Jnk-nlrp3 dual-target inhibitor and preparation method and application thereof

Abstract

This invention discloses compounds of Formula 1, or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof. These compounds exhibit excellent JNK inhibitory activity and NLRP3 inflammasome inhibitory activity. Therefore, the compounds of this invention lay a new material foundation for the development of therapeutic drugs for inflammation-related diseases. 1.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry. Specifically, this invention relates to compounds having JNK & NLRP3 inhibitory activity, pharmaceutical compositions comprising said compounds, and their use in medicines for JNK & NLRP3-related diseases. Background Technology

[0002] JNK (c-Jun N-terminal kinase) is a member of the MAPK (mitogen-activated protein kinase) family and plays a crucial role in cellular responses to various abiotic and biotic stresses. JNK regulates important physiological processes, including neuronal function, immune responses, and embryonic development, by influencing gene expression, cytoskeletal protein dynamics, and cell death / survival pathways. NLRP3 (NOD-like receptor protein 3) is a member of the NLR (NOD-like receptor) family. It forms an inflammasome complex in the cytoplasm and participates in the regulation of the innate immune system and inflammatory responses. The NLRP3 inflammasome can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), activate caspase-1, and promote the maturation and secretion of IL-1β and IL-18, thereby mediating the inflammatory response.

[0003] Dysregulation of the JNK signaling pathway is associated with the development and progression of a variety of human diseases, including diabetes, inflammatory diseases, and neurodegenerative diseases. Abnormal activation of the NLRP3 inflammasome is also associated with a range of diseases, including metabolic diseases, autoinflammatory diseases, and tumors.

[0004] It has been found that JNK can promote the activation of the NLRP3 inflammasome by directly phosphorylating NLRP3. This phosphorylation is one of the key steps in NLRP3 inflammasome activation. For example, in diabetic nephropathy, the Syk / JNK / NLRP3 signaling pathway is involved in the pathogenesis of kidney disease, where JNK activation is associated with the expression level of the NLRP3 inflammasome. Furthermore, JNK activation can also affect the NLRP3 inflammasome in other ways, such as by influencing NLRP3 ubiquitination and self-aggregation processes. In certain infectious diseases, such as Streptococcus pneumoniae infection, the ALK / JNK signaling pathway activates the NLRP3 inflammasome, thereby affecting pyroptosis and inflammatory responses.

[0005] Overall, the relationship between JNK and NLRP3 plays a crucial role in the development and progression of inflammatory diseases. JNK activation can promote the assembly and activation of NLRP3 inflammasomes, thereby influencing inflammatory responses and cell death processes. These findings offer potential therapeutic approaches for inflammatory diseases or other JNK & NLRP3-related conditions.

[0006] Aberrant activation of JNK and NLRP3 plays a crucial role in various diseases, and the two may have synergistic effects. Compared to simple drug combinations, using dual-target compounds may offer multiple advantages, such as simplifying treatment regimens, improving patient compliance, reducing drug interactions, and enhancing treatment efficacy.

[0007] Therefore, the development of drugs targeting both JNK and NLRP3 is of great clinical significance and application potential for the treatment of inflammatory diseases, cancer, and other related diseases. Summary of the Invention

[0008] The purpose of this invention is to provide a dual-target compound with JNK & NLRP3 inhibitory activity.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising the said compound.

[0010] Another object of the present invention is to provide the use of the compound in the preparation of a medicament for treating JNK & NLRP3-related diseases, and a method for treating JNK & NLRP3-related diseases using the compound or a pharmaceutical composition.

[0011] In a first aspect, the present invention provides compounds of Formula 1, or tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof. 1 In the formula, Y is or Y1 is selected from NR 14 O, S; R 14 Selected from H or optionally substituted C 1-3 alkyl; R1 is selected from: H, halogen, cyano, or optionally substituted C. 1-10 Alkyl, optionally substituted C 1-10 Alkyl group, -C(O)R7; R2 is H, or R2 and R1 together with the carbon atoms attached to them form an optionally substituted 3-10 membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S. R3 is H, and C is optionally substituted. 1-10 Alkyl groups; or, R3 together with R1 or R4, along with the atoms attached to them, forms an optionally substituted 3- to 10-membered heteroaryl or heterocyclic group containing one, two, or three independent heteroatoms selected from N, O, or S. Rings A and B are independently selected from: C 5-10 Aryl, 5-10 heteroaryl, C 3-10Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic aryl or 8-10 membered bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic carbocyclic or 8-10 membered bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Where valence is permissible, n can be 0, 1, 2, 3, 4 or 5, and m can be 0, 1, 2, 3, 4 or 5; R4 is selected from: H, hydroxyl group, or optionally substituted C. 1-10 Alkyl, optionally substituted C 5-10 Aryl, halogen, cyano, nitro, -C 0-6 -C(O)R7、-C 0-6 -OR8、-C 0-6 -N(R9)2, optionally substituted sulfonyl group, optionally substituted phosphonoyl group, optionally substituted 5-7 membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Alternatively, two adjacent R4s together with the atoms attached to them form an optionally substituted 3-10 membered heteroaryl or heterocyclic group containing one, two or three independent heteroatoms selected from N, O or S. R5 is selected from: H, hydroxyl, halogen, cyano, nitro, -C 0-6 -C(O)R 11 -C 0-6 -OR 12 -C 0-6 -N(R 13 2. Optionally substituted sulfonyl group, Optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl group, optionally substituted C 1-10 Alkoxy, optional substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; Given that they satisfy the given valence, A1, A2, A3, A4, and A5 can be independently selected from: C, N, C6, and C(R). 17 2. NR 18 ; R6, R 17 and R 18 Each is independently selected from: C that can be arbitrarily substituted1-6 Alkyl, optionally substituted C 1-6 Alkoxy, oxo, -C 0-6 -C(O)R 19 -C 0-6 -OR 20 -C 0-6 -N(R 21 2. Optional substitution of C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S. Or, two R atoms attached to the same carbon atom 17 Together with this carbon atom, it forms an optionally substituted C 3-10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic groups containing one, two, or three heteroatoms independently selected from N, O, or S. Or, R6, R 17 and R 18 The two atoms attached to adjacent atoms, together with the atoms they are attached to, form an optionally substituted C atom. 5-10 aryl or optionally substituted C-type compounds containing one, two, or three heteroatoms independently selected from N, O, or S. 5-10 Mixed aromatics; R7, R 11 and R 19 Each is independently selected from: H, optionally substituted hydroxyl group, optionally substituted amino group, optionally substituted C group. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R8, R 12 and R 20 Each is independently selected from: H, and optionally substituted C. 1-3 Acyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R9, R 13 and R21 Each is independently selected from: H, and optionally substituted C. 1-3 Acyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; Or, two R9s, two Rs 13 Or two Rs 21 Together with the nitrogen atoms attached to them, they form optional substituted 3-10 membered heterocyclic groups; R 10 For substituted or unsubstituted methylene, R 10 The substituents can be halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 cycloalkyl or heterocyclic groups; or, R 10 The two substituents are linked to form an optionally substituted C 3-10 Cycloalkyl or heterocyclic groups.

[0012] In a specific implementation method Y is or ; R1 is selected from: H, halogen, or optionally substituted C. 1-6 alkyl; R2 is H, or R2 and R1 together with the carbon atoms attached to them form an optionally substituted 3-10 membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S. R3 is H; Ring A is selected from: phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 3-6 membered cycloalkyl or 5-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Ring B is a phenyl, a 6-membered cycloalkyl, or a heterocyclic group; m can be 0, 1, 2, or 3; n is 0, 1, or 2; R4 is selected from: H, hydroxyl, halogen, cyano, nitro, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, -C 0-6-C(O)R7、-C 0-6 -OR8、-C 0-6 -N(R9)2; R5 is selected from: H, hydroxyl, halogen, cyano, nitro, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, -C 0-6 -C(O)R 11 -C 0-6 -OR 12 -C 0-6 -N(R 13 )2; for ; X is selected from: N or CR 24 ; R 22 Selected from: hydrogen, C 1-6 Alkyl, 3-6 membered cycloalkyl or heterocyclic, -C 0-6 -C(O)R 25 -C 0-6 -OR 26 -C 0-6 -N(R 27 )2, the C 1-6 Alkyl, 3-6 membered cycloalkyl or heterocyclic groups may be optionally substituted with halogens, hydroxyl groups or amino groups; R 23 Selected from: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 10-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R 24 It is hydrogen, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 10-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R 25 Independently selected from: H, hydroxyl, optionally substituted amino, optionally substituted C 1-6 Alkoxy; R 26 Independently selected from: H, optional substituted C 1-6 alkyl; R 27 Independently selected from: H, optional substituted C1-6 alkyl.

[0013] In a specific implementation, R1 is a halogen; preferably bromine.

[0014] In a specific implementation, when ring B is phenyl, R4 is -C(O)R7 or -OR8; R7 is selected from: H, hydroxyl group, optionally substituted amino group, optionally substituted C group. 1-6 Alkoxy; R8 is selected from: H, C which is optionally substituted by one or more groups independently selected from the following 1-6 Alkyl groups: halogen, hydroxyl, carboxyl, C 1-3 Acyloxy group, -N(R) 28 )2; Each R 28 Each is independently H, and the C can be arbitrarily substituted. 1-6 Alkyl; or, two Rs 28 Together with the nitrogen atom it is bonded to, it forms an optionally substituted 3-7 membered heterocycle, which optionally further contains one or two heteroatoms independently selected from N, O or S; m is 1, 2 or 3, and at least one of the R4s is -C(O)R7 and is substituted at the -NH- ortho position.

[0015] In a specific implementation method for ; R 22 C is unsubstituted or hydroxylated 1-6 Alkyl groups, unsubstituted or hydroxyl-substituted 3-6 membered cycloalkyl groups; R 29 It is hydrogen or halogen.

[0016] In a specific implementation method Y is or ; R1 is selected from: H, halogen; R2 is H, or R2 and R1 together with the carbon atoms attached to them form an optional substituted 5-6 membered heteroaryl group containing an N heteroatom; R3 is H; Ring A is selected from: phenyl, or 3-6 membered cycloalkyl; Ring B is a phenyl, a 6-membered cycloalkyl, or a heterocyclic group; m is 1, 2, or 3; n is 0, 1, or 2; R4 is selected from: H, C 1-6 Alkyl, -C 0-6 -C(O)R7、-C0-6 -OR8; R5 is selected from: H, hydroxyl, halogen, cyano, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy; for ; X is CR 24 ; R 22 Selected from: C 1-6 Alkyl, 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3-6 membered cycloalkyl groups may be optionally substituted with halogens, hydroxyl groups, or amino groups; R 23 Selected from: hydrogen, C 1-6 Alkyl, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 10-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R 24 It is hydrogen, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 6-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0017] In a specific embodiment, the compound is selected from the group consisting of: B29 B33 B34 B36 B37 B38 B39 B40 B41 B42 B43 B44 B45 B46 B47 B49 B48 B50 B51 B52 B55 B56 B57 B59 B60 B61 B62 B63 B64 B65 B66 B67 B68 B69 B70 B71 B72 B73 B74 B75 B76 B77 B80 B81; Preferably, the compound is selected from the group consisting of: B29 B33 B38 B42 B43 B44 B47 B48 B50 B51 B59 B64 B65 B68 B73 B76 B77.

[0018] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or its tautomers, mesosomes, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable transporter.

[0019] In a third aspect, the present invention provides the use of the compound described in the first aspect or its tautomers, mesosomes, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable salts thereof in the preparation of JNK inhibitors, NLRP3 inhibitors or JNK&NLRP3 dual-target inhibitors.

[0020] In a specific implementation, the JNK inhibitor, NLRP3 inhibitor, or JNK&NLRP3 dual-target inhibitor is a drug for treating and / or preventing JNK / NLRP3-related diseases.

[0021] In a preferred embodiment, the JNK / NLRP3-related diseases include fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, central nervous system diseases, gout, etc.

[0022] In a preferred embodiment, the fibrosis includes, but is not limited to, pulmonary fibrosis; The neurodegenerative diseases mentioned include, but are not limited to, Alzheimer's disease; The inflammatory diseases include, but are not limited to, arthritis and heart inflammation; The tumors include, but are not limited to, lung cancer and liver cancer; The central nervous system diseases mentioned include, but are not limited to, cerebral ischemia-reperfusion.

[0023] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0024] Through extensive and in-depth research, the inventors unexpectedly discovered a series of compounds with JNK & NLRP3 inhibitory activity, enabling the preparation of therapeutic drugs for JNK & NLRP3-related diseases, thereby treating these diseases. These compounds possess novel structures, thus laying a new material basis for the treatment of JNK & NLRP3-related diseases, upon which this invention was completed.

