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted heterocycloalkyl groups. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium.

[0777] In some embodiments, the compounds of the present invention are of formula VI-VII:

[0778] [ka]

[0779] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene) R 2 is an optionally substituted C1-C6 alkyl group, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted heterocycloalkyl groups. Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium.

[0780] In some embodiments, the compounds of the present invention are of formula VI-Va, formula VI-Vb, and formula VI-Vc:

[0781] [ka]

[0782] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein each D represents hydrogen having an isotopic enrichment factor of at least 5 for deuterium).

[0783] In some embodiments, the compounds of the present invention are of formulas VI-Vd, VI-Ve, and VI-Vf:

[0784] [ka]

[0785] or having the structure of a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (wherein each D represents hydrogen having an isotopic enrichment factor of at least 5 for deuterium).

[0786] In one embodiment, the present invention relates to a compound having the structure of formula XI:

[0787] [ka]

[0788] or characterized by pharmaceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof (wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene) W is an optionally substituted 3-10 member heterocycloalkyl group, or an optionally substituted 3-10 member cycloalkyl group. X 4It is CH2 or NH, R 1 These are optionally substituted C1-C6 alkyls, optionally substituted C1-C6 alkenyls, optionally substituted C1-C6 alkynyls, optionally substituted C1-C6 heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-15 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, and R 3 It is hydrogen, or R 2 and R 3 These, together with the atoms to which they are bonded, form optionally substituted 8-14 member heterocycloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of them is either hydrogen or R 4 and R 6 is hydrogen, and R 5 and R 7 These, together with the atoms to which they are bonded, form an optionally substituted four-membered cycloalkyl group, or R 5 and R 7 is hydrogen, and R 4 and R 6 These, together with the atoms to which they are bonded, form optionally substituted four-membered cycloalkyl groups. R 10 is -OR 11 or -NR 12 R 13 And, R 11 , R 12 , and R 13Each of these is independently either an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, or R 12 and R 13 They combine to form optionally substituted 3-10 member heterocycloalkyl groups. Each R 33 These are independently halogens, optionally substituted C1-C3 alkyls, optionally substituted C1-C3 alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. (t is 0, 1, 2, or 3).

[0789] In some embodiments, A is an optionally substituted thiazole-diyl, optionally substituted oxazole-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 thiazole-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 heteroarylene. In some embodiments, A is

[0790] [ka]

[0791] In some embodiments, A is

[0792] [ka]

[0793] That is the case. In some embodiments of the compounds of the present invention, A is optionally substituted phenylene. In some embodiments, A is

[0794] [ka]

[0795] In some embodiments, A is

[0796] [ka]

[0797] That is the case. In some embodiments of the compounds of the present invention, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is an optionally substituted 6-membered heterocycloalkylene. In some embodiments, A is selected from the following or their stereoisomers:

[0798] [ka]

[0799] In some embodiments, A is selected from the following or their stereoisomers:

[0800] [ka]

[0801] In some embodiments of the compounds of the present invention, R 1 R is hydrogen, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments of the compounds of the present invention, R 1 R is hydrogen, or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments of the compounds of the present invention, R 1 R is an optionally substituted 3- to 10-membered heterocycloalkyl group. In some embodiments of the compounds of the present invention, R 1 teeth,

[0802] [ka]

[0803] That is the case. In some embodiments of the compounds of the present invention, R 1 teeth,

[0804] [ka]

[0805] In the formula, each D represents hydrogen having an isotopic enrichment factor of at least 5 for deuterium. In some embodiments of the compounds of the present invention, R 2 teeth,

[0806] [ka]

[0807] That is the case. In some embodiments of the compounds of the present invention, R 2 teeth,

[0808] [ka]

[0809] In the formula, each D represents hydrogen having an isotopic enrichment factor of at least 5 for deuterium. In some embodiments of the compounds of the present invention, R 3 R is an optionally substituted C1-C6 alkyl or an optionally substituted 3-6 membered cycloalkyl. In some embodiments of the compounds of the present invention, R 3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R 3 teeth,

[0810] [ka]

[0811] In some embodiments, R 3 teeth,

[0812] [ka]

[0813] In some embodiments, R 3 teeth,

[0814] [ka]

[0815] In the formula, each D represents hydrogen having an isotopic enrichment factor of at least 5 for deuterium. In some embodiments of the compounds of the present invention, R 3 R is an optionally substituted 3- to 6-membered cycloalkyl group. In some embodiments, R 3 teeth,

[0816] [ka]

[0817] In some embodiments, R 3 teeth,

[0818] [ka]

[0819] That is the case. In some embodiments of the compounds of the present invention, R 2 teeth,

[0820] [ka]

[0821] And R 3 teeth,

[0822] [ka]

[0823] And A is,

[0824] [ka]

[0825] That is the case. In some embodiments, R 2 teeth,

[0826] [ka]

[0827] And R 3 teeth,

[0828] [ka]

[0829] And A is,

[0830] [ka]

[0831] That is the case. In some embodiments of the compounds of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X 1 This is CH2. In some embodiments, X 2 This is CH2. In some embodiments, X 3 is CH2. In some embodiments, m is 1, n is 1, and X 1 , X 2 , and X 3 Each of these is CH2.

