Cysteine covalent modifiers of akt1 and uses thereof

Abstract

Provided herein are covalent modifiers of AKT1 of Formula (I) and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides methods of modulating AKT1 using compounds or salts of Formula (I) and pharmaceutical compositions thereof. (I)

Description

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 590,256, filed October 13, 2023; U.S. Provisional Application No. 63 / 562,578, filed March 7, 2024; and U.S. Provisional Application No. 63 / 686,523, filed August 23, 2024, the entire contents of each of which are incorporated herein by reference. Background Technology

[0002] The AKT or protein kinase B (PKB) family of serine / threonine protein kinases consists of three highly homologous members: AKT1, AKT2, and AKT3. The AKT protein family is involved in signal transduction pathways that regulate cellular processes, including apoptosis, proliferation, differentiation, and metabolism. The AKT1 pathway is the most frequently dysregulated signal transduction pathway in human cancers. Enhanced activation of all isoforms is potentially associated with tumor development and progression, and has been demonstrated in breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, and other cancers (Song et al., 2019). In cancer cells, AKT1 is involved in proliferation and growth, promotes tumor initiation, and inhibits apoptosis, while AKT2 regulates cytoskeleton dynamics, favoring local tissue invasion and metastasis. It is hypothesized that excessive AKT3 activation in cancer may be related to stimulating cell proliferation (Hinz et al., 2019). Cell Commun Signal 2019, 17(1), 154; Pascual et al., Ann. Oncol. 2019, 30(7), 1051-1060). The expression of these AKT family members is altered in many human malignancies, including gastric, breast, prostate, ovarian, and pancreatic cancers. However, AKT family members are rarely mutated, with the most common mutation being AKT1 E17K, which has been reported in 6%–8% of breast cancers, 2%–6% of colorectal cancers, and 6% of meningiomas in humans (Yu et al., 2019, 30(7), 1051–1060). PLoS One 2015, 10 (10), Issue e0140479). Therefore, there is a need to develop novel therapies for regulating AKT1 and its mutants. Summary of the Invention

[0003] In one respect, this disclosure provides compounds represented by formula (I): (I); Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 3-8 A carbocyclic ring and 4- to 8-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 10 -SR 10 -N(R) 10 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and 4-10 yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) Heterocyclic compounds ranging from 4 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 ,- N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R11 、 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; and C 3-10 A carbocyclic ring and 4- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13-NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 1 L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16-N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16-OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; Ring D is selected from: , , and ; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each occurrence is independently selected from: hydrogen; C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is optionally composed of one or more independently selected from halogens, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

[0004] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) and a pharmaceutically acceptable excipient.

[0005] In another aspect, this disclosure provides a method for modulating the activity of wild-type AKT1, the method comprising administering to a desired subject a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.

[0006] In another aspect, this disclosure provides a method for modulating the activity of mutant AKT1, the method comprising administering to a subject in need a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.

[0007] In another aspect, this disclosure provides a method for selectively modulating the activity of wild-type AKT1 relative to wild-type AKT2, the method comprising administering to a desired subject a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.

[0008] In another aspect, this disclosure provides a method for selectively regulating the activity of mutant AKT1 relative to wild-type AKT2, the method comprising administering to a desired subject a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.

[0009] In another aspect, this disclosure provides a method for treating cancer in a subject of need, the method comprising administering to the subject a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) and a pharmaceutically acceptable excipient. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, and meningioma. In some embodiments, the activity of a mutant AKT1 is modulated. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the activity of a wild-type AKT1 is modulated.

[0010] In another aspect, this disclosure provides an AKT1 protein covalently bound to a compound, wherein the compound is covalently bound to a cysteine ​​residue of the AKT1 protein. In some embodiments, the compound is an exogenous AKT1 modulator. In some embodiments, the compound is an exogenous AKT1 inhibitor. In some embodiments, the exogenous AKT1 inhibitor is a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the AKT1 protein contains an E17K mutation, an E40K mutation, or an E49K mutation. In some embodiments, the cysteine ​​residue is selected from C296 and C310. In some embodiments, the cysteine ​​residue is C296. In some embodiments, the AKT1 protein is in vivo. In some embodiments, the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is produced by contacting the AKT1 protein with the compound in vivo. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein. In some embodiments, the covalent bond between the compound and the cysteine ​​residue is an irreversible covalent bond. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and a cysteine-sensitive electrophile on the compound, wherein the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonamide groups, and vinyl sulfonamide groups.

[0011] In another aspect, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a non-naturally occurring cysteine ​​residue, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfone groups, and vinyl sulfonamide groups. In some embodiments, the AKT1 protein contains an E17K mutation. In some embodiments, the cysteine ​​residue is selected from C296 and C310. In some embodiments, the cysteine ​​residue is C296. In some implementations, the in vivo engineered AKT1 protein is the human in vivo engineered AKT1 protein.

[0012] In another aspect, this disclosure provides a method for covalently modifying an AKT1 protein, the method comprising contacting the AKT1 protein with an exogenous AKT1 modulator, wherein the AKT1 modulator comprises a cysteine-sensitive electrophile, thereby forming a covalent AKT1 adduct. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the AKT1 modulator is an AKT1 inhibitor. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups.

[0013] In another embodiment, this disclosure provides a method for attenuating AKT1 activity, the method comprising contacting the AKT1 protein with an AKT1 inhibitor, wherein the AKT1 inhibitor comprises a cysteine-sensitive electrophile. In some embodiments, the contact is in vitro. In some embodiments, after contact, AKT1 activity is attenuated by 50% or more relative to a control without an exogenous AKT1 inhibitor. In some embodiments, after contact, AKT1 activity is attenuated by 70% or more relative to a control without an exogenous AKT1 inhibitor. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the exogenous AKT1 inhibitor is a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B).

[0014] Incorporation For the specific purposes specified herein, all publications, patents and patent applications mentioned in this specification are incorporated herein by reference. Attached Figure Description

[0015] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings, which illustrate illustrative embodiments utilizing the principles of the invention, in which: Figure 1A-1C A schematic diagram of the crystal structure of the compound 13 / AKT1 WT co-crystallized complex is provided. Figure 1A A 2-D schematic diagram of the crystal structure of compound 13 / AKT1 WT is provided, in which AKT1 WT is represented by a cartoon model and compound 13 having the cysteine ​​residue C296 of AKT1WT is represented by a rod model. Figure 1B A 2-D close-up schematic diagram of the crystal structure of compound 13 / AKT1 WT is provided, in which compound 13 is depicted by a coarser rod-shaped model and the residues of AKT1 WT are depicted by a finer rod-shaped model. Figure 1C A 2-D close-up schematic diagram of the crystal structure of compound 13 / AKT1 WT is provided, which shows in detail the interaction between the residues of AKT1 WT and compound 13, especially the covalent bond between the C296 cysteine ​​residue of AKT1 WT and compound 13.

[0016] Figure 2A-2C A schematic diagram of the crystal structure of the co-crystallized complex of compound 13 / AKT E17K is provided. Figure 2A A 2-D schematic diagram of the crystal structure of compound 13 / AKT E17K is provided, in which AKT E17K is represented by a cartoon model and compound 13 with AKTE17K cysteine ​​residue C296 is represented by a rod model. Figure 2B A 2-D close-up schematic diagram of the crystal structure of compound 13 / AKT E17K is provided, in which compound 13 is depicted by a coarser rod-shaped model and the residues of AKT E17K are depicted by a finer rod-shaped model. Figure 2C A 2-D close-up schematic diagram of the crystal structure of compound 13 / AKT E17K is provided, which shows in detail the interaction between the residues of AKT E17K and compound 13, especially the covalent bond between the C296 cysteine ​​residue of AKT E17K and compound 13. Detailed Implementation

[0017] The serine / threonine protein kinase family, AKT or protein kinase B (PKB), regulates a variety of key cellular functions, including apoptosis, proliferation, differentiation, and metabolism. The AKT family consists of three highly homologous members: AKT1, AKT2, and AKT3, each with a unique tissue distribution and performing a distinct set of biological functions. Aberrant expression and / or activation of all AKT isotypes are associated with tumor development, including breast, ovarian, pancreatic, and prostate cancers, as well as other cancers.

[0018] Inhibitors of the AKT protein have been developed for cancer treatment, including two main classes of small-molecule AKT inhibitors under clinical investigation: allosteric inhibitors and ATP-competitive inhibitors. First, allosteric inhibitors (such as miransertib (ARQ 092) and MK-2206) interfere with PH domain-mediated membrane recruitment (the first step in AKT activation) and inhibit AKT kinase activation and AKT phosphorylation. Second, ATP-competitive inhibitors of AKT (such as ipatasertib and capivasertib) bind to the active kinase, where the PH domain has shifted from the kinase domain and exposed the ATP-binding pocket site, thereby inhibiting ATP binding.

[0019] This document provides compounds for regulating (e.g., inhibiting) AKT1 function, as well as methods and compositions for treating cancer using the compounds disclosed herein. In some embodiments, the compound selectively inhibits (e.g., 2x, 5x, 10x, 50x, 100x, etc.) AKT1 protein relative to AKT2 and / or AKT3 proteins.

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications mentioned herein are incorporated herein by reference.

[0021] As used in the specification and claims, unless the context clearly indicates otherwise, the singular forms “a”, “an” and “the” include plural references.

[0022] "Alkyl" refers to a compound consisting only of carbon and hydrogen atoms, without any unsaturation, and preferably having one to twelve carbon atoms (i.e., C64). 1-12 An alkyl group is a straight-chain or branched hydrocarbon chain monovalent group. The alkyl group is linked to the rest of the molecule by a single bond. The alkyl chain may optionally be substituted with one or more substituents (such as those described herein). In some embodiments, the alkyl group comprises one to twelve carbon atoms (i.e., C12). 1-12 Alkyl groups. In some embodiments, the alkyl group comprises one to eight carbon atoms (i.e., C64-C ... 1-8 Alkyl groups. In other embodiments, the alkyl group comprises one to five carbon atoms (i.e., C16-C56). 1-5 Alkyl groups. In other embodiments, the alkyl group comprises one to four carbon atoms (i.e., C14-C24). 1-4 Alkyl groups. In other embodiments, the alkyl group comprises one to three carbon atoms (i.e., C14-C24). 1-3 Alkyl group). In other embodiments, the alkyl group comprises one or two carbon atoms (i.e., C12). 1-2 Alkyl group). In other embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (i.e., C1 alkyl). 5-15 Alkyl groups. In other embodiments, the alkyl group comprises five to eight carbon atoms (i.e., C64-C ... 5-8 Alkyl groups. In other embodiments, the alkyl group comprises two to five carbon atoms (i.e., C16-C56). 2-5 Alkyl groups. In other embodiments, the alkyl group comprises three to five carbon atoms (i.e., C14-C52). 3-5 Alkyl groups. For example, alkyl groups can be attached to the rest of the molecule by a single bond, such as methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), etc.

[0023] "Alkenyl" refers to a compound consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms (i.e., C2H2O). 2-12An alkenyl group is a straight-chain or branched hydrocarbon chain group. The alkenyl chain may optionally be substituted with one or more substituents (such as those described herein). In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C64-C ... 2-8 Alkenyl group). In some embodiments, the alkenyl group comprises two to six carbon atoms (i.e., C64-C ... 2-6 Alkenyl group). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C14-C24-C14). 2-4 Alkenyl groups are attached to the rest of the molecule by a single bond. Examples include ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pent-1,4-dienyl, etc.

[0024] "Alkyne" refers to a group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms (i.e., C2H2O). 2-12 An alkynyl group is a straight-chain or branched hydrocarbon chain group. The alkynyl chain may optionally be substituted with one or more substituents (such as those described herein). In some embodiments, the alkynyl group comprises two to eight carbon atoms (i.e., C64-C ... 2-8 (Alynyl group). In other embodiments, the alkynyl group comprises two to six carbon atoms (i.e., C64-C ... 2-6 (Alynyl group). In other embodiments, the alkynyl group comprises two to four carbon atoms (i.e., C24-C42). 2-4 Alynyl group). Alynyl groups are attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc.

[0025] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, free of unsaturation, and preferably having one to twelve carbon atoms, with the remainder of the molecule connected to a group. Examples include methylene, ethylene, propylene, (methyl)ethylene, butylene, etc. The alkylene chain is connected to the remainder of the molecule by single bonds and to the group via single bonds. The alkylene chain may optionally be substituted with one or more substituents (such as those described herein). In some embodiments, the alkylene comprises one to ten carbon atoms (i.e., C1 to C2). 1-10 Alkylene). In some embodiments, the alkylene comprises one to eight carbon atoms (i.e., C64-C ... 1-8 Alkylene). In other embodiments, the alkylene comprises one to five carbon atoms (i.e., C10-C50). 1-5 Alkylene). In other embodiments, the alkylene comprises one to four carbon atoms (i.e., C14-C24-C14). 1-4 Alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (i.e., C10-C20). 1-3 Alkylene). In other embodiments, the alkylene comprises one or two carbon atoms (i.e., C10). 1-2Alkylene). In other embodiments, the alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene comprises five to eight carbon atoms (i.e., C1 alkylene). 5-8 Alkylene). In other embodiments, the alkylene comprises two to five carbon atoms (i.e., C12-C52). 2-5 Alkylene). In other embodiments, the alkylene comprises three to five carbon atoms (i.e., C64-C ... 3-5 (alkylene).

[0026] "Alkenyl" refers to a straight-chain or branched divalent hydrocarbon chain in which the remainder of the molecule is connected to a group, consists only of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has two to twelve carbon atoms. The alkenyl chain is connected to the remainder of the molecule by single bonds and to the group by single bonds. The alkenyl chain may optionally be substituted with one or more substituents (such as those described herein). In some embodiments, the alkenyl group contains two to ten carbon atoms (i.e., C64-C ... 2-10 (Alkenyl group). In some embodiments, the alkenyl group contains two to eight carbon atoms (i.e., C64-C ... 2-8 (Alkenyl group). In other embodiments, the alkenyl group comprises two to five carbon atoms (i.e., C64-C ... 2-5 (Alkenyl group). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C64-C ... 2-4 (Alkenyl group). In other embodiments, the alkenyl group comprises two to three carbon atoms (i.e., C64-C ... 2-3 (Alkenyl group). In other embodiments, the alkenyl group comprises two carbon atoms (i.e., C2 alkenyl group). In other embodiments, the alkenyl group comprises five to eight carbon atoms (i.e., C2 alkenyl group). 5-8 (Alkenyl group). In other embodiments, the alkenyl group comprises three to five carbon atoms (i.e., C64-C ... 3-5 (alkenyl group).

[0027] "Imyynyl" refers to a straight-chain or branched divalent hydrocarbon chain in which the remainder of the molecule is connected to a group, consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and preferably has two to twelve carbon atoms. The ynylyl chain is connected to the remainder of the molecule by single bonds and to the group by single bonds. The ynylyl chain may optionally be substituted with one or more substituents (such as those described herein). In some embodiments, the ynylyl group contains two to ten carbon atoms (i.e., C64-C ... 2-10 (Imyynyl group). In some embodiments, the ynyl group contains two to eight carbon atoms (i.e., C64-C ... 2-8 (Imyynyl group). In other embodiments, the ynyl group comprises two to five carbon atoms (i.e., C24-C24-C24-C24). 2-5 (Imyynyl group). In other embodiments, the ynyl group comprises two to four carbon atoms (i.e., C24-C42). 2-4 (Imyynyl group). In other embodiments, the ynyl group comprises two to three carbon atoms (i.e., C24-C32-C42 ... 2-3(Alynyl group). In other embodiments, the alynyl group comprises two carbon atoms (i.e., C2 alynyl group). In other embodiments, the alynyl group comprises five to eight carbon atoms (i.e., C2 alynyl group). 5-8 (Imyynyl group). In other embodiments, the ynyl group comprises three to five carbon atoms (i.e., C364-C4 ... 3-5 (Imynyl group).

[0028] Term "C" x-y "When used in conjunction with chemical moieties such as alkyl, alkenyl, or ynyl, it means to include groups containing x to y carbons in the chain. For example, the term 'C'..." 1-6 "Alkyl" refers to a saturated hydrocarbon group containing 1 to 6 carbons, including straight-chain alkyl and branched-chain alkyl groups. (Term -C) x-y Alkylene refers to an alkylene chain having x to y carbons. For example, -C 1-6 The alkylene group can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which may be optionally substituted.

[0029] Term "C" x-y "Alkenyl" and "C" x-y "Alkyne" refers to an unsaturated aliphatic group with a similar length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond. Term -C x-y An alkenyl group refers to an alkenyl chain having x to y carbons. For example, -C 2-6 Alkenyl group – optionally selected from vinylene, propenylene, butenylene, pentenylene, and hexenylene, any of which may be optionally substituted. The alkenyl chain may have one or more double bonds. Terminology – C x-y The term "alkynyl group" refers to an alkynyl chain having x to y carbons. For example, -C 2-6 The ynyl group can be selected from ethynyl, propynyl, butynyl, pentyynyl, and hexynyl, any of which may be optionally substituted. The ynyl chain may have one or more triple bonds.

[0030] As used herein, the term "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom in the ring is carbon. Carbocyclic rings include 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring in a polycyclic carbocyclic ring may be self-saturated, unsaturated, or aromatic. Polycyclic carbocyclic rings may be fused, bridged, or spirocyclic systems. Each ring in a bicyclic carbocyclic ring may be self-saturated, unsaturated, or aromatic. Bicyclic carbocyclic rings may be fused, bridged, or spirocyclic systems. In some embodiments, the carbocyclic ring is aryl. In some embodiments, the carbocyclic ring is cycloalkyl. In some embodiments, the carbocyclic ring is cycloalkenyl. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring where the valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The carbon ring can be optionally substituted by one or more substituents (such as those described herein).