[0025] Terminology Definition The terms used herein to refer to groups, substituents, or structures of compounds have the same meaning as understood by those skilled in the art. For clarity, the terms used in this specification are defined as follows.

[0026] In this invention, "a", "a type" or "a class" means at least one / a type or more than one / a type.

[0027] In this paper, expressions such as "C1-n" refer to groups having 1 to n carbon atoms. For example, "C1-10" indicates that a group has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; similarly, "C6~C10" indicates that a group has 6, 7, 8, 9, or 10 carbon atoms. Furthermore, the descriptions of the range of carbon atom counts in this paper also include sub-ranges. For instance, when referring to 1-10 carbon atoms, this paper also includes cases with 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms.

[0028] As used herein, the term "alkyl" has the same meaning as commonly understood by those skilled in the art, referring to various saturated or unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups. For example, the alkyl group referred to herein refers to a lower alkyl group with 1-10 carbon atoms; preferably a lower alkyl group with 1-8 carbon atoms; more preferably a lower alkyl group with 1-6 carbon atoms. In specific embodiments, the alkyl group referred to herein includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, etc. Similarly, the terms "alkenyl" or "alkynyl" as used herein refer to various unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups containing carbon-carbon double or triple bonds.

[0029] As used herein, the terms "aryl" or "aromatic ring" have the same meaning as commonly understood by those skilled in the art, referring to a cyclic conjugated aromatic system; for example, the term "C6-C10 aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms in the ring, such as phenyl or naphthyl. The term "heteroaryl," as used herein, refers to a cyclic conjugated aromatic system containing one or more heteroatoms such as N, O, or S in the ring; for example, pyridyl or pyrazinyl.

[0030] As used herein, the term "halogen" has the meaning commonly understood by one of ordinary skill in the art. In specific embodiments, halogen refers to fluorine, chlorine, bromine, or iodine.

[0031] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. A specific substituent may be a substituent described above or a specific substituent appearing in the various embodiments. Therefore, in this invention, the substituents in Formula 1 can each independently be the corresponding group in the specific compounds of the embodiments; that is, this invention includes combinations of the substituents in Formula 1 above, as well as combinations of some of the substituents shown in Formula 1 with other specific substituents appearing in the embodiments.

[0032] Unless otherwise specified, a substituted group may have a particular substituent at any substituted site on that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a common carbon atom.

[0033] In particular, the various substituents defined above also include groups formed by further substitution of these substituents, which may also contain other groups. For example, the hydrogen atoms on alkyl and aryl groups are replaced by amino, halogen, or other groups to become groups belonging to the above definitions.

[0034] In specific embodiments, "optionally substituted" means optionally substituted with one or more substituents selected from the following: cyano, halogen, hydroxyl, optionally substituted amino, nitro, carboxyl, ester, oxo, deuterated, optionally substituted C1-3 alkyl, optionally substituted C1-3 alkoxy, optionally substituted C1-3 acyloxy, optionally substituted C5-10 aryl or heteroaryl, optionally substituted 3-7 membered cycloalkyl or heterocyclic, optionally substituted sulfonyl, optionally substituted acyl.

[0035] The compounds of the present invention The inventors have designed a dual-target compound, which is a single-component compound that can act on two or more molecular targets simultaneously. This dual-target design strategy is of great significance for the treatment of complex diseases, such as cancer, metabolic diseases, autoimmune diseases, and neurodegenerative diseases. Compared with single-target drugs, dual-target compounds have several advantages: (1) Improved efficacy: By acting on multiple key aspects of the disease simultaneously, dual-target compounds may produce a synergistic effect, thereby improving the therapeutic effect; (2) Reduced drug resistance: Since the drug acts on multiple targets, disease cells need to generate drug resistance mutations on multiple targets simultaneously to evade the drug's effect, thus making it difficult to develop drug resistance; (3) Reduced side effects: The synergistic effect of dual targets can achieve therapeutic effects at lower doses, and side effects can be reduced by lowering the dose of single-target drugs; (4) Simplified treatment regimen: Compared with multi-drug combination therapy, dual-target compounds can simplify the treatment regimen, make it convenient for patients to take, and improve compliance.

[0036] Based on the inventors' understanding that the relationship between JNK and NLRP3 plays an important role in the occurrence and development of inflammatory diseases, the inventors have provided a pyrimidine derivative that targets and inhibits JNK and NLRP3, the structural formula of which is shown in Formula 1: 1 The substituents in the formula are as described above.

[0037] To achieve the objectives of this invention, the compounds of this invention can be formulated into pharmaceutical compositions comprising the above-described compounds or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

[0038] Furthermore, those skilled in the art will understand that the compound of the present invention is a JNK & NLRP3 inhibitor. In specific embodiments, the JNK & NLRP3 inhibitor of the present invention is a drug for treating and / or preventing JNK & NLRP3-related diseases. In specific embodiments, JNK & NLRP3-related diseases include, but are not limited to, neurodegenerative diseases, diabetes, inflammatory diseases, central nervous system diseases, fibrosis, gout, etc.

[0039] Based on conventional technical methods, those skilled in the art can prepare the compounds of this invention into various dosage forms and determine the dosage, administration method, and administration time according to the actual situation of the patient to be treated, including but not limited to age, gender, disease severity, and previous treatment history. Furthermore, given that the compounds of this invention possess therapeutic activity, they have the potential to be used as pharmaceuticals. Therefore, those skilled in the art can qualitatively and quantitatively detect various characteristics of the compounds of this invention as pharmaceuticals using conventional technical methods, including but not limited to therapeutic activity, toxicity, bioavailability, and drug-likeness. Performing these tests is obvious to those skilled in the art and requires no inventive effort.

[0040] Advantages of this invention: 1. The compounds of this invention exhibit excellent JNK inhibitory activity; 2. The compounds of the present invention exhibit excellent NLRP3 inhibitory activity; 3. The compounds of this invention lay a new material foundation for the development of therapeutic drugs for JNK & NLRP3-related diseases.

[0041] The technical solution of the present invention is further described below with reference to specific embodiments, but the following embodiments do not constitute a limitation of the present invention. All application methods based on the principles and technical means of the present invention are within the scope of the present invention.

[0042] Experimental methods in the following examples, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. There are no particular restrictions on the source of any raw materials used in this invention; they may be commercially available or prepared using conventional methods known to those skilled in the art.

[0043] Example Synthesis of intermediates Intermediate 1 Step 1: Dissolve 2,4-dichloro-5-bromopyrimidine (1 eq), 2-aminobenzamide (1.2 eq), and N,N-diisopropylethylamine (3 eq) in isopropanol, 90 o The reaction was stirred at C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with isopropanol to obtain a white to beige solid.

[0044] 1 H NMR (400 MHz, DMSO- d 6) δ 12.29 (s, 1H), 8.56 (s, 1H), 8.54 (dd, J =8.4, 1.1 Hz, 1H), 8.42 (s, 1H), 7.91 – 7.85 (m, 2H), 7.61 (ddd, J = 8.7, 7.4,1.5 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H). Step 2: Take the product from step 1 (1 eq), N-Boc-1,4-cyclohexanediamine (1.5 eq), and N,N-diisopropylethylamine (3 eq), dissolve them in N-methylpyrrolidone, seal and heat to 140°C. o C, react for 5 h. After the reaction is complete, extract with ethyl acetate / saturated brine, pass through silica gel column to give a pale yellow solid.

[0045] 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (s, 1H), 8.93 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.85 – 7.69 (m, 2H), 7.58 – 7.43 (m,1H), 7.08 (t, J = 7.5 Hz, 1H), 6.74 (m, 1H), 3.67 (m, 1H), 3.47 (m, 1H), 1.97– 1.47 (m, 8H), 1.39 (s, 9H). Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The ratio of the two solutions is 3:1, and the mixture is stirred at room temperature for 2 hours. After the reaction is complete, the liquid is removed by rotary evaporation and can be used directly for the next reaction.

[0046] Intermediate 2 Step 1: Same as step 1 of intermediate 1.

[0047] Step 2: Take the product from step 1 (1 eq), N-Boc-p-phenylenediamine (2 eq), and trifluoroacetic acid (3 eq) and dissolve them in sec-butanol, 110 o The reaction was stirred at C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with sec-butanol to obtain a purple solid.

[0048] Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 2 hours (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation to obtain a dark purple solid.

[0049] 1 H NMR (400 MHz, DMSO- d 6) δ 11.86 (s, 1H), 9.96 (s, 1H), 8.61 (s, 1H), 8.38 (d, J = 8.9 Hz, 2H), 7.88 – 7.80 (m, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.58– 7.48 (m, 2H), 7.41 (m, 1H), 7.36 – 7.30 (m, 2H), 7.21 – 7.14 (m, 1H). Intermediate 3 Step 1: 2-tert-butoxycarbonylamino-5-hydroxybenzoic acid (1 eq), ammonium chloride (3.25 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq), 1-hydroxybenzotriazole (1.65 eq), and N,N-diisopropylethylamine (6.5 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 16 h. After the reaction was completed, the mixture was extracted three times with ethyl acetate / water and filtered through a silica gel column to obtain a brown oily liquid.

[0050] 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 9.38 (s, 1H), 8.13 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.59 (s, 1H), 7.09 (d, J = 2.9 Hz, 1H), 6.89 (dd, J = 9.0, 2.8 Hz, 1H), 1.44 (s, 9H). Step 2: Dissolve the product from step 1 (1 eq), 1,2-dichloroethane (2 eq), and potassium carbonate (3 eq) in N,N-dimethylformamide at 80 °C. o The reaction was carried out at C for 16 h. After the reaction was completed, the sample was extracted three times with ethyl acetate / water and filtered through a silica gel column to obtain a white solid.

[0051] 1 H NMR (400 MHz, DMSO- d 6) δ 10.64 (s, 1H), 8.27 (s, 1H), 8.12 (d, J =9.2 Hz, 1H), 7.70 (s, 1H), 7.35 (d, J = 2.9 Hz, 1H), 7.12 (dd, J = 9.2, 2.9Hz, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.95 (t, J = 5.2 Hz, 2H), 1.46 (s, 9H). Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V三氟乙酸 The ratio of the two solutions was 3:1, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the liquid was removed by rotary evaporation and used directly in the next step.

[0052] Step 4: Dissolve 2,4-dichloro-5-bromopyrimidine (1 eq), the product of step 3 (1.2 eq), and N,N-diisopropylethylamine (3 eq) in isopropanol at 90°C. o The reaction was stirred at C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with isopropanol to obtain a white solid.

[0053] 1 H NMR (400 MHz, DMSO- d 6) δ 11.92 (s, 1H), 8.51 (s, 1H), 8.43 – 8.39 (m, 2H), 7.88 (s, 1H), 7.44 (d, J = 2.9 Hz, 1H), 7.26 (dd, J = 9.2, 2.9 Hz, 1H), 4.33 (dd, J = 6.0, 4.3 Hz, 2H), 3.99 (dd, J = 6.1, 4.1 Hz, 2H). Intermediate 4 Step 1: Dissolve 2,4-dichloro-5-bromopyrimidine (1 eq), 2-amino-N-methylbenzamide (1.2 eq), and N,N-diisopropylethylamine (3 eq) in isopropanol, 90 o The reaction was stirred at C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with isopropanol to obtain a white to beige solid.

[0054] 1 H NMR (400 MHz, DMSO- d 6) δ 12.02 (s, 1H), 8.98 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 8.48 (dd, J = 8.5, 1.2 Hz, 1H), 7.84 (dd, J = 7.9, 1.6 Hz, 1H), 7.60 (ddd,J = 8.6, 7.4, 1.5 Hz, 1H), 7.23 (td, J = 7.6, 1.2 Hz, 1H), 2.81(d, J = 4.5 Hz, 3H). Step 2: Take the product from step 1 (1 eq), N-Boc-1,4-cyclohexanediamine (1.5 eq), and N,N-diisopropylethylamine (3 eq), dissolve them in N-methylpyrrolidone, seal and heat to 140°C. o C, react for 5 h. After the reaction is complete, extract with ethyl acetate / saturated brine, pass through silica gel column to give a pale yellow solid.