[0832] In one embodiment, the present invention relates to a compound having the structure of formula Ic:

[0833] [ka]

[0834] or characterized by a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof (in the formula, Q is an optionally substituted 7-12 membered bicyclic arylene, an optionally substituted 7-12 membered bicyclic heteroarylene, or an optionally substituted 7-12 membered bicyclic heterocyclene, where the first ring in Q is bonded to X and the second ring in Q is bonded to A, where X is a linear C1-C3 alkylene, -O-, -S(O)O-2-, *-CH2-O-, *-CH2-S(O)O-2-, *-O-CH2-, or *-CH2-S(O)O-2-, where "*" is -C(R 7 )(R 8 ) represents the part of X that is joined to ), Y is -O-, -NH-, or -N(C1-C3 alkyl)-, A is an arbitrarily substituted C2-C4 alkylene, an arbitrarily substituted C1-C4 heteroalkylene, or an arbitrarily substituted C2-C4 alkenylene, an arbitrarily substituted 3- to 6-membered cycloalkylene, an arbitrarily substituted 3- to 6-membered heterocycloalkylene, an arbitrarily substituted 6-membered arylene, or an arbitrarily substituted 5- to 10-membered heteroarylene. L is a linker, T is the second linker, R 3 These are optionally substituted C1-C6 alkyl groups, optionally substituted C3-C6 cycloalkyl groups, optionally substituted C6 aryl groups, or optionally substituted 3-7 member heterocyclines. R 10is hydrogen, halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 heteroalkyl, R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, R 8 This includes hydrogen, halogens, -OH, -CN, -O- (optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and optionally substituted C6-C 10 It is an aryl, an optionally substituted 4-8 member heteroaryl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 3-7 member heterocycline, or R 7 and R 8 Together, they form =CH2, optionally substituted C3-C6 cycloalkyl groups, or 3-7 member saturated heterocyclines, or R 8 and the ring atoms in Q, R 7 The carbon atoms bonded to Q, as well as X, form a 4- to 9-membered saturated or unsaturated heterocycline condensed with Q, and R 6 is hydrogen or -CH3, Each R 5 These are independently halogens, optionally substituted C1-C3 alkyls, or optionally substituted C1-C3 haloalkyls. p is 0, 1, 2, or 3. z is 0, 1, or 2. X 9 -NR L6 -, -C(O)-, or -S(O)2-, R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6Each of these is independently hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl, or R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 Any two of these atoms, together with the atom to which they are bonded and any intervening atom, form an optionally substituted C3-C8 cycloalkyl or 3- to 8-membered heterocycline.

[0835] In some embodiments of the compounds described herein, T has the structure of formula XV:

[0836] [ka]

[0837] It holds. In some embodiments of equation XV, z is 0. In some embodiments of the compounds described herein, T is the structure of formula XVa:

[0838] [ka]

[0839] It holds. In some embodiments, T is

[0840] [ka]

[0841] It has the structure of [the object]. In some embodiments of equation XV, z is 1. In some embodiments of the compounds described herein, T is the structure of formula XVb:

[0842] [ka]

[0843] It holds. In some embodiments of the compounds described herein, T is the structure of formula XVc:

[0844] [ka]

[0845] It holds. In some embodiments of the compounds described herein, T is the structure of formula XVd:

[0846] [ka]

[0847] It holds. In some embodiments of the compounds described herein, T is the structure of formula XVe:

[0848] [ka]

[0849] It holds. In some embodiments of equation XV, z is 2. In some embodiments of the compounds described herein, T is a structure of formula XVf:

[0850] [ka]

[0851] It holds. In some embodiments, R L1 is hydrogen. In some embodiments, RL1 is an optionally substituted C1-C6 alkyl group. In some embodiments, R L1 is methyl, ethyl, or trifluoromethyl. In some embodiments, R L1 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R L1 is methoxy or ethoxy. In some embodiments, R L1 is an optionally substituted C2-C6 alkynyl. In some embodiments, R L1 It is ethynyl.

[0852] In some embodiments, R L2 is hydrogen. In some embodiments, R L2 is a halogen. In some embodiments, R L2 It is fluoro. In some embodiments, R L3 is hydrogen. In some embodiments, R L3 is an optionally substituted C1-C6 alkyl group. In some embodiments, R L3 It is methyl.

[0853] In some embodiments, R L4 It is hydrogen. In some embodiments, R L1 and R L4 These combine to form an optionally substituted C4 cycloalkyl group.

[0854] In some embodiments, R L1 and R L3 They combine to form an optionally substituted C4 cycloalkyl. In some embodiments, R L1 and R L3 These combine to form an optionally substituted C5 cycloalkyl group.

[0855] In some embodiments, two R L1 These combine to form an optionally substituted C3-C6 cycloalkyl group. In some embodiments, R L1 and R L2 These combine to form an optionally substituted C3-C6 cycloalkyl group.

[0856] In some embodiments, T is

[0857] [ka]

[0858] That is the case. In some embodiments, T is

[0859] [ka]

[0860] That is the case. In some embodiments of the compounds described herein, T has the structure of formula XVI:

[0861] [ka]

[0862] It holds. In some embodiments, X 9 -NR L6 - is In some embodiments of the compounds described herein, T is the structure of formula XVIa:

[0863] [ka]

[0864] It holds. In some embodiments of the compounds described herein, T is the structure of formula XVIb:

[0865] [ka]

[0866] It holds. In some embodiments, R L6 is an optionally substituted C1-C6 alkyl group. In some embodiments, R L6 It is methyl.

[0867] In some embodiments, X 9 is -C(O)-. In some embodiments, X 9 It is -S(O)2-. In some embodiments, R L5 is hydrogen. In some embodiments, R L5 is an optionally substituted C1-C6 alkyl group. In some embodiments, R L5 is an optionally substituted C3-C8 cycloalkyl. In some embodiments, two R L5 These combine to form an optionally substituted C3-C8 cycloalkyl group.