[0031] As used herein, the term "carbocyclic group" refers to a divalent saturated, unsaturated, or aromatic ring, wherein each atom in the ring is carbon. The carbocyclic group is connected to the remainder of the molecule by a single bond and also to a group by a single bond. The carbocyclic group may optionally be substituted with one or more substituents (such as those described herein). Carbocyclic groups include divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring in a polycyclic carbocyclic group may be self-saturated, unsaturated, or aromatic. Polycyclic carbocyclic groups may be fused, bridged, or spirocyclic systems. The single bonds connecting the carbocyclic group to the remainder of the molecule and the single bonds connecting the carbocyclic group to a group may be located on the same or different rings of the polycyclic carbocyclic group. In some embodiments, the carbocyclic ring is an arylene, such as a phenylene. As used herein, "phenylene" refers to a divalent phenyl group. The phenylene group is connected to the remainder of the molecule by a single bond and also to a group by a single bond. The phenylene group may optionally be substituted with one or more substituents (such as those described herein).

[0032] "Cycloalkyl" refers to a stable, fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused, bridged, or spirocyclic systems, and preferably having three to twelve carbon atoms (i.e., C64-C ... 3-12 Cycloalkyl groups. In some embodiments, cycloalkyl groups contain three to ten carbon atoms (i.e., C646). 3-10 (Cycloalkyl). In other embodiments, the cycloalkyl group contains five to seven carbon atoms (i.e., C64-C74-C6 ... 5-7Cycloalkyl groups. A cycloalkyl group can be attached to the rest of the molecule via a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclic [2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclic [2.2.1]heptyl, etc. A cycloalkyl group may optionally be substituted with one or more substituents (such as those described herein).

[0033] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon, and five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2) p-electron system. Ring systems that derive aryl groups include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene. The aryl group may optionally be substituted with one or more substituents (such as those described herein).

[0034] “C x-y "Carbon ring" is intended to include groups containing x to y carbon atoms in the ring. For example, the term "C" 3-6 "Carbon ring" can be a saturated, unsaturated or aromatic ring system containing 3 to 6 carbon atoms (any of which may be optionally substituted as provided herein).

[0035] As used herein, the term "heterocycle" refers to a saturated, unsaturated, non-aromatic, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic and polycyclic (e.g., 6- to 12-membered bicyclic) rings. Polycyclic heterocycles can be fused, bridged, or spirocyclic systems. Each ring in a polycyclic heterocycle can be selected from self-saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the remainder of the molecule by any atom of the heterocycle (such as a carbon or nitrogen atom of the heterocycle) where the valence allows. In some embodiments, the heterocycle is a heteroaryl group. In some embodiments, the heterocycle is a heterocyclic alkyl group. Exemplary heterocycles include pyrrolidinyl, pyrrolithyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazole, indolyl, and quinolinyl. The heterocycle may optionally be substituted with one or more substituents (such as those described herein). Bicyclic heterocycles may be fused, bridged, or spirocyclic systems. In one exemplary embodiment, the heterocycle (e.g., pyridinyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. The heterocycle may optionally be substituted with one or more substituents (such as those described herein).

[0036] As used herein, the term "hypoheterocyclic group" refers to a divalent saturated, unsaturated, non-aromatic, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The hypoheterocyclic group is connected to the remainder of the molecule by a single bond and to a group by a single bond. The single bonds connecting the hypoheterocyclic group to the remainder of the molecule and the single bonds connecting the hypoheterocyclic group to the group can be independently linked by any atom of the hypoheterocyclic group, including carbon atoms or heteroatoms in the hypoheterocyclic ring, as valence allows. The hypoheterocyclic group may optionally be substituted with one or more substituents (such as those described herein). Hypoheterocyclic groups include 3- to 10-membered monocyclic and polycyclic (e.g., 6- to 12-membered bicyclic) rings. Each ring in a polycyclic hypoheterocyclic group may be self-saturated, unsaturated, or aromatic. Polycyclic hypoheterocyclic groups may be fused, bridged, or spirocyclic systems. The single bonds connecting the heterocyclic group to the remainder of the molecule and the single bonds connecting the heterocyclic group to the functional group may be located on the same or different rings of the polycyclic heterocyclic group, and may be connected to the remainder of the molecule or the functional group through any atom of the heterocyclic group (such as a carbon or nitrogen atom of the heterocycle), subject to valence. In some embodiments, the heterocyclic group contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclic group contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclic group contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclic group contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclic group is a heteroaryl group. In some embodiments, the heterocyclic group is a heterocyclic alkyl group.

[0037] "Heterocyclic alkyl" refers to a stable 3- to 12-membered non-aromatic cyclic group comprising two to twelve carbon atoms and at least one heteroatom, wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocyclic alkyl contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclic alkyl contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclic alkyl contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclic alkyl contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocyclic alkyl can be selected from monocyclic or bicyclic and fused, bridged, or spirocyclic systems. The heteroatom in the heterocyclic alkyl is optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocyclic alkyl is partially or fully saturated. The heterocyclic alkyl is linked to the remainder of the molecule by any atom of the heterocyclic alkyl (such as any carbon or nitrogen atom of the heterocyclic alkyl) as permitted by valence. Examples of heterocyclic alkyl groups include, but are not limited to, dioxolanyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Heterocyclic alkyl groups may optionally be substituted with one or more substituents (such as those described herein).

[0038] The term "heteroaryl" refers to a group derived from a 5- to 12-membered aromatic ring group whose ring structure contains at least one heteroatom, preferably one to four heteroatoms. In some embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2) p-electron system. The heteroatom in the heteroaryl may optionally be oxidized. If one or more nitrogen atoms are present, they may optionally be quaternized. The heteroaryl may be linked to the remainder of the molecule via any atom of the heteroaryl (such as a carbon or nitrogen atom of the heteroaryl), provided the valence allows. Heteroaryl groups include aromatic monocyclic structures, preferably 5- to 6-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups may optionally be substituted with one or more substituents (such as those described herein). Heteroaryl groups also include polycyclic systems having two or more rings, wherein two or more atoms are shared by two adjacent rings, wherein at least one ring is heteroaromatic, and for example, the other rings may be aromatic or non-aromatic carbocyclic or heterocyclic. Heteroaryl groups may optionally be substituted with one or more substituents (such as those described herein).

[0039] "X-membered heterocyclic ring" refers to the number of inner ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocyclic ring has 5 inner ring atoms, such as triazole, oxazole, thiophene, etc.

[0040] "Alkoxy" refers to a group of the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0041] "Halogen" or "halogenated" refers to halogenated substituents, such as bromine, chlorine, fluorine, and iodine substituents.

[0042] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that has been substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group may optionally be further substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., chloroform, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of alkanes (or substituted alkanes) with halogens (e.g., Cl, Br, F, and I). When the alkyl group is substituted with more than one halogen group, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[0043] The term “substituted” refers to a portion of a compound having a substituent that replaces a hydrogen atom on one or more carbon atoms or substituted heteroatoms (e.g., NH or NH2). Unless otherwise specified (e.g., by using the terms “substituted” or “optionally substituted,” or by including a “-R” group), the chemical groups described herein are not substituted. It will be understood that “substituted” or “replaced by” includes implied limitations: such substitution conforms to the permissible valence of the substituted atom and the substituent, and the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. In some embodiments, substituted refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with an oxo, imino, or thio group. As used herein, the term “substituted” is contemplated to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, one or more substituents are permitted, and they may be the same or different.

[0044] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)R a -R b -OC(O)OR a -Rb -OC(O)N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 0, 1, or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (where t is 1 or 2) and -P(O)(R a )2; and alkyl, alkenyl, alkynyl, aryl, aralkyl, arylenyl, arynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which may optionally be substituted by the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)R a -R b -OC(O)OR a -R b -OC(O)N(R a )2、-R b -N(R a )2、-R b -C(O)R a-R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 0, 1, or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (where t is 1 or 2) and -P(O)(R a )2; where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a Subject to permissible valence, it may optionally be substituted with the following groups: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a)2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 0, 1, or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (where t is 1 or 2) and -P(O)(R a )2; and each of R b Independently selected from direct-chain or straight-chain or branched alkylene, alkenyl, or ynylene chains, and each R c It is a straight-chain or branched alkylene, alkenylene, or ynylene chain. Those skilled in the art will understand that, where appropriate, the substituent itself can be substituted.

[0045] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[0046] The phrase “pharmaceutically acceptable” is used in this document to refer to those compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0047] As used herein, the phrase “pharmaceuticalally acceptable excipient” or “pharmaceuticalally acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is harmless to the patient.

[0048] The terms “object,” “individual,” and “patient” are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, suidae, bovids, ungulates, lagos, etc.). In various implementations, the object may be a human being under the care of a physician or other healthcare worker in a hospital, as an outpatient, or in another clinical setting (e.g., adult males, adult females, adolescent males, adolescent females, boys, girls). In some implementations, the object may not be under the care or prescription of a physician or other healthcare worker.

[0049] As used herein, the phrase “objects in need” refers to those who have or are at risk of developing a disease that is preventively or therapeutically treated by the compounds or salts described herein, as described below.

[0050] The term "administer" is defined as providing a subject with the composition via routes known in the art, including but not limited to intravenous, intra-arterial, oral, parenteral, buccal, topical, percutaneous, rectal, intramuscular, subcutaneous, intraosseous, mucosal, or intraperitoneal administration. In some embodiments, the composition may be administered orally. The term "administer" should be understood as meaning intended to provide an individual in need with a compound or salt of the invention, or a prodrug of a compound or salt of the invention.

[0051] As used herein, “treatment / treating” refers to a means of obtaining a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventive benefits) with respect to a disease, condition, or medical condition. In some embodiments, treatment / treating involves administering a compound or composition disclosed herein to a subject. Therapeutic benefits may include eradicating or improving the underlying condition being treated. Moreover, therapeutic benefits may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition, such as observing improvement in the subject, even though the subject may still have the underlying condition. In some embodiments, to obtain preventive benefits, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even if the disease may not yet be diagnosed. Treatment may include, for example, reducing or delaying one or more symptoms of a disease or condition or lessening the severity of such symptoms, or may include reducing the frequency with which a patient experiences symptoms of a disease, defect, condition, or adverse condition. Treatment may be used herein to refer to a method of treatment or improvement that causes a disease or condition to a certain extent, and may encompass a range of results for that purpose, including but not limited to complete prevention of the condition.

[0052] In some implementations, the term "preventing" in relation to a disease or condition may refer to a compound reducing the incidence of the disease or condition in a treated sample relative to an untreated control sample, or delaying the onset or reducing the severity of one or more symptoms of the disease or condition relative to an untreated control sample.

[0053] As used herein, the term "therapeutic effect" encompasses the therapeutic benefits and / or preventive benefits described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0054] compound A compound represented by the structure of formula (I): (I); Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR10 -N(R) 10 2. -NO2 and -CN; and C 3-8 A carbocyclic ring and 4- to 8-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 10 -SR 10 -N(R) 10 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R)11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and 4-10 yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) Heterocyclic compounds ranging from 4 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11), -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; and C 3-10 A carbocyclic ring and 4- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-、-N(R15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 1 L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , -N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; Ring D is selected from: , , and ; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each occurrence is independently selected from: hydrogen; C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is optionally composed of one or more independently selected from halogens, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

[0055] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from (i) and (ii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; and (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11)2、-NO2、=O、=S、=N(R 11 ) and -CN; and 3- to 10-yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN.

[0056] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from (i) and (ii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11-S(O)2N(R) 11 )2, -NO2 and - CN; and (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: 3-membered to 10-membered heterocycles and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN.

[0057] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from (i) and (ii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 2. -NO2 and -CN; and (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from 3- to 10-membered heterocycles, wherein the 3- to 10-membered heterocycles are optionally substituted by one or more substituents independently selected from halogens, halogens, -OR 11 -SR 11 -N(R) 11 )2, -NO2 and- CN is substituted with substituents.

[0058] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -SR 11 -N(R) 11 2, -NO2 and -CN; and optionally, -OR, selected independently from one or more halogens. 11 -SR 11 -N(R) 11 )2, -NO2, -CN, tricyclic to deuterium heterocycles and C 3-10 Substituents of the carbon ring substituted C 1-6 Alkyl groups, 3- to 10-membered heterocycles and C 3-10 Each carbon ring is optionally selected by one or more independently chosen from halogens, -OR 11 -SR 11 -N(R) 11 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, halogen, -OR 11 -SR 11 -N(R) 11 2, -NO2 and -CN; and optionally, -OR, selected independently from one or more halogens. 11 -SR 11 -N(R) 11 )2, -NO2, -CN, 3- to 6-membered heterocycles and C 3-6 Substituents of the carbon ring substituted C 1-6 Alkyl groups, 3- to 6-membered heterocycles and C 3-6 Each carbon ring is optionally selected by one or more independently chosen from halogens, -OR 11 -SR 11 -N(R) 11 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -SR 11 -N(R) 11 2, -NO2 and -CN; and optionally, -OR, selected independently from one or more halogens. 11 -SR11 -N(R) 11 )2, -NO2, -CN, C substituents of 3- to 6-membered heterocyclic rings 1-6 Alkyl group, wherein the 3- to 6-membered heterocycle is optionally composed of one or more independently selected from halogens, -OR 11 -SR 11 -N(R) 11 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 yes .

[0059] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from (i) and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; and (iii) Heterocyclic compounds ranging from 4 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11-OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; and C 3-10 A carbocyclic ring and 4- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

[0060] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from (i) and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R)11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; and (iii) Heterocyclic compounds ranging from 4 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 ) and -CN; and C 3-10 A carbocyclic ring and 4- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group and C 2-6 Halogenated alkynyl group.

[0061] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is selected independently from: Hydrogen, halogen, -OR11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、 - CN; and 4- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or independently of a substituent selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0062] In some implementations, for compounds or salts of formula (I), A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11-S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、 - CN and 4- to 10-membered heterocycles and C 3-10 Carbon rings, these 4- to 10-membered heterocycles and C 3-10 The carbon ring is optionally composed of one or more independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substitution of the carbocyclic ring and 4- to 10-membered heterocyclic rings. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -SR 11 -N(R) 11 )2、-NO2、 - CN and 4- to 10-membered heterocycles and C 3-10 Carbon rings, these 4- to 10-membered heterocycles and C 3-10 The carbon ring is optionally composed of one or more independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substitution of the carbocyclic ring and 4- to 10-membered heterocyclic rings. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -SR 11 -N(R) 11 )2、-NO2、 - CN and 4- to 10-membered heterocycles and C 3-10 Carbon rings, these 4- to 10-membered heterocycles and C 3-10 The carbon ring is optionally composed of one or more independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of the carbocyclic ring and 4- to 6-membered heterocycles. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -SR 11 -N(R) 11 )2、-NO2、 - CN and 4- to 6-membered heterocycles and C3-6 Carbon rings, these 4- to 6-membered heterocycles and C 3-6 The carbon ring is optionally composed of one or more independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of the carbocyclic ring and 4- to 6-membered heterocycles. In some embodiments, A 2 Selected from and .

[0063] In some embodiments, for compounds or salts of formula (I), ring D is selected from: , and In some implementations, ring D is selected from: , and And m is selected from 0, 1, and 2. In some implementations, ring D is And m is selected from 0, 1, and 2. In some implementations, ring D is And m is selected from 0, 1, and 2. In some implementations, ring D is And m is selected from 0, 1, and 2.

[0064] In some embodiments, for compounds or salts of formula (I), ring D is selected from: , and m is selected from 0, 1, and 2; and each R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN.

[0065] In some implementations, for compounds or salts of formula (I), ring D is And m is selected from 0 and 1. In some implementations, ring D is ;m is selected from 0 and 1; and R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN. In some implementations, ring D is .

[0066] In some implementations, for compounds or salts of formula (I), ring D is And m is selected from 0 and 1. In some implementations, ring D is ;m is selected from 0 and 1; and R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN. In some implementations, ring D is .

[0067] In some implementations, for compounds or salts of formula (I), ring D is And m is selected from 0 and 1. In some implementations, ring D is ;m is selected from 0 and 1; and R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN. In some implementations, ring D is selected from , , , , and In some implementations, ring D is In some implementations, ring D is selected from... , and In some implementations, ring D is In some implementations, ring D is .

[0068] In some implementations, for compounds or salts of formula (I), ring D is And m is selected from 1, 2, and 3. In some implementations, ring D is ;m is selected from 1, 2, and 3; and each R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN. In some implementations, ring D is composed of express.

[0069] In some implementations, for compounds or salts of formula (I), ring D is ;m is selected from 0, 1, 2, and 3; and each R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12)2 and -CN. In some implementations, ring D is composed of express.

[0070] In some implementations, for compounds or salts of formula (I), ring D is And each R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN. In some implementations, ring D is composed of express.

[0071] In some respects, structural formula (I) is derived from the structure of formula (II): (II), Or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen, halogens, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and- CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11)2、-NO2、=O、=S、=N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 、 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R15 and R 16 Each occurrence is independently selected from: hydrogen, C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is optionally composed of one or more independently selected from halogens, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

[0072] In some embodiments, for compounds or salts of formula (I) or (II), the cysteine-sensitive electrophile is selected from haloacetamides, haloalkyl ketones, haloamidines, halobenzylphosphonates, acyloxyalkyl ketones, sulfonyl ethylene oxides, epoxides, diazonyl ketones, halotriazines, acrylamides, cyanoacrylamides, vinyl sulfones, vinyl sulfonamides, acrylates, fumarates, carbonyl acrylates, maleimides, ketoamides, nitriles, alkenes, alkynes, ketone heterocycles, and alkyne amides. In some embodiments, the cysteine-sensitive electrophile is selected from haloacetamides, haloalkyl ketones, and haloamidines. In some embodiments, the cysteine-sensitive electrophile is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, alkyne amides, alkenes, alkynes, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from acrylate groups, acrylamide groups, vinyl sulfone groups, vinyl sulfonamide groups, alkenes, and alkynes. In some implementations, the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, alkenes, and alkynes.

