Use of inhibitor in treatment or prevention of radioactive damage

Abstract

Disclosed is the use of an inhibitor in the treatment or prevention of radioactive damage. Specifically, disclosed is the use of the inhibitor in the preparation of a drug for treating or preventing radioactive damage.

Description

Use of an inhibitor in the treatment or prevention of radiation damage Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the use of RIPK1 inhibitors in the treatment or prevention of radiation damage. Background Technology

[0002] Ionizing radiation can induce multiple signaling pathways associated with cell damage, including DNA damage, upregulation of reactive oxygen species, transcription of inflammatory factors, and programmed cell death, thereby leading to radiation-induced damage.

[0003] One manifestation of radiation damage is radiation dermatitis. Studies have shown that the pathogenesis of radiation dermatitis involves multiple factors, including changes in the expression of apoptosis-related genes and growth factors, as well as changes in epithelial cells and subcutaneous blood vessels. Basal germinal layer cells are sensitive to radiation, and the free radicals and reactive oxygen species generated by radiation easily damage basal cells, affecting cell division, proliferation, migration to the surface, and keratinization, thereby affecting the normal metabolism of epidermal cells and causing radiation dermatitis. In the early stages of radiotherapy, histamine-like substances are released at the irradiated site, increasing capillary permeability and causing transient erythema and itching; in the later stages of radiotherapy, the exudation of red blood cells and white blood cells from dermal blood vessels leads to erythema. With increasing radiation dose, basal cells are damaged, leading to dry peeling, wet peeling, and even ulceration and necrosis.

[0004] Currently, treatment options for radiation dermatitis are limited. Acute radiation dermatitis is treated according to its severity. Grade 1 dermatitis requires general care and may involve topical corticosteroids. Grades 2 and 3 require topical dressings such as silver sulfadiazine dressings. When complicated by infection, topical and systemic antibiotics are used. However, the effectiveness is very limited, and patients with radiation dermatitis often face the dilemma of discontinuing treatment. New treatment methods are urgently needed for radiation dermatitis.

[0005] RIPK1 (Receptor Interacting Protein Kinase 1) is a key protein regulating programmed cell death. RIPK1 is involved in the pathogenesis of various human diseases, including autoimmune diseases, infectious and inflammatory diseases, and neurodegenerative diseases. Published RIPK1 inhibitors include, but are not limited to, the following compounds: Nec-1, Nec-1S, GSK772, GSK547, GSK-064, GSK3145095, GSK481, DNL104, DNL747, DNL758, DNL788, R-552, GNE684, VRN-04, RIPA-56, SIR1-365, GFH-312, ABBV-668, JRF-401, RI-962, AC-003, and ZL-24. Summary of the Invention

[0006] Through dedicated research, the inventors of this invention have discovered an effective strategy for treating radiation damage by targeting RIPK1. RIPK1 inhibitors have good therapeutic and preventive effects on radiation damage.

[0007] One aspect of the present invention provides the use of RIPK1 inhibitors in the preparation of medicaments for treating or preventing radiation damage.

[0008] In this invention, RIPK1 inhibitors that can be used to prepare drugs for treating or preventing radiation damage include compounds of formula A, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs, or metabolites thereof, wherein the compound of formula A has the structure shown below:

[0009] in:

[0010] Ring A is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0011] L is selected from: C 1- 10 alkylene groups, or chemical bonds;

[0012] When L is Or C 1- 10 In the case of alkylene, ring B is selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; the ring C and ring D are each independently selected from the group consisting of substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group may be aryl, substituted or unsubstituted, or absent, and may contain 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0013] When L is a chemical bond, ring E and ring B are directly linked through this chemical bond, and rings B, C, and D are each independently selected from either substituted or unsubstituted C atoms. 3-8Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0014] R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0015] R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0016] R3 is selected from H, oxo, substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2- 6-Alynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0017] R4 is selected from H, oxo, substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2- 6-Alynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0018] R5 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0019] R6 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0020] n, m, q, and t are each independent integers from 0, 1, 2, and 3;

[0021] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups comprise 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S;

[0022] This indicates that the part is connected to the other parts of the molecule via chemical bonds.

[0023] In this invention, RIPK1 inhibitors that can be used to prepare medicaments for treating or preventing radiation damage include the following compounds, or pharmaceutically acceptable salts thereof, or their enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs, or metabolites: DNL104, DNL747 R552, GSK-064, GSK3145095, GSK481, DNL104, DNL747, DNL758, DNL788, R-552, GNE684, V RN-04, RIPA-56, SIR1-365, GFH-312, ABBV-668, JRF-401, RI-962, AC-003 and ZL-24.

[0024] A second aspect of the invention provides a pharmaceutical composition for treating or preventing radiation damage, the pharmaceutical composition comprising: (a) an RIPK1 inhibitor as an active ingredient, and (b) a pharmaceutically acceptable carrier or excipient. The PIPK1 inhibitor may be selected from the following compounds or pharmaceutically acceptable salts thereof, or their enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs, or metabolites: compound of formula A, Nec-1, Nec-1S, GSK772, GSK547, GSK-064, GSK3145095, GSK481, DNL104, DNL747, DNL758, DNL788, R-552, GNE684, VRN-04, RIPA-56, SIR1-365, GFH-312, ABBV-668, JRF-401, RI-962, AC-003, and ZL-24. Attached Figure Description

[0025] Figure 1 shows an example photograph of skin damage at corresponding time points in the PBS control group mice after radiation irradiation in Example 3.1.

[0026] Figure 2 shows example photographs of skin damage at corresponding time points in mice treated with compound 1 in Example 3.1 after receiving radiation irradiation.

[0027] Figure 3 is a line graph showing the skin damage scores of mice in the compound 1 treatment group and the PBS control group in Example 3.1.

[0028] Figure 4 shows example photographs of skin damage at corresponding time points in the PBS control group mice after radiation irradiation in Example 3.2.

[0029] Figure 5 shows example photographs of skin damage at corresponding time points in mice treated with compound Nec-1 in Example 3.2 after receiving radiation irradiation.

[0030] Figure 6 is a line graph showing the skin damage scores of mice in the Nec-1 treatment group and the PBS control group in Example 3.2.

[0031] Figure 7 shows HE staining images of the skin of mice in the compound 1 treatment group and the PBS control group in Example 4.

[0032] Figure 8 shows fluorescence micrographs of the cell nuclear staining solutions in the control group, compound 1 treatment group, and Nec-1 treatment group in Example 5.

[0033] Figure 9 shows fluorescence micrographs of cells from the control group, compound 1 treatment group, and Nec-1 treatment group in Example 6.

[0034] Figure 10 shows the flow cytometry results of cells in the control group, compound 1 treatment group, and Nec-1 treatment group in Example 7. Detailed Implementation

[0035] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used herein are explained and defined in general terms below. Unless otherwise specified, all technical and scientific terms used herein have the common meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0036] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0037] In this document, the terms “contains,” “includes,” “containing,” and similar terms encompass the meanings of “basically composed of” and “composed of.” For example, when this document discloses “A contains B and C,” “A is basically composed of B and C” and “A is composed of B and C” should be considered as having been disclosed in this document.

[0038] In this document, all features defined by numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0039] Unless otherwise specified, percentages refer to mass percentages and proportions refer to mass ratios in this article.

[0040] In this article, the sum of the percentages of all components in the composition is 100%.

[0041] In this document, when describing embodiments or examples, it should be understood that it is not intended to limit the invention to those embodiments or examples. Rather, all alternatives, modifications, and equivalents of the methods and materials described herein are covered within the scope of this invention.

[0042] For the sake of brevity, not all possible combinations of the technical features in each implementation scheme or embodiment are described herein. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each implementation scheme or embodiment can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[0043] the term

[0044] Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein in their entirety through reference.

[0045] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “containing” are not limiting, and can be open-ended, semi-closed, and closed. In other words, the terms also include the meaning of “substantially constituted by” or “composed of.”

[0046] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0047] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0048] The chapter headings used in this article are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this invention, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0049] In this invention, certain chemical groups are preceded by simplified symbols to indicate the total number of carbon atoms present in that group. For example, C 1-6 Alkyl refers to an alkyl group having a total of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbol does not include carbons that may be present in substituents of the group.

[0050] In this invention, when a variable is mentioned as "selected from: ...", it means that the variable is selected from any of the options listed after the colon, or, where possible, it means that the variable is selected from one or more of the options listed after the colon.

[0051] All numerical ranges mentioned in this invention refer to the range including its two endpoints, all integers within the range, and subranges formed by these integers.

[0052] In addition to the foregoing, when used in the specification and claims of this invention, the following terms shall have the following meanings unless otherwise specifically indicated.

[0053] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0054] "Hydroxy group" refers to the -OH group.

[0055] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group (-OH) as defined below.

[0056] "Carbonyl" refers to the -C(=O)- group.

[0057] "Cyano" refers to -CN.

[0058] "Oxytochemical" means =O.

[0059] "Thio" refers to the =S group.

[0060] "Nitro" refers to -NO2.

[0061] "Amino" refers to -NH2.

[0062] "Substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, aryl, heteroaryl, heterocyclic, or heteroaryl groups as defined below, such as monoalkylamino, dialkylamino, alkylcarbonylamino, aralkylamino, heteroarylalkylamino, heterocyclic amino, heteroarylamino, and arylamino. In some embodiments herein, "substituted amino" is represented as -NR'R", where R' and R" are each independently selected from H, C1-C4 alkyl, C1-C4 alkyl-S(O)2-, and halo-C1-C4 alkyl (provided that at least one of R' and R" is not H).

[0063] "Carboxyl group" refers to -COOH.

[0064] "Amino" refers to -NH2.

[0065] In this invention, the term "Ci-Cj" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point between the endpoints, where j is greater than i. For example, C1-C6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. As another example, the term "C1-C12" represents 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

[0066] In this invention, as a group or part of other groups (e.g., in alkyl groups substituted with halogens such as fluorine, chlorine, bromine, or iodine), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which is attached by a single bond to the rest of the molecule. In some embodiments, the alkyl group has 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. For the purposes of this invention, the term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. Unless otherwise specifically specified in this specification, alkyl groups may optionally be substituted.

[0067] In this invention, as part of a group or other group, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing at least one double bond, which is connected to the rest of the molecule by a single bond. In some embodiments, the alkenyl group contains 2 to 20 atoms. In some embodiments, the alkenyl group contains 2 to 19 carbon atoms. In some embodiments, the alkenyl group contains 2 to 18 carbon atoms. In some embodiments, the alkenyl group contains 2 to 17 carbon atoms. In some embodiments, the alkenyl group contains 2 to 16 carbon atoms. In some embodiments, the alkenyl group contains 2 to 17 carbon atoms. In some embodiments, the alkenyl group contains 2 to 16 carbon atoms. In some embodiments, the alkenyl group contains 2 to 15 carbon atoms. In some embodiments, the alkenyl group contains 2 to 14 carbon atoms. In some embodiments, the alkenyl group contains 2 to 13 carbon atoms. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 10 carbon atoms. In some embodiments, the alkenyl group contains 2 to 9 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In some embodiments, the alkenyl group contains 2 to 7 carbon atoms. In some embodiments, the alkenyl group contains 2 to 6 carbon atoms. In some embodiments, the alkenyl group contains 2 to 5 carbon atoms. In some embodiments, the alkenyl group contains 2 to 4 carbon atoms. In some embodiments, the alkenyl group contains 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of the alkenyl group include, but are not limited to, vinyl, propenyl, allyl, butenyl, but-1-enyl, but-2-enyl, pentenyl, pent-1-enyl, pentadienyl, pent-1,4-dienyl, etc. Unless otherwise specifically specified in this specification, the alkenyl group may optionally be substituted.

[0068] In this invention, as part of a group or other group, the term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds (-C≡C-), which are connected to the rest of the molecule by single bonds. In some embodiments, the alkynyl group contains 2 to 20 carbon atoms. In some embodiments, the alkynyl group contains 2 to 19 carbon atoms. In some embodiments, the alkynyl group contains 2 to 18 carbon atoms. In some embodiments, the alkynyl group contains 2 to 17 carbon atoms. In some embodiments, the alkynyl group contains 2 to 16 carbon atoms. In some embodiments, the alkynyl group contains 2 to 17 carbon atoms. In some embodiments, the alkynyl group contains 2 to 16 carbon atoms. In some embodiments, the alkynyl group contains 2 to 15 carbon atoms. In some embodiments, the alkynyl group contains 2 to 14 carbon atoms. In some embodiments, the alkynyl group contains 2 to 13 carbon atoms. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms. In some embodiments, the alkynyl group contains 2 to 9 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In some embodiments, the alkynyl group contains 2 to 7 carbon atoms. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms. In some embodiments, the alkynyl group contains 2 to 5 carbon atoms. In some embodiments, the alkynyl group contains 2 to 4 carbon atoms. In some embodiments, the alkynyl group contains 2 to 3 carbon atoms. In some embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of the alkynyl group include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl. Unless otherwise specifically specified in this specification, the alkynyl group may optionally be substituted.

[0069] In this invention, as part of a group or other group, the term "alkylene" refers to a group that is identical to an alkyl group but has a divalent oxidation state. In some embodiments, the alkylene group has 1-20 carbon atoms. For example, C 1-10 Alkylene, C 1-6 Alkylene, C 1-4 Alkylenes. Examples of alkylenes include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), etc.

[0070] In this invention, as part of a group or other group, the term "alkoxy" refers to an "O-alkyl" group, wherein the alkyl group has the meaning described above. In some embodiments, the alkoxy group is C 1- 20 Alkoxy, C 1-19 Alkoxy, C 1-18 Alkoxy, C1-17 Alkoxy, C 1-16 Alkoxy, C 1-15 Alkoxy, C 1-14 Alkoxy, C 1-13 Alkoxy, C 1-12 Alkoxy, C 1-11 Alkyl group. In some embodiments, the alkoxy group is C60. 1-10 Alkyl group. In some embodiments, the alkoxy group is C60. 1-8 Alkyl group. In some embodiments, the alkoxy group is C60. 1-6 Alkyl group. In some embodiments, the alkoxy group is C60. 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 Alkoxy groups. Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, etc. Alkenyloxy group refers to "alkenyl-O-", where alkenyl has the meaning described above. Alkynyloxy group refers to "alkynyl-O-", where alkynyl has the meaning described above. "Substituted alkoxy group" refers to substituted alkyl-O-.

[0071] In this invention, as part of a group or other group, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group has the meaning described above and the number of halogens may be as many as the number of hydrogens that can be substituted on the alkyl group.

[0072] In this invention, as a group or part of other groups, the term "acyl" refers to the monovalent group remaining after removing the hydroxyl group from an aliphatic carboxylic acid, and can be represented by the general formula "GC(=O)-", where G represents H or an alkyl, alkenyl, or alkynyl group as described above. For example, specific examples of C1-C4 acyl groups include, but are not limited to, formyl, acetyl, propionyl, butyryl, etc.

[0073] In this invention, as part of a group or other group, the term "cycloalkyl group" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic alkyl group or moiety (a structural segment of an organic molecule) consisting only of carbon and hydrogen atoms and optionally having one or more carbon-carbon double bonds (-C=C-) or carbon-carbon triple bonds (-C≡C-), which may be connected to the rest of the molecule via any suitable carbon atom, and includes "cycloalkyl", "cycloalkenyl", and "cycloalkynyl". In some embodiments, the cycloalkyl group contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and cyclooctynyl. Unless otherwise specifically indicated in this specification, the carbon atom in the cycloalkyl group may optionally be oxidized (thus forming an oxo (=O) group), and the cycloalkyl group may optionally be substituted.