[0055] 1 H NMR (400 MHz, DMSO- d 6) δ 11.30 (s, 1H), 8.72 (s, 2H), 8.08 (d, J =8.4 Hz, 1H), 7.71 (dd, J = 7.9, 1.6 Hz, 1H), 7.59 – 7.34 (m, 1H), 7.28 – 6.90(m, 2H), 6.74 (d, J = 21.2 Hz, 1H), 2.80 (d, J = 4.3 Hz, 3H), 2.00 – 1.46 (m,5H), 1.38 (d, J = 1.9 Hz, 12H), 1.26 (d, J = 12.0 Hz, 2H). Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The ratio of the two solutions is 3:1, and the mixture is stirred at room temperature for 2 hours. After the reaction is complete, the liquid is removed by rotary evaporation and can be used directly for the next reaction.

[0056] Intermediate 5 Step 1: Same as step 1 of intermediate 4.

[0057] Step 2: Take the product from step 1 (1 eq), N-Boc-p-phenylenediamine (2 eq), and trifluoroacetic acid (3 eq) and dissolve them in sec-butanol, 110 o The reaction was stirred at C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with sec-butanol to obtain a purple solid.

[0058] 1 H NMR (400 MHz, DMSO- d 6) δ 11.51 (s, 1H), 9.50 (s, 1H), 9.24 (s, 1H), 8.78 (q, J = 4.5 Hz, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.74 (dd, J = 7.9, 1.6Hz, 1H), 7.47 (t, J = 9.1 Hz, 3H), 7.36 (d, J = 8.6 Hz, 2H), 7.16 (td, J =7.6, 1.2 Hz, 1H), 2.81 (d, J = 4.5 Hz, 3H), 1.48 (s, 9H). Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 2 hours (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation to obtain a dark purple solid, which could be used directly in the next reaction.

[0059] Intermediate 6 Step 1: Ethyl 4H-thiophene[3,2-b]pyrrole-5-carboxylate (1 eq) was dissolved in ethanol, and hydrazine hydrate (10 eq) was added with stirring. o The reaction was carried out at C for 18 hours. After the reaction was completed, the mixture was filtered to obtain a white solid.

[0060] 1 H NMR (400 MHz, DMSO- d 6) δ 11.71 (s, 1H), 9.49 (s, 1H), 7.36 (d, J =5.2 Hz, 1H), 7.05 (d,J = 1.8 Hz, 1H), 6.97 – 6.93 (m, 1H), 4.40 (s, 2H). Step 2: Dissolve the product from step 1 (1 eq) and isobutyryl imide hydrochloride (1.2 eq) in DMF, stir vigorously for 5 min, and then add potassium tert-butoxide (2.2 eq). Place the mixture in a container preheated to 90°C. o The reaction was carried out in an oil bath at C for 1 hour. After the reaction was completed, the temperature was lowered to 0°C. o After C, water was added for quenching, and the mixture was acidified to pH 5. The solution was then extracted with dichloromethane and passed through a silica gel column to obtain a pale yellow solid.

[0061] 1 H NMR (400 MHz, DMSO- d 6) δ 11.79 (s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.48 (s, 1H), 3.64 (p, J = 6.7 Hz, 1H), 1.33 (s, 3H), 1.32 (s, 3H). Step 3: The product from step 2 (1 eq) and cesium carbonate (3 eq) were dissolved in DMF, and ethyl bromoacetate (1.2 eq) was added with stirring. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated brine, and the organic layer was evaporated to dryness and used directly in the next step.

[0062] Step 4: Dissolve the product from step 3 in a small amount of tetrahydrofuran, add 20% sodium hydroxide solution, and react overnight at room temperature. After the reaction is complete, acidify, filter, and obtain a white solid.

[0063] 1 H NMR (400 MHz, DMSO- d 6) δ 13.00 (s, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.54 (s, 1H), 4.65 (s, 2H), 3.66 (h, J= 6.6 Hz, 1H), 1.32 (d, J = 6.7 Hz, 6H). Intermediate 7 Step 1: Intermediate 6 (1 eq), N-Boc p-phenylenediamine (1.5 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.3 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 4 h. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with n-hexane / ethyl acetate to give a pale yellow solid.

[0064] 1 H NMR (400 MHz, DMSO- d 6) δ 10.07 (s, 1H), 9.30 (s, 1H), 7.83 (d, J =5.5 Hz, 1H), 7.60 (d, J = 5.5 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 4.75 (s, 2H), 3.67 (p, J = 6.7 Hz, 1H), 1.46(s, 9H), 1.33 (d, J = 6.7 Hz, 6H). Step 2: Dissolve the product from step 1 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The ratio of the two solutions was 3:1, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the liquid was removed by rotary evaporation and used directly in the next step.

[0065] Intermediate 8 Steps 1-2: Same as steps 1-2 for intermediate 6.

[0066] Step 3: Dissolve the product from step 2 (1 eq) and N-chlorosuccinimide (1.3 eq) in tetrahydrofuran at 60 °C. o After reacting at C for 18 h, the mixture was extracted with 1M sodium carbonate solution / ethyl acetate / saturated brine. After removing the liquid from the organic layer, the residue was slurried with cyclohexane / ethyl acetate to give a white to pale yellow solid.

[0067] 1 H NMR (400 MHz, DMSO- d 6) δ 11.86 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 3.58 (p, J = 6.6 Hz, 1H), 1.30 (d, J = 6.6 Hz, 6H). Step 4: The product from step 3 (1 eq) and cesium carbonate (3 eq) were dissolved in DMF, and ethyl bromoacetate (1.2 eq) was added with stirring. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated brine, and the organic layer was evaporated to dryness and used directly in the next step.

[0068] Step 5: Dissolve the product from step 4 in a small amount of tetrahydrofuran, add 20% sodium hydroxide solution, and react overnight at room temperature. After the reaction is complete, acidify, filter, and obtain a white solid.

[0069] 1 H NMR (400 MHz, DMSO- d 6) δ 13.02 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 4.65 (s, 2H), 3.61 (p, J = 6.7 Hz, 1H), 1.30 (d, J = 6.6 Hz, 6H). Intermediate 9 The raw material is ethyl indole-2-carboxylic acid, and the synthesis steps are the same as intermediate 6.

[0070] 1 H NMR (400 MHz, DMSO- d 6)) δ 12.62 (s, 1H), 7.65 (d, J= 8.7 Hz, 1H), 7.49 (dd, J = 8.0, 1.3 Hz, 1H), 7.16 – 7.08 (m, 2H), 7.01 (t, J = 7.5 Hz,1H), 4.22 (s, 2H), 3.44 (hept, J = 6.6 Hz, 1H), 0.93 (s, 3H), 0.91 (s, 3H). Intermediate 10 The raw material is ethyl 6H-thiopheno[2,3-B]pyrrole-5-carboxylic acid, and the synthesis steps are the same as intermediate 6.

[0071] 1 H NMR (400 MHz, DMSO- d 6) δ 13.03 (s, 1H), 7.60 (d, J = 5.4 Hz, 1H),7.40 (s, 1H), 7.32 (d, J = 5.4 Hz, 1H), 4.66 (s, 2H), 3.39 (q, J = 6.6 Hz,1H), 1.36 (s, 3H), 1.35 (s, 3H). Intermediate 11 and Intermediate 12 , Step 1: Same as intermediate 1 Step 2: Take the product from step 1 (1 eq), N-Boc-1,4-cyclohexanediamine (1.5 eq, cis or trans), and N,N-diisopropylethylamine (3 eq) and dissolve them in N-methylpyrrolidone. Seal and heat to 140°C. o C, react for 5 h. After the reaction is complete, extract with ethyl acetate / saturated brine, pass through silica gel column to give a pale yellow solid.

[0072] 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (s, 1H), 8.85 (m, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.78 (dd, J= 7.9, 1.6 Hz, 1H), 7.71 (s, 1H), 7.49 (ddd, J =8.7, 7.2, 1.6 Hz, 1H), 7.08 (td, J = 7.5, 1.2 Hz, 1H), 7.01 – 6.83 (m, 1H), 6.71 (s, 1H), 3.68 (m, 1H), 3.43 (m, 1H), 1.76 – 1.48 (m, 6H), 1.39 (m, 11H). 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (s, 1H), 9.11 – 8.57 (m, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.50 (m, 1H),7.04 (m, 2H), 6.76 (s, 1H), 3.51 (m, 1H), 3.15 (m, 1H), 2.04 – 1.64 (m, 3H),1.38 (m, 14H). Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The ratio of the two solutions is 3:1, and the mixture is stirred at room temperature for 2 hours. After the reaction is complete, the liquid is removed by rotary evaporation and can be used directly for the next reaction.

[0073] Intermediate 13 The raw material is 3-ethoxycarbonylpyrazole, and the synthesis steps are the same as intermediate 6.

[0074] 1 H NMR (400 MHz, DMSO- d 6) δ 13.14 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 4.71 (s, 2H), 3.64 (p, J = 6.8 Hz, 1H), 1.33 (d,J = 6.9 Hz, 6H). Intermediate 14 The starting material is ethyl 5-cyclopropyl-1H-pyrazole-3-carboxylate, and the synthesis steps are the same as those for intermediate 6.

[0075] 1 H NMR (400 MHz, DMSO- d 6) δ 13.14 (s, 1H), 7.00 (s, 1H), 4.67 (s, 2H), 3.56 (hept, J = 6.8 Hz, 1H), 2.14 (tt, J = 8.4, 5.0 Hz, 1H), 1.30 (d, J = 6.9Hz, 6H), 1.11 – 1.01 (m, 2H), 0.91 – 0.81 (m, 2H). Intermediate 15 Steps 1-3: Same as steps 1-3 for intermediate 6.

[0076] Step 4: Dissolve the product from step 3 (1 eq) in ethanol, and add hydrazine hydrate (10 eq) with stirring. o The reaction was carried out at C for 18 hours. After the reaction was completed, the mixture was filtered to obtain a white solid.

[0077] 1 H NMR (400 MHz, DMSO- d 6) δ 9.19 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 7.50 (s, 1H), 4.54 (s, 2H), 4.27 (s, 2H), 3.63 (p, J = 6.7 Hz, 1H), 1.31 (d, J = 6.7 Hz, 6H). Step 5: Take the product from step 4 (1 eq) and N,N'-carbonyldiimidazole (CDI, 1.2 eq) and dissolve them in 1,4-dioxane, 100o The reaction was carried out at C for 18 hours. After the reaction was completed, water was added and the mixture was filtered to obtain a white solid.

[0078] 1 H NMR (400 MHz, DMSO- d 6) δ 12.38 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.59 (t, J = 2.7 Hz, 2H), 5.11 (s, 2H), 3.66 (p, J = 6.6 Hz, 1H), 1.30 (d, J = 6.6 Hz, 6H). Intermediate 16 The raw material is ethyl pyrrole-2-carboxylate, and the synthesis steps are the same as intermediate 6.

[0079] 1 H NMR (400 MHz, DMSO- d 6) δ 12.82 (s, 1H), 7.16 (t, J = 2.2 Hz, 1H), 6.83 (dd, J = 3.9, 1.7 Hz, 1H), 6.23 (dd, J = 3.9, 2.6 Hz, 1H), 5.15 (s, 2H), 3.20 (h, J = 6.9 Hz, 1H), 1.32 (d, J = 7.0 Hz, 6H). Intermediate 17 Step 1: 2,4-Dichloro-7H-pyrrolo[2,3-D]pyrimidine (1 eq), 4-dimethylaminopyridine (0.1 eq), and triethylamine (5 eq) were dissolved in N,N-dimethylformamide. After stirring for 5 minutes, p-toluenesulfonyl chloride (1.1 eq), dissolved in N,N-dimethylformamide, was added dropwise. The reaction was continued for 0.5 h after the addition was complete. After the reaction was complete, water was added and the mixture was filtered to obtain a pale yellow solid.

[0080] 1 H NMR (500 MHz, DMSO) δ 8.12 (d, J= 4.0 Hz, 1H), 8.07 – 8.01 (m,2H), 7.51 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 4.0 Hz, 1H), 2.39 (s, 3H). Step 2: Methyl anthranilate (1 eq) was dissolved in tetrahydrofuran and methanol (V 四氢呋喃 V 甲醇 In a mixed solution of (1:1), a 30% sodium hydroxide aqueous solution was added, and the mixture was refluxed at 80°C for 3 h. After the reaction was complete, the solution was acidified and filtered to obtain anthranilic acid.

[0081] 1 H NMR (500 MHz, DMSO) δ 8.54 (s, 2H), 7.68 (dd, J = 8.1, 1.7 Hz, 1H), 7.22 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 6.73 (dd, J = 8.4, 1.1 Hz, 1H), 6.50 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H). The product from step 1 (1 eq), aminobenzoic acid (1.2 eq), and N,N-diisopropylethylamine (1.2 eq) were dissolved in isopropanol and reacted overnight at 90°C. After the reaction was complete, the mixture was filtered, and the residue was washed three times with isopropanol to obtain a yellow solid.