[0073] In some embodiments, for compounds or salts of formula (I) or (II), the cysteine-sensitive electrophile is an α-β-unsaturated carbonyl group, an α-β-unsaturated sulfone, an α-β-unsaturated amide, and an α-β-unsaturated sulfonamide. In some embodiments, the cysteine-sensitive electrophile is selected from α-β-unsaturated carbonyl groups and α-β-unsaturated amides. In some embodiments, the cysteine-sensitive electrophile is an α-β-unsaturated carbonyl group.

[0074] In some implementations, for compounds or salts of formula (I) or (II), R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each occurrence is independently selected from: hydrogen, C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbocyclic rings and 3- to 6-membered heterocycles, wherein each is optionally composed of one or more independently selected from halogens, -OH, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

[0075] In some implementations, for compounds or salts of formula (I) or (II), R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each occurrence is independently selected from: hydrogen, C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0076] In some implementations, for compounds or salts of formula (I) or (II), R 15 Selected from each occurrence: hydrogen, C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C3-6 Carbocyclic rings and 3- to 6-membered heterocycles, wherein each is optionally composed of one or more independently selected from halogens, -OH, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

[0077] In some embodiments, for compounds or salts of formula (I), (IA), (II), (II-A), (III), or (III-A), R 15 Selected from each occurrence: hydrogen, C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0078] In some implementations, for compounds or salts of formula (I) or (II), R 15 Each time it appears, it is selected from hydrogen and optionally by one or more independently selected from halogen, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 C-rings substituted with substituents of carbocyclic rings and 3- to 6-membered heterocycles 1-6 Alkyl group. In some embodiments, R 15 It is optionally selected by one or more independently chosen from halogen, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 C-rings substituted with substituents of carbocyclic rings and 3- to 6-membered heterocycles 1-6 Alkyl group. In some embodiments, R 15 It is optionally selected by one or more independently chosen from halogen, -OC 1-6 C-substituted alkyl groups and 3- to 6-membered heterocyclic groups 1-6 Alkyl group. In some embodiments, R 15 It is optionally selected by one or more independently chosen from -OC 1-6 C-substituted alkyl groups and 3- to 6-membered heterocyclic groups 1-6 Alkyl group. In some embodiments, R 15 It is optionally selected by one or more independently chosen from -OC 1-3 C-substituted alkyl groups and 4- to 5-membered heterocyclic groups 1-6 Alkyl group. In some embodiments, R 15C is optionally substituted with -OCH3 or oxecyclobutane. 1-6 alkyl.

[0079] In some implementations, for compounds or salts of formula (I) or (II), L 1 It is -N(R) 15 )-; and R 15 Each time it appears, it is optionally selected by one or more independent selections from -OC. 1-6 C-substituted alkyl groups and 3- to 6-membered heterocyclic groups 1-6 Alkyl group. In some embodiments, L 1 It is -N(R) 15 )-; and R 15 Each time it appears, it is optionally selected by one or more independent selections from -OC. 1-3 C-substituted alkyl groups and 4- to 5-membered heterocyclic groups 1-3 Alkyl group. In some embodiments, L 1 It is -N(R) 15 )-; and R 15 Each occurrence is selected from C groups optionally substituted with one or more substituents independently selected from -OCH3 and oxecyclobutane. 1-3 alkyl.

[0080] In some embodiments, for compounds or salts of formula (I) or (II), L is selected from... and In some implementations, L is... In some implementations, L is... .

[0081] In some respects, structural formula (I) or (II) is derived from the structure of formula (II-A): (II-A), Or a pharmaceutically acceptable salt thereof, wherein: The cysteine-sensitive electrophilic reagent is R 5 ; R 5 Selected from: -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 ) and -CN; C 1-6 Alkyl groups, which are independently selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 Substitution of ) and -CN; C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally composed of one or more groups independently selected from -C(O)R 19 -S(O)2R 19 -N(R) 19 )C(O)(R 19 -C(O)N(R) 19 )2、-N(R 19 )S(O)2R 19 -S(O)2N(R) 19 (R) 19 Substitution of ) and -CN; and C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is independently selected from O, C, and C rings. 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 Substitution of -CN and -CN substituents; R 17 Selected independently each time it appears: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and C 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and R 18 and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0082] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 ) and -CN. In some implementations, R 5 Selected from -C(O)R 17 -、N(R 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 -S(O)2R 17 and -CN. In some implementations, R 5 Selected from -C(O)R 17 -、N(R 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 -S(O)2R 17 and -CN, where each R 19 Each time it appears, it is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 5 Selected from -C(O)R 17 -、N(R 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 -S(O)2R 17 and -CN, where each R 19 Each time it appears, it is independently selected from hydrogen and methyl. In some embodiments, R 5 Selected from -CN , , and In some implementations, R 5 Selected from and In some implementations, R 5 Selected from and In some implementations, R5 Yes - CN.

[0083] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 It is selected independently by one or more of -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 C substituents of -CN and -CN 1-6 Alkyl group. In some embodiments, R 5 It is selected independently by one or more of -N(R) 19 )C(O)(R 17 ) and -C(O)N(R 17 (R) 19 The substituents of C are substituted with substituents. 1-6 Alkyl group. In some embodiments, R 5 It is controlled by one or more -N(R) 19 )C(O)(R 17 ) replaced by C 1-6 Alkyl group. In some embodiments, R 5 It is caused by one or more -N(H)C(O)(R 17 ) replaced by C 1-6 Alkyl group. In some embodiments, R 5 yes In some implementations, R 5 Selected from , , , , and .

[0084] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 Selected from C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally composed of one or more groups independently selected from -C(O)R 19 -S(O)2R 19 -N(R) 19 )C(O)(R 19 -C(O)N(R) 19)2、-N(R 19 )S(O)2R 19 -S(O)2N(R) 17 (R) 19 Substituents of ) and -CN. In some embodiments, R 5 It is selected independently by one or more of -C(O)R 19 -S(O)2R 19 -N(R) 19 )C(O)(R 19 -C(O)N(R) 19 )2、-N(R 19 )S(O)2R 19 -S(O)2N(R) 17 (R) 19 C substituents of -CN and -CN 2-6 Alkenyl. In some embodiments, R 5 It is selected independently by one or more of -N(R) 19 )C(O)(R 19 ) and -C(O)N(R 19 C substituted with a substituent of )2 2-6 Alkenyl. In some embodiments, R 5 It is controlled by one or more -C(O)N(R) 19 )2 replaced by C 2-3 Alkenyl. In some embodiments, R 5 yes .

[0085] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 Selected from C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is independently selected from O, C, and C rings. 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 -S(O)2R 17 Substituents of -CN are used. In some embodiments, R... 5 It is selected independently by one or more of the following: =O, C 2-6alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 -S(O)2R 17 The 3- to 6-membered heterocycles are substituted with -CN. In some embodiments, R 5 It is selected independently by one or more of the following: =O, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 3- to 6-membered heterocycles substituted with -CN.

[0086] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 Selected from aziridine and pyrrolidinyl, wherein each is independently selected from one or more of =O, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 -S(O)2R 17 Substituents of -CN are used. In some embodiments, R... 5 Selected from aziridine and pyrrolidinyl, wherein each is independently selected from one or more of =O, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R)17 (R) 19 -S(O)2R 17 Substituents of -CN are used. In some embodiments, R... 5 Selected from aziridine and pyrrolidinyl, wherein each is independently selected from one or more of =O, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 Substituents of -CN are used. In some embodiments, R... 5 Selected from and In some implementations, R 5 yes In some implementations, R 5 yes .

[0087] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 17 Selected independently each time it appears: C 1-6 Alkyl groups, which are halogenated, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )Cd(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN substitution; C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18-OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and C 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0088] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 17 Is it halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R)18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 C replaced by -NO2 and -CN 1-6 Alkyl group. In some embodiments, R 17 Is it halogen, -OR 18 -N(R) 18 )2、-C(O)N(R 18 2. C substituted with -NO2 and -CN 1-6 alkyl.

[0089] In some embodiments, for compounds or salts of formula (II) or (II-A), R 17 Each time it appears, it is independently selected from C. 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN. In some implementations, R 17Each time it appears, it is independently selected from C. 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted independently by a substituent selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -N(R) 18 2. -NO2 and -CN.

[0090] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 Selected from -CN , , , , , , and .

[0091] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 5 Selected from -CN , , , , , , , , , , , and .

[0092] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), Selected from: , , , , , , , and .

[0093] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), Selected from: , , , , , , , , , , , , and .

[0094] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 18 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 18 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 18 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 18 Each time it appears, it is independently selected from: hydrogen and C. 1-3 Alkyl group. In some embodiments, R 18 Each time it appears, it is independently selected from: hydrogen and methyl. In some embodiments, R 18 It is a methyl group.

[0095] In some embodiments, for compounds or salts of formula (I), (II), or (II-A), R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 19 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 19 Each time it appears, it is independently selected from: hydrogen and C. 1-3 Alkyl group. In some embodiments, R 19 Each time it appears, it is independently selected from: hydrogen and methyl.

[0096] In some respects, the structure of equations (I), (II), or (II-A) is derived from the structure of equation (III): (III), Or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen, halogens, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11)C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11-OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12-N(R) 12 2. -NO2 and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14)2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a)-O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b)C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16-S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

[0097] In some embodiments, for compounds or salts of formula (I), (II), (II-A), or (III), the cysteine-sensitive electrophile is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylene amides, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonamide groups, and acetylene amide groups. In some embodiments, the cysteine-sensitive electrophile is selected from acrylamide groups, vinyl groups, vinyl sulfonamide groups, and acetylene amides. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group.

[0098] In some embodiments, for compounds or salts of formula (I), (II), (II-A), or (III), A 3 The cysteine-sensitive electrophilic reagent is R 5 , where R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 and -S(O)2N(R 17 (R) 19 ); R 17 Each time it appears, it is independently selected from C. 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and R 18 and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0099] In some embodiments, for compounds or salts of formula (I), (II), (II-A), or (III), the cysteine-sensitive electrophile is R. 5 , where R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 and -S(O)2N(R 17 (R) 19 ); R 17 Each time it appears, it is independently selected from C. 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R18 -S(O)2R 18 -NO2 and -CN; and R 18 and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0100] In some embodiments, for compounds or salts of formula (I), (II), (II-A), or (III), the cysteine-sensitive electrophile is R. 5 , where R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 and -S(O)2N(R 17 (R) 19 ); R 17 Each time it appears, it is independently selected from C. 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and R 18and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0101] In some embodiments, for compounds or salts of formula (I), (II), (II-A), or (III), the cysteine-sensitive electrophile is R. 5 , where R 5 The group is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups.

[0102] In some respects, the structure of equations (I), (II), (II-A), or (III) is derived from the structure of equation (III-A): (III-A), Or a pharmaceutically acceptable salt thereof, wherein: The cysteine-sensitive electrophilic reagent is R 5 ; R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 and -S(O)2N(R 17 (R) 19 ); R 17 Each time it appears, it is independently selected from C. 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18)S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and R 18 and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0103] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), q is selected from 1, 2, and 3. In some embodiments, q is selected from 1 and 2. In some embodiments, q is 1.

[0104] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), m is selected from 0, 1, 2, and 3. In some embodiments, m is selected from 0, 1, and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is 0.

[0105] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is 0.

[0106] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), p is selected from 0, 1, 2, 3, 4, and 5. In some embodiments, p is selected from 0, 1, 2, 3, and 4. In some embodiments, p is selected from 0, 1, 2, and 3. In some embodiments, p is selected from 0, 1, and 2. In some embodiments, p is selected from 0 and 1. In some embodiments, p is 0.

[0107] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 1 Selected from hydrogen, halogens, -OR 10 -SR10 -N(R) 10 )2, -NO2, -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN.

[0108] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 1 Selected from hydrogen, halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2 and -CN; and R 10 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

[0109] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 1 Selected from hydrogen, halogens, -OR 10 -N(R) 10 )2, -NO2, -CN; and optionally selected independently by one or more halogens, -OR 10 and -N(R) 10 C substituted with a substituent of )2 1-6 Alkyl group. In some embodiments, R 1 Selected from hydrogen, -OR 10 and -CN; and optionally by one or more -OR 10 Replacement C 1-6 alkyl.

[0110] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 1 Selected from hydrogen, -OR 10 and -CN; and optionally by one or more -OR 10 Replacement C 1-6 Alkyl; and R 10Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 1 Selected from hydrogen, -OR 10 and -CN; and optionally by one or more -OR 10 Replacement C 1-6 Alkyl; and R 10 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0111] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 1 Selected from hydrogen, methoxy, -CN, methyl, ethyl, and (methoxy)methyl. In some embodiments, R 1 Selected from hydrogen, methoxy, and methyl. In some embodiments, R 1 It is hydrogen.

[0112] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 )2, -NO2, and -CN. In some implementations, R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -N(R) 12 )2 and -CN. In some implementations, R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 2 In each case, it is independently selected from halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0113] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 12 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 12 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 12 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 12 Each time it appears, it is independently selected from: hydrogen and C. 1-3 alkyl.

[0114] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN.

[0115] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 3 In each case, it is independently selected from halogen, -OR 13 -N(R) 13 )2、-CN、C1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 3 In each case, it is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 3 In each case, it is independently selected from halogens, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0116] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 13 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 13 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 13 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 13 Each time it appears, it is independently selected from: hydrogen and C. 1-3 alkyl.

[0117] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14-N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN.

[0118] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 4 In each case, it is independently selected from halogen, -OR 14 -N(R) 14 )2、-NO2、=O、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 In each case, it is independently selected from halogen, -OR 14 -N(R) 14 )2、=O、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 In each case, it is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 In each case, it is independently selected from halogens, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0119] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 4 Selected from hydrogen, halogens, -OR 14 -N(R) 14 )2, -NO2, -CN; and optionally selected independently by one or more halogens, -OR 14 and -N(R) 14 C substituted with a substituent of )2 1-6 Alkyl group. In some embodiments, R 4 Selected from halogens, -OR 14 C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 4 Selected from fluorine, -OH and -OCH3.

[0120] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), R 14 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 14 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 14 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 14 Each time it appears, it is independently selected from: hydrogen and C. 1-3 alkyl.

[0121] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11-N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11-SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11-NO2, =O, =S, =N(R) 11 ) and -CN.

[0122] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -S(O)2R 11 -S(O)2N(R) 11 2. -NO2 and -CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -S(O)2R 11 -S(O)2N(R) 11 )2, -NO2, =O and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11)S(O)2R 11 -S(O)2R 11 -S(O)2N(R) 11 )2, -NO2, =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O and -CN; and C 3-10 A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O and - CN.

[0123] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 3-10 A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and - CN.

[0124] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogen, -OR 11 -N(R) 11 )2 and -CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 Halogen, -OR 11 -N(R) 11 )2, =O and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2, =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2, =O and -CN; and C 3-10 A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 11 -N(R) 11 )2、=O and -CN.

[0125] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 and A 2 Each is selected independently from: Hydrogen, halogen, -OR 11 -N(R) 11 ) 2、 =O、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and 5 to 10 yuan heterocyclic rings and C 3-10 Carbon rings, wherein any one of them is optionally selected independently from halogens, -OR 11 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Substitution of carbocyclic rings and 3- to 10-membered heterocycles, wherein C1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Each of the carbocyclic ring and the 3- to 10-membered heterocycle may optionally be substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and =O.

[0126] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 and A 2 Each is independently selected from hydrogen, halogen, and -OR 11 -N(R) 11 )2、=O、C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 5- to 10-membered heterocycles and C 3-10 Carbon ring. In some implementations, A 1 and A 2 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and -CN. In some implementations, A 1 and A 2 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 5- to 10-membered heterocycles and C 3-10 Carbon ring. In some implementations, A 1 and A 2 Each is independently selected from hydrogen, 5- to 10-membered heterocycles, and C. 3-10 Carbon ring. In some implementations, A 1 and A 2 Each is independently selected from hydrogen, 5- to 6-membered heterocycles, and C. 3-6 Carbon ring. In some implementations, A 1 and A 2 Each is independently selected from hydrogen, 5- to 6-membered heteroaryl groups, and C. 3-6 Saturated carbon ring. In some implementations, A 1 and A 2 Each is independently selected from hydrogen, 5-membered heteroaryl, and C. 3-6Cycloalkyl. In some embodiments, A 1 and A 2 Each is independently selected from hydrogen, pyrazole, triazole, and cyclopropyl.

[0127] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 Selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

[0128] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 Selected from: hydrogen, halogen, -OR 11 -N(R) 11 )2、-CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 5- to 6-membered heterocycles and C 3-6 Carbon ring. In some implementations, A 1 Selected from: hydrogen, halogens, C 1-6 Alkyl, C 1-6Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and -CN. In some implementations, A 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and -CN. In some implementations, A 1 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, A 1 Selected from hydrogen, fluorine, and methyl. In some embodiments, A 1 It is hydrogen.

[0129] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), or (III-A), A 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2, -CN, 5- to 10-membered heterocyclic rings and C 3-10 Carbon ring. In some implementations, A 1 Selected from hydrogen, halogens and C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, 3- to 6-membered heterocycles and C 3-6 Carbon ring. In some implementations, A 1 Selected from hydrogen, fluorine, methyl, , and .

[0130] In some respects, the structure of equations (I), (II), (II-A), (III), or (III-A) is derived from the structure of equation (III-B): (III-B); Or its pharmaceutically acceptable salt.

[0131] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11)C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11)2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

[0132] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from: -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11)S(O)2R 11 =O and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and - CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R)11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and - CN.

[0133] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; (ii) C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 =O and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R)11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 =O and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 =O and -CN.