[0868] In some embodiments of the compounds described herein, T is

[0869] [ka]

[0870] That is the case. In some embodiments of the compounds described herein, T is

[0871] [ka]

[0872] That is the case. In some embodiments of the compounds described herein, T does not have the following structure:

[0873] [ka]

[0874] In some embodiments, 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 has (In the formula, A 1 This is the bond between the linker and the remainder of the macroring, A 2 This is the link between A and the linker, and Z 1 , Z 2 , Z 3 , and Z 4 These are, independently, arbitrarily substituted C1-C3 alkylenes, arbitrarily substituted C1-C3 heteroalkylenes, arbitrarily substituted C1-C2 alkenylenes, arbitrarily substituted 3- to 8-membered heterocycloalkylenes, arbitrarily substituted 3- to 8-membered cycloalkylenes, O, NR N , or a crosslinking group containing vinyl ketone, inone, vinyl sulfone, alkynyl sulfone, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, aziridine, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium, or glycal, R N is hydrogen, optionally substituted C1-C4 alkyl, or optionally substituted 6-membered arylene, C 1 and C 2Each is independently carbonyl or O, and f, g, h, i, j, and k are independently 0 or 1, D 1 This includes optionally substituted C1-C2 alkylenes, optionally substituted C2-C6 alkenylenes, optionally substituted C2-C6 alkynylenes, optionally substituted 3-8 member heterocycloalkylenes, optionally substituted 3-8 member cycloalkylenes, or optionally substituted C1-C3 heteroalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-10 member heteroarylenes, or A 1 -(Z 1 ) f -(C 1 ) g -(Z 2 ) h -and-(Z 3 ) i -(C 2 ) j -(Z 4 ) k -A 2 (A chemical bond that connects two things.)

[0875] In some embodiments of the linker 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.

[0876] In some embodiments of the linker of formula XIII, Z 1 , NR N In some embodiments, R N is an optionally substituted C1-C4 alkyl group. In some embodiments, R N It is methyl.

[0877] In some embodiments of the linker of formula XIII, C 1 It is a carbonyl group. In some embodiments of the linker of formula XIII, D 1 It is a 3- to 8-membered cycloalkylene. In some embodiments, D 1 is an optionally substituted C1-C2 alkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C2-C6 alkylylene, or an optionally substituted C1-C3 heteroalkylene. In some embodiments, D 1 These are arbitrarily substituted 3- to 8-membered heterocycloalkylenes.

[0878] In some embodiments of the linker of formula XIII, Z 4 In some embodiments, Z 4 is an optionally substituted C1-C3 alkylene. In some embodiments, Z 3 This is an arbitrarily substituted C1-C3 alkylene.

[0879] In some embodiments, L has the structure of formula VIII:

[0880] [ka]

[0881] (wherein X 5 It is either O or CH2 and is bonded to ring A. Z is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted C1-C6 alkylene, or an optionally substituted C1-C6 heteroalkylene.

[0882] In some embodiments of the linker of formula VIII, X 5 It is O. In some embodiments of the linker of formula VIII, Z is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, Z is an optionally substituted 5-membered heterocycloalkylene. In some embodiments, Z is an optionally substituted pyrrolidine-diyl.

[0883] In some embodiments, L has the structure of formula VIIIa:

[0884] [ka]

[0885] (wherein X 9 It is NR, O, or CH2, and is bonded to ring A. X 10 is CH or N, X 11 These are 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, or an optionally substituted 3-6 member heterocycloalkylene. R 30 and R 32 These are, independently, hydrogen, and optionally substituted C6-C 10 These are aryl or optionally substituted C1-C6 alkylenes. R 31 This consists of hydrogen and optionally substituted C6-C 10 The aryl, optionally substituted 4-8 member heteroaryl, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene, (q and r are independently 0, 1, 2, or 3).

[0886] In some embodiments, L has the structure of formula VIIIb:

[0887] [ka]

[0888] It holds. In some embodiments, L has the structure of formula VIIIc:

[0889] [ka]

[0890] It holds. In some embodiments, L has the structure of formula VIIId:

[0891] [ka]

[0892] It holds. In some embodiments, L has the structure of formula VIIIe:

[0893] [ka]

[0894] It holds. In some embodiments, L has the structure of formula VIIIf:

[0895] [ka]

[0896] It holds. In some embodiments, L has the structure of formula VIIIg:

[0897] [ka]

[0898] It holds. In some embodiments of the linker of formula VIIIa, the linker is

[0899] [ka]

[0900] That is the case. In some embodiments, the linker has the following structure:

[0901] [ka]

[0902] (wherein R 37 is a hydrogen or substituted C1-C4 alkyl group, R 38 These are hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 8-11 member spirocyclic heterocycloalkylene. q is 0, 1, 2, or 3).

[0903] In some embodiments, the linker has the following structure:

[0904] [ka]

[0905] (wherein R 38 These are hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 8-11 member spirocyclic heterocycloalkylene. (Y and e are independently 1, 2, or 3).

[0906] In some embodiments, the linker has the structure of formula XII:

[0907] [Chemistry]

[0908] having (wherein the left O atom is bonded to ring A, R 35 is NR 36 C(O)CH2N(R 36 )2 or optionally substituted 3- to 6-membered heterocycloalkylene, each R 36 is optionally substituted C1-C4 alkyl).

[0909] [[ID=2३]] In some embodiments, the linker has the structure of Formula XIV:

[0910] [Chemistry]

[0911] having (wherein, X 5 is O and is bonded to ring A, each X 13 is independently O or NR 34 , each R 34 is independently hydrogen or optionally substituted C1-C6 alkyl).

[0912] In some embodiments, L has the structure of Formula IX:

[0913] [Chemistry]

[0914] having (wherein, B is optionally substituted 3- to 6-membered heterocycloalkylene, R 22This includes hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member heterocyclyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 5-10 member heteroaryl, and optionally substituted C6-C 10 Ariel,

[0915] [ka]

[0916] And, R 23 and R 24 Each of these is independently a hydrogen- or optionally substituted C1-C6 alkyl group. R 25 These are optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-6 member heterocyclyl groups. R 26 This includes optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, optionally substituted C1-C6 heteroalkyl groups, and optionally substituted C3-C6 groups. 10 Cycloalkyl, optionally substituted 3-6 member heterocyclyl, optionally substituted 5-10 member heteroaryl, or optionally substituted C6-C 10 It is Ariel, R 27 This includes 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 alkynyl, optionally substituted C2-C6 heteroalkynyl, and optionally substituted C3-C 10 Cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3-C 10 Cycloalkenyls, optionally substituted 3-10 member heterocycloalkenyls, optionally substituted C6-C 10 (An aryl, or optionally substituted 5- to 10-membered heteroaryl).