[0074] In this invention, as a group or part of other groups, the term "cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic alkyl group or portion consisting only of carbon and hydrogen atoms, which may be linked to the remainder of the molecule via any suitable carbon atom. In some embodiments, the cycloalkyl group may comprise a fused ring system, a bridged ring system, or a spirocyclic system. In some embodiments, the cycloalkyl group contains 3 to 15 carbon atoms, 3 to 14 carbon atoms, 3 to 13 carbon atoms, 3 to 12 carbon atoms, 3 to 11 carbon atoms, 3 to 10 carbon atoms, 3 to 9 carbon atoms, or 3 to 8 carbon atoms. In some embodiments, the cycloalkyl group has 3, 4, 5, 6, 7, or 8 carbon atoms. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkyl group may optionally be oxidized. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 5,6,7,8,9,10-hexahydro-benzene. Cyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

[0075] In this invention, as part of a group or other group, the term "cycloalkenyl" refers to a partially unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon group or portion consisting only of carbon and hydrogen atoms and having one or more carbon-carbon double bonds (-C=C-), which may be linked to the remainder of the molecule via any suitable carbon atom. In some embodiments, the cycloalkenyl contains 5 to 12 cyclic carbon atoms, 5 to 10 cyclic carbon atoms, 5 to 9 cyclic carbon atoms, 5 to 8 cyclic carbon atoms, 5 to 7 cyclic carbon atoms, or 5 to 6 cyclic carbon atoms. Non-limiting examples of cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkenyl may optionally be oxidized (thus forming an oxo (=O) group), and the cycloalkenyl may optionally be substituted.

[0076] In this invention, as a group or part of other groups, the term "cycloalkynyl" refers to a partially unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group or portion consisting only of carbon and hydrogen atoms and having one or more carbon-carbon triple bonds (-C=C-), which may be linked to the rest of the molecule via any suitable carbon atom. In some embodiments, the cycloalkynyl group contains 8 to 12 cyclic carbon atoms, 8 to 11 cyclic carbon atoms, 8 to 10 cyclic carbon atoms, or 8 to 9 cyclic carbon atoms. Non-limiting examples of cycloalkynyl groups include cyclooctynyl groups, etc. Unless otherwise specifically indicated in this specification, the carbon atoms in the cycloalkynyl group may optionally be oxidized (thus forming an oxo (=O) group), and the cycloalkynyl group may optionally be substituted.

[0077] In this invention, as part of a group or other group, the term "spirocyclic" or "spirocyclic" refers to a ring system consisting of a plurality of (e.g., two, three, or more) rings, wherein at least two rings are cyclic hydrocarbon groups bonded to each other by sharing a carbon atom. In some embodiments, the spirocyclic group contains 6 to 12, 6 to 11, 6 to 10, 6 to 9, 6 to 8, or 6 to 7 cyclic carbon atoms. Non-limiting examples of spirocyclic groups include, but are not limited to, spiro[5.5]undecyl, spiro-pentadienyl, spiro[3.6]decyl, etc. Unless otherwise specifically specified in this specification, the spirocyclic group may optionally be substituted.

[0078] In this invention, as part of a group or other group, the term "fused cyclic group" or "fused ring (also called "fused ring") refers to a ring system consisting of a plurality of (e.g., two, three or more) rings, wherein at least two rings are linked to each other by sharing two adjacent carbon atoms (i.e., the at least two rings share a covalent bond, thereby directly connecting the bridgehead atoms). In some embodiments, the fused cyclic group contains 5 to 12 ring carbon atoms, 5 to 11 ring carbon atoms, 5 to 10 ring carbon atoms, 5 to 9 ring carbon atoms, 5 to 8 ring carbon atoms, 5 to 7 ring carbon atoms, or 5 to 6 ring carbon atoms. Non-limiting examples of cyclofusing groups include, but are not limited to, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and 5,6,7,8,9,10-hexahydro-benzocyclooctenyl. Unless otherwise specifically specified in this specification, the cyclofusing group may optionally be substituted.

[0079] In this invention, as part of a group or other group, the term "bridged ring" or "bridged ring" refers to a ring system consisting of a plurality of (e.g., two, three, or more) rings, wherein at least two rings are linked to each other by sharing three or more carbon atoms (the at least two rings are separated by two bridgehead atoms by a bridge containing at least one atom). In some embodiments, the bridged ring contains 8 to 12 ring carbon atoms, 8 to 11 ring carbon atoms, 8 to 10 ring carbon atoms, or 8 to 9 ring carbon atoms. Non-limiting examples of bridged rings include, but are not limited to, bicyclo[1.1.1]pentenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]octenyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.3]undecyl, adamantyl, etc. Unless otherwise specifically specified in this specification, the bridge ring base may be optionally replaced.

[0080] In this invention, as a group or part of other groups, the term "heterocyclic group" or "heterocycle" refers to a stable saturated or partially unsaturated ternary to 20-membered non-aromatic cyclic group or part consisting of 2 to 14 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur (e.g., 1, 2, 3, 4, 5, or 6 heteroatoms). In some embodiments, the heterocyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20-membered heterocyclic group, such as 3 to 20-membered heterocyclic groups, 3 to 19-membered heterocyclic groups, 3 to 18-membered heterocyclic groups, 3 to 17-membered heterocyclic groups, 3 to 16-membered heterocyclic groups, 3 to 15-membered heterocyclic groups, 4 to 12-membered heterocyclic groups, 4 to 10-membered heterocyclic groups, 4 to 9-membered heterocyclic groups, 4 to 8-membered heterocyclic groups, 4 to 7-membered heterocyclic groups, 4 to 6-membered heterocyclic groups, and 4 to 5-membered heterocyclic groups. Unless otherwise specifically indicated in this specification, a heterocyclic base can be a monocyclic, bicyclic, tricyclic, or more ring system, which may include fused / fused ring systems (i.e., fused heterocyclic bases, such as 4-9 membered fused heterocyclic bases), bridged ring systems (i.e., bridged heterocyclic bases, such as 6-12 membered bridged heterocyclic bases), or spirocyclic systems (i.e., spirocyclic bases, such as 6-12 membered spirocyclic bases). A fused heterocyclic base refers to a ring system consisting of multiple (e.g., two, three, or more) rings, wherein at least two rings are bonded to each other by sharing two adjacent atoms (i.e., the at least two rings share a covalent bond, thereby directly connecting the bridgehead atoms). In some embodiments, the heterocyclic base is a bicyclic fused heterocyclic base. A bridged heterocyclic base refers to a ring system consisting of multiple (e.g., two, three, or more) rings, wherein at least two rings are bonded to each other by sharing three or more atoms (the at least two rings are separated by a bridge containing at least one atom between the two bridgehead atoms). A spirocyclic heterocycle is a ring system consisting of multiple (e.g., two, three, or more) rings, wherein at least two rings are heterocyclic groups bonded to each other by sharing a carbon atom. The nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In some cases, the heterocyclic group may be carbon-linked, nitrogen-linked, or sulfur-linked. In some embodiments, the heterocyclic group is carbon-linked. In some embodiments, the heterocyclic group is nitrogen-linked. In some embodiments, the heterocyclic group is sulfur-linked. Unless otherwise specifically specified in this specification, the heterocyclic group may optionally be substituted. Unless otherwise specifically specified in this specification, the heterocyclic group may optionally be substituted.

[0081] Heterocyclic groups also include groups in which the heterocyclic group is fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) cyclic hydrocarbon group, aryl, heterocyclic group, or heteroaryl group. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below. Examples of fused heterocyclic groups include, but are not limited to, phenyl-fused heterocyclic groups or pyridyl-fused heterocyclic groups, as well as quinolinyl, isoquinolinyl, quinoxalinyl, quinazinyl, quinazolinyl, azidoindolazinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolazinyl, indazole, purine, benzofuranyl, isobenzofuranyl, benzoimidazolyl, benzothiophene, benzothiazolyl, carbazolyl, phenazinyl, phenthiazolyl, phenanthidyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazo[4,3-a]pyridinyl, and [1,2,3]triazo[4,3-a]pyridinyl fused heterocyclic groups, etc.

[0082] In some embodiments, the heterocyclic group is a stable 3- to 12-membered, 4- to 11-membered, 5- to 12-membered, 6- to 10-membered, 4- to 10-membered, 4- to 9-membered, or 3- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group is a stable 3- to 10-membered (e.g., 3- to 8-membered, 5- to 10-membered, or 4- to 9-membered) non-aromatic monocyclic, bicyclic, tricyclic, or more cyclic group (including fused, bridged, or spirocyclic groups) containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2-oxa-6-aza-spiro[3.4]octane-7-yl, 8-oxa-2-aza-spiro[4.5]decane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, azacyclobutane, oxacyclobutane, thiohexa ... Heterocyclic pentyl, pyranyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, isothiazolinyl, isoxazolinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolyl, phthalimide, dioxothiomorpholinyl, dioxothioheterocyclic pentyl, dioxothiocyclic butyl, thiohexyl, dioxothiocyclic cyclohexyl, thiomorpholinyl, 1,4-oxothiohexyl, etc.

[0083] In this invention, as a group or part of another group, the term "aryl" or "aromatic ring" refers to a conjugated hydrocarbon ring system group or part having 6 to 18 carbon atoms (e.g., 6 to 14 carbon atoms or 6 to 10 carbon atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms). For the purposes of this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with cyclic hydrocarbon groups or heterocyclic groups as defined above. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc. Unless otherwise specifically specified in this specification, the aryl group may optionally be substituted.

[0084] In this invention, as a group or part of another group, the term "heteroaryl" or "heteroary ring" refers to a conjugated cyclic group or part thereof having carbon atoms (e.g., 1 to 15 carbon atoms, 1 to 14 carbon atoms, 1 to 13 carbon atoms, 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and heteroatoms selected from nitrogen, oxygen and sulfur (e.g., 1 to 6 heteroatoms, e.g., 1, 2, 3, 4, 5 or 6 heteroatoms). In some embodiments, the heteroaryl group may contain 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cyclic atoms, such as 5 to 20 cyclic atoms, 5 to 19 cyclic atoms, 5 to 18 cyclic atoms, 5 to 17 cyclic atoms, 5 to 16 cyclic atoms, 5 to 15 cyclic atoms, 5 to 14 cyclic atoms, 5 to 13 cyclic atoms, 5 to 12 cyclic atoms, 5 to 10 cyclic carbon atoms, 5 to 9 cyclic atoms, 5 to 8 cyclic atoms, 5 to 7 cyclic atoms, or 5 to 6 cyclic atoms. Unless otherwise specifically indicated in this specification, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more cyclic system, and may be fused with cyclic hydrocarbon groups, aryl groups, or heterocyclic groups as defined above. Examples of heteroaryl-aryl fusion include, but are not limited to, benzopyridyl, benzopyrazolyl, benzimidazolyl, benzopyrroleyl, etc. The nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of this invention, in some embodiments, the heteroaryl group is a stable 5- to 12-membered aromatic group comprising 1 to 5 (e.g., 1, 2, 3, 4, or 5) heteroatoms selected from nitrogen, oxygen, and sulfur; in some embodiments, it is a stable 5- to 10-membered aromatic group comprising 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered aromatic group comprising 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically specified in this specification, the heteroaryl group may optionally be substituted.

[0085] Non-limiting examples of heteroaryl groups include, but are not limited to, thiopheneyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolithyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridyl, carbazolyl, carbazolyl, phenanthridine, phenanthroxolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiapheneyl, oxadiazolyl, and oxadiazolyl. Azolyl, cyclolinyl, quinazolinyl, indene, o-diazaphenyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-c]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, etc.

[0086] In this invention, as a group or part of other groups, the term "heterocyclic spirocyclic group" or "heterocyclic spirocyclic ring" refers to a fully saturated 5- to 20-membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered) polycyclic ring that shares a single carbon atom (called a spiro atom) among the heterocyclic groups, and one or more ring atoms in the polycyclic ring are selected from heteroatoms of sulfur, silicon, phosphorus, oxygen, and / or nitrogen (e.g., 1 or 2 heteroatoms), while the remaining ring atoms are carbon atoms. Spirocyclic rings are classified into monospirocyclic, bispirocyclic, or multispirocyclic rings based on the number of shared spiro atoms between the rings. In some embodiments, the heterocyclic spirocyclic group is a monospirocyclic or bispirocyclic ring. In some embodiments, the heterocyclic spiroheterocyclic base is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered single-spiroheterocyclic ring. Non-limiting examples of heterocycles include...

[0087] In this invention, all cyclic groups can exist as substituents on the parent nucleus, or they can exist as part of a chain-like (including straight and branched) structure, the parent nucleus, or a part of the parent nucleus.

[0088] In this invention, the term "heteroarylalkyl" or "heteroarylalkyl" refers to an alkyl group defined above that has been replaced by a heteroaryl group as defined above.

[0089] In this invention, "optionally" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups. The substituents used in the claims and description of this invention are selected from alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, hydroxyl, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclic groups.

[0090] In this invention, the term "substitution," regardless of whether the term "optionally" (i.e., equivalent to substituted or unsubstituted) precedes it, refers to the substitution of one or more hydrogen atoms of a specified group or portion by a "suitable substituent." The number of substituents herein can be one or more, i.e., 1, 2, 3, 4, 5, or 6 or more, depending on the substituted group and the nature of the substituents. For example, when the substituent of an ethyl group is a halogen, the group can be substituted by 1, 2, 3, 4, or 5 substituents, such as trifluoroethyl, pentafluoroethyl, etc., depending on the structure of the substituted group. In some embodiments, the number of substituents is 1, 2, or 3. In some embodiments, the number of substituents is 1 or 2. In some embodiments, the number of substituents is 1. It will be understood that "substitution" or "replaced by" includes the implicit condition that such substitution is based on the permissible valence of the substituted atom and that the substitution produces a stable or chemically viable compound, such as a compound that does not spontaneously transform, for example, through rearrangement, cyclization, elimination, etc. Unless otherwise stated, an "optionally substituted" group may have suitable substituents at each substituted position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the specified group, the substituents may be the same or different at each position. Those skilled in the art will understand that the substituent itself may be substituted, if appropriate. Unless specifically indicated as "unsubstituted," references to the chemical term herein should be understood to include substituted variants. For example, references to an "aryl" group or part thereof implicitly include both unsubstituted aryl groups and substituted variants.

[0091] For the purposes of this invention, the term "suitable substituents" as used above should be understood to include, but is not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cyclic hydrocarbon (e.g., cycloalkyl, cycloalkenyl, etc.), heterocyclic groups, etc., as described herein. These substituents, including alkyl, alkenyl, alkynyl, alkyl in haloalkyl, alkenyl in haloalkenyl, alkynyl in haloalkynyl, alkoxy, alkyl in monoalkylamino, alkyl in dialkylamino, aryl, heteroaryl, cyclic hydrocarbon, and heterocyclic groups, are themselves optionally substituted, for example, they may also be optionally substituted by one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cyclic hydrocarbon, and heterocyclic groups.

[0092] In some embodiments, the “suitable substituent” is selected from hydroxyl, halogen, optionally halogen-substituted C1-C4 alkoxy, C1-C4 alkoxy carbonyl, cyano, optionally halogen-substituted -S(O)2-C1-C4 alkyl, optionally halogen-substituted C1-C4 alkyl, -NR'R", -S(O)2-NR'R", -S(O)2-NH2, -C(O)-C1-C4 alkyl, -NR'-C(O)-C1-C4 alkyl, C3-C8 cycloalkyloxy, and optionally 1-substituted C1-C4 alkyl. Two or three substituents selected from C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, halogen, cyano, C1-C4 alkyl-S(O)2-, hydroxyl, carboxyl, -NR'R”, 6-14 aryl, 5-10 heteroaryl, C3-C8 cyclic hydrocarbon, and 4-9 heterocyclic groups, wherein R' and R” are each independently selected from H and C1-C4 alkyl. In some embodiments, the “suitable substituent” is hydroxyl, amino, halogen, substituted or unsubstituted alkyl, -NR'R”, and substituted or unsubstituted alkoxy, wherein R' and R” are each independently selected from H, C1-C4 alkyl, C1-C4 alkyl-S(O)2-, and halo-C1-C4 alkyl. In some embodiments, the "suitable substituent" is selected from deuterium, hydroxyl, cyano, C1-C4 alkyl, halogen, and C1-C4 alkoxy. In some embodiments, the "suitable substituent" is deuterium, hydroxyl, methyl, F, and methoxy. In some embodiments, the "suitable substituent" is selected from hydroxyl, halogen, C1-C4 alkoxy, cyano, and -S(O)2-C1-C4 alkyl. In some embodiments, the "suitable substituent" is selected from halogen, hydroxyl, cyano, -S(O)2-C1-C4 alkyl, C1-C4 alkyl, and C1-C4 alkoxy. In some embodiments, the "suitable substituent" is selected from hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, and cyano. In some embodiments, the "suitable substituent" is F, hydroxyl, and cyano.