[0134] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from (i), (ii), and (iii): (i) Hydrogen, halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 S = O; (ii) C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11-N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 and = O; and (iii) 5-10 yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

[0135] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from (i), (ii), and (iii): (i) Hydrogen, halogen, -OR 11 -N(R) 11 )2 and =O; (ii) C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 Substitution of )2 and =O substituents; and (iii) 5-10 yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2 and =O; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 Substitution of )2 and =O by substituents.

[0136] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from: hydrogen, halogen, -OR 11 -N(R) 11 2. C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and 5 to 10 yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 2. C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0137] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from: hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and 5- to 10-membered heterocycles and C 3-10 Carbon ring. In some implementations, A 2 Selected from hydrogen, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, A 2 Selected from 5- to 10-membered heterocycles and C 3-10 Carbon ring. In some implementations, A 2 Selected from 5- to 6-membered heterocycles and C 3-6 Carbon ring.

[0138] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from hydrogen, halogens, -OR 11 -N(R) 11 2. CN and =O; and optionally selected independently by one or more halogens, -OR 11 -N(R) 11 C substituted with substituents of )2 and =O 1-6 Alkyl group. In some embodiments, A 2 Selected from hydrogen, halogens, -OR 11 -N(R) 112. CN and =O; and optionally selected independently by one or more halogens and -OR 11 The substituents of C 1-6 Alkyl group. In some embodiments, A 2 Selected from A 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and -CN. In some implementations, A 2 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, A 2 It is C 1-4 Alkyl group. In some embodiments, A 2 Selected from hydrogen and methyl. In some embodiments, A 2 It is a methyl group.

[0139] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from 5- to 10-membered heterocycles and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11)S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

[0140] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from 5- to 10-membered heterocycles and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and - CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; and C1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and - CN.

[0141] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from 5- to 10-membered heterocycles and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and = O; and C 3-10 A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R)11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 And = O.

[0142] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from 5- to 10-membered heterocycles and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 Selected from 5- to 10-membered heterocycles and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

[0143] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from 5- to 6-membered heteroaryl groups and C 3-6 A saturated carbide ring, wherein any of the carbide rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11-N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 Selected from 5- to 6-membered heteroaryl groups and C 3-6 A saturated carbide ring, wherein any of the carbide rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

[0144] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from pyrazolyl, triazolyl, and cyclopropyl, any of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A2 Selected from pyrazolyl, triazolyl, and cyclopropyl, any of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2. In some embodiments, A 2 Selected from pyrazolyl, triazolyl, and cyclopropyl, any of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2; and R 11 Each time it appears, it is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, A 2 Selected from pyrazolyl, triazolyl, and cyclopropyl, any one of which may optionally be independently selected from halogen, -OR 11 -N(R) 11 )2、-CN、C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

[0145] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11)C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11)2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

[0146] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 ,- N(R 11 )S(O)2R 11 -NO2, =O and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN.

[0147] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11)2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -NO2, =O and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 =O and -CN.

[0148] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and = O; and C 3-10A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 And = O.

[0149] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

[0150] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 10-membered heterocyclic ring, optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 and -N(R) 11 2. In some implementation schemes, A 2 Selected from 5- to 10-membered heterocycles, each of which is optionally selected independently by one or more halogens, -OR 11 -N(R) 11 2. C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 Selected from heterocyclic compounds ranging from 5 to 10 yuan.

[0151] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2. In some embodiments, A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

[0152] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally selected by one or more independently selected from halogen, -OR 11 -N(R) 11 )2、-CN、C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally selected by one or more independently selected from halogens, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 The group is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally substituted by one or more substituents independently selected from fluorine, methyl, and -CHF2. In some embodiments, A 2 Selected from , , , , , , , , , and In some implementations, A 2 yes In some implementations, A 2 Selected from , , , , , , , and In some implementations, A 2 yes .

[0153] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 6-membered heteroaryl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 and -N(R) 11 2. In some implementation schemes, A 2 Selected from 5- to 6-membered heteroaryl groups, each of which is optionally selected independently by one or more halogens, -OR 11 -N(R) 11 2. C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 Selected from 5- to 6-membered heteroaryl groups. In some embodiments, A 2 It is a 5-membered heteroaryl group.

[0154] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from pyrazolyl and triazolyl groups, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11)C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 and -N(R) 11 2. In some implementation schemes, A 2 Selected from pyrazolyl and triazolyl groups, wherein each is optionally selected independently by one or more groups from halogens, -OR 11 -N(R) 11 2. C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 Selected from pyrazolyl and triazolyl groups. In some embodiments, A 2 It is a pyrazol group.

[0155] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 Selected from and Each of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 and -N(R) 11 2. In some implementation schemes, A 2 Selected from and Each of which is optionally selected independently from one or more halogens, -OR 11 -N(R) 11 2. C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 Selected from and In some implementations, A 2 yes .

[0156] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 It is a 5- to 10-membered heterocyclic ring, optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 Substituents of =O and -CN. In some embodiments, A 2 It is a 5- to 10-membered saturated heterocycle, optionally composed of one or more independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 Substituents of =O and -CN. In some embodiments, A 2 It is a 5- to 10-membered heteroaryl group, optionally composed of one or more independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 Substitution with =O and -CN substituents.

[0157] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a 5- to 8-membered heterocyclic ring, optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11Substituents of =O and -CN are used. In some embodiments, a 5- to 8-membered saturated heterocycle is optionally replaced by one or more substituents independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 Substituents of =O and -CN. In some embodiments, A 2 Selected from , , , , , and In some implementations, A 2 Selected from , , , , In some implementations, A 2 Selected from and .

[0158] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is optionally selected by one or more independently chosen from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 The 5- to 6-membered heteroaryl groups are substituted with -CN. In some embodiments, A 2 It is optionally selected by one or more independently chosen from halogens, -OR 11 -N(R) 11 The 5- to 6-membered heteroaryl groups are substituted with substituents of )2 and -CN. In some embodiments, A 2 It is optionally selected by one or more independently chosen from halogens, -OR 11 -N(R) 11 )2 and -CN substituents substituted with 5 to 6 heteroaryl groups; and R11 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, A 2 Selected from , , , and .

[0159] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 10-membered heterocycles, the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O, and -CN. In some implementations, A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 8-membered heterocycles, the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O, and -CN. In some implementations, A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 8-membered saturated heterocycles, the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11)2, -NO2, =O, and -CN. In some implementations, A 2 yes .

[0160] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 6-membered heteroaryl groups, the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2 and -CN. In some implementations, A 2 It is optionally controlled by one or more Cs 1-3 Alkyl-substituted 5- to 6-membered heteroaryl groups, the C 1-3 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 2. -NO2 and -CN. In some implementations, A 2 Selected from , , , , , , and In some implementations, A 2 It is optionally controlled by one or more Cs 1-3 Alkyl-substituted 5-membered heteroaryl, the C 1-3 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 2. -NO2 and -CN. In some implementations, A 2 Selected from , , , , , and In some implementations, A2 It is optionally controlled by one or more Cs 1-3 Alkyl-substituted 6-membered heteroaryl, the C 1-3 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 2. -NO2 and -CN. In some implementations, A 2 yes .

[0161] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is optionally controlled by one or more Cs 3-10 Carbocyclic rings and 5- to 10-membered heterocycles substituted with 3- to 10-membered heterocycles, the C 3-10 The carbon ring and any of the 3- to 10-membered heterocycles are optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 It is optionally controlled by one or more Cs 3-6 Saturated carbocyclic rings and 5- to 10-membered heterocycles substituted with 3- to 6-membered saturated heterocycles, this C 3-6 The saturated carbon ring and any of the 3- to 6-membered saturated heterocycles are optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 It is optionally controlled by one or more Cs 3-6 Saturated carbocyclic rings and 5- to 6-membered heterocycles substituted with 3- to 6-membered saturated heterocycles, this C 3-6 The saturated carbon ring and any of the 3- to 6-membered saturated heterocycles are optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11-C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 It is optionally controlled by one or more Cs 3-6 The C-ring and 5- to 6-membered heteroaryl groups substituted with saturated carbocyclic rings and 3- to 6-membered saturated heterocycles, 3-6 The saturated carbon ring and any of the 3- to 6-membered saturated heterocycles are optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups. In some embodiments, A 2 Selected from , , , and In some implementations, A 2 Selected from , , and In some implementations, A 2 yes .

[0162] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-10 Carbon ring: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R)11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

[0163] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-10 Carbon ring: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R)11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN.

[0164] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-10 Carbon ring: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and = O; and C 3-10 Carbon rings and 3- to 10-membered heterocycles; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocycle are each optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 And = O.

[0165] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-10 Carbon rings: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

[0166] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Saturated carbon rings: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11Substituents of =O are used. In some embodiments, A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Saturated carbon rings: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Saturated carbon rings: halogens, -OR 11 -N(R) 11 2. C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 It is C 3-6 Saturated carbon rings.

[0167] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Cycloalkyl groups: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2C is optionally substituted by one or more substituents independently selected from the following 3-6 Cycloalkyl groups: halogens, -OR 11 -N(R) 11 2. C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Cycloalkyl groups: halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 It is C 3-6 Cycloalkyl.

[0168] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is a cyclopropyl group optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 It is a cyclopropyl group optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 2. C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 It is a cyclopropyl group optionally substituted with one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 It is cyclopropyl.

[0169] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 It is optionally substituted by one or more substituents independently selected from the following. Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 It is optionally substituted by one or more substituents independently selected from the following. Halogen, -OR 11 -N(R) 11 2. C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 It is substituted by one or more substituents independently selected from the following. Halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, A 2 yes .

[0170] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Carbon rings: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R)11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substituents of =O are used. In some embodiments, A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Carbon rings: halogens, -OR 11 -N(R) 11 )2、-CN、C 1-6 Alkyl group. In some embodiments, A 2 Selected from , , , and .

[0171] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 11 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 11 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 11 Each time it appears, it is independently selected from: hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, R 11 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 11 Each time it appears, it is independently selected from: hydrogen and C. 1-3 Alkyl group. In some embodiments, R 11 Each time it appears, it is independently selected from: hydrogen and methyl.

[0172] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L is derived from -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3and L 4 Each is independently selected from (a) and (b): (a)-O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b)C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent.

[0173] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-、-N(R 15 )-、-S-、-N(R 15 )C(O)-、-N(R 15)C(O)O-、-N(R 15 S(O)2、-N(R) 15 )N(R 15 )- and -(R 15 )NC(O)N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-6 Carbocyclic groups and 3- to 6-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR 15 Substitution of =O and -CN groups; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent.

[0174] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-、-N(R 15 )- and -N(R 15 )C(O)-; (b) C 1-6 Alkylene; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; and R 15 Selected from hydrogen and C 1-4 alkyl.

[0175] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 L2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-, -N(H)- and -N(H)C(O)-; (b) C 1-6 Alkylene; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent.

[0176] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -N(H)- and -N(H)C(O)-; (b) Methylene; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent.

[0177] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 2 L 3 and L 4 Each can optionally not exist. In some implementations, L 3 and L 4 Each can optionally not exist. In some implementations, L 4 It does not exist. In some implementations, L 3 It does not exist.

[0178] In some embodiments, for compounds or salts of formula (II), (II-A), (III), (III-A), or (III-B), L 2Not found or selected from: (a) -O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic groups and 3- to 8-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR 15 -SR 15 =O, =S and - CN is substituted with substituents.

[0179] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 2 Not found or selected from: (a) -O-、-N(R 15 )-、-S-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2、-N(R) 15 )N(R 15 )- and -(R 15 )NC(O)N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-6 Carbocyclic groups and 3- to 6-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR15 Substitution with =O and -CN substituents.

[0180] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 2 It does not exist or is selected from -O-, -N(R) 15 )- and -N(R 15 C(O)- and C 1-6 Alkylene.

[0181] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 2 Does not exist or selected from -N(R) 15 )- and -N(R 15 C(O)- and C 1-3 Alkyl; and R 15 Each time it appears, it is selected from hydrogen and methyl. In some embodiments, L 2 It is absent or selected from -N(H)-, -N(H)C(O)-, and methylene. In some embodiments, L 2 It is absent or methylene. In some implementations, L 2 It does not exist.

[0182] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 Selected from: (a) -O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b) C1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic groups and 3- to 8-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR 15 -SR 15 =O, =S and - CN is substituted with substituents.

[0183] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 Selected from: (a) -O-、-N(R 15 )-、-S-、-N(R 15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2、-N(R) 15 )N(R 15 )- and -(R 15 )NC(O)N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-6 Carbocyclic groups and 3- to 6-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR 15 Substitution with =O and -CN substituents.

[0184] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L 1 Selected from -O-, -N(R) 15 )- and -N(R 15 C(O)- and C 1-6 Alkylene. In some embodiments, L 1 Selected from -O-, -N(R) 15 )- and -N(R 15 C(O)- and C 1-6 Alkylene, and R 15 Each time it appears, it is selected from hydrogen and C. 1-4 alkyl.

[0185] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 Selected from -N(R) 15 )- and -N(R 15 )C(O)-; and R 15 Each time it appears, it is selected from hydrogen and methyl. In some embodiments, L 1 Selected from -N(H)- and -N(H)C(O)-. In some embodiments, L 1 It is -N(H)C(O)-.

[0186] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L is selected from -O-, -N(R 15 )-、-N(R 15 )-C 1-3 Alkyl- and -N(R) 15 )C(O)-; and R 15 Selected from hydrogen and C 1-4 Alkyl group. In some embodiments, L is selected from -O-, -N(R) 15 )-、-N(R 15 )-C 1-3 Alkyl- and -N(R) 15 )C(O)-; and R 15 Independently selected from hydrogen and methyl. In some embodiments, L is selected from -O-, -NH-, and In some implementations, L is selected from -NH- and .

[0187] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L is selected from -O-, -NH-, -N(CH3)-, and .

[0188] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 is selected from -O-, -N(R 15 )-、-N(R 15 C(O)-, C 1-6 Alkylene and 3- to 6-membered heterocyclic groups. In some embodiments, L is selected from -O-, -NH-, -CH2-, -N(CH3)-, , and In some embodiments, L is selected from -O-, -NH-, -CH2-, and -N(CH3)-. and In some implementations, L is... .

[0189] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 15 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 15 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 15 Each time it appears, it is independently selected from: hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, R 15 Each time it appears, it is independently selected from: hydrogen and C. 1-4 Alkyl group. In some embodiments, R 15 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 15 Each time it appears, it is independently selected from: hydrogen and C. 1-3 Alkyl group. In some embodiments, R 15 Each time it appears, it is independently selected from: hydrogen and methyl. In some embodiments, R 15 It is hydrogen.

[0190] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 3- to 10-membered heterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16)2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16-S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN.

[0191] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 3- to 10-membered heterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0192] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 3- to 10-membered heterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and 4- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0193] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 3- to 10-membered heterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0194] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 3- to 10-membered heterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0195] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 5- to 10-membered heterocyclic groups and C 3-6 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0196] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 5- to 10-membered heterocyclic groups and C 3-6 Carbocyclic groups, any of which may optionally be selected independently from halogens, -OR 16 and C 1-3 Alkyl substituent substitution. In some embodiments, ring B is selected from 5- to 10-membered heterocyclic groups and C. 3-6 Carbocyclic groups, any of which may optionally be selected independently from halogens, -OR 16 and C 1-3 Alkyl substituents; and R 16 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl group. In some embodiments, ring B is selected from 5- to 10-membered heterocyclic groups and C. 3-6 Carbocyclic groups, wherein any one of them is optionally selected independently from halogens and C. 1-3 Alkyl substituent substitution. In some embodiments, ring B is selected from 5- to 10-membered heterocyclic groups and C. 3-6 Carbocyclic groups, wherein any one of them may be substituted by one or more substituents independently selected from fluorine and methyl.

[0197] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from 5- to 10-membered saturated heterocyclic groups, 5- to 10-membered unsaturated heterocyclic groups, and C. 3-6 Unsaturated carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0198] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, 3-azabicyclo[3.2.1]octane, cyclobutane, cyclohexane, pyrazolidine, 1,2,3,4-tetrahydroquinoline, azirospi[3.5]nonane, and aziridine. Spiro[3.3]heptane, azerospiro[3.4]octane, 1,4-oxazabicycloheptane, 3-azabicyclo[3.1.1]heptane, 3-oxa-6-azabicyclo[3.2.2]nonane, piperazine, azerospicycloheptane, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptane, wherein each is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16-SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0199] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from azacyclobutane subunit, pyrrolidine subunit, piperidinyl subunit, phenylene, pyridinyl subunit, indoline subunit, isoindolinyl subunit, tetrahydroisoquinolinyl, 3-azabicyclo[3.2.1]octane subunit, cyclobutane subunit, cyclohexane subunit, pyrazolyl subunit, 1,2,3,4-tetrahydroquinolinyl subunit, azaspiro[3.5]nonane subunit, azaspiro[3.3]heptane subunit, azaspiro[3.4]octane subunit, 1,4-oxazo Heterocyclic heptanediol, 3-azabicyclo[3.1.0]heptanediol, 3-azabicyclo[3.1.1]heptanediol, 3-oxa-6-azabicyclo[3.2.2]nonanediol, 3-oxa-7-azabicyclo[3.3.1]nonanediol, 3-azabicyclo[3.3.1]nonanediol, piperazinediol, azabicycloheptanediol, 2-azabicyclo[2.2.2]octanediol, 2-azabicyclo[2.2.1]heptanediol, 2-azabicyclo[3.2.1]octanediol, wherein each is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0200] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, and 3-azirbicyclo[3.2.1]octane, wherein each is optionally substituted by one or more substituents independently selected from: Halogen, -OR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 -NO2, =O, and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

[0201] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, and 3-azirbicyclo[3.2.1]octane, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -CN and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally halogenated and -OR 16 Replace; and R16 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Haloalkyl. In some embodiments, ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, and 3-azirbicyclo[3.2.1]octane, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 and C 1-3 Alkyl; and R 16 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0202] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 16 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles. In some embodiments, R 16 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R 16 Each time it appears, it is independently selected from: hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups. In some embodiments, R 16 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 16 Each time it appears, it is independently selected from: hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 16 It is hydrogen.