[0917] In some embodiments, the linker of Formula IX has the structure of Formula X:

[0918]

Chemical formula

[0919] having. In some embodiments of the linker of Formula IX or X, R 22 is

[0920]

Chemical formula

[0921] is. In some embodiments, R 27 is optionally substituted C1-C6 alkyl. In some embodiments, R 27 is optionally substituted C2-C6 alkenyl. In some embodiments, R 27 is optionally substituted C2-C6 alkynyl. In some embodiments, R 27 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R 27 is optionally substituted C2-C6 heteroalkenyl. In some embodiments, R 27 is optionally substituted C2-C6 heteroalkynyl. In some embodiments, R 27 is optionally substituted C3-C 10 cycloalkenyl. In some embodiments, R 27 is hydrogen. In some embodiments, R 27 is optionally substituted C3-C 10 cycloalkyl. In some embodiments, R 27 is optionally substituted 3- to 10-membered heterocyclyl.

[0922] In some embodiments of the linker of Formula IX or X, R 22 is

[0923] [ka]

[0924] In some embodiments, R 26 is an optionally substituted 5-10 member heteroaryl. In some embodiments, R 26 These are arbitrarily substituted 3- to 10-membered heterocyclines.

[0925] In some embodiments of the linker of formula IX or X, R 22 These are arbitrarily substituted 3- to 6-membered heterocyclines. In some embodiments of compounds of formulas I, II, III, IV, IVa, IVb, IVc, V, or VI, A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is an optionally substituted 6-membered arylene. In some embodiments, A is

[0926] [ka]

[0927] That is the case. In some embodiments, A is

[0928] [ka]

[0929] That is the case. In any embodiment described herein, the compounds of the present invention may be modified by substituents found in one or more of the following applications (which are incorporated herein by reference in whole): WO2024 / 060966, WO2024 / 017859, WO2024 / 008834, WO2024 / 008610, WO2023 / 232776, WO2023 / 208005, WO2023 / 086341, WO2023 / 025832, WO2023 / 015559, CN117720556, CN117720555, CN117720554, CN117534687, CN117534685, and CN117534684.

[0930] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or atropisomers thereof.

[0931] [Table 1-1]

[0932] [Table 1-2]

[0933] [Table 1-3]

[0934] [Table 1-4]

[0935] [Table 1-5]

[0936] [Table 1-6]

[0937] Table 1-7

[0938] Table 1-8

[0939] Table 1-9

[0940] Table 1-10

[0941] Table 1-11

[0942] Table 1-12

[0943] Table 1-13

[0944] Table 1-14

[0945] Table 1-15

[0946] Table 1-16

[0947] Table 1-17

[0948] Table 1-18

[0949] Table 1-19

[0950] Table 1-20

[0951] Table 1-21

[0952] Table 1-22

[0953] Table 1-23

[0954] Table 1-24

[0955] Table 1-25

[0956] Table 1-26

[0957] Table 1-27

[0958] Table 1-28

[0959] Table 1-29

[0960] Table 1-30

[0961] Table 1-31

[0962] Table 1-32

[0963] Table 1-33

[0964] Table 1-34

[0965] Table 1-35

[0966] Table 1-36

[0967] Furthermore, pharmaceutical compositions comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also provided. Furthermore, a conjugate or salt thereof of the compound of the present invention is provided, the compound of the present invention having a covalent warhead bonded to a monovalent organic moiety.

[0968] In some embodiments of the conjugate 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.

[0969] The compounds of the present invention are also suitable for use in antibody-drug conjugates and degradation inducer applications. Furthermore, a method is provided for treating a cancer in a subject requiring treatment, 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 cancer, 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 includes a Ras mutation such as K-Ras Q61H, H-Ras Q61H, or N-Ras Q61H. Other Ras mutations are described herein.

[0970] Furthermore, a method is provided for treating a subject requiring treatment for a Ras protein-related disorder, comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0971] A method for inhibiting the Ras protein in cells is further provided, 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 cancer 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.

[0972] With respect to the compounds of the present invention, one stereoisomer may exhibit better inhibition than another. For example, one atropisomer may exhibit inhibition, while other atropisomers may exhibit little to no inhibition.

[0973] In some embodiments, the methods or uses described herein further include administering additional anticancer therapies. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are described herein.

[0974] Synthesis method The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0975] The compounds of the present invention (e.g., the compounds in Table 1) can be prepared in several ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized by using the methods described in the following scheme, together with synthetic methods known in the field of organic synthesis chemistry or variations thereof that are understood to those skilled in the art. Further examples include the synthetic methods described in WO2020 / 132597, WO2021 / 091982, WO2021 / 091967, WO2021 / 091956, WO2022 / 060836, WO2022 / 235864, WO2022 / 235870, WO2023 / 060253, and WO2023 / 133543 (the respective disclosures are incorporated herein by reference), which may be useful for preparing the compounds of the present invention. These methods include, but are not limited to, the methods described in the following scheme.

[0976] Scheme 1. General synthesis of functionalized bis-macro rings

[0977] [ka]

[0978] The general synthesis of functionalized bis-macrocyclic compounds is outlined in Scheme 1. A well-substituted biaryl intermediate (1) can be prepared in one step from a well-substituted 3-(5-bromo-2-iodo-1H-indole-3-yl)-2,2-dimethylpropan-1-ol intermediate and a well-substituted methylpiperazic acid ester-containing arylboronic acid ester by palladium-mediated coupling followed by ester hydrolysis. Macrolactonization, followed by deprotection of amines and phenols, can yield the macrocyclic ester (2).