[0093] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0094] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, amidine, guanidinyl, mercapto, and carboxyl groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidinyl protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R. X (where R) X It can be alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl esters, aryl esters, or aralkyl esters.

[0095] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds, but with different three-dimensional structures. This invention will cover various stereoisomers and mixtures thereof.

[0096] When the compounds of the present invention contain alkene double bonds, unless otherwise stated, the compounds of the present invention are intended to contain E- and Z-geometric isomers.

[0097] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0098] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers, and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention aims to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention may select racemic, diastereomer, or enantiomer as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0099] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0100] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key It represents the absolute configuration of the center of a solid.

[0101] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). See, for instance, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128, the contents of which are incorporated herein by reference in their entirety.

[0102] The compounds of the present invention also include all suitable isotopic substitutes (or isotopic variants) of their pharmaceutically acceptable salts. An isotopic variant of a compound of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that commonly found in nature. Isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts include, but are not limited to, isotopes of H, C, N, and O, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 35 S, 18 F, 36 Cl and 125 I. Isotopic variants of the compounds described in this invention or of their pharmaceutically acceptable salts can be prepared using conventional techniques and appropriate isotopic variants with suitable reagents.

[0103] Unless otherwise specified, the wavy lines on each structural formula or group generally indicate the position where the structural formula or group is connected to other parts of the compound.

[0104] As used herein, a "solvent" refers to a solvent containing stoichiometric or non-stoichiometric amounts, which is often formed during crystallization. A solvate comprises an aggregate of one or more molecules of the compound of the present invention with one or more solvent molecules. When the solvent is water, a hydrate is formed; or, the solvent may be an organic solvent (e.g., when the solvent is an alcohol, an alcohol is formed). Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and as corresponding solvated forms. The compounds of the present invention can be true solvates, while in other cases, the compounds of the present invention may simply be indeterminate water or a mixture of water and some indeterminate solvent.

[0105] As used herein, the term "polymorph" refers to different crystalline arrangements (all having the same elemental composition) comprising a compound (or its salts, solvates, or other derivatives such as prodrugs or metabolites). Polymorphs typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical or electrical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, can cause a single crystal form to dominate.

[0106] In this invention, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0107] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0108] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0109] As used herein, the term "prodrug" refers to those compounds that, after administration, will be metabolized (i.e., converted in the body) into the pharmacologically active compounds of the present invention. When the compounds of the present invention are difficult to absorb from the gastrointestinal tract on their own, their bioavailability can be improved by formulating them as prodrugs. Examples of prodrugs of the compounds of the present invention may include simple esters of compounds containing a carboxyl group (e.g., esters obtained by condensation with a C1-C4 alcohol according to methods known in the art); esters of compounds containing a hydroxyl group (e.g., esters obtained by condensation with a C1-C4 monocarboxylic acid, a C3-C6 dicarboxylic acid, or an anhydride thereof, such as succinic anhydride or fumaric anhydride, according to methods known in the art); imines of compounds containing an amino group (e.g., imines obtained by condensation with a C1-C4 aldehyde or ketone according to methods known in the art); carbamates of compounds containing an amino group, such as those esters described by Leu et al. (J. Med. Chem., 42: 3623-3628 (1999)) and Greenwald et al. (J. Med. Chem., 42: 3657-3667 (1999)); and aldol acetals or ketal acetals of compounds containing a hydroxyl group (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0110] In this invention, a "pharmaceutical composition" refers to a formulation of the compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof, and a medium generally accepted in the art for delivering a biologically (pharmacologically) active compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and thus exerting its biological (pharmacological) activity. Generally, the pharmaceutical compositions of the present invention contain 0.1% to 99.5% by weight of the pharmaceutically active ingredient (i.e., the compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope-substituted product, polymorph, prodrug, or metabolite thereof). In some embodiments, the pharmaceutical composition of the present invention contains 0.5% to 90% by weight, for example 1% by weight, 1.5% by weight, 2% by weight, 5% by weight, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, or 50% by weight of the active pharmaceutical ingredient.

[0111] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0112] In this invention, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or livestock use.

[0113] As used herein, the terms “preventive,” “prevention,” and “prevent” include the prevention of the occurrence of an individual disease or symptom. “Preventive,” “prevention,” and “prevent” mean preventing the occurrence of the disease or symptom in a mammal (preferably a human), particularly when the mammal is susceptible to the symptom but has not yet been diagnosed with the symptom, or preventing the recurrence of a cured disease or symptom in a mammal (preferably a human).

[0114] As used herein, the term "treatment" encompasses the treatment of the disease or symptom of interest in mammals (preferably humans), including one or more of the following:

[0115] (i) To suppress a disease or symptom, that is, to curb its development;

[0116] (ii) To alleviate the disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0117] (iii) To alleviate the symptoms caused by the disease or condition, that is, to relieve pain without addressing the underlying disease or condition.

[0118] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is the amount of a composition containing a compound of the invention described herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0119] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or pharmaceutical composition to the desired site for biological action. Methods of administration known in the art are applicable to this invention. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intrapulmonary, intranasal; intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques applicable to the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds discussed herein, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope-substituted products, polymorphs, prodrugs, or metabolites, or pharmaceutical compositions thereof, are administered orally.

[0120] The terms “drug combination,” “drug composition,” “combination therapy,” “drug co-administration,” “combined drug therapy,” “administration of other treatments,” and “administration of other therapeutic agents” as used herein refer to pharmaceutical treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one other active ingredient in a single entity or dosage form. The term “non-fixed combination” refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one other active ingredient in a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0121] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (where R is alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0122] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, TW & PGMUTS, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymeric resins.

[0123] RIPK1 inhibitors

[0124] In some embodiments, the RIPK1 inhibitor of the present invention can be a RIPK1 inhibitor known in the art, including but not limited to Nec-1. Nec-1S GSK772 GSK547 GSK-064, GSK3145095 GSK481 DNL104, DNL747, DNL758, DNL788, R-552, GNE684, VRN-04, RIPA-56 SIR1-365 One or more of GFH-312, ABBV-668, JRF-401, RI-962, AC-003, and ZL-24.

[0125] In some embodiments, the RIPK1 inhibitor of the present invention may be a compound of formula A having the structure shown below:

[0126] in:

[0127] Ring A is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0128] L is selected from: C 1- 10 alkylene groups, or chemical bonds;

[0129] When L is Or C 1- 10 In the case of alkylene, ring B is selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; the ring C and ring D are each independently selected from the group consisting of substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group may be aryl, substituted or unsubstituted, or absent, and may contain 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0130] When L is a chemical bond, ring E and ring B are directly linked through this chemical bond, and rings B, C, and D are each independently selected from either substituted or unsubstituted C atoms. 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0131] R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0132] R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0133] R3 is selected from H, oxo, substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2- 6-Alynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0134] R4 is selected from H, oxo, substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2- 6-Alynyl, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0135] R5 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0136] R6 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0137] n, m, q, and t are each independent integers from 0, 1, 2, and 3;

[0138] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups comprise 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S;

[0139] This indicates that the part is connected to the other parts of the molecule via chemical bonds.

[0140] In some embodiments, ring A is a substituted or unsubstituted aryl group. Ring A is a 6-14-membered aryl, 6-12-membered aryl, 6-10-membered aryl, or 6-8-membered aryl. In some embodiments, ring A is phenyl or naphthyl. In some embodiments, ring A is phenyl.

[0141] In some embodiments, ring A is a substituted or unsubstituted heteroaryl group. In some embodiments, ring A is selected from 5-14-membered heteroaryl, 5-12-membered heteroaryl, 5-10-membered heteroaryl, 5-8-membered heteroaryl, and 5-6-membered heteroaryl. In some embodiments, ring A is selected from thiophene, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrroloyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, ring A is pyridyl.

[0142] In some embodiments, ring B is a substituted or unsubstituted heterocyclic group. Ring B is selected from 5-14 membered heterocyclic groups, 5-12 membered heterocyclic groups, 5-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. In some embodiments, ring B is selected from pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. In some embodiments, ring B is piperidinyl.

[0143] In some embodiments, ring B is a substituted or unsubstituted heteroaryl group. In some embodiments, ring B is a 5-14-membered heteroaryl, 5-12-membered heteroaryl, 5-10-membered heteroaryl, 5-8-membered heteroaryl, or 5-6-membered heteroaryl. In some embodiments, ring B is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, azinyl, furanyl, pyrroleyl, triazolyl, triazinyl, and pyridoneyl. In some embodiments, ring B is pyrazolyl or pyridinyl.

[0144] In some embodiments, ring C is a substituted or unsubstituted heteroaryl group. In some embodiments, ring C is a 5-14-membered heteroaryl, 5-12-membered heteroaryl, 5-10-membered heteroaryl, 5-8-membered heteroaryl, or 5-6-membered heteroaryl. In some embodiments, ring C is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, azinyl, furanyl, pyrroleyl, triazolyl, triazinyl, and pyridoneyl. In some embodiments, ring C is pyrazolyl.

[0145] In some embodiments, ring C is a substituted or unsubstituted heterocyclic group. Ring C is selected from 5-14 membered heterocyclic groups, 5-12 membered heterocyclic groups, 5-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. In some embodiments, ring C is selected from pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. In some embodiments, ring C is pyrrolidinyl.

[0146] In some embodiments, ring D is a substituted or unsubstituted heterocyclic group. Ring D is selected from 5-14 membered heterocyclic groups, 5-12 membered heterocyclic groups, 5-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. In some embodiments, ring D is selected from pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, or oxazacyclohexane. In some embodiments, ring D is pyrrolidinyl or 1,3-oxazacyclohexane. In some embodiments, ring D is pyrrolidinyl. In some embodiments, ring D is 1,3-oxazacyclohexane or morpholinyl. In some embodiments, ring D is 1,3-oxazacyclohexane.

[0147] In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 The heterocyclic group comprises alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C. 2-5 Alkyne group, substituted or unsubstituted C 1-3 The heterocyclic group comprises an alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic group, or a spirocyclic 4-6 membered heterocyclic group, wherein the heterocyclic group contains one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the C 2-5 alkynyl group, C 1-3 Alkoxy groups and 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups are selected from C 1- 6-alkyl, 3-5-membered cycloalkyl, 4-6-membered heterocyclic, hydroxyl C 2-5 Alkyl substituents. In some embodiments, the C... 2-5 alkynyl group, C 1-3 The alkoxy group and the 5-6 membered heterocyclic spiro-4-6 membered heterocyclic group are substituted with substituents selected from cyclopropyl, pyranyl, and hydroxyisopropyl.

[0148] In some implementations, R1 is selected from the following group:

[0149] H, Methoxy, cyano, chlorine, and bromine.

[0150] In some embodiments, R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10Aryl, substituted or unsubstituted 5-14 membered heteroaryl groups, said heteroaryl group comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P, wherein in some embodiments, the C 1-6 Alkoxy and C 1-6 Alkyl groups are each independently oxidized (=O) and C-substituted. 6-10 Aryl, -OH, cyano, or -NO2 substitution. In some embodiments, R2 is selected from H, oxo (=O), or optionally C. 6-10 aryl-substituted C 1-6 An alkoxy, halogen, substituted or unsubstituted 5-10-membered heteroaryl group, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In some embodiments, R2 is H, oxo, or C-substituted. 6-10 aryl-substituted C 1-4 Alkoxy, benzopyrazole.

[0151] In some implementations, R3 is selected from: H, substituted or unsubstituted C. 6-10 aryl, substituted or unsubstituted C 1-6 Alkoxy, halogen, cyano, -NO2, -OH, in some embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with an oxo (=O), -OH, cyano, or -NO2 group. In some embodiments, R3 is H or C. 6-10 Aryl.

[0152] In some implementations, R4 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, and in some embodiments, the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently bonded by one, two, or three atoms selected from H, halogen, -OH, C. 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-8 Alkoxy substitution. In some embodiments, t is 1 or 2.

[0153] In some embodiments, R4 is selected from halogens, difluoropropyl, phenyl, benzyl, difluorophenyl, tolyl, methoxyphenyl, and pyridyl. In some embodiments, R4 is selected from: And halogens.

[0154] In some implementations, R4 is selected from:

[0155] And F.

[0156] In some implementations, R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl group. In some embodiments, R5 is methyl.

[0157] In some implementations, R6 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R6 is H.

[0158] In some embodiments, the compound of formula A of the present invention has the structure shown in formula I:

[0159] In Formula I:

[0160] Rings A, B, C, and D are each independently selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0161] R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0162] R2, R3, R4, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0163] n, m, q, and t are each independent integers of 0, 1, 2, or 3;

[0164] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C)1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S.

[0165] In some implementations, ring A is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0166] In some implementations, ring B is selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic groups, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0167] In some implementations, ring C is selected from: substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0168] In some implementations, ring D is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic groups, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0169] In some implementations, R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 The cycloalkyl group, or heterocyclic or heteroaryl group, comprises one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C atoms. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic groups, and substituted or unsubstituted C-shaped groups. 3-8 cycloalkylspiroC 3-8 The heterocyclic group comprises one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C atoms. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0170] In some embodiments, R2, R3, R4, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2, R3, R4, R5, and R6 are each independently selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2, R3, R4, R5, and R6 are each independently selected from H, oxo (=O), halogen, substituted, or unsubstituted C. 1- 6-alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0171] In some embodiments, ring A is a substituted or unsubstituted aryl group. Ring A is a 6-14-membered aryl, 6-12-membered aryl, 6-10-membered aryl, or 6-8-membered aryl. In some embodiments, ring A is phenyl or naphthyl. In some embodiments, ring A is phenyl.

[0172] In some embodiments, ring A is a substituted or unsubstituted heteroaryl group. In some embodiments, ring A is selected from 5-14-membered heteroaryl, 5-12-membered heteroaryl, 5-10-membered heteroaryl, 5-8-membered heteroaryl, and 5-6-membered heteroaryl. In some embodiments, ring A is selected from thiophene, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyrroloyl, triazolyl, triazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, ring A is pyridyl.

[0173] In some embodiments, ring B is a substituted or unsubstituted heterocyclic group. Ring B is selected from 5-14 membered heterocyclic groups, 5-12 membered heterocyclic groups, 5-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. In some embodiments, ring B is selected from pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. In some embodiments, ring B is piperidinyl.

[0174] In some embodiments, ring C is a substituted or unsubstituted heteroaryl group. In some embodiments, ring C is a 5-14-membered heteroaryl, 5-12-membered heteroaryl, 5-10-membered heteroaryl, 5-8-membered heteroaryl, or 5-6-membered heteroaryl. In some embodiments, ring C is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, azinyl, furanyl, pyrroleyl, triazolyl, triazinyl, and pyridoneyl. In some embodiments, ring C is pyrazolyl.

[0175] In some embodiments, ring D is a substituted or unsubstituted heterocyclic group. Ring D is selected from 5-14 membered heterocyclic groups, 5-12 membered heterocyclic groups, 5-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. In some embodiments, ring D is selected from pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, or oxazacyclohexane. In some embodiments, ring D is pyrrolidinyl or 1,3-oxazacyclohexane. In some embodiments, ring D is pyrrolidinyl. In some embodiments, ring D is 1,3-oxazacyclohexane or morpholinyl. In some embodiments, ring D is 1,3-oxazacyclohexane.

[0176] In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 The heterocyclic group comprises alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C. 2-5 Alkyne group, substituted or unsubstituted C 1-3 The heterocyclic group comprises an alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic group, or a spirocyclic 4-6 membered heterocyclic group, wherein the heterocyclic group contains one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the C 2-5 alkynyl group, C 1-3 Alkoxy groups and 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups are selected from C 1- 6-alkyl, 3-5-membered cycloalkyl, 4-6-membered heterocyclic, hydroxyl C 2-5 Alkyl substituents. In some embodiments, the C... 2-5 alkynyl group, C 1-3 The alkoxy group and the 5-6 membered heterocyclic spiro-4-6 membered heterocyclic group are substituted with substituents selected from cyclopropyl, pyranyl, and hydroxyisopropyl.

[0177] In some implementations, R1 is selected from the following group:

[0178] H, Methoxy, cyano, chlorine, and bromine.