[0203] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17and -S(O)2N(R 17 (R) 19 );and R 17 Each time it appears, it is independently selected from C. 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0204] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 ;and R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0205] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 ;and R 17 Selected from C 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0206] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 ;and R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0207] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 And R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2、-C(O)N(R18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 -NO2 and -CN.

[0208] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 And R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 2. -NO2 and -CN.

[0209] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -C(O)R 17 And R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18-NO2 and -CN.

[0210] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -C(O)R 17 And R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN. In some implementations, R 5 It is -C(O)R 17 And R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2, -NO2, and -CN. In some implementations, R 5 It is -C(O)R 17 ;R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0211] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -C(O)R 17 ;and R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -N(R) 18 2. -NO2 and -CN.

[0212] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -C(O)R 17 ; R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0213] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -C(O)R 17 ;and R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogens and -N(R) 18 )2.

[0214] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5It is -C(O)R 17 ; R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogens and -N(R) 18 )2; and R 18 Selected from hydrogen and methyl.

[0215] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -C(O)R 17 ; R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Fluorine and -N(CH3)2.

[0216] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 );and R 17 Selected from C 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18-OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0217] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 );and R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0218] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 );and R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -N(R)18 2. -NO2 and -CN.

[0219] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 ); R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 and R 19 Each of them is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0220] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 ); R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne groups, wherein each of them may optionally be substituted with one or more halogens.

[0221] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 ); R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne groups, wherein each of which is optionally substituted with one or more halogens; and R 19 It is independently selected from hydrogen and methyl.

[0222] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )C(O)(R 17 ); R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne groups, wherein each of which is optionally substituted with one or more fluorine groups; and R 19 It is independently selected from hydrogen and methyl.

[0223] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )S(O)2R 17 ;and R 17 Selected from C 2-6 alkenyl and C 2-6 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0224] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )S(O)2R 17 ;and R17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

[0225] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )S(O)2R 17 ;and R 17 Selected from C 2-4 alkenyl and C 2-4 The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -N(R) 18 2. -NO2 and -CN.

[0226] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )S(O)2R 17 ; R 17 Selected from C 2-4 alkenyl and C 2-4The alkynyl group, wherein each of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 and R 19 Each of them is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0227] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )S(O)2R 17 And R 17 It is C 2-4 Alkenyl group.

[0228] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 It is -N(R) 19 )S(O)2R 17 ;R 17 It is C 2-4 alkenyl; and R 19 It is hydrogen.

[0229] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from: R 5 Selected from: , , , , , , , , , , , and .

[0230] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), R 5 Selected from: , , , , , , , and .

[0231] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), A 3 It is R 5 , where R 5 As defined in equation (II-A). In some implementations, A 3 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 and -S(O)2N(R 17 (R) 19 ), where R 17 and R 19 As defined in equation (II-A). In some implementations, A 3 Selected from: , , , , , , , and .

[0232] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0233] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0234] In some embodiments, for compounds or salts of formula (I), (II), (II-A), (III), (III-A), or (III-B), Selected from: , , , , , , , , , , , , , , , , , , , , and .

[0235] In some respects, for compounds or salts of formula (I), q is 2; and the structure of formula (I) is determined by... express.

[0236] In some embodiments, for compounds or salts of formulas (I), (II), (II-A), (III), (III-A), or (III-B), the cysteine-sensitive electrophile is selected from haloacetamides, haloalkyl ketones, haloamidines, halobenzylphosphonates, acyloxyalkyl ketones, sulfonyl ethylene oxides, epoxides, diazonyl ketones, halotriazines, acrylamides, cyanoacrylamides, vinyl sulfones, vinyl sulfonamides, acrylates, fumarates, carbonyl acrylates, maleimides, ketoamides, nitriles, alkenes, alkynes, ketone heterocycles, and alkynesamides. In some embodiments, the cysteine-sensitive electrophile is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, alkynesamides, alkenes, alkynes, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from acrylate groups, acrylamide groups, vinyl sulfone groups, vinyl sulfonamide groups, alkenes, and alkynes. In some implementations, the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, alkenes, and alkynes.

[0237] In some embodiments, for compounds or salts of formulas (I), (II), (II-A), (III), (III-A), or (III-B), the cysteine-sensitive electrophile is an α-β-unsaturated carbonyl group, an α-β-unsaturated sulfone, an α-β-unsaturated amide, or an α-β-unsaturated sulfonamide. In some embodiments, the cysteine-sensitive electrophile is selected from α-β-unsaturated carbonyl groups and α-β-unsaturated amides. In some embodiments, the cysteine-sensitive electrophile is an α-β-unsaturated carbonyl group.

[0238] In some respects, this disclosure provides compounds or salts represented by the structure of formula (I), wherein: R 1 Selected from hydrogen, halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN and C optionally substituted by one or more substituents independently selected from the following 1-6 Alkyl groups: halogens, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN, for example, R 1 It is hydrogen; A 1 Selected from hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, such as A 1 It is hydrogen; A 2 Selected from: C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and 4- to 8-membered heterocyclic rings and C 3-8 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 -CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, such as A 2 It is a pyrazol group; n is 0 or 1, for example, n is 0; p is 0 or 1, for example, p is 0; q is 1; L by -L 1 -L 2 - indicates that L 1 and L 2 Each is independently selected from (a) and (b): (a) -O-、-N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-、-N(R15 )C(O)-、-N(R 15 )C(O)O-、-N(R 15 S(O)2-、-N(R) 15 )S(O)2N(R 15 )-、-S(O)(NR 15 )N(R 15 )-、-N(R 15 )N(R 15 )-、-(R 15 )NC(O)N(R 15 )-、-(R 15 )NC(O)N(R 15 )N(R 15 )-;and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic groups and 3- to 8-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR 15 -SR 15 =O, =S and - Substituents of CN; Where L 2 The optional location does not exist; Where L 1 and L 2 When both exist, L 1 Selected from (a) and L 2 Selected from (b); or L 1 Selected from (b) and L 2 Selected from (a); Cycle B is selected from 3- to 8-membered subheterocyclic groups and C. 3-8 Carbocyclic groups, each of which is an optionally substituted halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 -CN, C 1-6 Alkyl and C 1-6 Haloalkyl; for example, ring B is a piperidinyl group; Ring D is selected from: ; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN, for example, R 2 It is -N(R) 12 )2; A 3 Selected from halogenated acetamides, halogenated alkyl ketones, halogenated amidines, halogenated benzylphosphonates, acyloxyalkyl ketones, sulfonyl ethylene oxides, epoxides, diazoalkyl ketones, halogenated triazines, acrylamides, cyanoacrylamides, vinyl sulfones, vinyl sulfonamides, acrylates, fumarates, carbonyl acrylates, maleimides, ketoamides, nitriles, alkenes, alkynes, ketone heterocycles, and acetylene amides, such as A. 3 It is an acrylate; and R 10 R 11 R 12 R 15 and R 16 Each time it appears, it is independently selected from: hydrogen. C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogen, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Substitution of carbocyclic rings and 3- to 6-membered heterocycles; and C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is optionally composed of one or more independently selected from halogens, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

[0239] In some embodiments, the compounds or salts of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) are the compounds in Table 1. * indicates a stereocenter with undetermined absolute stereochemistry in a single isomer.

[0240] Table 1. Chemical structures of the selected compounds. While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The following claims are intended to define the scope of the invention and therefore cover the methods and structures within the scope of these claims and their equivalents.

[0241] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can be... Z -or E - It exists in the form (either cis or trans). Furthermore, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, compounds or salts of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) are also intended to include all Z -、 E - and tautomerism.

[0242] "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of atoms. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to designate racemic mixtures. "Diastereoisomer" or "diastereomer" is a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by R or S. Resolved compounds with unknown absolute configuration may be designated as (+) or (-) according to the direction (dextrorotatory or levorotatory) of the plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers, and thus can produce enantiomers, diastereomers, and other stereoisomers, whose asymmetric centers can be defined by absolute stereochemistry as (R)- or (S)-. These chemical entities, pharmaceutical compositions, and methods are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and mixtures of intermediates. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation determination, and can determine the degree of dominance of one stereoisomer over another.

[0243] Compounds or salts of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) may, in some cases, be present in diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomers, enantiomers, and epimers, as well as racemates, mixtures of diastereomers, and other mixtures thereof, which may be prepared to some extent by those skilled in the art through routine experiments. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley And Sons, Inc., 1981, for which this disclosure is incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, mixtures of two enantiomers enriched in one of them can be purified by recrystallization and / or grinding to provide a further optically enriched form of the primary enantiomer.

[0244] In some embodiments, the compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) may comprise two or more enantiomers or diastereomers of the compound, wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer (e.g., an enantiomer) substantially free of its stereoisomers can be obtained by resolving a racemic mixture using methods such as forming diastereomers using an optically active resolving agent (Stereochemistry of Carbon Compounds, (1962), EL Eliel, McGraw Hill; Lochmuller (1975)). J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated by any suitable method, including but not limited to: (1) forming ionic diastereomeric salts with the chiral compound and separating them by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomeric isomers and converting them to pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. Another method for separating enantiomers is to use a Diacel chiral column and elute with an organic mobile phase, such as through Chiral Technologies (www.chiraltech.com) on a service-based fee basis.

[0245] A "tautomer" is a molecule in which a proton may translocate from one atom of the molecule to another atom of the same molecule. In some embodiments, compounds or salts of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) exist as tautomers. A chemical equilibrium of tautomers may exist where tautomerization is possible. The precise ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibria include: In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, such as enriched isotopes. 2 H, 3 H, 11 C 13 C and / or 14 The content of C. In one particular embodiment, the compound may be deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thus increasing the duration of drug action.

[0246] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art and include (by way of non-limiting example only) the following synthetic methods.

[0247] Deuterium-substituted compounds are synthesized using various methods described in the following literature: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Published in: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0248] Deuteration starting materials are readily available and can be synthesized using the methods described herein to provide materials for the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and structural units are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0249] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds where hydrogen is replaced by deuterium or tritium, or carbon by... 13 C- or 14 C-enriched carbon substitutions and compounds having this structure are all within the scope of this disclosure.

[0250] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may employ isotopes such as, for example, deuterium (…). 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Mark it. 2 H, 11 C 13 C 14 C15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 Isotopic substitutions of I are all included. All isotopic variants of the compounds of this invention, whether or not they are radioactive, are covered within the scope of this invention.

[0251] Including in this disclosure are salts of compounds of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), especially pharmaceutically acceptable salts. The compounds of this disclosure may have sufficiently acidic functional groups, sufficiently basic functional groups, or both, and may react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, inherently charged compounds (such as those having quaternary nitrogen) may form salts with suitable counterions, such as halide ions, such as bromide, chloride, or fluoride ions, especially bromide ions.

[0252] The methods and compositions of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in pharmaceutically acceptable salt forms. In some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Additionally, the compounds described herein may be present in unsolvable forms and in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0253] Compounds of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of those compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0254] Salts of compounds represented by formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) are included in this disclosure, especially pharmaceutically acceptable salts. Compounds of the present invention having sufficiently acidic, sufficiently basic, or both functional groups can react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, inherently charged compounds (such as those having quaternary nitrogen) can form salts with suitable counterions, such as halides, bromides, chlorides, or fluorides, especially bromides.

[0255] In some embodiments, compounds or salts of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) may be prodrugs, for example, wherein the hydroxyl group in the parent compound is presented as an ester or carbonate, or the carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to cover compounds that are converted to the pharmaceutical agents of this disclosure under physiological conditions. A method for preparing a prodrug comprises hydrolyzing one or more selected portions under physiological conditions to produce the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphonates) are preferred prodrugs of this disclosure.

[0256] pharmaceutical preparations In some aspects, this disclosure provides a pharmaceutical composition comprising a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B) and a pharmaceutically acceptable excipient.

[0257] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers comprising excipients and adjuvants. The formulation may be modified according to the chosen route of administration. Pharmaceutical compositions comprising compounds, salts, or conjugates can be prepared, for example, by lyophilizing the compound, salt, or conjugate, mixing, dissolving, emulsifying, encapsulating, or embedding the conjugate. Pharmaceutical compositions may also comprise compounds, salts, or conjugates in free base form or in pharmaceutically acceptable salt form.

[0258] Compounds or salts of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B) can be formulated in any suitable pharmaceutical formulation. Pharmaceutical formulations disclosed herein typically contain an active ingredient (e.g., a compound or salt of any of formulas (I), (IA), (II), (II-A), (III), (III-A), or (III-B)) and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solutions, and various organic solvents, penetration enhancers, antioxidants, solubilizers, and adjuvants.

[0259] Treatment The compounds described herein can be used to prepare medicaments for the prevention or treatment of diseases or conditions. Additionally, methods for treating any of the diseases or conditions described herein in a subject requiring such treatment involve administering a therapeutically effective amount of a pharmaceutical composition to the subject, the pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0260] Compositions containing the compounds described herein may be applied for preventative and / or therapeutic treatment. In therapeutic use, the composition is administered to a patient with the disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. The effective amount for this purpose will depend on the severity and course of the disease or condition, prior therapy, the patient's health status, weight and response to the drug, and the judgment of the treating physician.

[0261] In prophylactic use, a composition containing the compounds described herein is administered to a patient who is susceptible to a specific disease, condition, or illness, or who is otherwise at risk of such a disease, condition, or illness. Such an amount is defined as a “preventative effective amount or dose.” In this application, the precise amount also depends on the patient’s health condition, weight, etc. When used on a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or illness, prior therapy, the patient’s health condition and response to the drug, and the judgment of the treating physician.

[0262] In some aspects, this disclosure provides a method for treatment, the method comprising administering to a subject in need an effective amount of a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B). In some aspects, this disclosure provides a method for treating cancer in a patient in need, the method comprising administering to the subject an effective amount of a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the cancer is selected from breast cancer, colorectal cancer, and meningioma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is meningioma. In some embodiments, the administration modulates the activity of wild-type AKT1. In some embodiments, the administration modulates the activity of mutant AKT1. In some embodiments, the mutant AKT1 is AKT1 E17K.

[0263] In some aspects, this disclosure can be used as a method for inhibiting the AKT1 protein of a desired object, the method comprising administering to the object a compound or salt of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition of formula (I), (IA), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the AKT protein is wild-type AKT1. In some embodiments, the AKT protein is a mutant AKT1 protein. In some embodiments, the mutant AKT1 protein comprises an E17K mutant. In some embodiments, the administration modulates the activity of mutant AKT1. In some embodiments, the administration modulates the activity of wild-type AKT1. In some aspects, this disclosure provides a method for modulating the activity of mutant AKT1. In some embodiments, the administration selectively modulates the activity of wild-type AKT1 relative to wild-type AKT2. In some embodiments, the administration selectively modulates the activity of mutant AKT1 relative to wild-type AKT2.

[0264] AKT1 protein In some aspects, this disclosure provides an AKT1 protein covalently bound to a compound, wherein the compound is covalently bound to a cysteine ​​residue of the AKT1 protein. In some embodiments, the compound is exogenous. In some embodiments, the exogenous compound is selected from exogenous AKT1 inhibitors and exogenous AKT1 activators. In some embodiments, the exogenous compound is an exogenous AKT1 modulator. In some embodiments, the exogenous compound is an exogenous AKT1 inhibitor.

[0265] In some embodiments, the AKT1 protein is selected from wild-type AKT1 protein and mutant AKT1 protein. In some embodiments, the AKT1 protein is a mutant AKT1 protein. In some embodiments, the mutant AKT1 protein contains a mutation selected from E17K, E40K, and E49K mutations. In some embodiments, the mutant AKT1 protein contains an E17K mutation. In some embodiments, the mutant AKT1 protein contains an E40K mutation. In some embodiments, the mutant AKT1 protein contains an E49K mutation.

[0266] In some embodiments, the exogenous compound contacts a cysteine ​​residue of the AKT1 protein as described herein. In some embodiments, the contact between the cysteine ​​residue of the AKT1 protein and the exogenous compound is covalent. In some embodiments, the cysteine ​​residue is selected from C296 and C310. In some embodiments, the cysteine ​​residue is C296. In some embodiments, the cysteine ​​residue is C310.

[0267] In some embodiments, the covalent bond between the exogenous compound and the cysteine ​​residue is an irreversible covalent bond. In some embodiments, the irreversible covalent bond is a single bond. In some embodiments, the irreversible covalent bond is a single bond between a carbon atom on the exogenous compound and a sulfur atom on the side chain of the cysteine ​​residue.

[0268] In some embodiments, the covalent bond between the exogenous compound and the cysteine ​​residue is an irreversible covalent bond, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the covalent bond between the exogenous compound and the cysteine ​​residue is an irreversible single covalent bond, wherein the cysteine ​​residue is C296. In some embodiments, the covalent bond between the exogenous compound and the cysteine ​​residue is an irreversible single covalent bond, wherein the cysteine ​​residue is C296. In some embodiments, the covalent bond between the exogenous compound and the cysteine ​​residue is an irreversible covalent bond, wherein the cysteine ​​residue is C310. In some embodiments, the covalent bond between the exogenous compound and the cysteine ​​residue is an irreversible single covalent bond, wherein the cysteine ​​residue is C310.

[0269] In some embodiments, the irreversible covalent bonds in the AKT1 protein in vivo involve carbon-sulfur interactions. In some embodiments, the carbon-sulfur interaction is a carbon-sulfur single bond.