[0979] A properly substituted 2-(tosyloxymethyl)-3-(amide)cyclic amine (3) can be prepared by coupling an O-protected N-methyl-L-valine (4) with a properly substituted 2-(hydroxymethyl)-3-carboxylate cyclic amine using a peptide coupling reagent, followed by tosylation of the alcohol and deprotection of the carboxylic acid.

[0980] Next, the final functionalized bis-macrocyclic ring can be prepared by peptide coupling of the macrocyclic ester (1) with the intermediate (3), followed by macrocyclic ether formation in the presence of a base. Deprotection of the amine and coupling with a appropriately substituted carboxylic acid (or other coupling partner) can yield the bis-macrocyclic product (5).

[0981] Scheme 2. Alternative general synthesis of macrocyclic ester intermediate (2)

[0982] [ka]

[0983] Alternatively, the macrocyclic ester intermediate (2) can be prepared as described in Scheme 2. A appropriately substituted arylboronic acid ester (5) can be coupled with a appropriately protected 3-(5-bromo-indole-3-yl)-2,2-dimethylpropan-1-ol (6) in the presence of a palladium catalyst. This may be followed by iodination of the indole, deprotection of the alcohol, and hydrolysis of the ester. Subsequently, coupling with a methyl(S)-piperazic acid ester, hydrolysis of the ester, and macrolactonization can yield the iodized macrocyclic intermediate (7). Intermediate (2) can be obtained by coupling with a appropriately substituted arylboronic acid ester (8) in the presence of a palladium catalyst, followed by N-alkylation of the indole, and subsequent deprotection of the amine and phenol.

[0984] Scheme 3. General synthesis of functionalized amine bis-macro rings

[0985] [ka]

[0986] The general synthesis of functionalized bis-macrocycles is outlined in Scheme 3. A well-protected hydroxyalkyl amino acid can be coupled with O-protected N-methyl-L-valine (3) using a peptide coupling reagent. Subsequent deprotection of the alcohol and carboxylic acid can yield a well-substituted intermediate (7).

[0987] The protected amine bis-macrocyclic intermediate can be prepared by peptide coupling of the macrocyclic ester intermediate (2) with a carboxylic acid (7), followed by bis-macrocyclic ether formation in the presence of triphenylphosphine and azodicarboxylate. The final bis-macrocyclic product (8) can be obtained by deprotection of the amine and coupling with a appropriately substituted carboxylic acid (or other coupling partner).

[0988] Scheme 4. General synthesis of functionalized amine bis-macro rings

[0989] [ka]

[0990] The general synthesis of functionalized bis-macro rings is outlined in Scheme 4. A appropriately substituted terminal alkyne (9) can be coupled with an appropriately substituted iodized bromoalene (10) in the presence of a palladium catalyst. A macrocyclic intermediate (12) can then be obtained by reduction of the aryl alkyne intermediate (11), followed by amino acid N-deprotection, carboxylic acid deprotection, macrocyclization in the presence of a peptide coupling reagent, ester hydrolysis, and peptide coupling with a methyl(S)-piperazic acid ester. The functionalized bis-macro ring (13) can then be obtained by palladium-mediated coupling with an appropriately substituted 3-(5-boronate-indole-3-yl)-2,2-dimethylpropan-1-ol, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner).

[0991] Scheme 5. General synthesis of functionalized amine bis-macro rings

[0992] [ka]

[0993] The general synthesis of functionalized bis-macrorings is outlined in Scheme 5. A suitably substituted 2-bromo-4-bromomethyl-5-ethenyl five-membered heteroarene (14) can be reacted with ethyl 2-((diphenylethylene)amino)acetate in the presence of a base and a chiral auxiliary. Subsequently, macrorings (16) can be obtained by amide coupling wi...