[0179] In some embodiments, R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, in some embodiments, the C 1-6 Alkoxy and C1-6 Each alkyl group is independently substituted with an oxo (=O), -OH, cyano, or -NO2. In some embodiments, R2 is oxo.

[0180] In some implementations, R3 is selected from: H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, cyano, -NO2, -OH, in some embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with an oxo group (=O), -OH, cyano group, or -NO2. In some embodiments, R3 is H.

[0181] In some implementations, R4 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, and in some embodiments, the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently bonded by one, two, or three atoms selected from H, halogen, -OH, C. 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-8 Alkyl groups are substituted. In some embodiments, t is 1 or 2.

[0182] In some embodiments, R4 is selected from halogens, tolyl, difluoropropyl, phenyl, benzyl, difluorophenyl, methoxyphenyl, and pyridyl. In some embodiments, R4 is selected from: And halogens.

[0183] In some implementations, R4 is selected from:

[0184] And F.

[0185] In some implementations, R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl group. In some embodiments, R5 is methyl.

[0186] In some implementations, R6 is selected from H, substituted or unsubstituted C. 1-6Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R6 is H.

[0187] In some implementations, n, m, q, and t are each independently any integer from 0, 1, or 2.

[0188] In some embodiments, the compound of formula A of the present invention has the structure shown in formula II:

[0189] In Formula II:

[0190] Rings A, B, and C are each independently selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0191] L is selected from: and C 1- 10 Alkylene;

[0192] R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0193] R2, R3, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0194] n, m, and q are each an independent integer from 0, 1, 2, or 3;

[0195] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0196] In some implementations, ring A is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0197] In some implementations, ring B is selected from: substituted or unsubstituted C. 6-10 aryl, substituted or unsubstituted 5-10-membered heteroaryl, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0198] In some implementations, ring C is selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclic groups, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0199] In some implementation schemes, L is selected from: and C 1-10 Alkylene. In some embodiments, L is selected from: In some implementations, L is

[0200] In some implementations, R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C. 1-6Alkyl, substituted or unsubstituted C 1-6 Alkyl group, cyano group, -NO2, -OH.

[0201] In some embodiments, R2, R3, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2- 6-Alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R3, R4, R5, and R6 are each independently selected from H, oxo (=O), substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R3, R4, R5, and R6 are each independently selected from H, oxo (=O), substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl.

[0202] In some implementations, n, m, and q are each independently any integer from 0, 1, or 2. In some implementations, n, q, and t are each independently any integer from 0 or 1.

[0203] In some embodiments, the compound of formula A of the present invention has the structure shown in formula III:

[0204] In Formula III:

[0205] Ring A and ring B are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0206] L is selected from: and C 1- 10 Alkylene;

[0207] R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0208] R2, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0209] n and m are each an independent integer from 0, 1, 2 or 3;

[0210] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0211] In some implementations, ring A and ring B are each independently selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0212] In some implementation schemes, L is selected from: and C 1-10 Alkylene. In some embodiments, L is selected from: In some implementations, L is selected from:

[0213] In some implementations, R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 The heterocyclic group comprises cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted 3-8 membered heterocyclic spiro 3-8 membered heterocyclic group, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0214] In some implementations, R2, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2, R5, and R6 are each independently selected from H, oxo (=O), substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2, R5, and R6 are each independently selected from H, oxo (=O), substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 5-10-membered heteroaryl groups, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0215] In some implementations, n and m are each independently any integer from 0, 1, or 2.

[0216] In some embodiments, the compound of formula A of the present invention has the structure shown in formula I-1:

[0217] In Equation I-1:

[0218] A1, A2, A3, and A4 are each independently selected from: CR1 or N;

[0219] B1, B2, B3, and B4 are each independently selected from: C(R2) m Or N(R2) m ;

[0220] C1, C2, and C3 are each independently selected from: C(R3) q Or N(R3) q ;

[0221] Rings B, C, and D are each independently selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0222] R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0223] R2, R3, R4, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0224] m, q, and t are each independent integers of 0, 1, 2, or 3;

[0225] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0226] In some implementations, ring B is selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, said heterocyclic group comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. In some embodiments, ring B is a substituted or unsubstituted 3-8 membered heterocyclic group, said heterocyclic group comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. In some embodiments, ring B is a substituted or unsubstituted 3-7 membered heterocyclic group, a substituted or unsubstituted 4-7 membered heterocyclic group, a substituted or unsubstituted 4-6 membered heterocyclic group, or a substituted or unsubstituted 5 or 6 membered heterocyclic group. In some embodiments, ring B is a substituted or unsubstituted 5-7 membered heterocyclic group. In some embodiments, ring B contains 1 or 2 N atoms.

[0227] In some embodiments, ring B is selected from pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. In some embodiments, ring B is piperidinyl.

[0228] In some implementations, ring C is selected from: substituted or unsubstituted C. 6-10The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, the ring C is a substituted or unsubstituted 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl, or 5-6 membered heteroaryl. In some embodiments, the ring C is a substituted or unsubstituted 5-10 membered heteroaryl group, and in some embodiments, the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, the ring C is a substituted or unsubstituted 5-7 membered heteroaryl group. In some embodiments, the ring C contains 1, 2, or 3 N atoms, and in some embodiments, the ring C contains 1 or 2 N atoms. In some embodiments, ring C is selected from thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, azinyl, furanyl, pyrroleyl, triazolyl, triazinyl, and pyridoneyl. In some embodiments, ring C is pyrazolyl.

[0229] In some implementations, ring D is selected from: substituted or unsubstituted C 3-8 The ring D is a cycloalkyl, substituted, or unsubstituted 3-8 membered heterocyclic group, wherein the heterocyclic group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, ring D is a substituted or unsubstituted 3-8 membered heterocyclic group, wherein the heterocyclic group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, ring D is selected from: 5-10 membered heterocyclic groups, 5-9 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. In some embodiments, ring D is a substituted or unsubstituted 5-7 membered heterocyclic group. In some embodiments, ring D contains 1 or 2 N atoms. In some embodiments, ring D is selected from pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, or oxazacyclohexane. In some embodiments, ring D is pyrrolidinyl or 1,3-oxazacyclohexane. In some embodiments, ring D is pyrrolidinyl. In some embodiments, ring D is 1,3-oxazacyclohexane or morpholinyl. In some embodiments, ring D is 1,3-oxazacyclohexane.

[0230] In some implementations, the structure consisting of rings B, C, and D is selected from the group consisting of:

[0231] In some implementations, the structure consisting of rings B, C, and D is selected from the group consisting of:

[0232] In some implementations, the structure consisting of rings B, C, and D is selected from the group consisting of:

[0233] In some implementations, the structure consisting of rings B, C, and D is selected from the group consisting of:

[0234] In some implementations, A1 and A2 are each independently selected from: CR1 or N; A3 and A4 are C.

[0235] In some implementations, B1 is N(R2). m In some implementations, B2 is C(R2). m In some implementations, B3 is C(R2). m In some implementations, B4 is C(R2). m .

[0236] In some implementations, C1 is N(R3). q In some implementations, C2 is N(R3). q .

[0237] In some implementations, R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic groups, and substituted or unsubstituted C-shaped groups. 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 The heterocyclic group comprises one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C atoms. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 The heterocyclic group may contain alkoxy, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, or substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, wherein the heterocyclic group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 1-6The heterocyclic group comprises alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, or substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 alkynyl group, C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, wherein C 2-6 The alkynyl group is optionally C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, 3-8 membered heterocyclic substituted, said heterocyclic group comprising 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogen, substituted or unsubstituted C. 2-5 Alkyne group, substituted or unsubstituted C 1-3 The heterocyclic group comprises an alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic group, or a spirocyclic 4-6 membered heterocyclic group, wherein the heterocyclic group contains one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the C 2-5 alkynyl group, C 1-3 Alkoxy groups and 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic, hydroxyl C 2-5 Alkyl substituents. In some embodiments, the C... 2-5 alkynyl group, C 1- The 3-alkoxy group and the 5-6-membered heterocyclic spiro-4-6-membered heterocyclic group are substituted with substituents selected from cyclopropyl, pyranyl, and hydroxyisopropyl.

[0238] In some implementations, R1 is selected from the group consisting of: H, Methoxy, cyano, chlorine, and bromine.

[0239] In some embodiments, R2 and R3 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R2 and R3 are each independently selected from: H, oxo, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R2 and R3 are each independently selected from: H and oxo (=O).

[0240] In some embodiments, R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with an oxo (=O), -OH, cyano, or -NO2. In some embodiments, R2 is oxo.

[0241] In some implementations, R3 is selected from: H, substituted or unsubstituted C. 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl, halogen, cyano, -NO2, -OH, in some embodiments, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted with an oxo group (=O), -OH, cyano group, or -NO2. In some embodiments, R3 is H.

[0242] In some embodiments, R4 is selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R4 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R4 is selected from H, halogens, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted, or unsubstituted 5-10-membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, the substitution refers to one or more hydrogen atoms on the group being replaced by a substituent selected from the group consisting of halogens, C, and N. 1-8 Alkyl and C 1-8Alkyl group. In some embodiments, R4 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, and in some embodiments, the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently bonded by one, two, or three atoms selected from H, halogen, -OH, C. 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-8 Alkyl groups are substituted. In some embodiments, t is 1 or 2.

[0243] In some embodiments, R4 is selected from halogens, tolyl, difluoropropyl, phenyl, benzyl, difluorophenyl, methoxyphenyl, and pyridyl. In some embodiments, R4 is selected from: halogen.

[0244] In some implementations, R4 is selected from:

[0245] And F.

[0246] In some implementations, R5 and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R5 and R6 are each independently selected from: H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R5 and R6 are each independently selected from: H, C 1-6 Alkyl group. In some embodiments, R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6Alkyl group. In some embodiments, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl group. In some embodiments, R5 is methyl.

[0247] In some implementations, R6 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group. In some embodiments, R6 is H.

[0248] In some implementations, m is any integer of 0, 1, or 2. In some implementations, m is 1.

[0249] In some implementations, q is any integer from 0, 1, or 2. In some implementations, q is any integer between 0 and 1. In some implementations, q is 0.

[0250] In some implementations, t is any integer from 0, 1, or 2. In some implementations, t is 1 or 2.

[0251] In some embodiments, the compound of formula A of the present invention has the structure shown in formula II-1:

[0252] In Equation II-1:

[0253] A1, A2, A3, and A4 are each independently selected from: CR1 or N;

[0254] B1, B2, B3, and B4 are each independently selected from: C(R2) m Or N(R2) m ;

[0255] Ring B and ring C are each independently selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0256] L is selected from: and C 1- 10 Alkylene;

[0257] R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0258] R2, R3, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0259] m and q are each independent integers of 0, 1, 2 or 3;

[0260] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S.

[0261] In some implementations, A1, A2, A3, and A4 are C.

[0262] In some implementations, B1 and B4 are C(R2). m B2 and B3 are N(R2). m .

[0263] In some implementations, ring B is substituted or unsubstituted C. 6-10 The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, the ring B is a substituted or unsubstituted 5-7 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 nitrogen atoms.

[0264] In some implementations, ring C is substituted or unsubstituted C. 3-8The cycloalkyl, substituted, or unsubstituted 3-8 membered heterocyclic group comprises one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, the ring C is a substituted or unsubstituted 3-8 membered heterocyclic group comprising one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, the ring C is a substituted or unsubstituted 5-7 membered heterocyclic group comprising one, two, or three nitrogen atoms.

[0265] In some implementation schemes, L is selected from: In some implementation schemes, L is selected from: In some implementations, L is

[0266] In some implementations, R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R1 is selected from: H, halogen, substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R1 is selected from H and halogens.

[0267] In some implementations, R2 and R3 are each independently selected from: H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3- 8-cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2 and R3 are each independently selected from H, halogen, substituted or unsubstituted C. 1-6 Alkyl, cyano, -NO2, substituted or unsubstituted C 6-10 The heteroaryl group is an aryl, substituted, or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2 and R3 are each independently selected from H, halogen, substituted, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C6-10 Aryl. In some embodiments, R2 and R3 are each independently selected from: H, C 1-6 Alkyl and C 6-10 Aryl.

[0268] In some implementations, R5 and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C. 1-6 Alkyl group. In some embodiments, R5 and R6 are each independently selected from H and C. 1-6 alkyl.

[0269] In some implementations, m is any integer of 0, 1, or 2. In some implementations, m is 0 or 1. In some implementations, m is 0.

[0270] In some implementations, q is any integer of 0, 1, or 2. In some implementations, q is 0 or 1. In some implementations, q is 1.

[0271] In some implementations, the structure consisting of ring B and ring C is selected from the group consisting of: In some implementations, the structure consisting of ring B and ring C is as follows: For example In some implementations, the structure consisting of ring B and ring C is selected from the group consisting of:

[0272] In some embodiments, the compound of formula A of the present invention has the structure shown in formula III-1:

[0273] In Equation III-1:

[0274] A1, A2, A3, and A4 are each independently selected from: CR1 or N;

[0275] Ring B is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0276] L is selected from: and C 1- 10 Alkylene;

[0277] R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0278] R2, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P;

[0279] m is any integer among 0, 1, 2 or 3;

[0280] The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S.

[0281] In some implementations, A1, A2, A3, and A4 are C.

[0282] In some implementations, ring B is substituted or unsubstituted C. 6-10The aryl, substituted, or unsubstituted 5-10 membered heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, ring B is a substituted or unsubstituted 5-10 membered heteroaryl group comprising 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, ring B is a substituted or unsubstituted 5-7 membered heteroaryl group comprising 1, 2, or 3 nitrogen atoms. In some embodiments, ring B is selected from: pyridinyl, imidazolyl, pyrroleyl, pyrazolyl, pyrimidinyl, pyrazinyl, triazolyl, and triazineyl. In some embodiments, ring B is pyridinyl.

[0283] In some implementation schemes, L is selected from: In some implementation schemes, L is selected from:

[0284] In some implementations, R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic groups, and substituted or unsubstituted C-shaped groups. 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 The heterocyclic group comprises one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C atoms. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 The heterocyclic group comprises an alkoxy group, a substituted or unsubstituted 3-8 membered heterocyclic group, or a substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic group, wherein the heterocyclic group contains one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, unsubstituted or C-substituted... 3-8 Cycloalkyl-substituted C 2-6The heterocyclic group comprises an alkynyl group, a substituted or unsubstituted 3-8 membered heterocyclic group, or a substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic group, wherein the heterocyclic group contains one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R1 is selected from H, halogens, substituted or unsubstituted C. 2-6 alkynyl group, C 1-6 Alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted 3-8 membered heterocyclic spiro-3-8 membered heterocyclic groups, wherein C 2-6 The alkynyl group is optionally C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl or 3-8 membered heterocyclic groups are substituted, wherein the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P.

[0285] In some implementations, R2 is selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 The aryl, substituted, or unsubstituted 5-10 membered heteroaryl group comprises one, two, or three heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2 is selected from H, substituted, or unsubstituted C. 1- 6-alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted, or unsubstituted 5-10-membered heteroaryl group, wherein the heteroaryl group comprises 1, 2, or 3 heteroatoms selected from the group consisting of N, O, S, and P. In some embodiments, R2 is selected from H, optionally C. 6-10 aryl-substituted C 1-6 Alkoxy, substituted or unsubstituted 7-10 membered heteroaryl groups, wherein the heteroaryl group contains 1, 2 or 3 nitrogen atoms.

[0286] In some implementations, R5 and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH. In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6Alkyl, cyano, -NO2, -OH. In some embodiments, R5 and R6 are each independently selected from: H, oxo (=O), substituted or unsubstituted C. 1-6 alkyl.

[0287] In some implementations, m is any integer of 0, 1, or 2. In some implementations, m is 0 or 1. In some implementations, m is 1.

[0288] In some embodiments, the compound of formula A has the structure shown in formula A':

[0289] In the formula, R1-R6, ring A-ring E, L, n, m, q and t are as described in any of the above embodiments.

[0290] In some embodiments, the compound of formula A has the structure shown in formula A”:

[0291] In the formula, R1-R6, ring A-ring E, L, n, m, q and t are as described in any of the above embodiments.