[0082] 1 H NMR (400 MHz, DMSO) δ 11.51 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.00 (t, J = 7.9 Hz, 3H), 7.78 (d, J = 3.9 Hz, 1H), 7.65 (td, J = 7.8, 1.7Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 4.0Hz, 1H), 2.39 (s, 3H). Step 3: The product from step 2 (1 eq) was dissolved in a mixed solution of tetrahydrofuran and N,N-dimethylformamide, and oxalyl chloride (2 eq) was added dropwise with stirring. After the reaction was complete, water was added and the mixture was filtered to obtain a light green solid.

[0083] 1 H NMR (400 MHz, DMSO) δ 9.29 (d, J = 8.9 Hz, 1H), 8.17 (dd, J = 7.9, 1.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.86 (ddd, J = 9.0, 7.2, 1.8 Hz, 1H),7.60 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 4.2 Hz, 1H), 7.08 (d, J = 4.3 Hz, 1H), 2.39 (s, 3H). Step 4: The product from step 3 (1 eq), N-Boc-1,4-cyclohexanediamine (1.1 eq), and N,N-diisopropylethylamine (2.5 eq) were dissolved in N-methylpyrrolidone and reacted at 80 °C for 0.5 h. After the reaction was complete, water was added and the mixture was filtered to obtain a yellow solid.

[0084] Step 5: Take the product from step 4 (1 eq), dissolve it in tetrahydrofuran in 28% ammonium hydroxide aqueous solution (10 eq), and react at 70°C overnight. After the reaction is complete, extract with dichloromethane / saturated brine, and pass through a silica gel column to give a pale yellow solid.

[0085] 1 H NMR (400 MHz, DMSO) δ 12.08 (s, 1H), 8.96 (s, 1H), 8.30 (s, 1H), 7.98 (s, 2H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.74 (s, 1H), 7.45 (dd,J =15.6, 7.6 Hz, 3H), 7.29 (d, J = 4.0 Hz, 1H), 7.09 – 6.94 (m, 1H), 6.69 (s,1H), 6.44 (dd, J = 4.1, 2.3 Hz, 1H), 3.63 (m, 1H), 2.38 (d, J = 5.8 Hz, 3H), 2.03 – 1.55 (m, 4H), 1.41 (s, 9H). Step 6: Dissolve the product from step 5 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 0.5 h (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation and the mixture could be used directly for the next reaction.

[0086] Intermediate 18 and Intermediate 19 , Steps 1-6: Same as intermediate 17. Step 4 uses trans- or cis-N-Boc-1,4-cyclohexanediamine as the starting material, and Step 5 yields the product... 1 H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 8.97 (s, 1H), 8.31 (s, 1H), 7.98 (s, 2H), 7.89 – 7.68 (m, 2H), 7.46 (d, J = 8.1 Hz, 3H), 7.30 (s, 1H),7.15 – 6.71 (m, 3H), 6.44 (d, J = 4.0 Hz, 1H), 3.60 (s, 1H), 2.39 (s, 3H), 1.95 (d, J = 29.8 Hz, 5H), 1.41 (s, 9H). 1 H NMR (400 MHz, DMSO) δ 12.08 (s, 1H), 8.97 (s, 1H), 8.30 (s, 1H), 7.99 (s, 2H), 7.83 (dd, J= 7.9, 1.6 Hz, 1H), 7.74 (s, 1H), 7.53 – 7.40 (m,3H), 7.29 (d, J = 4.0 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.69 (s, 2H), 6.44(d, J = 4.0 Hz, 1H), 3.76 (s, 1H), 3.50 (s, 1H), 2.38 (s, 3H), 1.94 – 1.52(m, 8H), 1.40 (s, 9H). Intermediate 20 Step 1: 2,4-Dichloropyrimidine-5-carboxamide (1 eq), 3-aminocyclohexanol (1.1 eq), and N,N-diisopropylethylamine (1.5 eq) were dissolved in isopropanol and reacted overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated brine and filtered through a silica gel column to give a white solid.

[0087] 1 H NMR (400 MHz, DMSO) δ 9.36 (d, J = 8.2 Hz, 1H), 8.57 (s, 1H), 8.23(s, 1H), 7.70 (s, 1H), 4.61 (d, J = 3.6 Hz, 1H), 4.31 (qt, J = 8.1, 3.5 Hz, 1H), 3.83 (d, J = 6.3 Hz, 1H), 1.85 – 1.25 (m, 8H). Step 2: The product from step 1 (1 eq), N-Boc-1,4-cyclohexanediamine (1.5 eq), and N,N-diisopropylethylamine (2.5 eq) were dissolved in N-methylpyrrolidone, sealed, and heated to 140 °C for 5 h. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated brine and filtered through a silica gel column to obtain a pale yellow solid.

[0088] 1 H NMR (400 MHz, DMSO) δ 9.04 (d, J= 7.9 Hz, 1H), 8.34 (d, J = 8.1Hz, 1H), 7.60 (s, 1H), 7.13 – 6.42 (m, 2H), 4.51 (d, J = 3.6 Hz, 1H), 4.30(d, J = 29.2 Hz, 1H), 3.80 (s, 1H), 2.01 – 1.85 (m, 1H), 1.80 – 1.51 (m,13H), 1.38 (d, J = 5.2 Hz, 11H). Step 3: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 0.5 h (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation and the mixture could be used directly for the next reaction.

[0089] Intermediate 21 Step 1: Same as step 1 of intermediate 1.

[0090] Step 2: The product from step 1 (1 eq), 4-fluoro-3-nitroaniline (2 eq), and trifluoroacetic acid (3 eq) were dissolved in sec-butanol and reacted with stirring at 100 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with sec-butanol to obtain an orange solid.

[0091] 1 H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 10.05 (s, 1H), 8.67 – 8.48(m, 2H), 8.40 (s, 1H), 8.35 (s, 1H), 8.01 (dt, J = 9.1, 3.4 Hz, 1H), 7.86 –7.78 (m, 2H), 7.59 – 7.43 (m, 2H), 7.16 (td, J = 7.6, 1.1 Hz, 1H). Step 3: The product from step 2 (1 eq), N,N,N'-trimethylethylenediamine (1.2 eq), and potassium carbonate (2 eq) were dissolved in N,N-dimethylformamide and reacted at 60 °C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was filtered to obtain a red solid.

[0092] 1 H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 9.63 (s, 1H), 8.64 (s, 1H), 8.31 (d, J = 2.9 Hz, 2H), 8.12 (s, 1H), 7.84 – 7.75 (m, 2H), 7.70 (dd, J =9.0, 2.6 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 9.1 Hz, 1H), 7.12(td, J = 7.6, 1.2 Hz, 1H), 3.09 (dd, J = 8.3, 5.9 Hz, 2H), 2.74 (s, 3H), 2.34(t, J = 7.1 Hz, 2H), 2.10 (s, 6H). Step 4: The product from step 3 (1 eq) and Pd / C (0.1 eq) were dissolved in methanol and reacted at room temperature for 1 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and washed three times with methanol. The filtrates were combined and the liquid was removed by rotary evaporation, and the solution was passed through a silica gel column to obtain a brown solid.

[0093] 1 H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 9.14 (s, 1H), 8.83 (d, J =8.4 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.83 – 7.72 (m, 2H), 7.48 (ddd, J =8.6, 7.3, 1.6 Hz, 1H), 7.10 (td, J = 7.5, 1.2 Hz, 1H), 6.94 – 6.85 (m, 2H), 6.80 (dd, J= 8.5, 2.4 Hz, 1H), 3.09 – 2.96 (m, 2H), 2.56 (s, 6H). Intermediate 22 Step 1: 2,4-Dichloropyrimidin-5-carboxamide (1 eq), (R)-1-tert-butoxycarbonyl-3-aminopiperidine (1.1 eq), and N,N-diisopropylethylamine (1.5 eq) were dissolved in isopropanol and reacted at room temperature for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated brine and filtered through a silica gel column to obtain a white solid.

[0094] 1 H NMR (400 MHz, DMSO) δ 9.47 (d, J = 7.2 Hz, 1H), 8.62 (s, 1H), 8.24(s, 1H), 7.71 (s, 1H), 3.95 (s, 1H), 3.72 – 3.61 (m, 1H), 3.15 (s, 1H), 2.90– 2.59 (m, 1H), 1.86 (tq, J = 8.5, 5.3 Hz, 2H), 1.72 – 1.51 (m, 3H), 1.34 –1.17 (m, 9H). Step 2: The product from step 1 (1 eq), 1,4-cyclohexanediamine (2.5 eq), and N,N-diisopropylethylamine (2.5 eq) were dissolved in N,N-dimethylformamide and stirred at 50 °C for 3 h. After the reaction was complete, the mixture was extracted with ethyl acetate / saturated brine and filtered through a silica gel column to obtain a pale yellow solid.

[0095] 1 H NMR (400 MHz, DMSO) δ 9.15 (d, J = 38.2 Hz, 1H), 8.39 (s, 1H), 6.99 (s, 1H), 3.86 (d, J = 37.6 Hz, 3H), 3.68 – 3.16 (m, 8H), 2.90 (d, J=6.2 Hz, 3H), 1.84 (s, 1H), 1.56 (s, 5H), 1.31 – 1.11 (m, 7H), 1.07 – 0.86 (m, 1H). Intermediate 23 Steps 1-2: Same as intermediate 22. The raw material for step 1 is 4-amino-1-tert-butoxycarbonylpiperidine.

[0096] 1 H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.37 (s, 1H), 7.00 (s, 1H), 3.99 (s, 1H), 3.81 (d, J = 13.0 Hz, 3H), 2.93 (d, J = 13.6 Hz, 3H), 1.89 (s,1H), 1.54 (s, 6H), 1.40 (s, 9H), 1.36 – 1.18 (m, 3H), 0.94 (dd, J = 6.9, 5.6Hz, 2H).z Intermediate 24 Step 1: Intermediate 3 (1 eq) and trans-(4-aminocyclohexyl)carbamate tert-butyl ester (1.5 eq) were dissolved in N-methylpyrrolidone, sealed, and heated to 140 °C for 5 h. After the reaction was completed, water was added and the mixture was filtered to obtain a pale yellow solid.

[0097] 1 H NMR (400 MHz, DMSO) δ 11.27 (s, 1H), 8.73 (dd, J = 37.9, 15.2 Hz,1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.38 (d, J = 3.0 Hz, 1H), 7.09(d, J = 29.9 Hz, 1H), 6.76 (s, 1H), 4.32 (d, J = 5.4 Hz, 2H), 4.00 (d, J=7.5 Hz, 1H), 3.73 – 3.43 (m, 1H), 3.27 – 3.06 (m, 1H), 1.87 (d, J = 46.4 Hz, 5H), 1.39 (s, 9H), 1.27 – 1.22 (m, 4H). Step 2: Dissolve the product from step 2 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 0.5 h (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation and the mixture could be used directly for the next reaction.

[0098] Intermediate 25 Steps 1-4: Same as intermediate 3, except that the starting material for step 2 is 1,3-dichloropropane, and the product for step 4 is... 1 H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.50 (s, 1H), 8.44 – 8.36 (m,2H), 7.87 (s, 1H), 7.42 (d, J = 2.9 Hz, 1H), 7.24 (dd, J = 9.2, 2.9 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.82 (t, J = 6.4 Hz, 2H), 2.20 (p, J = 6.2 Hz, 2H). Step 5: The product from step 4 (1 eq), N-Boc-p-phenylenediamine (2 eq), and trifluoroacetic acid (3 eq) were dissolved in sec-butanol and reacted with stirring at 100 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the residue was washed three times with sec-butanol to obtain an orange solid.

[0099] 1 H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 9.88 (s, 1H), 9.36 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 7.41 (t, J= 3.2 Hz, 5H), 7.02 (dd, J = 9.1, 2.9 Hz, 1H), 4.18 (t, J = 5.9 Hz, 2H), 3.82 (t, J = 6.4 Hz, 2H), 2.20 (p, J = 6.1 Hz, 2H), 1.49 (s, 9H). Step 6: Dissolve the product from step 5 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 0.5 h (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation and the mixture could be used directly for the next reaction.

[0100] Intermediate 26 Steps 1-6: Same as intermediate 25, except that the starting material for step 1 is 1,4-dichlorobutane. Step 4 product. 1 H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 8.49 (s, 1H), 8.38 (d, J =9.4 Hz, 2H), 7.84 (s, 1H), 7.41 (d, J = 2.9 Hz, 1H), 7.22 (dd, J = 9.2, 2.9Hz, 1H), 4.08 (t, J = 5.8 Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 1.96 – 1.82 (m,4H). Intermediate 27 Steps 1-4: Same as intermediate 21, where the raw material in step 3 is N,N-dimethylethylenediamine.