[0270] In some embodiments, the AKT1 protein covalently binds to an exogenous compound, wherein the exogenous compound binds to only one residue of the AKT1 protein. In some embodiments, the AKT1 protein covalently binds to the exogenous compound via a single covalent bond. In some embodiments, the AKT1 protein covalently binds to the exogenous compound, wherein the exogenous compound binds to a cysteine ​​residue. In some embodiments, the AKT1 protein has a single covalent bond between the cysteine ​​residue and the exogenous compound. In some embodiments, the AKT1 protein has a single covalent bond between C296 and the exogenous compound. In some embodiments, the AKT1 protein has a single covalent bond between C310 and the exogenous compound.

[0271] In some embodiments, when covalently bound to a cysteine ​​residue selected from C296 and C310, binding of the exogenous compound to other cysteine ​​residues is reduced. In some embodiments, the exogenous compound is contacted with one cysteine ​​residue selected from C296 and C310, and binding to the remaining cysteine ​​residues is reduced. In some embodiments, the exogenous compound is contacted with C296, and binding at C310 is reduced. In some embodiments, the exogenous compound is contacted with C310, and binding at C296 is reduced.

[0272] In some embodiments, the AKT1 protein has a single cysteine ​​residue that covalently binds to the exogenous compound. In some embodiments, the AKT1 protein has a single cysteine ​​residue that covalently binds to the exogenous compound, wherein the single cysteine ​​residue is selected from C296 and C310. In some embodiments, the AKT1 protein has a single cysteine ​​residue that covalently binds to the exogenous compound, wherein the single cysteine ​​residue is C296. In some embodiments, the AKT1 protein has a single cysteine ​​residue that covalently binds to the exogenous compound, wherein the single cysteine ​​residue is C310.

[0273] In some embodiments, the AKT1 protein is in vivo. In some embodiments, the AKT1 protein is in vitro. In some embodiments, the AKT1 protein is ex vivo. In some embodiments, the AKT1 protein is an in vivo engineered protein.

[0274] In some embodiments, the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is produced by contacting the AKT1 protein with an exogenous compound in vivo. In some embodiments, the AKT1 protein is a mammalian in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is produced by contacting the AKT1 protein with an exogenous compound in vivo. In some embodiments, the AKT1 protein is a human in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is produced by contacting the AKT1 protein with an exogenous compound in vivo.

[0275] In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom and a sulfur atom. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of a cysteine ​​residue. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of a cysteine ​​residue selected from C296 and C310. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of a C296 cysteine ​​residue. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of a C310 cysteine ​​residue.

[0276] In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond between an exogenous compound and a cysteine ​​residue. In some embodiments, the carbon-sulfur single bond is between the exogenous compound and a cysteine ​​residue, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is between the exogenous compound and a C296 cysteine ​​residue. In some embodiments, the carbon-sulfur single bond is between the exogenous compound and a C310 cysteine ​​residue.

[0277] In some embodiments, the exogenous compound comprises a cysteine-sensitive electrophile. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylenamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile is selected from acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group. In some embodiments, the exogenous compound comprises acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylenamide groups, and epoxy groups. In some embodiments, the exogenous compound comprises acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the exogenous compound comprises acrylate groups and acrylamide groups. In some embodiments, the exogenous compound comprises an acrylamide group.

[0278] In some embodiments, the irreversible covalent bond is between the cysteine-sensitive electrophile and a cysteine ​​residue. In some embodiments, the irreversible covalent bond is between the cysteine-sensitive electrophile and a cysteine ​​residue selected from C296 and C310. In some embodiments, the irreversible covalent bond is between the cysteine-sensitive electrophile and a C296 cysteine ​​residue. In some embodiments, the irreversible covalent bond is between the cysteine-sensitive electrophile and a C310 cysteine ​​residue.

[0279] In some embodiments, the carbon-sulfur bond is an irreversible bond formed by an irreversible reaction. In some embodiments, the carbon-sulfur bond is an irreversible bond formed by an irreversible reaction between an exogenous compound and a cysteine ​​residue selected from C296 and C310. In some embodiments, the carbon-sulfur bond is an irreversible bond formed by an irreversible reaction between an exogenous compound and a C296 cysteine ​​residue. In some embodiments, the carbon-sulfur bond is an irreversible bond formed by an irreversible reaction between an exogenous compound and a C310 cysteine ​​residue.

[0280] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a cysteine-sensitive electrophile on an exogenous compound. In some embodiments, the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and a cysteine-sensitive electrophile on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and a cysteine-sensitive electrophile on an exogenous compound.

[0281] In some embodiments, the cysteine-sensitive electrophile of the exogenous compound is selected from: acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile of the exogenous compound is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile of the exogenous compound is selected from: acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile of the exogenous compound is an acrylamide group.

[0282] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an acrylate group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an acrylate group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and an acrylate group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and an acrylate group on an exogenous compound.

[0283] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an acrylamide group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an acrylamide group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and an acrylamide group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and an acrylamide group on an exogenous compound.

[0284] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a vinyl group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a vinyl group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and a vinyl group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and a vinyl group on an exogenous compound.

[0285] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a vinyl sulfone group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a vinyl sulfone group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and a vinyl sulfone group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and a vinyl sulfone group on an exogenous compound.

[0286] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a vinylsulfonamide group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and a vinylsulfonamide group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and a vinylsulfonamide group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and a vinylsulfonamide group on an exogenous compound.

[0287] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an acetylamide group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an acetylamide group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and an acetylamide group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and an acetylamide group on an exogenous compound.

[0288] In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an epoxy group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of a cysteine ​​residue and an epoxy group on an exogenous compound, wherein the cysteine ​​residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and an epoxy group on an exogenous compound. In some embodiments, the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C310 and an epoxy group on an exogenous compound.

[0289] In some embodiments, the exogenous compound is a compound or salt as disclosed herein. In some embodiments, the exogenous compound is selected from compounds or salts of formula (II), (II-A), or (III). In some embodiments, the exogenous compound is selected from compounds or salts in Table 1.

[0290] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a non-naturally occurring cysteine ​​residue, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the cysteine-sensitive electrophile undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0291] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous acrylate group and a cysteine ​​residue of AKT1, wherein the acrylate group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0292] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous acrylamide group and a cysteine ​​residue of AKT1, wherein the acrylamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0293] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous vinyl group and a cysteine ​​residue of AKT1, wherein the vinyl group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0294] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous vinyl sulfone group and a cysteine ​​residue of AKT1, wherein the vinyl sulfone group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl sulfone group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0295] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and a cysteine ​​residue of AKT1, wherein the vinylsulfonamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0296] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally occurring, generated by an in vivo nucleophilic reaction between an exogenous acetylacetamide group and a cysteine ​​residue of AKT1, wherein the acetylacetamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acetylacetamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0297] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous epoxy group and a cysteine ​​residue of AKT1, wherein the epoxy group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous epoxy group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0298] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0299] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous acrylate group and a cysteine ​​residue of AKT1, wherein the exogenous acrylate group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0300] In another aspect, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous acrylamide group and a cysteine ​​residue of AKT1, wherein the exogenous acrylamide group undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0301] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous vinyl group and a cysteine ​​residue of AKT1, wherein the exogenous vinyl group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0302] In another aspect, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous vinyl sulfone group and a cysteine ​​residue of AKT1, wherein the exogenous vinyl sulfone group undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous vinyl sulfone group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0303] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and a cysteine ​​residue of AKT1, wherein the exogenous vinylsulfonamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0304] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous acetylacetamide group and a cysteine ​​residue of AKT1, wherein the exogenous acetylacetamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acetylacetamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0305] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine ​​residue selected from C296 and C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous epoxy group and a cysteine ​​residue of AKT1, wherein the exogenous epoxy group undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous epoxy group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0306] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at cysteine ​​residue C296, which is generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0307] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at cysteine ​​residue C296, which is generated by an in vivo nucleophilic reaction between an exogenous acrylate group and a cysteine ​​residue of AKT1, wherein the exogenous acrylate group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0308] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C296 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous acrylamide group and a cysteine ​​residue of AKT1, wherein the exogenous acrylamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0309] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C296 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous vinyl group and a cysteine ​​residue of AKT1, wherein the exogenous vinyl group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0310] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C296 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous vinyl sulfone group and a cysteine ​​residue of AKT1, wherein the exogenous vinyl sulfone group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl sulfone group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0311] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at cysteine ​​residue C296, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and a cysteine ​​residue of AKT1, wherein the exogenous vinylsulfonamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0312] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C296 that is not naturally occurring, arising from an in vivo nucleophilic reaction between an exogenous acetylacetamide group and a cysteine ​​residue of AKT1, wherein the exogenous acetylacetamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acetylacetamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0313] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C296 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous epoxy group and a cysteine ​​residue of AKT1, wherein the exogenous epoxy group undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous epoxy group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0314] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at cysteine ​​residue C310, the irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0315] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous acrylate group and a cysteine ​​residue of AKT1, wherein the exogenous acrylate group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0316] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous acrylamide group and a cysteine ​​residue of AKT1, wherein the exogenous acrylamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0317] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at cysteine ​​residue C310, the irreversible covalent modification arising from an in vivo nucleophilic reaction between an exogenous vinyl group and a cysteine ​​residue of AKT1, wherein the exogenous vinyl group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0318] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous vinyl sulfone group and a cysteine ​​residue of AKT1, wherein the exogenous vinyl sulfone group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinyl sulfone group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0319] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and a cysteine ​​residue of AKT1, wherein the exogenous vinylsulfonamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0320] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous acetylacetamide group and a cysteine ​​residue of AKT1, wherein the exogenous acetylacetamide group undergoes nucleophilic addition to a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous acetylacetamide group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0321] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an irreversible covalent modification at cysteine ​​residue C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous epoxy group and a cysteine ​​residue of AKT1, wherein the exogenous epoxy group undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous epoxy group and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0322] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising mutations selected from E17K, E40K, and E49K, namely, an irreversible covalent modification at a cysteine ​​residue that is not naturally present, generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue and forms a carbon-sulfur single bond between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue.

[0323] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an E17K mutation, i.e., an irreversible covalent modification at a non-naturally present cysteine ​​residue, which is generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylenic amide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group.

[0324] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an E17K mutation, namely, an irreversible covalent modification at a cysteine ​​residue selected from C296 and C310 that is not naturally present. This irreversible covalent modification is generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

[0325] In some aspects, this disclosure provides an in vivo engineered AKT1 protein comprising an E17K mutation, i.e., an irreversible covalent modification at a non-naturally present cysteine ​​residue, which is generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, and a carbon-sulfur single bond is formed between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylenic amide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group.

[0326] On the other hand, this disclosure provides an in vivo engineered AKT1 protein comprising an E17K mutation, i.e., an irreversible covalent modification at a non-naturally present cysteine ​​residue, which is generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue, forming a carbon-sulfur single bond between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylenic amide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group.

[0327] Methods of modifying AKT1 protein In some aspects, this disclosure provides a method for modifying the AKT1 protein as disclosed herein. In some embodiments, the method of covalently modifying the AKT1 protein includes contacting the AKT1 protein with an exogenous compound, wherein the exogenous compound comprises an irreversible electrophilic moiety, thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contact is in vitro or in vivo. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the AKT1 protein is wild-type AKT1 or a mutant AKT1. In some embodiments, the mutant AKT1 is E17K AKT1. In some embodiments, the wild-type AKT1 protein is wild-type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the exogenous compound is an AKT1 inhibitor. In some embodiments, the irreversible covalent moiety on the AKT1 inhibitor is a cysteine-sensitive electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine ​​residue selected from C296 and C310 of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a cysteine ​​residue selected from C296 and C310 of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a C296 cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a C310 cysteine ​​residue of the AKT1 protein. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylenic amide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group.

[0328] On the other hand, methods of covalently modifying the AKT1 protein include contacting the AKT1 protein with an exogenous AKT1 regulator, wherein the AKT1 regulator contains an irreversible electrophilic moiety, thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contact is in vitro or in vivo. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the AKT1 protein is wild-type AKT1 or a mutant AKT1. In some embodiments, the mutant AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutant AKT1 is E17K AKT1. In some embodiments, the wild-type AKT1 protein is wild-type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the irreversible covalent moiety on the AKT1 regulator is a cysteine-sensitive electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine ​​residue selected from C296 and C310 of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a cysteine ​​residue selected from C296 and C310 of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a C296 cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a C310 cysteine ​​residue of the AKT1 protein. In some embodiments, the exogenous AKT1 modulator is an AKT1 inhibitor. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups. In some embodiments, the cysteine-sensitive electrophile is selected from: acrylate groups and acrylamide groups. In some embodiments, the cysteine-sensitive electrophile is an acrylamide group.

[0329] In some aspects, this disclosure provides a method for attenuating AKT1 activity. In some embodiments, the method of covalently modifying the AKT1 protein includes contacting the AKT1 protein with an exogenous AKT1 inhibitor, wherein the AKT1 modulator contains an irreversible electrophilic moiety, thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contact is in vitro or in vivo. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the AKT1 protein is wild-type AKT1 or a mutant AKT1. In some embodiments, the mutant AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutant AKT1 is E17K AKT1. In some embodiments, the wild-type AKT1 protein is wild-type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the irreversible covalent moiety on the AKT1 inhibitor is a cysteine-sensitive electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine ​​residue selected from C296 and C310 of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a cysteine ​​residue selected from C296 and C310 of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a C296 cysteine ​​residue of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between a cysteine-sensitive electrophile and a C310 cysteine ​​residue of the AKT1 protein.

[0330] In some aspects, methods for attenuating AKT1 activity include contacting the AKT1 protein with an exogenous compound, wherein the exogenous compound contains an irreversibly electrophilic moiety. In some embodiments, the AKT1 protein is wild-type AKT1 or a mutant AKT1. In some embodiments, the mutant AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutant AKT1 is E17K AKT1. In some embodiments, the wild-type AKT1 protein is wild-type. In some embodiments, the contact is in vitro or in vivo. In some embodiments, the contact is in vitro.

[0331] In some embodiments, after exposure, AKT1 activity is reduced by 50% to 95% compared to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by 75% to 95% compared to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by 50% or more compared to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by 70% or more compared to a control without exogenous compounds.

[0332] In some embodiments, after exposure, AKT1 activity is reduced by about 50% to about 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by about 75% to about 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by about 50% or more relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by about 70% or more relative to a control without exogenous compounds.

[0333] In some embodiments, after exposure, AKT1 activity is reduced by at least 50% to at least 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at least 75% to at least 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at least 50% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at least 70% relative to a control without exogenous compounds.

[0334] In some embodiments, after exposure, AKT1 activity is reduced by at most 50% to at most 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at most 75% to at most 95% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at most 50% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at most 70% relative to a control without exogenous compounds. In some embodiments, after exposure, AKT1 activity is reduced by at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, or at most 95% relative to a control without exogenous compounds.

[0335] In some embodiments, the exogenous compound exhibits higher selectivity fo...

Claims

1. A compound represented by the structure of formula (I): (I)， Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 3-8 A carbocyclic ring and 4- to 8-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 10 -SR 10 -N(R) 10 )2、-NO2、-CN、C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2, =O, =S, =N(R 11 ) and -CN; as well as 4-10 yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) Heterocyclic compounds ranging from 4 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -NO2, =O, =S, =N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =S, =N(R 11 ), -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; and C 3-10 A carbocyclic ring and 4- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-, -N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-, -N(R 15 )C(O)-, -N(R 15 )C(O)O-, -N(R 15 )S(O)2-, -N(R 15 )S(O)2N(R 15 )-, -S(O)(NR 15 )N(R 15 )-, -N(R 15 )N(R 15 [[ID=2L]] 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-; andIt should be noted that there seems to be an error in the original text where "[[ID=2L]]" should probably be "". This might affect the overall understanding and accuracy of the translation if it's a significant part of the technical content. (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 1 L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 , -S(O)2N(R 16 )2, -N(R 16 )C(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 )2, -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; Ring D is selected from: , , and ; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each occurrence is independently selected from: hydrogen; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles; and C 3-6 A carbocyclic ring and 3- to 6-membered heterocycles, each optionally substituted by one or more substituents independently selected from: halogen, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

2. The compound or salt according to claim 1, wherein A 1 and A 2 Each is independently selected from (i) and (ii): (iii) hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; and (ⅳ) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )^2, -NO2, =O, =S, =N(R 11 ) and -CN; and 3- to 10-yuan heterocyclic rings and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN.

3. The compound or salt according to claim 1 or claim 2, wherein A 1 and A 2 Each is independently selected from (i) and (ii): (iii) hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; and (ⅳ) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: 3-membered to 10-membered heterocycles and C 3-10 A carbon ring, wherein any of the carbon rings may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN.

4. The compound or salt according to any one of claims 1 to 3, wherein A 1 and A 2 Each is independently selected from (i) and (ii): (iii) Hydrogen, halogens, -OR 11 -SR 11 -N(R) 11 2. -NO2 and -CN; and (ⅳ) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group, wherein any one of them is optionally substituted by one or more substituents independently selected from 3- to 10-membered heterocycles, wherein the 3- to 10-membered heterocycles are optionally substituted by one or more substituents independently selected from halogens, halogens, -OR 11 -SR 11 -N(R) 11 )2, -NO2 and - CN is substituted with substituents.

5. The compound or salt according to claim 4, wherein A 2 yes .

6. The compound or salt according to claim 1, wherein A 1 and A 2 Each is independently selected from (i) and (iii): (ii) hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; and (iv) Heterocyclic compounds ranging from 3 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -NO2, =O, =S, =N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =S, =N(R 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN.

7. The compound or salt according to claim 6, wherein A 1 and A 2 Each is independently selected from (i) and (iii): (ii) hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; and (iv) Heterocyclic compounds ranging from 3 to 10 yuan and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 ) and -CN; and C 3-10 A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group and C 2-6 Halogenated alkynyl group.