[0292] In some embodiments, the compound of formula A has the structure shown in formula I':

[0293] In the formula, R1-R6, ring A-ring E, L, n, m, q and t are as described in any of the above embodiments.

[0294] In some embodiments, the compound of formula A has the structure shown in formula I”:

[0295] In the formula, R1-R6, ring A-ring E, L, n, m, q and t are as described in any of the above embodiments.

[0296] In some embodiments, the compound of formula A has the structure shown in formula II':

[0297] In the formula, R1-R3, R5-R6, ring A-ring C, ring E, L, n, m and q are as described in any of the above embodiments.

[0298] In some embodiments, the compound of formula A has the structure shown in formula II”:

[0299] In the formula, R1-R3, R5-R6, ring A-ring C, ring E, L, n, m and q are as described in any of the above embodiments.

[0300] In some embodiments, the compound of formula A has the structure shown in formula III':

[0301] In the formula, R1-R2, R5-R6, ring A, ring B, ring E, L, n and m are as described in any of the above embodiments.

[0302] In some embodiments, the compound of formula A has the structure shown in formula III”:

[0303] In the formula, R1-R2, R5-R6, ring A, ring B, ring E, L, n and m are as described in any of the above embodiments.

[0304] In some embodiments, the compound of formula A has the structure shown in formula I'-1:

[0305] In the formula, A1-A4, B1-B4, C1-C3, R2-R6, ring A-ring E, m, q and t are as described in any of the above embodiments.

[0306] In some embodiments, the compound of formula A has the structure shown in formula I”-1:

[0307] In the formula, A1-A4, B1-B4, C1-C3, R2-R6, ring A-ring E, m, q and t are as described in any of the above embodiments.

[0308] In some embodiments, the compound of formula A has the structure shown in formula II'-1:

[0309] In the formula, A1-A4, B1-B4, R2-R3, R5-R6, ring A, ring B, ring C, ring E, L, m, and q are as described in any of the above embodiments.

[0310] In some embodiments, the compound of formula A has the structure shown in formula II'-2:

[0311] In the formula, A1-A4, B1-B4, R2-R3, R5-R6, ring A, ring B, ring C, ring E, L, m, and q are as described in any of the above embodiments.

[0312] In some embodiments, the compound of formula A has the structure shown in formula III'-1:

[0313] In the formula, A1-A4, R2, R5-R6, ring A, ring B, ring E, L and m are as described in any of the above embodiments.

[0314] In some embodiments, the compound of formula A has the structure shown in formula III'-2:

[0315] In the formula, A1-A4, R2, R5-R6, ring A, ring B, ring E, L and m are as described in any of the above embodiments.

[0316] In some embodiments, the compound of formula A of the present invention is selected from the following structures:

[0317] Pharmaceutical Composition

[0318] This invention provides a pharmaceutical composition for treating or preventing radiation damage, the pharmaceutical composition comprising: (a) an RIPK1 inhibitor as the active ingredient, the RIPK1 inhibitor being selected from: compounds of formula A as described in any embodiment herein or any sub-formula thereof (including but not limited to compounds of formula I, formula II, and formula III), Nec-1, Nec-1S (Necrostatin-1s), GSK772 (GSK2982772, GlaxoSmithKline), GSK547 (GlaxoSmithKline), GSK-064 (GlaxoSmithKline), GSK3145095 (GlaxoSmithKline), GSK481 (GlaxoSmithKline), DNL104 (Denali Therapeutics), DNL747 (Denali Therapeutics), DNL758 (also known as SAR443122, Eclitasertib, Denali Therapeutics and Sanofi collaborated to develop the DNL788 (also known as SAR443820, Denali). Therapeutics, Inc. and Sanofi, R-552 (Rigel and Eli Lilly), and GNE684 (Genentech), VRN-04 (Voronoi), RIPA-56 (Beijing Institute of Life Sciences), SIR1-365, GFH-312 (Jingfang Pharmaceutical), ABBV-668 (AbbVie), JRF-401 (Chengdu Jinrui Jiyue Biotechnology), RI-962 (West China Hospital of Sichuan University), AC-003 (Aikeno Biomedical (Suzhou) Co., Ltd.), ZL-24 (Chengdu Zeling Biomedical Technology Co., Ltd.), or any one or more of the following compounds, or pharmaceutically acceptable salts thereof, or their enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs or metabolites, and (b) pharmaceutically acceptable excipients or carriers.

[0319] The pharmaceutical compositions described herein may contain 0.01-99% w (weight percentage), 0.05-80% w, 0.10-70% w, and / or even 0.10-50% w of a RIPK1 inhibitor as the active ingredient (such as the sole active ingredient), depending on the administration method.

[0320] In another aspect, the present invention further provides a method for preparing the pharmaceutical composition of the present invention, the pharmaceutical composition comprising mixing an RIPK1 inhibitor with a pharmaceutically acceptable excipient or carrier.

[0321] In this document, the pharmaceutical composition may be administered topically (e.g., through the skin or lungs and / or airways), for example in the form of creams, solutions, suspensions, hexafluoroethane aerosols, and dry powder formulations; or systemically, for example, orally in the form of tablets, capsules, syrups, powders, or granules; or via the gastrointestinal tract in the form of solutions or suspensions; or subcutaneously; or via the rectum in the form of suppositories; or via transdermal administration.

[0322] The compositions of the present invention can be obtained using conventional pharmaceutical excipients well known in the art and by conventional methods. Therefore, pharmaceutical compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0323] Suitable pharmaceutically acceptable excipients for tablet preparation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrants such as corn starch or algenic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablets may be uncoated or coated using conventional coating materials and methods known in the art to improve their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance.

[0324] Compositions for oral administration may be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert diluent such as calcium carbonate, calcium phosphate or kaolin; or may be in the form of soft gelatin capsules, wherein the active ingredient may be mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

[0325] Aqueous suspensions typically contain active ingredients in fine powder form and one or more suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersing or wetting agents such as lecithin or condensation products of 1,2-epoxyalkanes and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), or condensation products of ethylene oxide and fatty acids and hexitol-derived esters (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and fatty acids and hexitol-derived esters (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl or propyl parabens, antioxidants (such as ascorbic acid), colorants, flavoring agents and / or sweeteners (such as sucrose, saccharin or aspartame)).

[0326] Oily suspensions can be prepared by suspending the active ingredient in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oily suspensions may also contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents, as listed above, can be added to obtain palatable oral formulations. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0327] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water typically contain an active ingredient and dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents have been illustrated by those mentioned above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be present.

[0328] In some embodiments, the pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or any mixture thereof. Suitable emulsifiers may be, for example, naturally occurring gums such as gum arabic or tragacanth gum, naturally occurring phospholipids such as soybean lecithin, lecithin, esters or metaesters derived from fatty acids and hexadiol anhydrides (e.g., sorbitan monooleate), and condensation products of said metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, and preservatives.

[0329] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, aspartame, or sucrose, and may also contain analgesics, preservatives, flavoring agents, and / or coloring agents.

[0330] The pharmaceutical compositions described herein may also be in the form of sterile injectable aqueous or oily suspensions, which may use one or more of the suitable dispersants or wetting agents and suspending agents mentioned herein according to known methods. Sterile injectable formulations may also be sterile injectable solutions or suspensions in toxic, parenteral-acceptable diluents or solvents (e.g., solutions in 1,3-butanediol).

[0331] Suppositories can be prepared by mixing the active ingredient with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycol.

[0332] Topical formulations such as creams, ointments, gels, or aqueous or oily solutions or suspensions are typically prepared using conventional methods well known in the art by using the active ingredient with conventional, locally acceptable excipients or diluents.

[0333] Compositions for inhalation administration may be administered containing, for example, a finely dispersed powder with an average particle size of 30 μm or less, which contains only the active ingredient itself or is diluted with one or more physiologically acceptable carriers such as lactose. The powder for inhalation is then conveniently placed in a capsule containing, for example, 1-50 mg of the active ingredient, and used with a turbo-inhaler device, for example, for inhaling the known drug sodium cromoglycate.

[0334] The inhaled composition can be in the form of a conventional pressurized aerosol, which disperses the active ingredient into an aerosol containing finely dispersed solids or droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used, and the aerosol device allows for convenient measurement of the amount of active ingredient.

[0335] According to well-known medical principles, the dosage of the compounds of the present invention used for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0336] Generally, RIPK1 inhibitors are administered to obtain a daily dose, for example, ranging from 0.1 mg to 1000 mg of active ingredient per kg of body weight, and may also be administered in fractionated doses if necessary. However, the daily dose must vary depending on the host being treated, the specific route of administration, and the severity of the disease being treated. Therefore, the optimal dose can be determined by the physician treating any specific patient. Generally, lower doses are administered when using non-gastrointestinal routes. Thus, for example, for intravenous administration, doses of, for example, 0.1 mg to 30 mg of active ingredient per kg of body weight are typically used. Similarly, for inhalation administration, doses of, for example, 0.1 mg to 25 mg of active ingredient per kg of body weight are typically used. However, oral administration is preferred. For example, formulations intended for oral administration typically contain 0.1 mg to 2 g of active ingredient.

[0337] For information on other formulations, routes of administration, and dosage regimens, please refer to the publications in Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board).

[0338] The pharmaceutical compositions of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0339] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0340] use

[0341] Radiation damage refers to tissue damage caused by radiation exposure. Generally, radiation consists of high-energy electromagnetic waves or high-energy particles generated by natural or artificial energy sources. Both instantaneous exposure to high-dose radiation and prolonged exposure to low-dose radiation can cause tissue damage. Radiation generally includes X-rays, alpha rays, beta rays, and gamma rays. In some embodiments, radiation damage as described herein refers to damage caused by X-rays. In some embodiments, radiation damage as described herein refers to damage caused by gamma rays.

[0342] Tissue damage can manifest as cellular damage. For example, when cells are exposed to radiation, it can lead to DNA damage or an increase in reactive oxygen species, causing apoptosis and ultimately resulting in tissue damage.

[0343] This study found that RIPK1 inhibitors can suppress radiation-induced DNA damage, reactive oxygen species (ROS) generation, and programmed cell death. DNA damage, ROS generation, and other factors can lead to cell damage and apoptosis, which in turn can cause tissue damage.

[0344] Therefore, in some embodiments, the present invention provides a method for treating or preventing radiation damage to a subject, the method comprising administering to the subject a therapeutically effective amount of a RIPK1 inhibitor, or a pharmaceutical composition of the present invention. The present invention also provides the use of a RIPK1 inhibitor in the preparation of a medicament or pharmaceutical composition for treating or preventing radiation damage.

[0345] In some embodiments, the radiation damage can be radiation-induced damage to skin and subcutaneous tissue. More specifically, the radiation damage is radiation dermatitis.

[0346] In some embodiments, the radiation damage can be skin and subcutaneous tissue damage caused by X-rays. More specifically, the radiation damage is radiation dermatitis caused by X-rays.

[0347] In some implementations, radiation damage can be treated by subcutaneous or intramuscular injection of RIPK1 inhibitors.

[0348] In some implementations, RIPK1 inhibitors can be used to treat radiation damage. In some implementations, when potential exposure to radiation is anticipated, the RIPK1 inhibitor or a pharmaceutical composition thereof can be applied, for example, to the skin surface that may be exposed to radiation, to prevent or reduce cell damage, thereby achieving the purpose of preventing radiation damage such as radiation dermatitis.

[0349] In the methods and uses described above, the drug or drug composition may be administered in a suitable manner, such as topically (e.g., through the skin or lungs and / or airways) in the form of creams, solutions, suspensions, hexafluoroethane aerosols, and dry powder formulations; or systemically, such as orally in the form of tablets, capsules, syrups, powders, or granules; or via the gastrointestinal tract in the form of solutions or suspensions; or subcutaneously; or via the rectum in the form of suppositories; or via transdermal administration.

[0350] The present invention will be described below by way of specific embodiments. It should be understood that these embodiments are merely illustrative and are not intended to limit the scope of the invention. The methods, reagents, and materials used in the embodiments, unless otherwise stated, are conventional methods, reagents, and materials in the art. The raw material compounds in the embodiments are all commercially available. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0351] The starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidex, and Energie, or can be synthesized by known methods.

[0352] Example 1: Synthesis of the compound

[0353] Example 1.1: Synthesis of Compound 1

[0354] (S)-5-methyl-4-oxo-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrole[1',2':1,5]pyrazol[3,4-c]pyridin-2(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxacyclopropane-7-nitrile (Compound 1)

[0355] Step 1: Under argon protection, at 0°C, a DMF (400 mL) suspension of sodium hydride (60% dispersed in mineral oil, 18.2 g, 454.5 mmol) was added dropwise to a DMF (100 mL) suspension of A-SM-2 (46.6 g, 227.3 mmol). The reaction was stirred at 0°C for 1 hour. A DMF (50 mL) suspension of A-SM-1 (50.0 g, 227.3 mmol) was then added dropwise. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate (3 × 800 mL), and the organic phases were combined. The mixture was washed with water (3 × 1.5 L), washed with saturated brine (2 × 1.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give a yellow oily substance A-1 (35.0 g, yield: 38.0%). LCMS:m / z:304.7[M-100+H] + .

[0356] Step 2: Zinc powder (28.1 g, 432.0 mmol) was added in portions to a suspension of A-1 (35.0 g, 86.4 mmol) and ammonium chloride (46.2 g, 863.7 mmol) in ethanol (350 mL) and water (70 mL) under ice-water bath conditions, with the temperature not exceeding 30°C. The mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove ethanol. Water (100 mL) and ethyl acetate (300 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (2 × 250 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance A-2 (25.0 g, yield: 77.1%). The crude product was used directly in the next step. LCMS: m / z = 376.8 [M+H] + .

[0357] Step 3: Under argon protection, N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (20.6 g, 73.4 mmol) was added to an acetonitrile (400 mL) solution of A-2 (25.0 g, 66.6 mmol) and N-methylimidazole (11.4 g, 140.0 mmol). The reaction was carried out at room temperature for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate (3 × 300 mL), the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid A-3 (13.0 g, yield: 54.6%). LCMS: m / z = 300.7 [M+H-56] + .

[0358] 1 H NMR (400MHz, DMSO-d6) δppm: 10.04 (s, 1H), 7.30 ~ 7.26 (m, 2H), 7.15 (d, J = 8.0Hz, 1H), 7.09 (d, J = 8.4Hz, 1H), 4.37 ~ 4.27 (m, 3H), 1.37 (s, 9H).

[0359] Step 4: Under argon protection, potassium carbonate (10.7 g, 77.27 mmol) and methyl iodide (11.0 g, 77.27 mmol) were added to a dry DMF (100 mL) solution of A-3 (9.2 g, 25.76 mmol). The reaction mixture was allowed to react overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate (3 × 150 mL), and the organic phases were combined. The mixture was washed with water (3 × 300 mL), washed with saturated brine (2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a white solid A-4 (8.4 g, yield: 87.9%). LCMS: m / z = 315.0 [M+H-56] + .

[0360] 1 H NMR(400MHz,DMSO-d6)δppm:7.74(d,J=2.4Hz,1H),7.46~7.43(m,1H),7.20(d,J =8.4Hz,1H),7.17(d,J=8.4Hz,1H),4.40~4.26(m,3H),3.28(s,3H),1.35(s,9H).

[0361] Step 5: Add 7 mL of trifluoroacetic acid dropwise to a solution of A-4 (3.5 g, 9.43 mmol) in dichloromethane (35 mL) at 0 °C. React at room temperature for 1 hour. Slowly pour the reaction solution into a saturated sodium bicarbonate aqueous solution, extract with ethyl acetate (3 × 200 mL), combine the organic phases, wash with saturated brine (400 mL), dry to anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (dichloromethane / methanol = 20 / 1) to give a white solid A (2.5 g, yield: 97.8%). LCMS: m / z = 271.1 [M+H] + .

[0362] 1 H NMR (400MHz, DMSO-d6) δppm: 7.67 (d, J=2.4Hz, 1H), 7.41~7.38 (m, 1H), 7.13 (d, J=8.4Hz, 1H),4.26~4.24(m,1H),4.03~3.98(m,1H),3.65~3.60(m,1H),3.29(s,3H),1.73(s,2H).

[0363] ee% = 100%.