[0101] 1 H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 8.84 (d, J = 31.3 Hz, 2H), 8.24 (s, 1H), 8.16 (s, 1H), 7.77 (dd, J= 7.9, 1.6 Hz, 1H), 7.69 (s, 1H),7.43 (t, J = 7.8 Hz, 1H), 7.10 – 7.02 (m, 1H), 6.81 – 6.69 (m, 2H), 6.40 (d, J = 8.4 Hz, 1H), 4.46 (s, 2H), 3.08 (t, J = 6.5 Hz, 2H), 2.21 (s, 6H). Intermediate 28 Step 1: Same as step 1 of intermediate 1.

[0102] Step 2: Same as step 2 of intermediate 21.

[0103] Step 3: N,N-dimethylethanolamine (4 eq) was dissolved in acetonitrile, sodium hydride (4 eq) was added, and the mixture was stirred at room temperature for 20 min. Then, the product from step 2 (1 eq) was added, and the mixture was reacted at 60 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was filtered to obtain a red solid.

[0104] 1 H NMR (500 MHz, DMSO) δ 11.68 (s, 1H), 9.66 (s, 1H), 8.63 (s, 1H), 8.31 (d, J = 13.3 Hz, 2H), 8.24 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.76 (s,1H), 7.44 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 4.20 (t, J = 5.8 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.22 (s, 6H). Step 4: The product from step 3 (1 eq) and Pd / C (0.1 eq) were dissolved in methanol and reacted at room temperature for 1 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and washed three times with methanol. The filtrates were combined and the liquid was removed by vortexing to give an orange-red solid.

[0105] Example 1: Synthesis of compound B29 Intermediate 1 (1 eq), intermediate 6 (1 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.3 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 4 h. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with ethyl acetate / methanol to give a pale yellow solid.

[0106] 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (m, 1H), 8.76 (m, 1H), 8.27 (s, 1H), 8.09 (d, J = 11.2 Hz, 1H), 7.99 (dd, J = 21.0, 7.4 Hz, 1H), 7.80 (ddd, J =15.1, 6.7, 2.6 Hz, 2H), 7.72 (s, 1H), 7.59 (t, J MS (ESI): m / z 680.16 [M+H] + . Example 2: Synthesis of compound B33 The raw materials are intermediate 2 and intermediate 6, and the rest are the same as in Example 1.

[0107] 1 H NMR (400 MHz, DMSO- d 6) δ 11.95 (s, 1H), 10.25 (s, 1H), 9.87 (s, 1H), 8.59 (s, 1H), 8.35 (d, J= 10.0 Hz, 2H), 7.87 – 7.80 (m, 3H), 7.61 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 6.1 Hz, 5H), 7.45 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 4.80 (s, 2H), 3.68 (p, J = 6.7 Hz, 1H), 1.35 (s, 3H), 1.33 (s,3H). MS (ESI): m / z 674.11 [M+H] + . Example 3: Synthesis of compound B34 Step 1: Intermediate 3 (1 eq), intermediate 7 (2 eq), and trifluoroacetic acid (3 eq) were dissolved in sec-butanol, 110 o The mixture was stirred at C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the residue was washed three times with sec-butanol to obtain a brown solid.

[0108] 1 H NMR (400 MHz, DMSO- d 6) δ 11.97 (s, 1H), 10.37 (s, 1H), 10.28 –10.17 (m, 2H), 8.39 (d, J = 25.7 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J = 5.5 Hz,1H), 7.63 – 7.56 (m, 3H), 7.55 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 2.9 Hz, 1H), 7.03 (dd, J = 9.3, 2.8 Hz, 1H), 4.81 (s, 2H), 4.30 (t, J = 5.1Hz, 2H), 3.90 (t, J = 5.1 Hz, 2H), 3.68 (p, J= 6.6 Hz, 1H), 1.35 (s, 3H), 1.33 (s, 3H). Step 2: Dissolve the product from step 1 (1 eq), dimethylamine aqueous solution (5 eq), potassium carbonate (5 eq), and potassium iodide (0.1 eq) in N,N-dimethylformamide, 100 o The reaction was carried out at C for 16 h. After the reaction was completed, water was added to quench the reaction. After adding excess water, a solid precipitated out. The solid was filtered and then slurried with ethyl acetate / methanol to obtain a brown solid.

[0109] 1 H NMR (400 MHz, DMSO- d 6) δ 11.18 (s, 1H), 10.11 (s, 1H), 9.39 (s,1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.75(s, 1H), 7.61 (d, J = 5.6 Hz, 1H), 7.58 – 7.53 (m, 3H), 7.47 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 2.9 Hz, 1H), 7.04 (dd, J = 9.2, 2.9 Hz, 1H), 4.77 (s, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.67 (p, J = 6.6 Hz, 1H), 2.12 (s, 6H), 1.35 (s, 3H), 1.33 (s, 3H). MS (ESI): m / z 761.18 [M+H] + . Example 4: Synthesis of compounds B36, B70, and B71 The raw materials are intermediate 1 and intermediate 8, and the rest are the same as in Example 1.

[0110] 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (m, 1H), 8.84 (m, 1H), 8.26 (s, 1H), 8.09 (d,J = 9.6 Hz, 1H), 7.98 (dd, J = 19.0, 7.4 Hz, 1H), 7.80 (dd, J =12.4, 5.9 Hz, 2H), 7.72 (s, 1H), 7.52 – 7.43 (m, 2H), 7.16 – 7.03 (m, 2H),4.56 (d, J = 16.4 Hz, 2H), 3.73 (m, 1H), 3.59 (m, 2H), 1.78 (m, 6H), 1.29 (m,8H). MS (ESI): m / z 714.12 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.50 (s, 1H), 8.80 (m, 1H), 8.18 (s, 1H),8.03 (s, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.72 (d, J = 15.1 Hz, 2H), 7.63 (s,1H), 7.45 – 7.38 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), 4.51 (s, 2H), 3.79 – 3.45(m, 3H), 1.65 (s, 6H), 1.50 (s, 2H), 1.22 (s, 6H). MS (ESI): m / z 714.12 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.46 (s, 1H), 8.77 (m, 1H), 8.21 (s, 1H),7.96 (m, 1H), 7.74 (d, J = 19.8 Hz, 2H), 7.48 – 7.29 (m, 2H), 7.05 (d, J=28.1 Hz, 2H), 4.47 (s, 2H), 3.53 (s, 3H), 1.84 (m, 4H). MS (ESI): m / z 714.12[M+H] + . Example 5: Synthesis of compound B37 The raw materials are intermediate 2 and intermediate 8, and the rest are the same as in Example 1.

[0111] 1 H NMR (400 MHz, DMSO- d 6) δ 12.13 (s, 1H), 10.34 (s, 1H), 10.10 (s, 1H), 8.53 (s, 1H), 8.39 (d, J = 11.1 Hz, 2H), 7.89 – 7.81 (m, 3H), 7.57 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 7.7 Hz, 3H), 7.44 (t, J = 7.9 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 4.80 (s, 2H), 1.32 (s, 3H), 1.31 (s, 3H). MS (ESI): m / z 708.07 [M+H] + . Example 6: Synthesis of compounds B38, B72, and B73 The raw materials are intermediate 4 and intermediate 6, and the rest are the same as in Example 1.

[0112] 1 H NMR (400 MHz, DMSO- d 6) δ 11.27 (m, 1H), 8.72 (m, 1H), 8.08 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.83 (m, 2H), 7.71 (s, 1H), 7.60 (d, J= 5.5 Hz,1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.15 – 7.07 (m, 2H), 4.55 (s, 2H), 3.71 –3.50 (m, 3H), 2.80 (d, J = 4.3 Hz, 3H), 2.03 – 1.76 (m, 6H), 1.31 (m, 8H). MS(ESI): m / z 694.17 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.29 (s, 1H), 8.71 (d, J = 4.7 Hz, 1H),8.10 (s, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.82 (dd, J = 5.5, 2.5 Hz, 2H), 7.71(dd, J = 7.9, 1.6 Hz, 1H), 7.58 (dd, J = 5.7, 2.2 Hz, 1H), 7.53 – 7.45 (m,2H), 7.13 – 7.06 (m, 1H), 4.59 (s, 2H), 3.76 (s, 1H), 3.65 (pd, J = 6.6, 2.9Hz, 1H), 2.81 (d, J = 4.5 Hz, 3H), 1.75 – 1.70 (m, 6H), 1.60 – 1.58 (m, 2H),1.32 (t, J = 3.4 Hz, 6H). MS (ESI): m / z 694.17 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.27 (s, 1H), 8.79 (m, 2H), 8.08 (s, 1H),7.92 (dd, J= 19.8, 7.9 Hz, 1H), 7.84 – 7.66 (m, 2H), 7.59 (d, J = 5.7 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 7.7 Hz,1H), 4.55 (s, 2H), 3.65 (p, J = 6.8 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.02 –1.74 (m, 5H), 1.33 (d, J = 6.5 Hz, 9H). MS (ESI): m / z 694.17 [M+H] + . Example 7: Synthesis of compound B39 The raw materials are intermediates 5 and 6, and the rest are the same as in Example 1.

[0113] 1 H NMR (400 MHz, DMSO- d 6) δ 11.65 (s, 1H), 10.22 (s, 1H), 9.81 (s,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.84 (d, J = 5.5Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 5H), 7.45 (t, J = 7.9 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 4.79 (s,2H), 3.49 (h, J = 6.2 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H), 1.35 (s, 3H), 1.33(s, 3H). MS (ESI): m / z 688.13 [M+H] + . Example 8: Synthesis of compounds B40, B74, and B75 The raw materials are intermediate 4 and intermediate 8, and the rest are the same as in Example 1.

[0114] 1 H NMR (400 MHz, DMSO- d 6) δ 11.28 (m, 1H), 8.73 (m, 1H), 8.09 (d, J =10.9 Hz, 1H), 7.99 (dd, J = 20.1, 7.3 Hz, 1H), 7.85 – 7.79 (m, 2H), 7.71 (dd, J = 7.9, 1.6 Hz, 1H), 7.47 (d, J = 5.6 Hz, 2H), 7.09 (t, J = 7.6 Hz, 2H), 4.56 (d, J = 16.4 Hz, 2H), 3.81 – 3.49 (m, 3H), 2.80 (d, J = 4.4 Hz, 3H),1.77 (m, 6H), 1.29 (m, 8H). MS (ESI): m / z 728.14 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.30 (s, 1H), 8.71 (q, J = 4.7 Hz, 1H),8.10 (s, 1H), 7.99 (d, J = 6.6 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.71 (dd, J = 7.9, 1.6 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.09 (td, J= 7.5, 1.2 Hz, 1H), 4.58(s, 2H), 3.76 (s, 1H), 3.68 (s, 1H), 3.62 – 3.56 (m, 1H), 2.81 (d, J = 4.5Hz, 3H), 1.74 – 1.69 (m, 6H), 1.57 (d, J = 6.1 Hz, 2H), 1.29 (d, J = 6.6 Hz,6H). MS (ESI): m / z 728.14 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.29 (s, 1H), 8.80 (m, 2H), 8.15 – 7.60 (m, 4H), 7.48 (s, 2H), 7.05 (m, 2H), 4.53 (s, 2H), 3.59 (s, 3H), 2.80 (s,3H), 2.03 – 1.80 (m, 6H). MS (ESI): m / z 728.14 [M+H] + . Example 9: Synthesis of compound B41 The raw materials are intermediate 1 and intermediate 9, and the rest are the same as in Example 1.

[0115] 1 H NMR (400 MHz, DMSO- d 6) δ 11.52 (m, 1H), 8.76 (m, 1H), 8.27 (s, 1H), 8.09 (t, J = 8.2 Hz, 2H), 7.97 (dd, J = 19.7, 7.9 Hz, 2H), 7.85 – 7.66 (m,2H), 7.64 – 7.35 (m, 3H), 7.26 – 6.91 (m, 3H), 4.56 (m, 2H), 3.98 – 3.76 (m,1H), 3.60 (m, 2H), 2.23 – 1.59 (m, 6H), 1.37 (m, 8H). MS (ESI): m / z672.20 [M+H] + . Example 10: Synthesis of compound B42 The raw materials are intermediate 1 and intermediate 10, and the rest are the same as in Example 1.