8. The compound or salt according to claim 6 or claim 7, wherein A 1 and A 2 Each is selected independently from: Hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2, - CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or independently of a substituent selected from the following: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -NO2, =N(R) 11 -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

9. The compound or salt according to claim 8, wherein A 2 Selected from and .

10. The compound or salt according to any one of claims 1 to 9, wherein ring D is selected from: , and .

11. The compound or salt according to claim 10, wherein ring D is And m is selected from 0 and 1.

12. The compound or salt according to claim 11, wherein ring D is selected from... , , , , and .

13. The compound or salt according to claim 10, wherein ring D is And m is selected from 0 and 1.

14. The compound or salt according to claim 13, wherein ring D is .

15. The compound or salt according to claim 10, wherein ring D is And m is selected from 0 and 1.

16. The compound or salt according to claim 15, wherein ring D is .

17. The compound or salt according to claim 1, wherein ring D is ; and m is selected from 1, 2 and 3.

18. The compound or salt according to claim 17, wherein ring D is composed of... express.

19. The compound or salt according to claim 1, wherein the structure of formula (I) is derived from the structure of formula (II): (II), Or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen, halogens, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -S(O)2N(R 11 )2, -NO2, =O, =S, =N(R 11 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 、 -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =S, =N(R 11 )、-CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-, -N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-, -N(R 15 )C(O)-, -N(R 15 )C(O)O-, -N(R 15 )S(O)2-, -N(R 15 )S(O)2N(R 15 )-, -S(O)(NR 15 )N(R 15 )-, -N(R 15 )N(R 15 )-, -(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-; and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 , -S(O)2N(R 16 )2, -N(R 16 )C(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 )2, -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each occurrence is independently selected from: hydrogen, C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles; and C 3-6 A carbocyclic ring and 3- to 6-membered heterocycles, each optionally substituted by one or more substituents independently selected from: halogen, -OH, -OC. 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

20. The compound or salt according to any one of claims 1 to 19, wherein the cysteine-sensitive electrophilic agent is selected from haloacetamides, haloalkyl ketones, haloamidines, halobenzylphosphonates, acyloxyalkyl ketones, sulfonyl ethylene oxides, epoxides, diazonyl ketones, halotriazines, acrylamides, cyanoacrylamides, vinyl sulfones, vinyl sulfonamides, acrylates, fumarates, carbonyl acrylates, maleimides, ketoamides, nitriles, alkenes, alkynes, ketone heterocycles, and acetylides.

21. The compound or salt of claim 20, wherein the cysteine-sensitive electrophilic agent is selected from haloacetamides, haloalkyl ketones, and haloamidines.

22. The compound or salt of claim 20, wherein the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylene amides, alkenes, alkynes, and epoxy groups.

23. The compound or salt of claim 21, wherein the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, vinyl sulfonate groups, vinyl sulfonamide groups, alkenes, and alkynes.

24. The compound or salt according to claim 23, wherein the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, alkenes, and alkynes.

25. The compound or salt according to any one of claims 1 to 19, wherein the cysteine-sensitive electrophilic agent is an α-β-unsaturated carbonyl group, an α-β-unsaturated sulfone, an α-β-unsaturated amide, or an α-β-unsaturated sulfonamide.

26. The compound or salt according to claim 25, wherein the cysteine-sensitive electrophilic agent is selected from α-β-unsaturated carbonyl groups and α-β-unsaturated amides.

27. The compound or salt according to claim 26, wherein the cysteine-sensitive electrophilic agent is an α-β-unsaturated carbonyl group.

28. The salt compound according to any one of claims 1 to 27, wherein R 15 Selected from hydrogen and optionally by one or more independently selected from halogens, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-6 C-rings substituted with substituents of carbocyclic rings and 3- to 6-membered heterocycles 1-6 alkyl.

29. The compound or salt according to any one of claims 1 to 27, wherein L 1 It is -N(R) 15 )-; and R 15 Each time it appears, it is optionally selected by one or more independent selections from -OC. 1-6 C-substituted alkyl groups and 3- to 6-membered heterocyclic groups 1-6 alkyl.

30. The compound or salt according to claim 29, wherein L is selected from... and .

31. The compound or salt according to claim 1, wherein the structure of formula (II) is derived from the structure of formula (II-A): (II-A), Or a pharmaceutically acceptable salt thereof, wherein: The cysteine-sensitive electrophilic reagent is R 5 ; R 5 Selected from: -C(O)R 17 、-S(O)2R 17 、-N(R 19 )C(O)(R 17 )、-C(O)N(R 17 )(R 19 )、-N(R 19 )S(O)2R 17 、-S(O)2N(R 17 )(R 19 ) and -CN; C 1-6 Alkyl groups, which are independently selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 Substitution of -CN and -CN substituents; C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally composed of one or more groups independently selected from -C(O)R 19 -S(O)2R 19 -N(R) 19 )C(O)(R 19 -C(O)N(R) 19 )2、-N(R 19 )S(O)2R 19 -S(O)2N(R) 19 (R) 19 Substitution of ) and -CN; and C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is independently selected from O, C, and C rings. 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 Substitution of -CN and -CN substituents; R 17 Selected independently each time it appears: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and C 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and R 18 and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

32. The compound or salt according to claim 31, wherein R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 ) and -CN.

33. The compound or salt according to claim 32, wherein R 5 Selected from -C(O)R 17 -、N(R 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 -S(O)2R 17 and -CN.

34. The compound or salt according to claim 33, wherein R 5 Selected from -CN , , and .

35. The compound or salt according to claim 31, wherein R 5 It is selected independently by one or more of -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 C substituents of -CN and -CN 1-6 alkyl.

36. The compound or salt according to claim 35, wherein R 5 It is selected independently by one or more of -N(R) 19 )C(O)(R 17 ) and -C(O)N(R 17 (R) 19 The substituents of C are substituted with substituents. 1-6 alkyl.

37. The compound or salt according to claim 36, wherein R 5 yes .

38. The compound or salt according to claim 35, wherein R 5 Selected from , , , , and .

39. The compound or salt according to claim 31, wherein R 5 Selected from C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally composed of one or more groups independently selected from -C(O)R 19 -S(O)2R 19 -N(R) 19 )C(O)(R 19 -C(O)N(R) 19 )2、-N(R 19 )S(O)2R 19 -S(O)2N(R) 17 (R) 19 Substitution of -CN and -CN.

40. The compound or salt according to claim 39, wherein R 5 It is selected independently by one or more of -C(O)R 19 -S(O)2R 19 -N(R) 19 )C(O)(R 19 -C(O)N(R) 19 )2、-N(R 19 )S(O)2R 19 -S(O)2N(R) 17 (R) 19 C substituents of -CN and -CN 2-6 Alkenyl group.

41. The compound or salt according to claim 40, wherein R 5 It is selected independently by one or more of -N(R) 19 )C(O)(R 19 ) and -C(O)N(R 19 C substituted with a substituent of )2 2-6 Alkenyl group.

42. The compound or salt according to claim 41, wherein R 5 yes .

43. The compound or salt according to claim 31, wherein R 5 Selected from C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein each is independently selected from O, C, and C rings. 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 -S(O)2R 17 Substitution with -CN.

44. The compound or salt according to claim 43, wherein R 5 It is selected independently by one or more of the following: =O, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ), -N(R 19 )S(O)2R 17 -S(O)2N(R) 17 (R) 19 -S(O)2R 17 3- to 6-membered heterocycles substituted with -CN.

45. The compound or salt according to claim 44, wherein R 5 It is selected independently by one or more of the following: =O, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)R 17 3- to 6-membered heterocycles substituted with -CN.

46. ​​The compound or salt according to claim 45, wherein R 5 Selected from and .

47. The compound or salt according to any one of claims 31 to 46, wherein R 17 Selected independently each time it appears: C 1-6 Alkyl groups, which are -halogenated, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN substitution; C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and C 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

48. The compound or salt according to claim 47, wherein R 17 It is -halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 C replaced by -NO2 and -CN 1-6 alkyl.

49. The compound or salt according to claim 47, wherein R 17 Each time it appears, it is independently selected from C. 3-6 Carbocyclic alkenyl, 3- to 6-membered heterocyclic alkenyl, and 3- to 6-membered heterocyclic, wherein each is optionally substituted by one or more substituents independently selected from: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, halogens, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

50. The compound or salt according to claim 31, wherein R 5 Selected from -CN , , , , , , and .

51. The compound or salt according to claim 31, wherein R 5 Selected from -CN , , , , , , , , , , , and .

52. The compound or salt according to claim 31, wherein... Selected from: , , , , , , , and .

53. The compound or salt according to claim 31, wherein... Selected from: , , , , , , , , , , , , and .

54. The compound or salt according to claim 1 or claim 19, wherein formula (I) or formula (II) has the structure of formula (III): (III), Or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen, halogens, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; A 1 and A 2 Each is independently selected from (i), (ii), and (iii): (i) Hydrogen, halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R 11 )2, -S(O)R 11 , -S(O)2R 11 , -N(R 11 )S(O)2R 11 , -S(O)2N(R 11 )2, -NO2 and - CN; (ii) C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)N(R 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and (iii) 5-10 yuan heterocyclic rings and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 )2, -N(R 11 )C(O)N(R[[ID=​​​​​​​​ C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -C(O)OR 11 -OC(O)R 11 -N(R) 11 )C(O)OR 11 -OC(O)N(R) 11 )2、-N(R 11 )C(O)N(R 11 )2、-S(O)R 11 -S(O)2R 11 -N(R) 11 )S(O)2R 11 -S(O)2N(R) 11 )2、-NO2、=O、=S、=N(R 11 ) and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO2, =O, =S, =N(R 11 ), -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -SR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 -N(R) 11 )S(O)2R 11 -C(O)OR 11 -OC(O)R 11 -NO2, =O, =S, =N(R) 11 ) and -CN; R 2 In each case, it is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 12 -SR 12 -N(R) 12 2. -NO2 and -CN; R 3 Select independently in each case: Halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2 and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 13 -SR 13 -N(R) 13 )2、-C(O)R 13 -C(O)N(R) 13 )2、-N(R 13 )C(O)R 13 -C(O)OR 13 -OC(O)R 13 -NO2, =O, =S, =N(R) 13 ) and -CN; R 4 Select independently in each case: Halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 14 -SR 14 -N(R) 14 )2、-C(O)R 14 -C(O)N(R) 14 )2、-N(R 14 )C(O)R 14 -C(O)OR 14 -OC(O)R 14 -NO2, =O, =S, =N(R) 14 ) and -CN; L by -L 1 -L 2 -L 3 -L 4 - indicates that L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-, -N(R 15 )-, -S-, -S(O)-, -S(O)2-, -S(O)(NR 15 )-, -N(R 15 )C(O)-, -N(R 15 )C(O)O-, -N(R 15 )S(O)2-, -N(R 15 )S(O)2N(R 15 )-, -S(O)(NR 15 )N(R 15 )-, -N(R 15 )N(R 15 )-, -(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-; and (b) C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-8 Carbocyclic and 3- to 8-membered heterocyclic groups, either of which may optionally be substituted by one or more substituents independently selected from: halogen, -OR 15 -SR 15 =O, =S and - CN; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; Cycle B is selected from 3- to 10-membered subheterocyclic groups and C. 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 , -S(O)2N(R 16 )2, -N(R 16 )C(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 )2, -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ) and -CN; C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; and 3- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 16 -SR 16 -N(R) 16 )2、-C(O)N(R 16 )2、-C(O)OR 16 -OC(O)R 16 -N(R) 16 )C(O)R 16 , - N(R 16 )S(O)2R 16 -S(O)2N(R) 16 )2、-N(R 16 )C(O)N(R 16 )2、-N(R 16 )C(O)OR 16 -OC(O)N(R) 16 )2、-S(O)R 16 -S(O)2R 16 -NO2, =O, =S, =N(R) 16 ) and -CN; A 3 It is a cysteine-sensitive electrophilic reagent; R 10 R 11 R 12 R 13 R 14 R 15 and R 16 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

55. The compound or salt according to claim 54, wherein the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, vinyl groups, vinyl sulfonate groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups.

56. The compound or salt according to claim 55, wherein the cysteine-sensitive electrophilic agent is selected from acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups.

57. The compound or salt according to any one of claims 54-56, wherein the structure of formula (III) is derived from the structure of formula (III-A): (III-A), Or a pharmaceutically acceptable salt thereof, wherein: The cysteine-sensitive electrophilic reagent is R 5 ; R 5 Selected from -C(O)R 17 -S(O)2R 17 -N(R) 19 )C(O)(R 17 -C(O)N(R) 17 (R) 19 ) and -N(R 19 )S(O)2R 17 and -S(O)2N(R 17 (R) 19 ); R 17 Each time it appears, it is independently selected from C. 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN; and R 18 and R 19 Each time it appears, it is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Carbon rings and 3- to 6-membered heterocycles.

58. The compound or salt according to any one of claims 1-57, wherein q is 1.

59. The compound or salt according to any one of claims 1-58, wherein m is 0.

60. The compound or salt according to any one of claims 1-59, wherein n is 0.

61. The compound or salt according to any one of claims 1-60, wherein R 4 Selected from hydrogen, halogens, -OR 14 -N(R) 14 )2, -NO2, -CN; and optionally selected independently by one or more halogens, -OR 14 and -N(R) 14 C substituted with a substituent of )2 1-6 alkyl.

62. The compound or salt according to claim 61, wherein R 4 Selected from halogens, -OR 14 C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

63. The compound or salt according to claim 62, wherein R 4 Selected from fluorine, -OH and -OCH3.

64. The compound or salt according to any one of claims 1-60, wherein p is selected from 0, 1 and 2.

65. The compound or salt according to any one of claims 1-60, wherein p is 0.

66. The compound or salt according to any one of claims 1-65, wherein A 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and -CN.

67. The compound or salt according to claim 66, wherein A 1 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

68. The compound or salt according to claim 67, wherein A 1 Selected from hydrogen, fluorine, and methyl.

69. The compound or salt according to claim 68, wherein A 1 It is hydrogen.

70. The compound or salt according to any one of claims 1-65, wherein A 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2, -CN, 5- to 10-membered heterocyclic rings and C 3-10 Carbon ring.

71. The compound or salt according to claim 70, wherein A 1 Selected from hydrogen, halogens and C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, 3- to 6-membered heterocycles and C 3-6 Carbon ring.

72. The compound or salt according to claim 71, wherein A 1 Selected from hydrogen, fluorine, methyl, , and .

73. The compound or salt according to any one of claims 1-72, wherein R 1 Selected from hydrogen, halogens, -OR 10 -N(R) 10 )2, -NO2, -CN; and optionally selected independently by one or more halogens, -OR 10 and -N(R) 10 C substituted with a substituent of )2 1-6 alkyl.

74. The compound or salt according to claim 73, wherein R 1 Selected from hydrogen, -OR 10 and -CN; and optionally by one or more -OR 10 Replacement C 1-6 alkyl.

75. The compound or salt according to claim 74, wherein R 1 Selected from hydrogen, methoxy, -CN, methyl, ethyl and (methoxy)methyl.

76. The compound or salt according to claim 75, wherein R 1 It is hydrogen.

77. The compound or salt according to any one of claims 54-76, wherein the structure of formula (III) or formula (III-A) is derived from the structure of formula (III-B): (III-B); Or its pharmaceutically acceptable salt.

78. The compound or salt according to any one of claims 1-77, wherein A 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 11 -N(R) 11 )2 and -CN.

79. The compound or salt according to claim 78, wherein A 2 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

80. The compound or salt according to claim 79, wherein A 2 It is a methyl group.

81. The compound or salt according to any one of claims 1-77, wherein A 2 Selected from 5- to 10-membered heterocycles and C 3-10 The carbon ring, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: chlorinated, -OR 11 , -N(R 11 )2, -C(O)R 11 ,-C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 , = O sum - CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and - CN.

82. The compound or salt according to claim 81, wherein A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: chlorinated, -OR 11 , -N(R 11 )2, -C(O)R 11 ,-C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 , = O sum - CN; C 1-6 Alkyl, C 2-6 alkenyl and C 3-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O and -CN; and C 3-10 A carbocyclic ring and a 3- to 10-membered heterocycle, any of which may optionally be substituted by one or more substituents independently selected from the following: Halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN.

83. The compound or salt according to claim 82, wherein A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: chlorinated, -OR 11 , -N(R 11 )2, -C(O)R 11 ,-C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , = O sum - CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and = O; and C 3-10 A carbocyclic ring and 3- to 10-membered heterocycles, any of which may optionally be substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 And = O.

84. The compound or salt according to claim 83, wherein A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

85. The compound or salt according to claim 84, wherein A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

86. The compound or salt according to claim 85, wherein A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

87. The compound or salt according to claim 86, wherein A 2 Selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally selected by one or more independently selected from halogens, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

88. The compound or salt according to claim 87, wherein A 2 The group is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridyl, pyrazinyl and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, wherein each is optionally substituted by one or more substituents independently selected from fluorine, methyl and -CHF2.

89. The compound or salt according to claim 88, wherein A 2 Selected from , , , , , , , , , and .

90. The compound or salt according to claim 85, wherein A 2 It is a 5- to 6-membered heteroaryl group optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

91. The compound or salt according to claim 90, wherein A 2 Selected from pyrazolyl and triazolyl groups, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 and -N(R) 11 Substituents of )2.

92. The compound or salt according to claim 91, wherein A 2 Selected from and .

93. The compound or salt according to claim 81, wherein A 2 It is a 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN.

94. The compound or salt according to claim 93, wherein A 2 It is a 5- to 8-membered heterocycle optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN.

95. The compound or salt according to claim 94, wherein A 2 It is a 5- to 8-membered saturated heterocycle optionally substituted with one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 =O and -CN.