[0364] Step Six: Add propargyl alcohol (45 g, 0.79 mol) to a toluene solution of 1'-SM-1 (100 g, 0.87 mol). Stir the reaction mixture at 110 °C for 5 hours. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Add petroleum ether and ethyl acetate to the residue, and filter to give a white solid 1'-1, which is a mixture (82 g, yield: 60.0%). LCMS: m / z 171.1 [M+H] + .

[0365] Step 7: Add 2-(trimethylsilyl)ethoxymethyl chloride (132 g, 0.79 mol) to an acetone solution of 1'-1 (68 g, 0.40 mol) and cesium carbonate (390 g, 1.20 mmol). Stir the reaction mixture at room temperature for 5 hours. Filter the reaction mixture and concentrate the filtrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to obtain a yellow oily liquid 1'-2, which is a mixture (85 g, yield: 70.8%). LCMS: m / z 300.2 [M+H] + .

[0366] Step 8: Add Dysmart oxidant (212 g, 0.50 mol) to a solution of 1'-2 (75 g, 0.25 mol) in dichloromethane. Stir the reaction mixture at room temperature for 3 hours. Filter the reaction mixture and concentrate the filtrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to obtain a yellow oily liquid 1'-3 (12 g, yield: 16.1%). LCMS: m / z 298.3 [M+H] + .

[0367] 1 H NMR (400MHz, CDCl3) δppm: 10.01 (s, 1H), 7.51 (s, 1H), 5.92 (s, 2H), 4.48 (q, J = 7.2Hz, 2H), 3.66 (t, J = 8.0Hz, 2H), 1.46 (t, J = 7.2Hz, 3H), 0.93 (t, J = 8.0Hz, 2H), 0.01 (s, 9H).

[0368] Step 9: Add titanium tetrachloride (3.84 g, 20.2 mmol) to a dichloromethane solution of 1'-3 (2.98 g, 10.0 mmol) and trimethyl((1-phenylvinyl)oxy)silane (2.59 g, 13.5 mmol). React at 40 °C for 48 hours. Dilute the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow solid 1'-4 (1.0 g, yield: 37.0%). LCMS: m / z 271.1 [M+H] + .

[0369] Step 10: Add palladium / carbon (10%, 50 mg) and ammonia (2 drops) to a methanol solution of 1'-4 (270 mg, 1.0 mmol). Replace the air with hydrogen three times. Stir the reaction mixture at room temperature for 2 hours. Filter the mixture, and concentrate the filtrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to obtain a yellow oily substance 1'-5 (168 mg, yield: 61.3%). LCMS: m / z 275.1 [M+H] + .

[0370] Step 11: Add thionyl chloride (357 mg, 9.3 mmol) to an acetonitrile solution of 1'-5 (850 mg, 3.1 mmol). Stir the reaction at 50 °C for 5 hours. Concentrate the reaction mixture to dryness under reduced pressure. Dilute the residue with ethyl acetate and saturated sodium bicarbonate aqueous solution. Collect the organic phase and concentrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to give a yellow solid 1'-6 (680 mg, yield: 75.0%). LCMS: m / z 293.1 [M+H] + .

[0371] Step 12: Add cesium carbonate (978 mg, 3.0 mmol) to an acetonitrile solution of 1'-6 (292 mg, 1.0 mmol). Stir the reaction at room temperature for 2 hours. Filter, and concentrate the filtrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to give a yellow solid 1'-7 (155 mg, yield: 60.5%). LCMS: m / z 257.2 [M+H] + .

[0372] Step 13: Add liquid bromine (3.2 g, 20.0 mmol) to an acetonitrile solution of 1'-7 (2.56 g, 10.0 mmol). Stir the reaction mixture at 25 °C for 15 hours. Dilute the reaction mixture with ethyl acetate and saturated sodium sulfite aqueous solution. Collect the organic phase, dry it over anhydrous sodium sulfate, and concentrate it to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to give a yellow solid 1'-8 (2.8 g, yield: 83.6%).

[0373] LCMS:m / z 335.1 / 337.1[M+H] + .

[0374] 1 H NMR (400MHz, CDCl3) δppm:7.36~7.29(m,3H),7.03~7.01(m,2H),5.54~5.50(m,1H) ),4.42-4.35(m,2H),3.14-2.91(m,3H),2.57-2.51(m,1H),1.37(t,J=7.2Hz,3H).

[0375] Step Fourteen: Potassium carbonate (2.14 g, 15.5 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (568 mg, 0.78 mmol), were added to 1'-8 (2.6 g, 7.8 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3.1 g, 15.5 mmol), ethylene glycol dimethyl ether, and an aqueous solution. The reaction mixture was stirred at 90 °C for 15 hours under argon protection. The reaction solution was diluted with ethyl acetate and water, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give a white solid 1'-9 (1.62 g, yield: 64.0%). LCMS: m / z 327.2 [M+H] + .

[0376] Step 15: Add hydrochloric acid aqueous solution (6M, 7 mL) to a tetrahydrofuran solution of ethyl 1'-9 (2.4 g, 7.36 mmol). Stir at room temperature for 1 hour. Add hydrochloric acid aqueous solution (6M, 8 mL). Stir at room temperature for 1 hour, then stir at 60°C for 0.5 hours. Dilute the reaction solution with ethyl acetate and saturated sodium bicarbonate aqueous solution, collect the organic phase, dry to anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to give a yellow oily substance 1'-10 (1.3 g, yield: 59.1%). LCMS: m / z 299.1 [M+H] + .

[0377] Step 16: Add A (406 mg, 1.5 mmol) and acetic acid (1 drop) to a methanol solution of 1'-10 (298 mg, 1.0 mmol). Stir at room temperature for 0.1 h. Add sodium cyanoborohydride (125 mg, 2 mmol). Stir at room temperature for 15 h. Dilute the reaction solution with ethyl acetate and saturated sodium bicarbonate aqueous solution, collect the organic phase, dry to anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to give a colorless oil 1'-11 (380 mg, yield: 68.8%). LCMS: m / z 553.1 / 555.1 [M+H] + .

[0378] Step 17: Add a toluene solution of trimethylaluminum (1.0 M, 0.54 mL, 0.54 mmol) to a toluene solution of 1'-11 (100 mg, 0.18 mmol). Stir the reaction mixture at 110 °C for 15 hours. Dilute the reaction mixture with ethyl acetate and water, collect the organic phase, dry it over anhydrous sodium sulfate, and concentrate it to dryness under reduced pressure. Purify the crude product by silica gel column chromatography to give a white solid 1'-12 (50 mg, yield: 54.5%). LCMS: m / z 507.1 / 509.1 [M+H] + .

[0379] Step 18: Add zinc cyanide (9.1 mg, 0.08 mmol) to a solution of 1'-12 (30 mg, 0.06 mmol) in tetrahydrofuran (5.0 mL) and water (2.0 mL). Purge the air three times with argon. Add methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (5 mg, 0.006 mmol). Purge the air three more times with argon. React at 70 °C for 18 hours. Slowly pour the reaction mixture into ice water (10 mL), extract with ethyl acetate (3 × 10 mL), and filter out the insoluble matter. Combine the organic phases, wash with saturated brine (2 × 50 mL), dry to anhydrous sodium sulfate, and concentrate. Purify the crude product by Prep-HPLC to obtain a pale yellow solid 1'-13 (18 mg, yield: 67.1%).

[0380] LCMS: m / z 454.2 [M+H] + .

[0381] Step 19: 1'-13 (18 mg) were purified by SFC to obtain compound 1' (peak 1, 5 mg, yield: 27.8%) and compound 1 (peak 2, 8 mg, yield: 44.4%).

[0382] Compound 1' (peak 1): LCMS: m / z 454.2 [M+H] + ;

[0383] 1 H NMR (400MHz, MeOD-d4) δppm: 7.85 (d, J = 2.4Hz, 1H), 7.64~7.62 (m, 1H), 7.37~7.2 7(m,4H),7.10~7.08(m,2H),5.71-5.66(m,1H),5.47~5.43(m,1H),4.89~4.84(m, 1H),4.51~4.47(m,1H),4.15~4.10(m,1H),3.66~3.61(m,1H),3.35(s,3H),3.14~ 3.11(m,1H),3.04~2.93(m,3H),2.82~2.81(m,1H),2.55~2.49(m,1H).de%=100%.

[0384] Compound 1 (peak 2): LCMS: m / z 454.2 [M+H] + ;

[0385] 1 H NMR (400MHz, MeOD-d4) δppm: 7.85 (d, J = 2.4Hz, 1H), 7.65~7.62 (m, 1H), 7.37~7.2 7(m,4H),7.08~7.06(m,2H),5.71~5.66(m,1H),5.49~5.46(m,1H),4.99~4.94(m, 1H),4.51~4.47(m,1H),4.15~4.10(m,1H),3.68~3.63(m,1H),3.35(s,3H),3.17~ 3.12(m,1H),3.04~2.94(m,3H),2.85~2.82(m,1H),2.55~2.51(m,1H).de%=100%.

[0386] Example 1.2: Synthesis of Compound 2

[0387] (S)-7-(cyclopropylethynyl)-5-methyl-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1',2':1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxapine-4(5H)-one (Compound 2)

[0388] Step 1: Add 14 mg (0.02 mmol) of bis(triphenylphosphine)palladium dichloride to a solution of 1'-12 (50.7 mg, 0.1 mmol), cyclopropylacetylene (66 mg, 1.0 mmol), cuprous iodide (4 mg, 0.02 mmol), and N,N-diisopropylethylamine (38 mg, 0.3 mmol) in 20 mL of N,N-dimethylformamide. Stir at 80 °C for 15 hours under argon protection. Dilute the reaction solution with ethyl acetate and water, collect the organic phase, dry it with anhydrous sodium sulfate, and concentrate it to dryness under reduced pressure. The crude product was purified by Prep-HPLC to give a white solid 2” (20 mg). LCMS: m / z 493.2 [M+H] + .

[0389] 1 H NMR(400MHz,MeOD-d4)δppm:7.37~7.21(m,5H),7.12~7.07(m,3H),5.73~5.68(m, 1H),5.47~5.43(m,1H),4.84~4.81(m,1H),4.41~4.36(m,1H),4.18~4.12(m,1H),3 .66~3.61(m,1H),3.36(s,3H),3.13~3.10(m,1H),3.04~2.93(m,3H),2.82~2.81(m ,1H),2.55~2.51(m,1H),1.48~1.44(m,1H),0.90~0.86(m,2H),0.75~0.71(m,2H).

[0390] Step 2: 2” (35 mg, 0.07 mmol) was purified by SFC to give two white solids 2’ (peak 1, 8 mg, yield: 22.9%) and 2 (peak 2, 8 mg, yield: 22.9%).

[0391] 2'(peak 1):LCMS:m / z 493.3[M+H] + ;

[0392] 1H NMR(400MHz,MeOD-d4)δppm:7.37~7.28(m,4H),7.23~7.21(m,1H),7.12~7.07(m,3H),5.7 1~5.68(m,1H),5.47~5.43(m,1H),4.84~4.81(m,1H),4.41~4.36(m,1H),4.18~4.12(m,1H ),3.66~3.61(m,1H),3.35(s,3H),3.14~3.10(m,1H),3.04~2.93(m,3H),2.82~2.81(m,1H) ), 2.55~2.49(m,1H),1.48~1.44(m,1H),0.90~0.86(m,2H),0.75~0.71(m,2H).de%=100%.

[0393] 2(peak 2):LCMS:m / z 493.3[M+H] + ;

[0394] 1 H NMR (400MHz, DMSO-d6) δppm: 7.48 (d, J=1.6Hz, 1H), 7.36~7.29 (m, 3H), 7.26~7.24 (m, 1H), 7.18~7 .16(m,1H),7.11(s,1H),7.09(s,1H),5.56~5.46(m,2H),4.83(t,J=10.4Hz,1H),4.32(t,J=10.4 Hz,1H),3.99~3.96(m,1H),3.60~3.56(m,1H),3.27(s,3H),3.08~3.04(m,1H),2.96~2.81(m,3H) ,2.74~2.72(m,1H),2.44~2.39(m,1H),1.58~1.52(m,1H),0.91~0.86(m,2H),0.75~0.71(m,2H).

[0395] de% = 100%.

[0396] Example 1.3: Synthesis of compounds 4' and 4

[0397] (S)-7-chloro-5-methyl-3-((R)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1',2':1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxapine-4(5H)-one (compound 4')

[0398] (S)-7-chloro-5-methyl-3-((S)-1-oxo-7-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[1',2':1,5]pyrazolo[3,4-c]pyridin-2(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxapine-4(5H)-one (Compound 4)

[0399] Step 1: Under nitrogen protection at 0°C, add dropwise a DMF solution of Boc-L-serine (11.7 g, 56.97 mmol) in 70 mL of sodium hydride (60% dispersed in oil, 2.9 g, 72.5 mmol) in 30 mL of DMF. Stir the reaction mixture at 0°C for 1.5 hours. Add dropwise a DMF solution of 4-SM-1 (10.0 g, 56.97 mmol) in 20 mL of MF. React at room temperature for 4 hours. Pour the reaction mixture into water (600 mL) and adjust the pH to 6 with 1 M hydrochloric acid. Extract with ethyl acetate (3 × 150 mL). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate. Separate the crude product by column chromatography (dichloromethane:methanol = 10:1) to give a gray solid 4-1 (5.2 g, yield: 25.2%). LCMS: m / z 302.1 [M-56+H] + .

[0400] Step 2: At 0°C, ammonium chloride (8.6 g, 160.7 mmol) was added to a solution of 4-1 (5.8 g, 16.1 mmol) in ethanol (30 mL) and water (6 mL). Zinc powder (5.3 g, 80.4 mmol) was added under nitrogen protection. The mixture was heated to 25°C and reacted overnight. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (2 × 200 mL). The organic phases were combined, washed with water and brine, dried, and concentrated to obtain 4-2 (4.8 g, yield: 90.3%). The crude product was directly added to the next step. LCMS: m / z 275.0 [M-56+H] + .

[0401] Step 3: Under nitrogen protection, N-methylimidazolium (2.5 g, 30.5 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (4.5 g, 16.0 mmol) were added to a 20 mL solution of acetonitrile containing 4-2 (4.8 g, 14.5 mmol). The reaction mixture was reacted at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (2 × 200 mL). The organic phases were combined, washed with water and brine, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 4-3 (2.3 g, yield: 50.7%).

[0402] LCMS: m / z 257.0 [M-56+H] + .

[0403] Step 4: Iodomethane (5.2 g, 36.77 mmol) and potassium carbonate (4.1 g, 29.42 mmol) were added to a dry N,N-dimethylformamide (10 mL) solution of 4-3 (2.3 g, 7.35 mmol) at 0 °C. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was poured into water, filtered, and the filter cake was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give 4-4 (1.4 g, yield: 58.3%). LCMS: m / z 271.1 [M-56+H] + .

[0404] Step 5: Add 3 mL of trifluoroacetic acid to a 10 mL solution of dried dichloromethane (1.4 g, 4.28 mmol) of 4-4 at 0 °C. React at room temperature for 2 hours. Cool to 0 °C and slowly pour the reaction mixture into a saturated aqueous sodium bicarbonate solution. Extract with dichloromethane (2 × 50 mL), combine the organic phases, wash with water, wash with brine, dry, and concentrate to give 4-5 (800 mg, yield: 82.4%). LCMS: m / z 227.3 [M+H] + .

[0405] Step 6: Add acetic acid (543 mg, 9.05 mmol) and anhydrous magnesium sulfate (545 mg, 4.53 mmol) to a methanol (10 mL) solution of 4-5 (410 mg, 1.81 mmol) and 3-(2-oxoethyl)-6-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid ethyl ester (270 mg, 0.91 mmol). React at room temperature for 30 min. Add sodium cyanoborohydride (114 mg, 1.81 mmol). React overnight at room temperature. Add dichloromethane / methanol (V / V = 10 / 1, 10 mL), filter, concentrate the filtrate, and purify the residue by C18 to give 4-6 (120 mg, yield: 13.0%). LCMS: m / z 509.3 [M+H] + .