[0116] 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (m, 1H), 8.84 (m, 1H), 8.27 (s, 1H), 8.09 (d, J = 9.9 Hz, 1H), 7.98 (dd, J = 22.1, 7.4 Hz, 1H), 7.84 – 7.76 (m,1H), 7.72 (s, 1H), 7.59 (dd, J = 5.5, 2.8 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 5.8 Hz, 1H), 7.32 (dd, J = 5.5, 3.6 Hz, 1H), 7.08 (m, 2H), 4.57(m, 2H), 3.83 – 3.43 (m, 3H), 1.72 (m, 6H), 1.35 (m, 8H). MS (ESI): m / z 680.16 [M+H] + . Example 11: Synthesis of compound B43 The raw materials are intermediate 6 and intermediate 11, and the rest are the same as in Example 1.

[0117] 1 H NMR (400 MHz, DMSO- d 6) δ 11.56 (s, 1H), 8.87 (m, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 7.0 Hz, 1H), 7.86 – 7.75 (m, 2H), 7.72 (s, 1H), 7.58 (d, J= 5.5 Hz, 1H), 7.55 – 7.44 (m, 2H), 7.18 – 7.03 (m, 2H), 4.59 (s,2H), 3.80 – 3.58 (m, 3H), 1.65 (m, 8H), 1.32 (s, 3H), 1.30 (s, 3H). MS (ESI): m / z 680.16 [M+H] + . Example 12: Synthesis of compound B44 The raw materials are intermediate 6 and intermediate 12, and the rest are the same as in Example 1.

[0118] 1 H NMR (400 MHz, DMSO- d 6) δ 11.55 (m, 1H), 9.12 – 8.60 (m, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.81 (dd, J = 12.8, 6.9 Hz,2H), 7.73 (s, 1H), 7.59 (t, J = 5.4 Hz, 1H), 7.51 (d, J = 6.2 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.17 – 6.95 (m, 2H), 4.53 (d, J = 11.8 Hz, 2H), 3.64 (m,3H), 2.08 – 1.68 (m, 4H), 1.32 (m, 10H). MS (ESI): m / z 680.16 [M+H] + . Example 13: Synthesis of compound B45 The raw materials are intermediate 1 and intermediate 13, and the rest are the same as in Example 1.

[0119] 1 H NMR (400 MHz, DMSO- d6) δ 11.56 (s, 1H), 8.84 (m, 1H), 8.28 – 8.16 (m, 2H), 8.12 – 7.95 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.54 –7.40 (m, 1H), 7.24 (dd, J = 5.9, 2.0 Hz, 1H), 7.14 – 7.01 (m, 2H), 4.61 (d, J = 17.0 Hz, 2H), 3.95 – 3.44 (m, 3H), 1.77 (m, 6H), 1.33 (m, 8H). MS (ESI): m / z 623.18 [M+H] + . Example 14: Synthesis of compound B46 The raw materials are intermediate 1 and intermediate 14, and the rest are the same as in Example 1.

[0120] 1 H NMR (400 MHz, DMSO- d 6) δ 11.56 (s, 1H), 8.84 (m, 1H), 8.25 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.97 (dd, J = 23.0, 7.4 Hz, 1H), 7.79 (d, J = 7.7Hz, 1H), 7.70 (s, 1H), 7.54 – 7.39 (m, 1H), 7.08 (t, J = 7.6 Hz, 2H), 6.96(d, J = 6.6 Hz, 1H), 4.57 (d, J = 16.6 Hz, 2H), 3.85 – 3.45 (m, 3H), 2.14(dt, J = 8.4, 4.4 Hz, 1H), 1.77 (m, 6H), 1.30 (m, 8H), 1.10 – 0.99 (m, 2H),0.87 (m, 2H). MS (ESI): m / z 663.22 [M+H] +. Example 15: Synthesis of compounds B47, B76, and B77 Intermediate 1 (1 eq), intermediate 15 (1 eq), Carter's condensing agent (1.1 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 4 h. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with ethyl acetate / methanol to obtain a pale yellow solid.

[0121] 1 H NMR (400 MHz, DMSO- d 6) δ 11.57 (d, J = 8.3 Hz, 1H), 8.84 (m, 1H), 8.25 (s, 1H), 8.09 (d, J = 5.1 Hz, 1H), 7.86 – 7.75 (m, 2H), 7.70 (s, 1H), 7.63 – 7.41 (m, 3H), 7.16 – 6.92 (m, 2H), 5.23 (s, 1H), 3.76 – 3.49 (m, 3H), 2.07 – 1.49 (m, 6H), 1.44 – 1.12 (m, 8H). MS (ESI): m / z 720.17 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.57 (s, 1H), 8.84 (m, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.70 (s,1H), 7.58 (d, J = 4.5 Hz, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.08 (t, J = 7.6 Hz,1H), 5.23 (s, 2H), 3.65 (dt, J= 13.2, 6.6 Hz, 1H), 3.56 (s, 1H), 1.95 – 1.58 (m, 6H), 1.31 – 1.29 (m, 6H). MS (ESI): m / z 720.17 [M+H] + . 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.55 (m, 1H), 8.83 (m, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.71 (s,1H), 7.57 (q, J = 6.2 Hz, 3H), 7.46 (s, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.23(s, 2H), 3.76 – 3.44 (m, 3H), 2.00 (m, 5H), 1.31 (d, J = 6.5 Hz, 6H). MS(ESI): m / z 720.17 [M+H] + . Example 16: Synthesis of compound B49 The raw materials are intermediate 1 and intermediate 16, and the rest are the same as in Example 1.

[0122] 1 H NMR (400 MHz, DMSO- d 6) δ 11.56 (s, 1H), 8.84 (m, 1H), 8.25 (s, 1H), 8.13 – 8.05 (m, 1H), 8.06 – 7.91 (m, 1H), 7.85 – 7.63 (m, 2H), 7.53 – 7.45(m, 2H), 7.14 – 7.03 (m, 2H), 6.80 (s, 1H), 6.21 (s, 1H), 5.05 (d, J= 14.4Hz, 2H), 3.60 (m, 2H), 2.91 (s, 1H), 1.76 (m, 6H), 1.36 – 1.18 (m, 8H). MS(ESI): m / z 622.19 [M+H] + . Example 17: Synthesis of compound B48 Step 1: Intermediate 17 (1 eq), intermediate 6 (1 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.3 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with ethyl acetate / methanol to give a pale yellow solid.

[0123] Step 2: Take the product from step 1 and dissolve it in a mixed solution of tetrahydrofuran and methanol (V 四氢呋喃 V 甲醇 The mixture was prepared by adding a 20% potassium hydroxide aqueous solution (ratio 5:1) while stirring, and reacting at 60°C for 16 h. After the reaction was completed, a large amount of water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with ethyl acetate / methanol to obtain a brownish-yellow solid.

[0124] 1 H NMR (400 MHz, DMSO) δ 11.91 (d, J = 9.1 Hz, 1H), 11.07 (d, J =22.2 Hz, 1H), 9.15 (d, J = 8.3 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 11.1 Hz, 1H), 7.82 (d, J = 6.9 Hz, 2H), 7.70 (s, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.55 –7.40 (m, 2H), 6.99 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 6.33 – 6.09 (m, 2H), 4.57 (d, J = 15.2 Hz, 2H), 3.73 (d,J = 63.3 Hz, 3H), 2.04 (s, 1H), 1.94 –1.66 (m, 3H), 1.60 (s, 1H), 1.34 (s, 6H).MS (ESI): m / z 639.26 [M+H] + . Example 18: Synthesis of compound B50 The raw materials are intermediate 18 and intermediate 6, and the rest are the same as in Example 17.

[0125] 1 H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 11.04 (s, 1H), 9.15 (d, J =8.5 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 6.3 Hz,2H), 7.70 (s, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.52 (s, 1H), 7.45 (t, J = 8.0Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.26 (d, J = 7.8 Hz, 1H), 6.18 (d, J = 3.4 Hz, 1H), 4.55 (s, 2H), 3.64 (dd, J = 13.4, 6.8 Hz, 1H), 2.04(s, 2H), 1.86 (s, 2H), 1.34 (s, 6H).MS (ESI): m / z 639.26 [M+H] + . Example 19: Synthesis of Compound B51 The raw materials are intermediate 19 and intermediate 6, and the rest are the same as in Example 17.

[0126] 1 H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 11.10 (s, 1H), 9.16 (d, J=8.5 Hz, 1H), 8.27 (s, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.85 – 7.78 (m, 2H), 7.70 (s, 1H), 7.58 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 14.2 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.84 (t, J = 2.8 Hz, 1H), 6.19 (t, J = 2.6 Hz, 1H), 6.13 (d, J = 6.5 Hz, 1H), 4.59 (s, 2H), 3.79 (s, 2H), 3.64 (p, J = 6.7 Hz, 1H), 1.76(dd, J = 22.9, 9.1 Hz, 4H), 1.61 (d, J = 10.2 Hz, 3H), 1.32 (d, J = 6.6 Hz,6H).MS (ESI): m / z 639.26 [M+H] + . Example 20: Synthesis of compounds B52, B80, and B81 The raw materials are intermediate 20 and intermediate 6, and the rest are the same as in Example 1.

[0127] 1 H NMR (400 MHz, DMSO) δ 9.05 (d, J = 15.6 Hz, 1H), 8.35 (d, J = 10.4Hz, 1H), 8.01 – 7.87 (m, 2H), 7.82 (dt, J = 5.5, 1.1 Hz, 2H), 7.58 (d, J =5.5 Hz, 2H), 7.51 (d, J = 1.8 Hz, 2H), 4.58 (s, 2H), 4.51 (d, J= 6.9 Hz,2H), 3.80 (s, 1H), 3.73 (s, 1H), 3.70 – 3.58 (m, 3H), 1.65 (m, 13H), 1.30 (m,6H).MS (ESI): m / z 622.29 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (m, 1H), 8.36 (s, 1H), 7.97 (d, J =14.9 Hz, 1H), 7.82 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.51 (s,1H), 7.04 (d, J = 13.2 Hz, 1H), 4.69 – 4.44 (m, 3H), 3.77 (m, 3H), 3.65 (p, J = 6.6 Hz, 1H), 1.61 (m, 11H), 1.31 (d, J = 6.6 Hz, 6H). MS (ESI): m / z 622.29[M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.97 (m, 1H), 8.34 (s, 1H), 7.95 (s, 1H),7.82 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.52 (s, 1H), 7.15 – 6.80(m, 1H), 4.60 (m, 3H), 3.82 (s, 1H), 3.70 – 3.50 (m, 3H), 2.20 – 1.55 (m,7H), 1.31 (d, J = 6.6 Hz, 6H).MS (ESI): m / z 622.29 [M+H] + . Example 21: Synthesis of compound B55 The raw materials are intermediate 21 and intermediate 6, and the rest are the same as in Example 1.

[0128] 1 H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 9.92 (s, 1H), 9.40 (s, 1H), 8.77 (d, J = 8.3 Hz, 1H), 8.37 – 8.26 (m, 2H), 8.24 (s, 1H), 7.85 (d, J = 5.5Hz, 1H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.74 (s, 1H), 7.64 – 7.56 (m, 2H),7.42 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.14 – 7.04 (m, 1H), 4.81(s, 2H), 3.68 (p, J = 6.6 Hz, 1H), 2.78 (t, J = 6.3 Hz, 2H), 2.56 (s, 3H), 2.11 (s, 8H), 1.33 (d, J = 6.7 Hz, 6H).MS (ESI): m / z 774.21 [M+H] + . Example 22: Synthesis of compound B56 Step 1: Intermediate 22 (1 eq), intermediate 6 (1 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.3 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with ethyl acetate / methanol to obtain a brown solid.

[0129] 1 H NMR (400 MHz, DMSO) δ 9.17 (d, J= 44.1 Hz, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.82 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.51 (s,1H), 7.06 (s, 1H), 4.58 (s, 2H), 4.06 – 3.69 (m, 3H), 2.96 (d, J = 7.6 Hz, 3H), 2.42 (d, J = 7.1 Hz, 2H), 1.65 (s, 4H), 1.31 (d, J = 6.7 Hz, 6H), 1.23(t, J = 13.3 Hz, 7H), 0.94 (s, 9H). Step 2: Dissolve the product from step 1 in dichloromethane, and add trifluoroacetic acid (V) dropwise while stirring. 二氯甲烷 V 三氟乙酸 The mixture was stirred at room temperature for 0.5 h (ratio 3:1). After the reaction was complete, the liquid was removed by rotary evaporation and the mixture could be used directly for the next reaction.

[0130] Step 3: The product from step 2 (1 eq), paraformaldehyde (5 eq), sodium cyanoborohydride (2 eq), and acetic acid (1 eq) were dissolved in methanol. The reaction was carried out at 50°C for 1 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and filtered. The resulting solid was slurried with ethyl acetate / methanol to obtain a white solid.