96. The compound or salt according to claim 95, wherein A 2 Selected from , , , , , and .

97. The compound or salt according to claim 94, wherein A 2 It is a 5- to 6-membered heteroaryl group optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 and -CN.

98. The compound or salt according to claim 97, wherein A 2 Selected from , , , and .

99. The compound or salt according to claim 81, wherein A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 10-membered heterocycles, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O, and -CN.

100. The compound or salt according to claim 99, wherein A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 8-membered heterocycles, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2, =O, and -CN.

101. The compound or salt according to claim 100, wherein A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 8-membered saturated heterocycles, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2, -NO2, =O and -CN.

102. The compound or salt according to claim 101, wherein A 2 yes .

103. The compound or salt according to claim 100, wherein A 2 It is optionally controlled by one or more Cs 1-6 Alkyl-substituted 5- to 6-membered heteroaryl groups, wherein C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 , - N(R 11 )S(O)2R 11 -NO2 and -CN.

104. The compound or salt according to claim 103, wherein A 2 Selected from , , , , , , and .

105. The compound or salt according to claim 81, wherein A 2 It is optionally controlled by one or more Cs 3-10 Carbon rings and 5- to 10-membered heterocycles substituted with 3- to 10-membered heterocycles, wherein the C 3-10 The carbon ring and any of the 3- to 10-membered heterocycles are optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

106. The compound or salt according to claim 105, wherein A 2 It is optionally controlled by one or more Cs 3-6 Saturated carbocyclic rings and 5- to 10-membered heterocycles substituted with 3- to 6-membered saturated heterocycles, wherein the C 3-6 The saturated carbon ring and any of the 3- to 6-membered saturated heterocycles are optionally selected independently by one or more halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups.

107. The compound or salt according to claim 106, wherein A 2 Selected from , , , and .

108. The compound or salt according to claim 81, wherein A 2 C is optionally substituted by one or more substituents independently selected from the following 3-10 Carbon ring: chlorinated, -OR 11 , -N(R 11 )2, -C(O)R 11 ,-C(O)N(R 11 )2, -N(R 11 )C(O)R 11 , = O sum - CN; C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and = O; and C 3-10 Carbon rings and 3- to 10-membered heterocycles; wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocycle are each optionally substituted by one or more substituents independently selected from the following: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally substituted by one or more substituents independently selected from: halogen, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 And = O.

109. The compound or salt according to claim 93, wherein A 2 C is optionally substituted by one or more substituents independently selected from the following 3-10 Carbon rings: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 =O and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

110. The compound or salt according to claim 109, wherein A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Saturated carbon rings: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

111. The compound or salt according to claim 110, wherein A 2 C is optionally substituted by one or more substituents independently selected from the following 3-6 Cycloalkyl groups: halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 11 -N(R) 11 )2、-C(O)R 11 -C(O)N(R) 11 )2、-N(R 11 )C(O)R 11 Substitution with =O and substituents.

112. The compound or salt according to claim 111, wherein A 2 yes .

113. The compound or salt according to claim 109, wherein A 2 Selected from , , , and .

114. The compound or salt according to any one of claims 1-113, wherein L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a) -O-, -N(R 15 )-, -S-, -N(R 15 )C(O)-, -N(R 15 )C(O)O-, -N(R 15 )S(O)2, -N(R 15 )N(R 15 )- and -(R 15 )NC(O)N(R 15 )-; and (b)C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-6 Carbocyclic groups and 3- to 6-membered heterocyclic groups, any of which may optionally be independently selected from halogens, -OR 15 Substitution with -CN; Where L 2 L 3 and L 4 Each of them arbitrarily does not exist; and Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent.

115. The compound or salt according to claim 114, wherein L 1 L 2 L 3 and L 4 Each is independently selected from (a) and (b): (a)-O-, -N(R 15 )-sum-N(R 15 )C(O)-; (b)C 1-6 Alkylene; Where L 2 L 3 and L 4 Each of the two optional locations does not exist; Where L 1 L 2 L 3 and L 4 No more than two are selected from (a), and the two selected are not adjacent; and R 15 Selected from hydrogen and C 1-4 alkyl.

116. The compound or salt according to any one of claims 1-115, wherein L 4 It does not exist.

117. The compound or salt according to any one of claims 1-116, wherein L 3 It does not exist.

118. The compound or salt according to any one of claims 1-117, wherein L 2 It either does not exist or is methylene.

119. The compound or salt according to any one of claims 1-118, wherein L 1 Selected from -O-, -N(R) 15 )- and -N(R 15 )C(O)-.

120. The compound or salt according to claim 119, wherein L 1 Selected from -N(R) 15 )- and -N(R 15 )C(O)-; and R 15 Each time it appears, it is selected from hydrogen and methyl.

121. The compound or salt according to any one of claims 1-119, wherein L is selected from -O-, -NH-, -N(CH3)-, and .

122. The compound or salt according to any one of claims 1-119, wherein L is selected from -O-, -NH-, and .

123. The compound or salt according to any one of claims 1-122, wherein L is selected from -NH- and .

124. The compound or salt according to any one of claims 1-118, wherein L 1 Selected from -O-, -N(R) 15 )-、-N(R 15 C(O)-, C 1-6 Alkylenes and 3- to 6-membered heterocyclic groups.

125. The compound or salt according to claim 124, wherein L is selected from -O-, -NH-, -CH2-, -N(CH3)-, , and .

126. The compound or salt according to any one of claims 1-125, wherein ring B is selected from 3- to 10-membered heterocyclic groups and C 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and 4- to 6-membered heterocyclic rings and C 3-6 A carbon ring, wherein each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

127. The compound or salt according to claim 126, wherein ring B is selected from 3- to 10-membered heterocyclic groups and C 3-10 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

128. The compound or salt according to claim 127, wherein ring B is selected from 5- to 10-membered heterocyclic groups and C 3-6 Carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

129. The compound or salt according to claim 128, wherein ring B is selected from 5- to 10-membered saturated heterocyclic groups, 5- to 10-membered unsaturated heterocyclic groups, and C. 3-6 Unsaturated carbocyclic groups, wherein any one of them is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

130. The compound or salt according to claim 129, wherein ring B is selected from aziridine, pyrrolidine, piperidinium, phenylene, pyridinium, indoline, 3-azabicyclo[3.2.1]octane, cyclobutane, cyclohexane, pyrazolium, 1,2,3,4-tetrahydroquinoline, azispiro[3.5]nonane, azispiro[3.3]heptane, azispiro[3.5]heptanane, azispiro[3.3]heptane, etc. 3.4] Octane, 1,4-oxazabicycloheptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-oxa-6-azabicyclo[3.2.2]nonane, piperazine, azabicycloheptanyl, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.1]heptanyl, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

131. The compound or salt according to claim 129, wherein ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, isoindolin, tetrahydroisoquinolinyl, 3-azirbicyclo[3.2.1]octane, cyclobutane, cyclohexane, pyrazolyl, 1,2,3,4-tetrahydroquinolinyl, azirspiro[3.5]nonane, azirspiro[3.3]heptane, azirspiro[3.4]octane, 1,4-oxazazaheptanane, 3-azirbicyclo[3.2.1]octane, cyclobutane, cyclohexane, cycloheptan ... 1.0] heptane, 3-azabicyclo[3.1.1] heptane, 3-oxa-6-azabicyclo[3.2.2] nonane, 3-oxa-7-azabicyclo[3.3.1] nonane, 3-azabicyclo[3.3.1] nonane, piperazine, azabicycloheptane, 2-azabicyclo[2.2.2] octane, 2-azabicyclo[2.2.1] heptane, 2-azabicyclo[3.2.1] octane, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

132. The compound or salt according to claim 129, wherein ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, and 3-azirbicyclo[3.2.1]octane, wherein each is optionally substituted by one or more substituents independently selected from: Halogen, -OR 16 , -N(R 16 )2, -C(O)N(R 16 )2, -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -NO2, =O and -CN; C 1-4 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group, wherein any of them may optionally be substituted by one or more substituents independently selected from: halogen, -OR 16 -SR 16 -N(R) 16 2. -NO2 and -CN; and C 3-6 A carbon ring, optionally substituted by one or more substituents independently selected from: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OR 16 -N(R) 16 2. -NO2 and -CN.

133. The compound or salt according to claim 131, wherein ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, and 3-azirbicyclo[3.2.1]octane, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 -CN and C 1-3 Alkyl, wherein the C 1-3 Alkyl groups are optionally halogenated and -OR 16 Replace; and R 16 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

134. The compound or salt according to claim 131, wherein ring B is selected from aziridine, pyrrolidine, piperidinidine, phenylene, pyridinidine, indoline, and 3-azirbicyclo[3.2.1]octane, wherein each is optionally substituted by one or more substituents independently selected from: halogen, -OR 16 and C 1-3 Alkyl; and R 16 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

135. The compound or salt according to any one of claims 1-134, wherein: R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 ;and R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

136. The compound or salt according to any one of claims 1-134, wherein: R 5 Selected from -C(O)R 17 -N(R) 19 )C(O)(R 17 ) and -N(R 19 )S(O)2R 17 ;and R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

137. The compound or salt according to claim 135, wherein R 5 It is -C(O)R 17 And R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

138. The compound or salt according to claim 137, wherein R 5 It is -C(O)R 17 ;R 17 Selected from C 2-6 alkenyl and C 2-6 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

139. The compound or salt according to claim 136, wherein R 5 It is -C(O)R 17 And R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

140. The compound or salt according to claim 139, wherein R 5 It is -C(O)R 17 ;R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 Selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

141. The compound or salt according to claim 136, wherein R 5 It is -N(R) 19 )C(O)(R 17 ); and R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

142. The compound or salt according to claim 141, wherein R 5 It is -N(R) 19 )C(O)(R 17 ); R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 and R 19 Each of them is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

143. The compound or salt according to claim 136, wherein R 5 It is -N(R) 19 )S(O)2R 17 And R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -SR 18 -N(R) 18 )2、-C(O)N(R 18 )2、-C(O)OR 18 -OC(O)R 18 -N(R) 18 )C(O)R 18 , - N(R 18 )S(O)2R 18 -S(O)2N(R) 18 )2、-N(R 18 )C(O)N(R 18 )2、-N(R 18 )C(O)OR 18 -OC(O)N(R) 18 )2、-S(O)R 18 -S(O)2R 18 -NO2 and -CN.

144. The compound or salt according to claim 143, wherein R 5 It is -N(R) 19 )S(O)2R 17 ;R 17 Selected from C 2-4 alkenyl and C 2-4 Alkyne group, wherein each of them is optionally substituted by one or more substituents independently selected from: halogen, -OR 18 -N(R) 18 )2, -NO2 and -CN; and R 18 and R 19 Each of them is independently selected from hydrogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

145. The compound or salt according to claim 135, wherein R 5 Selected from: , , , , , , , , , , , and .

146. The compound or salt according to claim 136, wherein R 5 Selected from: , , , , , , , and .

147. The compound or salt according to any one of claims 1-131, wherein Selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , and .

148. The compound or salt according to any one of claims 1-126, 135 or 136, wherein Selected from: , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , and .

149. The compound or salt according to any one of claims 1-126 or 136, wherein Selected from: , , , , , 、 、 、 、 、 、 、 、 、 、 、 , , , , and .

150. The compound or salt according to any one of claims 1-149, wherein the compound of formula (I), (II), (II-A), (III), (III-A) or (III-B) is selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof.

151. A pharmaceutical composition comprising the compound or salt of any one of claims 1-150 and a pharmaceutically acceptable excipient.

152. A method for modulating the activity of wild-type AKT1, the method comprising administering to a subject in need a compound or salt of any one of claims 1-150 or a pharmaceutical composition of claim 151.

153. A method for modulating the activity of mutant AKT1, the method comprising administering to a subject in need a compound or salt of any one of claims 1-150 or a pharmaceutical composition of claim 151.

154. A method for selectively modulating the activity of wild-type AKT1 relative to wild-type AKT2, the method comprising administering to a subject in need a compound or salt of any one of claims 1-150 or a pharmaceutical composition of claim 151.

155. A method for selectively regulating the activity of mutant AKT1 relative to wild-type AKT2, the method comprising administering to a subject in need a compound or salt of any one of claims 1-150 or a pharmaceutical composition of claim 151.

156. A method of treating cancer in a subject of need, the method comprising administering to the subject a compound or salt of any one of claims 1-150 or a pharmaceutical composition of claim 151.

157. The method of claim 156, wherein the cancer is selected from breast cancer, colorectal cancer, and meningioma.

158. The method of claim 156, wherein the application modulates the activity of mutant AKT1.

159. The method according to claim 153, 155 or 158, wherein the mutant AKT1 is AKT1 E17K.

160. The method of claim 156, wherein the application modulates the activity of wild-type AKT1.

161. An AKT1 protein covalently bound to a compound, wherein the compound is covalently bound to a cysteine ​​residue of the AKT1 protein.

162. The AKT1 protein according to claim 161, wherein the compound is an exogenous AKT1 regulator.

163. The AKT1 protein according to claim 161, wherein the compound is an exogenous AKT1 inhibitor.

164. The AKT1 protein according to claim 163, wherein the exogenous AKT1 inhibitor is the compound or salt of claim 1 or the pharmaceutical composition of claim 150.

165. The AKT1 protein according to any one of claims 161-164, wherein the AKT1 protein comprises an E17K mutation, an E40K mutation, or an E49K mutation.

166. The AKT1 protein according to any one of claims 161-165, wherein the cysteine ​​residue is selected from C296 and C310.

167. The AKT1 protein according to claim 166, wherein the cysteine ​​residue is C296.

168. The AKT1 protein according to any one of claims 161-167, wherein the AKT1 protein is in vivo.

169. The AKT1 protein of claim 168, wherein the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is produced by contacting the AKT1 protein with the compound in vivo.

170. The AKT1 protein according to claim 169, wherein the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

171. The AKT1 protein according to any one of claims 161 to 170, wherein the covalent bond between the compound and the cysteine ​​residue is an irreversible covalent bond.

172. The AKT1 protein according to claim 171, wherein the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond.

173. The AKT1 protein according to claim 172, wherein the carbon-sulfur single bond is generated by an irreversible reaction between the thiol functional group of C296 and a cysteine-sensitive electrophile on the compound, wherein the cysteine-sensitive electrophile is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups.

174. The AKT1 protein according to claim 173, wherein the cysteine-sensitive electrophilic agent is selected from: acrylate groups, acrylamide groups, vinyl sulfone groups, and vinyl sulfonamide groups.

175. An in vivo engineered AKT1 protein comprising an irreversible covalent modification at a cysteine ​​residue that is not naturally occurring, said irreversible covalent modification being generated by an in vivo nucleophilic reaction between an exogenous cysteine-sensitive electrophile and a cysteine ​​residue of AKT1, wherein the exogenous cysteine-sensitive electrophile undergoes nucleophilic addition with a thiol functional group on the cysteine ​​residue and forms a carbon-sulfur single bond between the exogenous cysteine-sensitive electrophile and the thiol functional group on the cysteine ​​residue.

176. The in vivo engineered AKT1 protein according to claim 175, wherein the cysteine-sensitive electrophilic agent is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, acetylacetamide groups, and epoxy groups.

177. The in vivo engineered AKT1 protein according to claim 176, wherein the cysteine-sensitive electrophilic agent is selected from: acrylate group, acrylamide group, vinyl sulfone group and vinyl sulfonamide group.

178. The in vivo engineered AKT1 protein according to any one of claims 175-177, wherein the AKT1 protein comprises an E17K mutation.

179. The in vivo engineered AKT1 protein according to any one of claims 175-178, wherein the cysteine ​​residue is selected from C296 and C310.

180. The in vivo engineered AKT1 protein according to claim 179, wherein the cysteine ​​residue is C296.

181. The in vivo engineered AKT1 protein according to any one of claims 175-180, wherein the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.

182. A method of covalently modifying an AKT1 protein, the method comprising contacting the AKT1 protein with an exogenous AKT1 modulator, wherein the AKT1 modulator comprises a cysteine-sensitive electrophilic agent, thereby forming a covalent AKT1 adduct.

183. The method of claim 182, wherein the contact is in vitro.

184. The method of claim 182, wherein the contact is within the body.

185. The method according to any one of claims 182-184, wherein the AKT1 modulator is an AKT1 inhibitor.

186. The method according to any one of claims 182-185, wherein the cysteine-sensitive electrophilic agent is selected from: acrylamide group, vinyl group, vinyl sulfone group, vinyl sulfonamide group, acetylacetamide group, and epoxy group.

187. The method of claim 186, wherein the cysteine-sensitive electrophilic agent is selected from: acrylate groups, acrylamide groups, vinyl sulfone groups, and vinyl sulfonamide groups.

188. A method for attenuating AKT1 activity, the method comprising contacting an AKT1 protein with an AKT1 inhibitor, wherein the AKT1 inhibitor comprises a cysteine-sensitive electrophile.

189. The method of claim 188, wherein the contact is in vitro.

190. The method of claim 189, wherein after the contact, the AKT1 activity is reduced by 50% or more relative to a control in which the exogenous AKT1 inhibitor is absent.

191. The method of claim 190, wherein after the contact, the AKT1 activity is reduced by 70% or more relative to a control in which the exogenous AKT1 inhibitor is absent.

192. The method according to any one of claims 188-191, wherein the cysteine-sensitive electrophilic agent is selected from: acrylate groups, acrylamide groups, vinyl groups, vinyl sulfone groups, vinyl sulfonamide groups, acetylacetamides, and epoxy groups.

193. The method according to claim 192, wherein the cysteine-sensitive electrophilic agent is selected from: acrylate groups, acrylamide groups, vinyl sulfonate groups, and vinyl sulfonamide groups.

194. The method according to any one of claims 185-193, wherein the exogenous AKT1 inhibitor is a compound or salt of claim 1 or 54 or a pharmaceutical composition of claim 151.

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