[0406] Step 7: Add lithium hydroxide (47 mg, 2.0 mmol) to a solution of 4-6 (100 mg, 0.20 mmol) in methanol (10 mL) and water (4 mL). React at 45 °C for 3 hours. Pour the reaction mixture into water and adjust the pH to 4 with 1 M hydrochloric acid. Extract with dichloromethane (2 × 50 mL), combine the organic phases, wash with water, wash with brine, dry, and concentrate to give 4-7 (85 mg, yield: 90.0%). LCMS: m / z 481.5 [M+H] + .

[0407] Step 8: Under nitrogen protection, N-methylimidazole (31 mg, 0.37 mmol) and N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (55 mg, 0.19 mmol) were added to an acetonitrile (8 mL) solution of 4-7 (85 mg, 0.18 mmol). The reaction mixture was reacted at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, washed with water and brine, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 4” (82 mg, yield: 95%). LCMS: m / z 463.1 [M+H] + .

[0408] Step 9: 4” (82 mg, 0.18 mmol) was purified by SFC to give two white solids 4’ (peak 1, 26.16 mg, yield: 31.9%) and 4 (peak 2, 19.53 mg, yield: 23.8%).

[0409] Compound 4' (peak 1):

[0410] 1 H NMR (400MHz, CDCl3) δppm: 7.31~7.26(m,3H),7.21(d,J=2.0Hz,1H),7.18~7.15(m,1H),7.1 0~7.08(m,1H),7.00(d,J=6.8Hz,2H),5.97(dd,J=11.2,8.0Hz,1H),5.45~5.43(m,1H),4.65 ~4.60(m,1H),4.41(t,J=8.8Hz,1H),4.26~4.21(m,1H),3.60~3.55(m,1H),3.36(s,3H),3.1 4~3.07(m,2H),3.00~2.92(m,1H),2.89~2.83(m,1H),2.73~2.69(m,1H),2.55~2.50(m,1H).

[0411] de% = 100%.

[0412] Compound 4 (peak 2):

[0413] 1H NMR (400MHz, CDCl3) δppm:7.29~7.26(m,3H),7.21~7.15(m,2H),7.09~7.07(m,1H) ),7.04(d,J=6.0Hz,2H),5.96(dd,J=10.8,8.0Hz,1H),5.45~5.43(m,1H),4.65~4 .60(m,1H),4.39(t,J=8.4Hz,1H),4.24~4.21(m,1H),3.60~3.55(m,1H),3.36(s, 3H), 3.14~3.09(m,2H), 2.97~2.89(m,2H), 2.74~2.70(m,1H), 2.56~2.51(m,1H).

[0414] de% = 100%.

[0415] Example 2: RIPK1 enzyme activity test

[0416] The inhibitory effect of the compounds on RIPK1 enzyme activity was detected using the Promega ADP-GLO kinase kit.

[0417] The test compound was dissolved in 100% DMSO to obtain a 20 mM stock solution. The compound was further diluted with DMSO to a concentration 100-fold higher than the test concentration. 100 nmL of the diluted test compound was added to a 384-well plate. Then, to the 348-well plate containing the test compound, diluted human RIPK1, substrate MBP, and ATP were added sequentially to the reaction wells to final concentrations of 1.25 ng / μL, 0.125 ng / mL, and 12.5 μM, respectively. The 348-well plate containing the test compound was incubated at room temperature for 3 hours. After incubation, 10 μL of Promega ADP-GLO reagent was added to stop the reaction and remove any remaining ATP. The mixture after reaction termination was incubated at room temperature for 10 minutes. Then, 20 μL of Promega ADP-GLO kinase assay reagent was added to convert ADP produced by the kinase reaction into ATP. After reacting at room temperature for 30-60 minutes, the fluorescence signal was detected using a PerkinElmer EnVision plate reader. The half-maximal inhibitory activity (IC50) of each test compound was then fitted using the professional graphing and analysis software GraphPad Prism. The results are shown in Table 1.

[0418] Table 1: ADP-GLO enzyme activity

[0419] Example 3: Subcutaneous injection of compound to treat skin damage in a mouse model of radiation dermatitis

[0420] (1) Six male C57 mice aged 6-8 weeks were used in each group. The skin of the right hip of the mice was irradiated with 40 Gy, covering an area of ​​2×2 cm. The skin lesions were observed and scored.

[0421] (2) Small molecule drugs were injected subcutaneously daily for 7 consecutive days after irradiation. The concentration of Nec-1 was 1.6 mg / kg, and the dosage of compound 1 was 0.025 mg / kg.

[0422] (3) Take photos and score the skin lesions every three days. The scoring criteria are shown in Table 2. (Refer to Yu Yimin et al., Establishment of a mouse model of high-energy X-ray radiation dermatitis, Journal of Heze Medical College, Vol. 26, No. 2, 2014)

[0423] Table 2: Scoring Criteria for Radiation-Induced Skin Injuries

[0424] Example 3.1: Therapeutic effect of compound 1 on radiation dermatitis

[0425] Figure 1 shows an example of skin lesions in the PBS control group. Figure 2 shows an example of skin lesions in the compound 1 treatment group. Table 3 shows the skin damage scores at corresponding time points after radiation irradiation in the PBS control group. Table 4 shows the skin damage scores at corresponding time points after radiation irradiation in the compound 1 treatment group. Figure 3 shows a line graph of skin damage scores for mice in the compound 1 treatment group and the PBS control group.

[0426] In an X-ray-induced mouse model, mice in the PBS control group began to develop skin lesions such as erythema, desquamation, and edema 15 days after radiation. Compound 1, at very low doses, significantly inhibited X-ray-induced skin damage.

[0427] Table 3: Summary of skin lesion scores in the PBS control group

[0428] Table 4: Summary of skin lesion scores in the compound 1 treatment group

[0429] Example 3.2: Therapeutic effect of Nec-1 on radiation dermatitis

[0430] Figure 4 shows an example of skin lesions in the PBS control group. Figure 5 shows an example of skin lesions in the Nec-1 treatment group. Table 5 shows the skin damage scores at corresponding time points after radiation irradiation in the PBS control group mice. Table 6 shows the skin damage scores at corresponding time points after radiation irradiation in the Nec-1 treatment group mice. Figure 6 shows a line graph of skin damage scores for the Nec-1 treatment group mice and the PBS control group mice.

[0431] In an X-ray-induced mouse model, mice in the PBS control group began to develop skin lesions such as erythema, desquamation, and edema 13 days after radiation. As shown in Figure 6, Nec-1 can significantly inhibit X-ray-induced skin damage.

[0432] Table 5: Summary of skin lesion scores in the PBS control group

[0433] Table 6: Summary of skin lesion scores in the Nec-1 treatment group

[0434] Example 4: HE staining of skin from mice in the compound 1 treatment group and the PBS control group.

[0435] (1) Six male C57 mice aged 6-8 weeks were used in each group. The skin of the right hip of the mice was irradiated with 40 Gy, covering an area of ​​2×2 cm. The skin lesions were observed and scored.

[0436] (2) Small molecule drugs were injected subcutaneously daily for 7 consecutive days after irradiation. The concentration of Nec-1 was 1.6 mg / kg, and the dosage of compound 1 was 0.025 mg / kg.

[0437] (3) Mice were sacrificed on day 16, and skin tissue was collected. HE and Masson trichrome staining was used to detect histological changes and collagen deposition. Immunohistochemistry was used to detect the expression of PGE2, ROS, MDA, tnf-α, TGF-β1 and SDF-1. BALF cell count analysis showed the infiltration of inflammatory cells.

[0438] As shown in Figure 7, the control group in the PBS group exhibited small-scale necrosis and defects in the epidermis; small-scale thickening of the granular layer and large-scale acanthosis of the epidermis, with significant epidermal thickening and elongation of numerous dermal rete ridges; an increased number of dermal appendages (mainly hair and tufts); and extensive inflammatory cell infiltration, primarily composed of lymphocytes and granulocytes, in the subcutaneous tissue. Compared to the control group, no significant abnormalities were observed in the skin tissue of the compound 1 treatment group. This indicates that compound 1 can inhibit the pathological changes associated with radiation dermatitis at the histological level.

[0439] Example 5: Compound 1 and Nec-1 inhibit radiation-induced DNA damage

[0440] DNA double-strand breaks are considered the most serious form of DNA damage. When a cell’s DNA double strand breaks, H2AX (H2A histone family member X) undergoes phosphorylation modification to form phosphorylated H2AX, namely γ-H2AX.

[0441] The level of γ-H2AX can characterize the degree of DNA damage.

[0442] DNA damage (γ-H2AXs) detection:

[0443] (1) Seed cells at a rate of 6000 cells per well into 96-well plates, with a total volume of 100 μL per well. Add PBS to the edge wells to prevent evaporation. After culturing for 24 h, add the drug and continue culturing for 3 h. Then, administer the corresponding X-ray irradiation dose and continue culturing for 3 h to wait for acute DNA damage in the cells.

[0444] (2) Remove the culture medium and wash once with PBS.

[0445] (3) Add fixative and fix for 5-15 minutes. The amount of fixative should be enough to fully cover the sample. For samples in a 6-well plate, usually add 1 ml of fixative per well. For samples in a 96-well plate, usually add 100 μL of fixative per well.

[0446] (4) Remove the fixative and wash the sample three times with washing solution for 3-5 minutes each time. During each wash, try to remove as much residual liquid as possible, while keeping the sample surface slightly moist and not drying it out. After the last wash, remove all washing solution.

[0447] (5) Add immunostaining blocking solution and block at room temperature for 10-20 minutes. The amount of immunostaining blocking solution should be enough to cover the sample. For samples in a 6-well plate, usually 1 ml of immunostaining blocking solution is added.

[0448] (6) Remove the immunostaining blocking solution, add γ-H2AX rabbit monoclonal antibody, and incubate at room temperature for 1 hour or at 4°C overnight. The amount of γ-H2AX rabbit monoclonal antibody should be enough to cover the sample. For samples in 6-well or 96-well plates, usually 1 ml or 50 μl of γ-H2AX rabbit monoclonal antibody is added respectively.

[0449] (7) Wash 3 times with washing buffer, 5-10 minutes each time. γ-H2AX monoclonal antibody can usually be reused at least 5 times. Wash 3 times with washing buffer, 5-10 minutes each time. During each wash, try to remove as much residual liquid as possible, while keeping the sample surface slightly moist and not drying out. After the last wash, remove all washing buffer.

[0450] (8) Add anti-rabbit 488 and incubate at room temperature for 1 hour. The amount of anti-rabbit 488 should be enough to cover the sample. For samples in a 6-well plate, usually 1 ml of anti-rabbit 488 is added.

[0451] (9) Carefully aspirate the anti-rabbit 488 into a suitable container and store at 4°C for future use. Note: Anti-rabbit 488 can usually be reused at least 5 times.

[0452] (10) Wash twice with washing solution, 5-10 minutes each time. During each wash, try to remove as much residual liquid as possible, while keeping the sample surface slightly moist and not drying out. After the last wash, remove all washing solution.

[0453] (11) Add nuclear staining solution (DAPI) and stain at room temperature for about 5 minutes. The amount of nuclear staining solution should be enough to cover the sample. For samples in a 6-well plate, usually 1 ml of nuclear staining solution (DAPI) is added.

[0454] (12) Remove the staining solution from the cell nuclei and wash the sample three times with washing solution for 3-5 minutes each time. Each time you wash the sample, you should try to remove as much residual liquid as possible, while keeping the sample surface slightly moist. Observe the sample under a fluorescence microscope.

[0455] Figure 8 illustrates the inhibition of radiation-induced DNA damage by compounds 1 and Nec-1. As shown in Figure 8, compared with the control group, the proportion of γ-H2AX-positive cells in the radiation group was significantly increased. Compared with the radiation group, compounds 1 and Nec-1 significantly reduced the proportion of γ-H2AX-positive cells. This indicates that the RIPK1 inhibitors compounds 1 and Nec-1 can significantly inhibit radiation-induced cellular DNA damage.

[0456] Example 6: Compound 1 and Nec-1 inhibit radiation-induced reactive oxygen species (ROS) generation.

[0457] Intracellular reactive oxygen species (ROS) levels were detected using a DCFH-DA fluorescent probe. DCFH-DA itself is non-fluorescent and can freely cross the cell membrane. Once inside the cell, it is hydrolyzed by intracellular esterases to generate DCFH. Since DCFH is not permeable to the cell membrane, the fluorescent probe is easily accumulated intracellularly. Intracellular ROS oxidize the non-fluorescent DCFH to generate fluorescent DCF. The intensity of the green fluorescence is directly proportional to the ROS level.

[0458] ROS level detection

[0459] (1) Take 6×104 cells and seed them in a six-well plate, with three replicates for each treatment group. After the cells adhere to the plate for 24 hours, treat each group of cells with the corresponding drug.

[0460] (2) After culturing for 24 hours, the cells were irradiated with the corresponding X-rays. The medium was changed immediately after irradiation, and the cells were cultured until the predetermined detection time point was reached. The cells were then washed with serum-free medium to remove the medium. The detection solution was prepared by diluting DCFH-DA with serum-free culture medium at a ratio of 1:1000 and incubating for 20-30 minutes. After incubation, the cells were washed three times with PBS. The cells were then observed under a fluorescence microscope.

[0461] Figure 9 illustrates the inhibition of radiation-induced ROS generation by compounds 1 and Nec-1. As shown in Figure 9, compared with the control group, the mean fluorescence intensity of the DCFH fluorescent probe in the radiation-treated cells was significantly increased, indicating a significant increase in reactive oxygen species levels in the radiation-treated cells. Compared with the radiation-treated group, the mean fluorescence intensity of compounds 1 and Nec-1 was significantly decreased. This indicates that the RIPK1 inhibitors compounds 1 and Nec-1 can significantly inhibit the upregulation of radiation-induced cellular ROS levels.

[0462] Example 7: Compound 1 and Nec-1 inhibit radiation-induced programmed cell death

[0463] Annexin-V / Propidium iodide (PI) dual staining was used to detect programmed cell death. In the early stages of programmed cell death, phosphatidylserine residues flip from the inner side of the cell membrane to the surface, exposing them to the extracellular environment. Annexin-V specifically binds to phosphatidylserine, indicating cells in the early stages of programmed cell death. Propidium iodide is a nucleic acid dye that cannot penetrate the cell membranes of living cells, but can only penetrate the cell membranes of dead cells, staining their nucleic acids and indicating cells in the late stages of programmed cell death.

[0464] Annexin V / PI double staining flow cytometry was used to detect the effect of combined irradiation and drug on cell apoptosis.

[0465] (1) Each well in the 6-well plate is equipped with 2×10 5 Cells were divided into three replicates per treatment group. After cell attachment, the cells were treated with an appropriate concentration of small molecule drug and cultured in an incubator for 24 hours.

[0466] (2) After 24 hours, administer the appropriate dose of X-ray irradiation, and change the medium immediately after irradiation. After 48 hours, collect the supernatant, digest the cells with trypsin, add complete culture medium to stop digestion, centrifuge at 800 r / min for 3 min at 4°C to collect the cells, wash twice with PBS, and centrifuge again to collect the cells. Add 100 μL of 1× Binding Buffer to each tube to resuspend the cells, then add 5 μL of Annexin-V dye and 10 μL of PI dye, and mix gently. Incubate in the dark at 37°C for 20 min, then add 400 μL of 1× Binding Buffer, mix well, and analyze the samples by flow cytometry as soon as possible.

[0467] Figure 10 illustrates the inhibition of radioactively induced programmed cell death by compounds 1 and Nec-1. As shown in Figure 10, compared with the control group, the proportion of Annexin V / PI positive cells in the radiation group was significantly increased, indicating that radiation conditions can induce programmed cell death. Compared with the radiation group, compounds 1 and Nec-1 significantly reduced the proportion of Annexin V / PI positive cells, demonstrating that compounds 1 and Nec-1 can significantly inhibit radiation-induced programmed cell death.

[0468] Example 8: Skin lesion model of a mouse radiation dermatitis model treated with a topical compound.

[0469] (1) Six male C57 mice aged 6-8 weeks were used in each group. The skin of the right hip of the mice was irradiated with 40 Gy, covering an area of ​​2×2 cm. The skin lesions were observed and scored.

[0470] (2) Apply compound 1 gel preparation (2% drug content) and cream preparation (2% drug content) after irradiation, and apply daily.

[0471] (3) Take photos and score the skin lesions every three days. The scoring criteria are shown in Table 2.