[0131] 1 H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.82 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.51 (s, 1H), 6.96 (d, J = 48.7 Hz, 2H), 4.58 (s, 2H), 4.10 (dq, J= 12.0, 6.4 Hz, 1H), 3.91 – 3.52(m, 3H), 2.76 – 2.57 (m, 1H), 2.34 (s, 1H), 2.16 (s, 3H), 1.65 (d, J = 8.2Hz, 8H), 1.55 (d, J = 12.3 Hz, 2H), 1.31 (d, J = 6.7 Hz, 6H).MS (ESI): m / z621.31 [M+H] + . Example 23: Synthesis of compound B57 The raw materials are intermediate 23 and intermediate 6, and the rest are the same as in Example 22.

[0132] 1 H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.82 (d, J = 5.4 Hz, 1H), 7.58 (d, J = 5.6 Hz, 1H), 7.51 (s, 1H), 7.15 – 6.49(m, 1H), 4.59 (s, 2H), 3.97 – 3.54 (m, 4H), 2.67 (s, 1H), 2.18 (s, 3H), 2.07(t, J = 10.8 Hz, 2H), 1.91 (d, J = 10.1 Hz, 1H), 1.78 – 1.59 (m, 5H), 1.49(dd, J = 45.0, 9.4 Hz, 2H), 1.32 (d, J = 6.7 Hz, 6H), 1.25 (d, J = 9.6 Hz,1H).MS (ESI): m / z 621.31 [M+H] + . Example 24: Synthesis of compound B59 Step 1: Intermediate 24 (1 eq), intermediate 6 (1 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.3 eq), and N,N-diisopropylethylamine (3 eq) were dissolved in N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The resulting solid was then slurried with ethyl acetate / methanol to give a pale yellow solid.

[0133] 1 H NMR (400 MHz, DMSO) δ 11.26 (s, 1H), 8.91 – 8.54 (m, 1H), 8.31 (s,1H), 8.09 – 7.90 (m, 2H), 7.83 (d, J = 5.5 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.52 (s, 1H), 7.44 – 7.34 (m, 1H), 7.16 – 6.81 (m, 2H), 4.55(s, 2H), 4.44 – 4.11 (m, 2H), 3.98 (t, J = 5.1 Hz, 2H), 3.66 (td, J = 13.4,6.8 Hz, 1H), 3.09 – 2.86 (m, 2H), 2.42 (d, J = 7.1 Hz, 1H), 1.90 (d, J = 51.5Hz, 5H), 1.38 – 1.32 (m, 6H). Step 2: Dissolve the product from Step 1 (1 eq), dimethylamine aqueous solution (5 eq), potassium carbonate (5 eq), and potassium iodide (0.1 eq) in N,N-dimethylformamide and react at 100℃ for 16 h. After the reaction is complete, quench the reaction with water. After adding excess water, a solid precipitates out. Filter the solid and slurry it with ethyl acetate / methanol to obtain a brown solid.

[0134] 1 H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 8.94 – 8.47 (m, 1H), 8.29 (s,1H), 8.10 – 7.91 (m, 2H), 7.83 (d, J = 5.5 Hz, 1H), 7.76 (s, 1H), 7.60 (d, J= 5.5 Hz, 1H), 7.53 (s, 1H), 7.35 (s, 1H), 7.03 (d, J = 11.2 Hz, 2H), 4.55(s, 2H), 4.08 (t, J = 5.8 Hz, 2H), 3.70 – 3.47 (m, 4H), 2.60 (d, J = 6.1 Hz,2H), 2.22 (s, 6H), 1.90 (d, J = 50.5 Hz, 5H), 1.32 (s, 6H).MS (ESI): m / z767.23 [M+H] + . Example 25: Synthesis of compound B60 The raw materials are intermediate 25 and intermediate 6, and the rest are the same as in Example 24.

[0135] 1 H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 10.10 (s, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 7.74 (s,1H), 7.61 (d, J = 5.5 Hz, 1H), 7.59 – 7.54 (m, 3H), 7.50 – 7.43 (m, 2H), 7.32(d, J = 2.9 Hz, 1H), 7.03 (dd, J = 9.1, 2.9 Hz, 1H), 4.78 (s, 2H), 4.03 (t, J = 6.3 Hz, 2H), 3.68 (p, J = 6.6 Hz, 1H), 2.30 (t, J = 7.1 Hz, 2H), 2.08 (s, 6H), 1.80 (p, J = 6.8 Hz, 2H), 1.34 (d, J = 6.6 Hz, 6H).MS (ESI): m / z 775.20[M+H] + . Example 26: Synthesis of compound B61 The raw materials are intermediate 26 and intermediate 6, and the rest is the same as in Example 24.

[0136] 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 10.08 (s, 1H), 9.35 (s, 1H), 8.49 (d, J = 9.2 Hz, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.83 (d, J = 5.4 Hz,1H), 7.72 (s, 1H), 7.63 – 7.52 (m, 4H), 7.46 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 3.0 Hz, 1H), 7.03 (dd, J = 9.4, 2.8 Hz, 1H), 4.77 (s, 2H), 4.01 (t, J = 6.4Hz, 2H), 3.66 (q, J = 6.7 Hz, 1H), 2.26 (d, J = 7.5 Hz, 2H), 2.16 (s, 6H), 1.65 (d, J = 7.8 Hz, 2H), 1.53 (d, J = 7.4 Hz, 2H), 1.34 (d, J = 6.6 Hz, 6H).MS (ESI): m / z 789.21 [M+H] + . Example 27: Synthesis of compound B62 Steps 1-2: Same as steps 1-2 in Example 3, except that the raw material in step 2 is diethylamine.

[0137] 1 H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 10.08 (s, 1H), 9.36 (s, 1H), 8.50 (s, 1H), 8.25 (d, J = 25.6 Hz, 2H), 7.83 (d, J= 5.5 Hz, 1H), 7.73 (s,1H), 7.63 – 7.52 (m, 4H), 7.46 (d, J = 8.7 Hz, 2H), 7.34 (s, 1H), 7.04 (d, J = 9.4 Hz, 1H), 4.77 (s, 2H), 4.07 (s, 2H), 3.67 (p, J = 6.7 Hz, 1H), 2.70 (d, J = 22.6 Hz, 2H), 1.34 (d, J = 6.6 Hz, 6H), 1.23 (s, 1H), 0.95 (s, 6H).MS(ESI): m / z 789.21 [M+H] + . Example 28: Synthesis of compound B63 Steps 1-2: Same as steps 1-2 in Example 3, except that the raw material for step 2 is azacyclobutane.

[0138] 1 H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 10.12 (s, 1H), 9.39 (s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 7.74 (s,1H), 7.62 (d, J = 5.6 Hz, 1H), 7.56 (t, J = 4.5 Hz, 3H), 7.52 – 7.43 (m, 2H), 7.30 (d, J = 2.9 Hz, 1H), 7.01 (dd, J = 9.2, 2.9 Hz, 1H), 4.78 (s, 2H), 3.92(t, J = 5.5 Hz, 2H), 3.68 (p, J = 6.6 Hz, 1H), 3.07 (t, J = 6.9 Hz, 4H), 2.59(t, J = 5.5 Hz, 2H), 1.87 (p, J= 6.9 Hz, 2H), 1.35 (d, J = 6.6 Hz, 6H).MS(ESI): m / z 773.18 [M+H] + . Example 29: Synthesis of compound B64 Steps 1-2: Same as steps 1-2 in Example 3, except that the raw material in step 2 is tetrahydropyrrole.

[0139] 1 H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.11 (s, 1H), 9.39 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 5.4 Hz, 1H), 7.75 (s,1H), 7.65 – 7.52 (m, 4H), 7.47 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 2.9 Hz, 1H),7.09 – 7.01 (m, 1H), 4.78 (s, 2H), 4.11 (s, 2H), 3.73 – 3.62 (m, 1H), 2.83(d, J = 52.3 Hz, 2H), 1.63 (s, 4H), 1.34 (d, J = 6.4 Hz, 6H).MS (ESI): m / z787.20 [M+H] + . Example 30: Synthesis of compound B65 Steps 1-2: Same as steps 1-2 in Example 3, except that the raw material in step 2 is piperidine (obtained by deprotection of N-Boc-piperidine).

[0140] 1 H NMR (400 MHz, DMSO) δ 11.20 (d, J = 16.5 Hz, 1H), 10.12 (s, 1H), 9.39 (s, 1H), 8.51 (s, 1H), 8.26 (d, J = 30.0 Hz, 2H), 7.92 – 7.70 (m, 2H), 7.59 (dd,J = 20.8, 7.2 Hz, 4H), 7.47 (d, J = 8.7 Hz, 2H), 7.36 (s, 1H), 7.06(s, 1H), 4.78 (s, 2H), 4.04 (s, 1H), 3.69 (d, J = 17.7 Hz, 2H), 1.34 (d, J =6.5 Hz, 6H).MS (ESI): m / z 801.21 [M+H] + . Example 31: Synthesis of compound B66 Steps 1-2: Same as steps 1-2 in Example 3, except that the raw material in step 2 is N-methylpiperazine.

[0141] 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.11 (s, 1H), 9.39 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.75 (s,1H), 7.64 – 7.52 (m, 4H), 7.47 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 3.0 Hz, 1H), 7.04 (dd, J = 9.2, 2.9 Hz, 1H), 4.77 (s, 2H), 4.10 (t, J = 5.8 Hz, 2H), 3.68 (p, J = 6.6 Hz, 1H), 2.62 (t, J = 5.6 Hz, 2H), 2.31 (d, J = 14.0 Hz, 2H),2.13 (s, 3H), 1.34 (d, J = 6.5 Hz, 6H).MS (ESI): m / z 816.22 [M+H] + . Example 32: Synthesis of compound B67 Steps 1-2: Same as steps 1-2 in Example 3, except that the raw material in step 2 is morpholine.

[0142] 1 H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.11 (s, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.25 (d, J = 25.7 Hz, 2H), 7.84 (d, J = 5.5 Hz, 1H), 7.75 (s,1H), 7.65 – 7.52 (m, 4H), 7.47 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 2.9 Hz, 1H), 7.05 (dd, J = 9.6, 2.8 Hz, 1H), 4.78 (s, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.68 (p, J = 6.7 Hz, 1H), 3.52 (t, J = 4.7 Hz, 3H), 2.61 (t, J = 5.6 Hz, 2H), 2.38(s, 4H), 1.34 (d, J = 6.6 Hz, 6H).MS (ESI): m / z 803.19 [M+H] + . Example 33: Synthesis of compound B68 The raw materials are intermediate 27 and intermediate 6, and the rest are the same as in Example 1.

[0143] 1 H NMR (400 MHz, DMSO) δ 11.63 (s, 1H), 9.48 (s, 1H), 9.14 (s, 1H), 8.73 (s, 1H), 8.23 ​​(d, J = 25.1 Hz, 2H), 7.85 – 7.76 (m, 2H), 7.71 (s, 1H), 7.62 – 7.51 (m, 2H), 7.50 – 7.31 (m, 3H), 7.10 (t, J = 7.5 Hz, 1H), 6.65 (d, J= 8.8 Hz, 1H), 4.79 (s, 2H), 4.66 (s, 1H), 3.66 (p, J = 6.6 Hz, 1H), 3.16(t, J = 6.8 Hz, 2H), 2.55 (d, J = 6.4 Hz, 1H), 2.27 (s, 6H), 1.34 (d, J = 6.6Hz, 6H).MS (ESI): m / z 758.20 [M+H] + . Example 34: Synthesis of compound B69 The raw materials are intermediate 28 and intermediate 6, and the rest are the same as in Example 1.

[0144] 1 H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 9.76 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 8.38 – 8.08 (m, 3H), 7.88 – 7.66 (m, 3H), 7.64 – 7.37 (m, 4H),7.15 – 6.91 (m, 2H), 4.90 (s, 2H), 4.21 (s, 2H), 3.76 – 3.59 (m, 1H), 3.04(s, 1H), 1.99 (s, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.26 (s, 6H).MS (ESI): m / z761.18 [M+H] + . Determination of the inhibitory activity of the compounds of this invention against JNK kinase (1) Reagents and materials: ADP-Glo™ Kinase Assay (Promega, V4071), DMSO (Aladdin, 67-68-5), 384 white plate (Corning, 3570).

[0145] (2) Experimental instruments: microplate reader (Tecan Group Ltd., Swiss), microplate shaker (HangzhouAllsheng Instruments CO., Ltd., MB100-2A).