Claims

1. Compounds selected from formulas Ia, Ib, IIa, IIb, IIa-1, IIIa, IIIb, IIIa-1, IVa, IVb, Va, Vb, VIa, VIb, VIIa, VIIb, or XI, or pharmaceutically acceptable salts thereof. (Here, equation Ia is the structure: 【Chemistry 1】 It has, in the formula, Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein the first ring in Q is bonded to X and the second ring in Q is bonded to A, and X is a bond, fluoro, -CN, -C １ -C ３ alkyl, and -O-C １ -C ３ alkyl, and is optionally substituted with 1 to 3 substituents independently selected from linear C １ -C ３ alkylene, -O-, -S(O) ０ - ２ -, *-CH ２ -O-, *-CH ２ -S(O) ０ - ２ -, *-O-CH ２ -, or *-CH ２ -S(O) ０ - ２ -, where "*" represents the portion of X that is bonded to -C(R ７ )(R ８ )- Y is -O-, -NH-, or -N(C １ -C ３ Alkyl)-, A is C which is arbitrarily substituted. ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, or optionally substituted C ２ -C ４ Alkenylene, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-10 member heteroarylene, L is a linker, R ３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ６ It is an aryl, or optionally substituted, 3- to 7-membered heterocycline. R １０ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, R ７ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８ This is hydrogen, halogen, -OH, -CN, -O- (arbitrarily substituted C １ -C ３ Alkyl), optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkinyl, optionally substituted C ６ -C １０ Aryl, arbitrarily substituted 4- to 8-membered heteroaryls, arbitrarily substituted C ３ -C ６ It is a cycloalkyl or optionally substituted 3- to 7-membered heterocycline, or R ７ and R ８ Both are, =CH ２ , arbitrarily substituted C ３ -C ６ They form cycloalkyl groups or 3- to 7-membered saturated heterocyclines, or R ８ and the ring atom in Q, R ７ The carbon atoms bonded to Q, as well as X, form a 4- to 9-membered saturated or unsaturated heterocycline condensed with Q, and R ６ is hydrogen or -CH ３ And, Each R ５ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is a haloalkyl, p is 0, 1, 2, or 3. z is 0, 1, or 2. X ９ -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 independently is hydrogen, halogen, hydroxyl, optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C[[ID=2I]] ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, or optionally substituted C １ -C ６ heteroalkyl, 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 optionally substituted C ３ -C ８ cycloalkyl or a 3- to 8-membered heterocyclyl, Here, formula Ib is structure: 【Chemistry 2】 It has, in the formula, Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, where the first ring in Q is bonded to X and the second ring in Q is bonded to A, and X is a bond, fluoro, -CN, -C １ -C ３ alkyl, and -O-C １ -C ３ linear C optionally substituted with 1 to 3 substituents independently selected from １ -C ３ alkylene, -O-, -S(O) ０ -[[]]END]] ２ -, *-CH ２ -O-, *-CH ２ -S(O) ０ -[[]]END]] ２ -, *-O-CH ２ -, or *-CH ２ -S(O) ０ -[[]]END]] ２ -, where "*" represents the portion of X bonded to -C(R ７ )(R ８ )- Y is -O-, -NH-, or -N(C １ -C ３ Alkyl)-, A is C which is arbitrarily substituted. ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, or optionally substituted C ２ -C ４ Alkenylene, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-10 member heteroarylene, L is a linker, R ３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted C ６ It is an aryl, or optionally substituted, 3- to 7-membered heterocycline. R １０ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, R ７ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８ This is hydrogen, halogen, -OH, -CN, -O- (arbitrarily substituted C １ -C ３ Alkyl), optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkinyl, optionally substituted C ６ -C １０ Aryl, arbitrarily substituted 4- to 8-membered heteroaryls, arbitrarily substituted C ３ -C ６ It is a cycloalkyl or optionally substituted 3- to 7-membered heterocycline, or R ７ and R ８ Both = CH ２ , arbitrarily substituted C ３ -C ６ They form cycloalkyl groups or 3- to 7-membered saturated heterocyclines, or R ８ and the ring atom in Q, R ７ The carbon atoms bonded to Q, as well as X, form a 4- to 9-membered saturated or unsaturated heterocycline condensed with Q, and R ６ is hydrogen or -CH ３ And, Each R ５ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is a haloalkyl, p is 0, 1, 2, or 3. z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Here, equation IIa is, 【Transformation 3】 or having a pharmaceutically acceptable salt structure thereof, where the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is C which is arbitrarily substituted. ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, optionally substituted C ２ -C ４ Alkenylene, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-10 member heteroarylene, B does not exist, or -CH(R ９ ) -, > C = CR ９ R ９’ , or >CR ９ R ９’ (The carbon is -N(R) １１ (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C １ -C ４ Alkylene, optionally substituted C １ -C ４ Alkenylene, optionally substituted C １ -C ４ Heteroalkylene, -C(O)O-CH(R ６ ) - (C is -C(R ７ R ８ )-bonded),-C(O)NH-CH(R ６ ) - (C is -C(R ７ R ８ ) - bonded to), arbitrarily substituted C １ -C ４ These are heteroalkylenes or 3- to 8-membered heteroarylenes. L is a linker, X ３ is N or CH, q is 0, 1, or 2. R is hydrogen, cyano, or optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkinyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ And, Each R ’ These are independently hydrogen, or optionally substituted C １ -C ４ It is alkyl, Y １ is C, CH, or N, Y ２ , Y ３ , Y ４ , and Y ７ These are independently C or N, Y ５ CR ｘ CH, CH ２ , or N, Y ６ CR ｚ , C(O), CH, CH ２ , or N, R ｘ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R ｚ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R １３ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R １３ and R ２ These, together with the atoms to which they are bonded, form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ２ is either nonexistent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R １４ It does not exist, or R ２ and R １４ These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups. R １５ It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or one to three halogens. R ５ is hydrogen, halogen, cyano, hydroxy, or C １ -C ４ C arbitrarily substituted with heteroalkyl groups １ -C ４ Alkyl, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R ８ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ -C ３ Heteroalkyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R ７ and R ８ Together with the carbon atoms to which they are bonded, C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７ａ and R ８ａ These are independently hydrogen, halogen, and optionally substituted C １ -C ３ They are alkyl groups, or together with the carbon they are bonded to, they form a carbonyl group. R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ -C ３ Heteroalkyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R ７’ and R ８’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R ９ is hydrogen, F, and optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group, or R ９ And L, together with the atoms to which they are bonded, form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ９’ is hydrogen, or optionally substituted C １ -C ６ It is alkyl, or, R ９ and R ９’ These, together with the atoms to which they are bonded, form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. R １０ C is a hydrogen, halogen, hydroxyl, or optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, R １０ａ is hydrogen or halogen, R １１ is hydrogen, or optionally substituted C １ -C ３ It is alkyl, R ２１ is hydrogen, or optionally substituted C １ -C ３ It is alkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Here, equation IIb is, 【Chemistry 4】 or having a pharmaceutically acceptable salt structure thereof, where the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is C which is arbitrarily substituted. ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, optionally substituted C ２ -C ４ Alkenylene, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-10 member heteroarylene, B does not exist, or -CH(R ９ ) -, > C = CR ９ R ９’ Or > CR ９ R ９’ (The carbon is -N(R) １１ (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C １ -C ４ Alkylene, optionally substituted C １ -C ４ Alkenylene, optionally substituted C １ -C ４ Heteroalkylene, -C(O)O-CH(R ６ ) - (C is -C(R ７ R ８ )-bonded),-C(O)NH-CH(R ６ ) - (C is -C(R ７ R ８ ) - bonded to), arbitrarily substituted C １ -C ４ These are heteroalkylenes or 3- to 8-membered heteroarylenes. L is a linker, X ３ is N or CH, q is 0, 1, or 2. R is hydrogen, cyano, or optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkinyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ And, Each R' can independently be hydrogen or optionally substituted with carbon. １ -C ４ It is alkyl, Y １ is C, CH, or N, Y ２ , Y ３ , Y ４ , and Y ７ These are independently C or N, Y ５ CR ｘ CH, CH ２ , or N, Y ６ CR ｚ , C(O), CH, CH ２ , or N, R ｘ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R ｚ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R １３ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R １３ and R ２ These, together with the atoms to which they are bonded, form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ２ is either nonexistent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R １４ It does not exist, or R ２ and R １４ These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups. R １５ It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or one to three halogens. R ５ is hydrogen, halogen, cyano, hydroxy, or C １ -C ４ C arbitrarily substituted with heteroalkyl groups １ -C ４ Alkyl, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R ８ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ -C ３ Heteroalkyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R ７ and R ８ Together with the carbon atoms to which they are bonded, C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７ａ and R ８ａ These are independently hydrogen, halogen, and optionally substituted C １ -C ３ They are alkyl groups, or together with the carbon they are bonded to, they form a carbonyl group. R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ -C ３ Heteroalkyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R ７’ and R ８’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R ９ is hydrogen, F, and optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group, or R ９ And L, together with the atoms to which they are bonded, form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ９’ is hydrogen, or optionally substituted C １ -C ６ It is alkyl, or, R ９ and R ９’ These, together with the atoms to which they are bonded, form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. R １０ C is a hydrogen, halogen, hydroxyl, or optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, R １０ａ is hydrogen or halogen, R １１ is hydrogen, or optionally substituted C １ -C ３ It is alkyl, R ２１ is hydrogen, or optionally substituted C １ -C ３ It is alkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Here, equation IIa-1 is, 【Transformation 5】 or having a pharmaceutically acceptable salt structure thereof, where the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is C which is arbitrarily substituted. ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, optionally substituted C ２ -C ４ Alkenylene, optionally substituted 3-6 member cycloalkylene, optionally substituted 3-6 member heterocycloalkylene, optionally substituted 6 member arylene, or optionally substituted 5-10 member heteroarylene, B does not exist, or -CH(R ９ ) -, > C = CR ９ R ９’ Or > CR ９ R ９’ (The carbon is -N(R) １１ (bonded to the carbonyl carbon of C(O)-), 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, G is an arbitrarily substituted C １ -C ４ Alkylene, optionally substituted C １ -C ４ Alkenylene, optionally substituted C １ -C ４ Heteroalkylene, -C(O)O-CH(R ６ ) - (C is -C(R ７ R ８ )-bonded),-C(O)NH-CH(R ６ ) - (C is -C(R ７ R ８ ) - bonded to), arbitrarily substituted C １ -C ４ These are heteroalkylenes or 3- to 8-membered heteroarylenes. L is a linker, X １ is an arbitrarily substituted C １ -C ２ Alkylene, NR, O, or S(O) ｑ And, X ２ is O or NH, X ３ is N or CH, q is 0, 1, or 2. R is hydrogen, cyano, or optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkinyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ And, Each R' can independently be hydrogen or optionally substituted with carbon. １ -C ４ It is alkyl, Y １ is C, CH, or N, Y ２ , Y ３ , Y ４ , and Y ７ These are independently C or N, Y ５ CR ｘ CH, CH ２ , or N, Y ６ CR ｚ , C(O), CH, CH ２ , or N, R ｘ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R ｚ C is hydrogen, halogen, or optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. R １３ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R １３ and R ２ These, together with the atoms to which they are bonded, form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ２ is either nonexistent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R １４ It does not exist, or R ２ and R １４ These, together with the atoms to which they are bonded, form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups. R １５ It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or one to three halogens. R ５ is hydrogen, halogen, cyano, hydroxy, or C １ -C ４ C arbitrarily substituted with heteroalkyl groups １ -C ４ Alkyl, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl groups. R ８ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ -C ３ Heteroalkyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R ７ and R ８ Together with the carbon atoms to which they are bonded, C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７ａ and R ８ａ These are independently hydrogen, halogen, and optionally substituted C １ -C ３ They are alkyl groups, or together with the carbon they are bonded to, they form a carbonyl group. R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or optionally substituted C １ -C ３ Heteroalkyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6-10 membered aryl, or R ７’ and R ８’ These, together with the carbon atoms to which they are bonded, form optionally substituted 3-6 membered cycloalkyl groups, or optionally substituted 3-7 membered heterocycloalkyl groups. R ９ is hydrogen, F, and optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group, or R ９ And L, together with the atoms to which they are bonded, form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ９’ is hydrogen, or optionally substituted C １ -C ６ It is alkyl, or R ９ and R ９’ These, together with the atoms to which they are bonded, form a 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. R １０ C is a hydrogen, halogen, hydroxyl, or optionally substituted C １ -C ３ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, R １０ａ is hydrogen or halogen, R １１ is hydrogen, or optionally substituted C １ -C ３ It is alkyl, R ２１ is hydrogen, or optionally substituted C １ -C ３ It is alkyl, Here, equation IIIa is, 【Transformation 6】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, or an optionally substituted C ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, or optionally substituted C ２ -C ４ It is alkenylene, Y ８ teeth, 【Transformation 7】 And, L is a linker, R １３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ These are heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-15 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R １０ C is a hydrogen atom, a hydroxyl atom, or an optionally substituted C atom. １ -C ６ alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R ７ and R ８ These are, independently, F or CH ３ Selected from or R ７ and R ８ These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Here, equation IIIb is, 【Transformation 8】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, or an optionally substituted C ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, or optionally substituted C ２ -C ４ It is alkenylene, Y ８ teeth, 【Chemistry 9】 And, L is a linker, R １３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ These are heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-15 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R １０ C is a hydrogen atom, a hydroxyl atom, or an optionally substituted C atom. １ -C ６ alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R ７ and R ８ These are, independently, F or CH ３ Selected from or R ７ and R ８ These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Here, equation IIIa-1 is, 【Chemistry 10】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, or an optionally substituted C ２ -C ４ Alkylene, optionally substituted C １ -C ４ Heteroalkylenes, or optionally substituted C ２ -C ４ It is alkenylene, Y ８ teeth, 【Chemistry 11】 And, L is a linker, X ４ and X ５ Each is independent of CH ２ , CH (CH ３ ) or NH, R １３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ These are heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-15 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R １０ C is a hydrogen atom, a hydroxyl atom, or an optionally substituted C atom. １ -C ６ alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R ７ and R ８ These are, independently, F or CH ３ Selected from or R ７ and R ８ These, together with the atoms to which they are bonded, form a three-membered cycloalkyl group. Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation IVa is, 【Chemistry 12】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C １ -C ６ It is heteroalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, R ３ is an arbitrarily substituted C １ -C ６ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation IVb is, 【Chemistry 13】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, R １ is hydrogen, optionally substituted C １ -C ６ -alkyl, optionally substituted C １ -C ６ -alkenyl, optionally substituted C １ -C ６ -alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C １ -C ６ -heteroalkyl, and R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, R ３ is an arbitrarily substituted C １ -C ６ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation Va is, 【Chemistry 14】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C １ -C ６ It is heteroalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, R ３ is an arbitrarily substituted C １ -C ６ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, z is 0, 1, or 2. X ９ -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 which is, independently, hydrogen, halogen, hydroxyl, optionally substituted C １ -C ６ alkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted C ２ -C ６ alkynyl, or optionally substituted C １ -C ６ heteroalkyl, 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 C ３ -C ８ cycloalkyl or 3- to 8-membered heterocyclyl, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation Vb is, 【Chemistry 15】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, optionally substituted 3-10 member heterocycloalkyl, or optionally substituted C １ -C ６ It is heteroalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, R ３ is an arbitrarily substituted C １ -C ６ Alkyl or optionally substituted C １ -C ３ It is heteroalkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation VIa is, 【Chemistry 16】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, W is a crosslinking group containing aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycal. X ６ CH ２ or O, m is either 1 or 2. n is either 0 or 1, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation VIb is, 【Chemistry 17】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, W is a crosslinking group containing aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycal. X ６ CH ２ or O, m is either 1 or 2. n is either 0 or 1, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation VIIa is, [Chemistry 18] or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, X ６ , X ７ , and X ８ Each is independent of CH ２ CHF, CF ２ C=O or O is selected, m is either 1 or 2. n is either 0 or 1, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkinyl, optionally substituted C １ -C ６ Heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, R ３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted heterocycloalkyl, Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium. z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation VIIb is, 【Chemistry 19】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 3-6 member cycloalkylene, an optionally substituted 6 member arylene, or an optionally substituted 5-10 member heteroarylene. L is a linker, X ６ , X ７ , and X ８ Each is independent of CH ２ CHF, CF ２ C=O or O is selected, m is either 1 or 2. n is either 0 or 1, R １ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkinyl, optionally substituted C １ -C ６ Heteroalkyl or optionally substituted 3- to 10-membered heterocycloalkyl, R ２ is an arbitrarily substituted C １ -C ６ It is alkyl, R ３ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted heterocycloalkyl, Each hydrogen atom is independently and arbitrarily isotope-enriched with deuterium. z is 0, 1, or 2. X ９ -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 them independently consists of hydrogen, halogen, hydroxyl, and optionally substituted C. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, or optionally substituted C １ -C ６ It is heteroalkyl, or R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , R Ｌ４ , R Ｌ５ , and R Ｌ６ Any two of these atoms, along with the atom to which they are bonded and any intervening atom, are optionally substituted with C. ３ -C ８ Forming cycloalkyl or 3-8 membered heterocyclines, Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3. Here, equation XI is, 【Chemistry 20】 or having the structure of a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3-6 member cycloalkylene, an optionally substituted 3-6 member heterocycloalkylene, an optionally substituted 6 member arylene, an optionally substituted 5-6 member heteroarylene, or an optionally substituted C ２ -C ４ Alkylene, or optionally substituted C ２ -C ４ It is alkenylene, W is an optionally substituted 3- to 10-membered heterocycloalkyl group, or an optionally substituted 3- to 10-membered cycloalkyl group. X ４ CH ２ or NH, R １ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkenyl, optionally substituted C １ -C ６ Alkinyl, optionally substituted C １ -C ６ These are heteroalkyls, optionally substituted 3-6 membered cycloalkyls, optionally substituted 3-6 membered cycloalkenyls, optionally substituted 3-15 membered heterocycloalkyls, optionally substituted 6-10 membered aryls, or optionally substituted 5-10 membered heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 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 These, together with the atoms to which they are bonded, form optionally substituted 8-14 member heterocycloalkyl groups. R ４ , R ５ , R ６ , and R ７ Each of them is either hydrogen or R ４ and R ６ is hydrogen, and R ５ and R ７ These, together with the atoms to which they are bonded, form an optionally substituted four-membered cycloalkyl group, or R ５ and R ７ is hydrogen, and R ４ and R ６ These, together with the atoms to which they are bonded, form optionally substituted four-membered cycloalkyl groups. R １０ is, -OR １１ or -NR １２ R １３ And, R １１ , R １２ , and R １３ Each of these is an independently and arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ It is heteroalkyl, or R １２ and R １３ They combine to form optionally substituted 3- to 10-membered heterocycloalkyl groups. Each R ３３ These are, independently, halogens, and optionally substituted C １ -C ３ Alkyl, optionally substituted C １ -C ３ These are alkoxys, optionally substituted 3-6 member cycloalkyls, and optionally substituted 3-6 member heterocycloalkyls. t is 0, 1, 2, or 3).

2. Compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

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

4. A method for performing cancer treatment on a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3.

5. A method for carrying out treatment for a Ras protein-related disorder in a subject requiring such treatment, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3.

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

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