[0472] The results showed that, compared with the PBS group, the blank gel group, and the blank cream group, both the gel and cream formulations of compound 1 had significant therapeutic effects on radiation dermatitis.

Claims

Use of RIPK1 inhibitors in the preparation of drugs for the treatment or prevention of radiation damage. The use as described in claim 1, characterized in that, The RIPK1 inhibitor is a compound of formula A, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug, or metabolite thereof: In formula A: Ring A is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; L is selected from: C 1- 10 alkylene groups, or chemical bonds; When L is Or C 1- 10 In the case of alkylene, ring B is selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; the ring C and ring D are each independently selected from the group consisting of substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 The heterocyclic or heteroaryl group may be aryl, substituted or unsubstituted, or absent, and may contain 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P. When L is a chemical bond, ring E and ring B are directly linked through this chemical bond, and rings B, C, and D are each independently selected from either substituted or unsubstituted C atoms. 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the heterocyclic or heteroaryl comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R3 is selected from H, oxo, substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2- 6-Alynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R4 is selected from H, oxo, substituted, or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2- 6-Alynyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R5 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R6 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n, m, q, and t are each independent integers from 0, 1, 2, and 3; The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups comprise 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S; This indicates that the part is connected to the other parts of the molecule via chemical bonds. The use as described in claim 2, characterized in that, Ring A is substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, either aryl or substituted or unsubstituted; ring A is substituted or unsubstituted C. 6-10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; preferably, ring A is pyridyl or phenyl; Ring B is a substituted or unsubstituted 5-14 membered heterocyclic group or a substituted or unsubstituted 5-14 membered heteroaryl group; ring B is a substituted or unsubstituted 5-10 membered heterocyclic group or a substituted or unsubstituted 5-10 membered heteroaryl group; preferably, ring B is piperidinyl, pyrazolyl or pyridinyl. The ring C is a substituted or unsubstituted 5-14 membered heterocyclic group or a substituted or unsubstituted 5-14 membered heteroaryl group; the ring C is a substituted or unsubstituted 5-10 membered heterocyclic group or a substituted or unsubstituted 5-10 membered heteroaryl group; preferably, the ring C is a pyrazolyl or pyrrolidinyl group. Ring D is a substituted or unsubstituted 5-14 membered heterocyclic group; preferably, ring D is selected from pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl or oxazacyclohexane; preferably, ring D is pyrrolidinyl or 1,3-oxazacyclohexane. R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 The heterocyclic group comprises alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S; preferably, R1 is selected from H, halogen, substituted or unsubstituted C. 2-5 Alkyne group, substituted or unsubstituted C 1-3 Alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups, wherein C 2-5 alkynyl group, C 1-3 Alkoxy groups and 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic, hydroxyl C 2-5 Alkyl substituents; preferably, the C 2-5 alkynyl group, C 1-3 The alkoxy group and the 5-6 membered heterocyclic spiro-4-6 membered heterocyclic group are substituted with a substituent selected from cyclopropyl, pyranyl, and hydroxyisopropyl; preferably, R1 is selected from the group consisting of H, Methoxy, cyano, chlorine, and bromine; R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-14 membered heteroaryl, said heteroaryl comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P, said C 1-6 Alkoxy and C 1-6 Alkyl groups are each independently oxidized (=O) and C-substituted. 6-10 Aryl, -OH, cyano, or -NO2 substitution; preferably, R2 is selected from H, oxo (=O), or optionally C. 6-10 aryl-substituted C 1-6 Alkyl, halogen, substituted or unsubstituted 5-10-membered heteroaryl; preferably, R2 is H, oxo, or C-substituted. 6- 10 aryl-substituted C 1-4 Alkoxy, benzopyrazole; R3 is selected from: H, substituted or unsubstituted C. 6-10 aryl, substituted or unsubstituted C 1-6 Alkoxy, halogen, cyano, -NO2, -OH, the C 1-6 The alkoxy group is substituted with an oxo group (=O), -OH, cyano group, or -NO2; preferably, R3 is H or C. 6-10 Aryl; R4 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl groups, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, wherein the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently bonded by one, two, or three atoms selected from H, halogen, -OH, C. 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-8 The alkoxy group is substituted; preferably, R4 is selected from halogen, difluoropropyl, phenyl, benzyl, difluorophenyl, tolyl, methoxyphenyl and pyridyl; preferably, R4 is selected from: and halogens; Preferably, R4 is selected from: and F; t is 1 or 2; R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R6 is H. The use as described in claim 2, characterized in that, The compound of formula A has the structure shown in formula I: In Formula I: Rings A, B, C, and D are each independently selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2, R3, R4, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1- 6-alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n, m, q, and t are each independent integers from 0, 1, 2, and 3; The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl and unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S. The use as described in claim 4, characterized in that, In Formula I: Ring A is substituted or unsubstituted C 6-14 5-14 membered heteroaryl groups, either aryl or substituted or unsubstituted; ring A is substituted or unsubstituted C. 6-10 Aryl or substituted or unsubstituted 5-10 membered heteroaryl; preferably, ring A is pyridyl or phenyl; Ring B is a substituted or unsubstituted 5-14 membered heterocyclic group; ring B is a substituted or unsubstituted 5-10 membered heterocyclic group; preferably, ring B is piperidinyl; The ring C is a substituted or unsubstituted 5-14-membered heteroaryl group; the ring C is a substituted or unsubstituted 5-10-membered heteroaryl group; preferably, the ring C is a pyrazolyl group; Ring D is a substituted or unsubstituted 5-14 membered heterocyclic group; preferably, ring D is selected from pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl or oxazacyclohexane; preferably, ring D is pyrrolidinyl or 1,3-oxazacyclohexane. R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 The heterocyclic group comprises alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S; preferably, R1 is selected from H, halogen, substituted or unsubstituted C. 2-5 Alkyne group, substituted or unsubstituted C 1-3 Alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups, wherein C 2-5 alkynyl group, C 1-3 Alkoxy groups and 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic, hydroxyl C 2-5 Alkyl substituents; preferably, the C 2-5 alkynyl group, C 1-3 The alkoxy group and the 5-6 membered heterocyclic spiro-4-6 membered heterocyclic group are substituted with a substituent selected from cyclopropyl, pyranyl, and hydroxyisopropyl; preferably, R1 is selected from the group consisting of H, Methoxy, cyano, chlorine, and bromine; R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, the C 1-6 Alkoxy and C 1-6 Each alkyl group is independently substituted by an oxo (=O), -OH, cyano, or -NO2; preferably, R2 is oxo. R3 is selected from: H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, cyano, -NO2, -OH, the C 1-6 The alkoxy group is substituted by an oxo (=O), -OH, cyano, or -NO2; preferably, R3 is H; R4 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl groups, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, wherein the C 1-6 Alkoxy, C 1-6 Alkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently bonded by one, two, or three atoms selected from H, halogen, -OH, C. 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-8 The alkoxy group is substituted; preferably, R4 is selected from halogen, difluoropropyl, phenyl, benzyl, difluorophenyl, tolyl, methoxyphenyl and pyridyl; preferably, R4 is selected from: and halogens; Preferably, R4 is selected from: and F; R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R6 is H; n, m, q, and t are each independently any integer from 0, 1, or 2; preferably, n, m, q, and t are each independently any integer from 0 or 1. The use as described in claim 4, characterized in that, The compound of formula A has the structure shown in formula I-1: In Equation I-1: A1, A2, A3, and A4 are each independently selected from CR1 or N; preferably, A1 and A2 are each independently selected from CR1 or N; and A3 and A4 are C. B1, B2, B3, and B4 are each independently selected from: C(R2) m Or N(R2) m Preferably, B1 is N(R2). m Preferably, B2 is C(R2). m Preferably, B3 is C(R2). m Preferably, B4 is C(R2). m ; C1, C2, and C3 are each independently selected from: C(R3) q Or N(R3) q Preferably, C1 is N(R3). q Preferably, C2 is N(R3). q Preferably, C3 is C(R3). q . The use as described in claim 4 or 6 is characterized in that, The structure composed of rings B, C, and D is selected from the following group: Preferably, the structure composed of rings B, C, and D is selected from the group consisting of: Preferably, the structure composed of rings B, C, and D is selected from the group consisting of: Preferably, the structure composed of rings B, C, and D is selected from the group consisting of: The use as described in claim 2, characterized in that, The compound of formula A has the structure shown in formula II: In Formula II: Rings A, B, and C are each independently selected from: substituted or unsubstituted C. 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; L is selected from: and C 1- 10 Alkylene; R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2, R3, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n, m, and q are each independent integers from 0, 1, 2, and 3; The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S. The use as described in claim 8, characterized in that, In Equation II: Ring A is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S; preferably, ring A is phenyl; Ring B is selected from: substituted or unsubstituted C 6-10 The aryl, substituted or unsubstituted 5-10 membered heteroaryl group, wherein the heteroaryl group comprises one or two heteroatoms selected from the group consisting of N, O and S; preferably, ring B is a substituted or unsubstituted 5-10 membered heteroaryl group; preferably, ring B is a pyrazolyl group; The ring C is selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, said heterocyclic group comprising 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S; preferably, the ring C is a substituted or unsubstituted 3-8 membered heterocyclic group; preferably, the ring C is pyrroloalkyl; L is selected from: and C 1- 10 Alkylene; preferably, L is selected from: Preferably, L is R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; preferably, R1 is selected from H, halogen, cyano, -NO2, -OH; preferably, R1 is selected from H or halogen; R2 is selected from: H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH; preferably, R2 is selected from: H, halogen, cyano, -NO2, -OH; preferably, R2 is H; R3 is selected from: H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 The aryl, substituted or unsubstituted 5-10-membered heteroaryl group, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; preferably, R3 is selected from H, halogen, substituted or unsubstituted C. 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 Aryl; preferably, R3 is selected from: H or C 6-10 Aryl; R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R6 is H; n, m, and q are each independently any integer from 0, 1, or 2; preferably, n, m, and q are each independently any integer from 0 or 1. The use as described in claim 8, characterized in that, The compound of formula A has the structure shown in formula II-1: In Equation II-1: A1, A2, A3, and A4 are each independently selected from: CR1 or N; preferably, A1, A2, A3, and A4 are all C; B1, B2, B3, and B4 are each independently selected from: C(R2) m Or N(R2) m Preferably, B1 is C(R2). m Preferably, B2 is N(R2). m Preferably, B3 is N(R2). m Preferably, B4 is C(R2). m . The use as described in claim 2, characterized in that, The compound of formula A has the structure shown in formula III: In Formula III: Ring A and ring B are each independently selected from: substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; L is selected from: and C 1- 10 Alkylene; R1 is selected from: H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-8-membered heterocyclic spiro-3-8-membered heterocyclic, substituted or unsubstituted 3-8-membered heterocyclic and 3-8-membered heterocyclic, substituted or unsubstituted C 3-8 cycloalkylspiroC 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl-C 3-8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups with C 6-10 aryl, substituted or unsubstituted 3-8 membered heterocyclic and 5-10 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl-C 6-10 aryl, substituted or unsubstituted C 3-8 Cycloalkyl 5-10-membered heteroaryl groups, wherein the heterocyclo group or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; R2, R5, and R6 are each independently selected from: H, oxidized (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic groups, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heterocyclic or heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; n and m are each an independent integer from 0, 1, 2 or 3; The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, -OH, -NO2, -NH2, -NH (unsubstituted or halogenated C atoms). 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl group 2, -CN, unsubstituted or halogenated or hydroxyl-substituted C 1-8 Alkyl, unsubstituted or halogenated C 1-8 Alkoxy, unsubstituted or halogenated C 1-8 Alkoxy-C 1-8 Alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 Alkyl, unsubstituted or halogenated C 1-6 Alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxycarbonyl, isohydroxyoxime, unsubstituted or halogenated C 1-6 Alkyl mercapto, -S(O)2N (unsubstituted or halogenated C 1-6 alkyl)2, -S(O)2 unsubstituted or halogenated C 1-6 Alkyl, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)2N(unsubstituted or halogenated C 1-6 Alkyl)2, -S(O)N (unsubstituted or halogenated C) 1-6 Alkyl)2, -S(O) (unsubstituted or halogenated C) 1-6 Alkyl), -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)N(unsubstituted or halogenated C 1-6 Alkyl)2, -N (unsubstituted or halogenated C) 1-6 Alkyl)S(O)(unsubstituted or halogenated C 1-6 Alkyl), unsubstituted or halogenated C 5-10 aryl, unsubstituted or halogenated 5-10 heteroaryl, unsubstituted or halogenated C 3-8 Cycloalkyl, unsubstituted or halogenated 3-8 membered heterocyclic groups, wherein the heterocyclic and heteroaryl groups contain 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O or S. The use as described in claim 11, characterized in that, In Formula III: Ring A is selected from: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S; preferably, ring A is phenyl; Ring B is selected from: substituted or unsubstituted C 6-10 The aryl, substituted or unsubstituted 5-10-membered heteroaryl group, wherein the heteroaryl group comprises one or two heteroatoms selected from the group consisting of N, O and S; preferably, ring B is a substituted or unsubstituted 5-10-membered heteroaryl group; preferably, ring B is a pyridyl group; L is selected from: and C 1- 10 Alkylene; preferably, L is selected from: Preferably, L is selected from: R1 is selected from H, halogen, substituted or unsubstituted C. 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 The heterocyclic group comprises alkoxy, cyano, substituted or unsubstituted 3-8 membered heterocyclic groups, wherein the heterocyclic group contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S; preferably, R1 is selected from H, halogen, substituted or unsubstituted C. 2-5 Alkyne group, substituted or unsubstituted C 1-3 Alkoxy, cyano, substituted or unsubstituted 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups, wherein C 2-5 alkynyl group, C 1-3 Alkoxy groups and 5-6 membered heterocyclic spiro-4-6 membered heterocyclic groups are selected from C 1-6 Alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocyclic, hydroxyl C 2-5 Alkyl substituents; preferably, the C 2-5 alkynyl group, C 1-3 The alkoxy group and the 5-6 membered heterocyclic spiro-4-6 membered heterocyclic group are substituted with a substituent selected from cyclopropyl, pyranyl, and hydroxyisopropyl; preferably, R1 is selected from the group consisting of H, Methoxy, cyano, chlorine, and bromine; R2 is selected from H, oxo (=O), substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 1-6 Alkyl, cyano, -NO2, -OH, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-14 membered heteroaryl groups, wherein the heteroaryl group comprises 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and P; preferably, R2 is selected from H, oxo (=O), optionally C-substituted. 6-10 aryl-substituted C 1-6 Alkoxy, halogen, substituted or unsubstituted C 1- 6-alkyl, cyano, -NO2, -OH, substituted or unsubstituted 5-10-membered heteroaryl groups; preferably, R2 is selected from H, optionally C 6-10 aryl-substituted C 1-6 Alkyl groups, halogens, and 5-10 heteroaryl groups; R5 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R5 is selected from unsubstituted C4 groups. 1-6 Alkyl; preferably, R5 is methyl; R6 is selected from H, substituted or unsubstituted C. 1-6 Alkoxy, halogen, substituted or unsubstituted C 1-6 Alkyl group; preferably, R6 is H; n and m are each independently any integer from 0, 1 or 2; preferably, n and m are each independently any integer from 0 or 1. The use as described in claim 11, characterized in that, The compound of formula A has the structure shown in formula III-1: In the formula, A1, A2, A3 and A4 are each independently selected from CR1 or N; preferably, A1, A2, A3 and A4 are C. The use as described in claim 2, characterized in that, The compound of formula A is selected from the following compounds: The use as described in claim 1, characterized in that, The RIPK1 inhibitors are selected from the following compounds or their pharmaceutically acceptable salts, or their enantiomers, diastereomers, tautomers, solvates, polymorphs, prodrugs, or metabolites: Nec-1, Nec-1S, GSK772, GSK547, GSK-064, GSK3145095, GSK481, DNL104, DNL747, DNL758, DNL788, R-552, GNE684, VRN-04, RIPA-56, SIR1-365, GFH-312, ABBV-668, JRF-401, RI-962, AC-003, and ZL-24. The use as described in claim 1, characterized in that, The radiation damage is damage caused by X-rays, preferably skin tissue damage, and more preferably radiation dermatitis.

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