[0146] (3) Experimental methods: Dissolve the compound in DMSO to prepare a stock solution. Dilute the compound to eight final concentrations using Reaction Buffer according to the kit instructions, ensuring the final concentration of DMSO is 2%. Add 5 μL of the reaction mixture to a 384-well plate: 1 μL of the compound, 1 μL of p38 substrate (final concentration 0.2 μg / μL), 1 μL of ATP (final concentration 5 μM), and 2 μL of JNK enzyme (10 ng or 2 ng). Set up a positive control and a negative control. For the positive control, add 1 μL of 10% DMSO and 2 μL of Reaction Buffer instead of the compound and JNK enzyme. For the negative control, add 1 μL of 10% DMSO instead of the compound. Place the 384-well plate in a microplate shaker at 25°C for 1 h (JNK enzyme amount 10 ng) or 4 h (JNK enzyme amount 2 ng). Add 5 μL of ADP-Glo ​​reagent, place in a microplate shaker, and incubate at 25°C for 40 minutes. Terminate the reaction and remove any remaining ATP. Add 10 μL of Kinase Detection Reagent and incubate at 25°C for 30 minutes to convert ADP to ATP. The ATP then reacts with the newly synthesized ATP via a luciferase / luciferin reaction to produce chemiluminescence. Luminescence (RLU) is detected using a microplate reader, and the RLU reading is recorded. The formula is: Compound Inhibition Rate (%) = [(RLU)] 阴 -RLU 样 ) / (RLU 阴 -RLU 阳 )]×100%, RLU 阴 For the negative control group, RLU readings. 阳 For the positive control group, RLU readings. 样 The data represents the experimental group readings. The inhibition rate data were imported into GraphPad Prism 8.0 software for fitting, and the experimental results are shown in the table below.

[0147] (4) Experimental results The bioactivity of the compounds described in this invention was determined through the above experiments. All compounds showed some inhibitory activity against JNK1, as shown in the table below. The compounds designated as "A" for JNK1 inhibitory activity provided IC50 values. 50 Value is IC 50 ≤0.1µM; IC50 provided for compounds with activity specified as "B" 50 The value is 0.1 µM <IC 50 ≤1.0 µM; IC50 for compounds with activity specified as "C" 50 Value is IC 50 >1.0 µM; Determination of the inhibitory activity of the compounds of this invention against NLRP3 I. Experimental Reagents, Materials, and Main Instruments 1. Reagents and Materials: Dimethyl sulfoxide (Aladdin, 67-68-5), RPMI 1640 (VM-2101BM, Vistech), DMEM medium (Vistech, VM-1101BM), Opti-MEM medium (Gibco, 31985062), fetal bovine serum (FBS, Vistech, SE100-011), penicillin-streptomycin solution (double antibiotic) (PS, Gibco, 15140-122), macrophage colony-stimulating factor (M-CSFBio-techne, 416-ML), lipopolysaccharide (LPS, MedChemExpress, HY-D1056), nigericin (MedChemExpress, HY-127019), Mouse IL-1 beta / IL-1F2 Quantikine HS ELISA Kit (R&D Systems, MHSLB00), Mouse IL-1 beta / IL-1F2DuoSet ELISA (R&D Systems, DY401-05), ethanol (Shanghai Test, 10009159), RIPA lysis buffer (Beyotime, P0013B), chloroform (Shanghai Test, 10006818), methanol (Shanghai Test, 10014128), NLRP3 antibody (Cell Signaling Technologys, 15101), Caspase-1 antibody (Cell Signaling Technologys, 24232), IL-1β antibody (Cell Signaling Technologys, 12426), GAPDH antibody (Cell Signaling Technologys, 2118), HRP-Goat Anti-rabbit IgG (H+L) (Bioker, BK-R050), ECL exposure solution (NCM Biotech, P2300).

[0148] 2. Experimental instruments: Microplate reader (Tecan Group Ltd., Swiss), water bath (Shanghai Boxun Medical Bio-Instrument Co., Ltd., DK-8D), high-speed centrifuge (Eppendorf AG, Centrifuge 5420), protein electrophoresis apparatus (Bio-Rad Laboratories Co., Ltd., Tetra Blotting Module), exposure apparatus (Ebiotrade, e-Blot).

[0149] 3. Experimental consumables: dissecting scissors, cell scraper, 12-well cell culture plate (Corning, 3737), 24-well cell culture plate (Corning, 3738), disposable bacterial culture dishes (Bbi-life sciences, F611004). 4. Laboratory Animals: Male ICR mice (6-12 weeks old) were purchased from the Laboratory Animal Center of Hangzhou Normal University and housed in a temperature- and humidity-controlled environment. Husbandry and experimental use were carried out in accordance with the "Guidelines for the Husbandry, Management and Use of Laboratory Animals".

[0150] II. Experimental Methods: 1. Isolation and Differentiation of BMDM Cells 1) Mice leg bone harvesting: Mice were euthanized by dislocation, and their legs and backs were disinfected with sufficient 75% ethanol. The hind limb was then dissected along the greater trochanter at the base of the thigh, and the muscle tissue was removed before placing it in cold PBS. (This step was performed in a laminar flow hood; subsequent steps were transferred to the cell culture room.) 2) BMDM Cell Extraction and Induction: Rinse the leg bone with PBS to remove excess muscle, approximately 2-3 times. Cut the femur and tibia at both ends with scissors. Using a 1 mL syringe, draw cold induction medium and expel bone marrow from the femur and tibia, repeating this process 3 times until no obvious red color is visible inside the leg bone. Use a pipette to repeatedly pipette the culture medium containing bone marrow cells to disperse the cell clumps, then transfer to a 15 mL centrifuge tube and centrifuge at 1500 rpm for 5 min. Discard the supernatant, add approximately 1-2 mL of erythrocyte lysis buffer to resuspend the cells, and use a pipette to disperse the cells into single cells. Incubate at room temperature for 5 min, then add 10 mL of culture medium to terminate the reaction. Filter through a 0.45 μm cell filter membrane and centrifuge at 1500 rpm for 5 min. Discard the supernatant, resuspend the cells, and count the cells. The cells were resuspended in 1640 medium (10% FBS, 2% PS) containing 20 ng / mL M-CSF factor, and the cell suspension was transferred to a no-treated disposable bacterial culture dish for culture.

[0151] 2. Activation of the classic NLRP3 inflammasome Using well-differentiated BMDM cells (4-6 days old), discard the culture supernatant and wash the cells with an appropriate amount of PBS. Add 10 mL of DMEM medium, scrape the cells off using a cell scraper, resuspend the cells in a centrifuge tube, and centrifuge at 1500 rpm for 10 min. Remove the supernatant, resuspend the BMDM cells in DMEM medium, and divide them into 12-well plates, ensuring approximately 5 × 10⁶ cells per well. 5 / mL. The next day, 500 μL of Opti-MEM medium (containing 500 ng / mL LPS) was added to each well of BMDM cells for pretreatment for 4-5 hours. The compound was weighed using an analytical balance and placed in a sterile centrifuge tube, then dissolved in dimethyl sulfoxide (DMSO) to prepare the desired concentration. The drug was added for 30 min, followed by stimulation with 10 μM Nigericin for 60 min. The cell supernatant (SN) and cell lysis buffer (Input) were collected. Based on the obtained cell supernatant (SN) and cell lysis buffer (Input), Western blotting and ELISA were performed.

[0152] 3. Protein extraction and sample preparation 1) Protein extraction from cell culture supernatant: Place the sample in a centrifuge and centrifuge at 13000 rpm for 5 min to remove dead cells and impurities; transfer the supernatant to a new EP tube, add 500 μL methanol and 125 μL chloroform, vortex to mix well, and centrifuge at 13000 rpm for 5 min; remove the upper layer of liquid, at which point the middle layer is the protein solution, add 500 μL methanol, vortex to mix well, and centrifuge at 13000 rpm for 5 min; the protein precipitates at the bottom of the EP tube, remove the supernatant, let stand for 10 min to evaporate the methanol completely, add 60 μL 1×SDS loading buffer, dissolve thoroughly, and 100 o C High-temperature denaturation for 10 min.

[0153] 2) Extraction of cellular proteins: Add 120 μL of cell lysis buffer to cells after removing the cell supernatant. After thorough lysis, add 5×SDS loading buffer and 100 μL of lysate the cells. o C High-temperature denaturation for 10 min.

[0154] 4. Western Blot Detection Western blotting (WB) was performed using a 4-12% protein gel. The protein electrophoresis conditions were 70-80 V for 20-30 min, and the separating gel conditions were 130-160 V for 60-90 min. The PVDF membrane was pre-activated by soaking it in methanol for 5-10 min. The filter paper and sponge were pre-soaked in transfer buffer. After electrophoresis, the protein gel was soaked in transfer buffer for 5-10 min. Transfer was performed using a sandwich structure of sponge-filter paper-gel-membrane-filter paper-sponge at 250 mA for 90 min. Blocking was performed with 5% skim milk for 1 h. The primary antibody was diluted with 5% BSA according to the antibody dilution ratio. o Incubate overnight at C. The next day, wash three times with 1×TBST, 5 min apart. Dilute the secondary antibody with 1×TBST according to the antibody dilution ratio, incubate for 1 h, and wash three times with 1×TBST, 5 min apart. After washing, expose the membrane to ECL ultrasensitive exposure buffer.

[0155] The inhibitory effect of the compound on the NLRP3 inflammasome pathway was evaluated by measuring the amount of IL-1β secreted by BMDM cells stimulated with LPS+Nigericin after compound treatment. ImageJ was used to calculate the gray values ​​of the IL-1β band in the culture supernatant and the internal reference protein GAPDH band in the cell lysate, and their ratio was determined. The gray values ​​of the control group (DMSO treatment group) were normalized, and the IC50 was calculated using GraphPad Prism. 50 The experimental results are detailed in the table below.

[0156] III. Experimental Results The bioactivity of the compounds described in this invention was determined through the above experiments. All compounds exhibited varying degrees of inhibition against NLRP3, as shown in the table below. The compounds designated as "A" for their NLRP3 inhibitory activity provided an IC50 value. 50 Value is IC 50 ≤0.1 µM; IC50 provided for compounds with activity specified as "B" 50 The value is 0.1 µM <IC 50 ≤1.0 µM; IC50 for compounds with activity specified as "C" 50 Value is IC 50 >1.0 µM. All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The compound represented by Formula 1, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, 1 In the formula, Y is or Y1 is selected from NR 14 O, S; R 14 Selected from H or optionally substituted C 1-3 alkyl; R1 is selected from: H, halogen, cyano, or optionally substituted C. 1-10 Alkyl, optionally substituted C 1-10 Alkyl group, -C(O)R7; R2 is H, or R2 and R1 together with the carbon atoms attached to them form an optionally substituted 3-10 membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S. R3 is H, and C is optionally substituted. 1-10 Alkyl groups; or, R3 together with R1 or R4, along with the atoms attached to them, forms an optionally substituted 3- to 10-membered heteroaryl or heterocyclic group containing one, two, or three independent heteroatoms selected from N, O, or S. Rings A and B are independently selected from: C 5-10 Aryl, 5-10 heteroaryl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, C 3-10 Cycloalkenyl, 3-10 membered heterocyclic alkenyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic aryl or 8-10 membered bicyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 8-10 membered bicyclic carbocyclic or 8-10 membered bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Where valence is permissible, n can be 0, 1, 2, 3, 4 or 5, and m can be 0, 1, 2, 3, 4 or 5; R4 is selected from: H, hydroxyl group, or optionally substituted C. 1-10 Alkyl, optionally substituted C 5-10 Aryl, halogen, cyano, nitro, -C 0-6 -C(O)R7、-C 0-6 -OR8、-C 0-6 -N(R9)2, optionally substituted sulfonyl group, optionally substituted phosphonoyl group, optionally substituted 5-7 membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Alternatively, two adjacent R4s together with the atoms attached to them form an optionally substituted 3-10 membered heteroaryl or heterocyclic group containing one, two or three independent heteroatoms selected from N, O or S. R5 is selected from: H, hydroxyl, halogen, cyano, nitro, -C 0-6 -C(O)R 11 -C 0-6 -OR 12 -C 0-6 -N(R 13 2. Optionally substituted sulfonyl group, Optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl group, optionally substituted C 1-10 Alkoxy, optional substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; Given that they satisfy the given valence, A1, A2, A3, A4, and A5 can be independently selected from: C, N, C6, and C(R). 17 2. NR 18 ; R6, R 17 and R 18 Each is independently selected from: C that can be arbitrarily substituted 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, oxo, -C 0-6 -C(O)R 19 -C 0-6 -OR 20 -C 0-6 -N(R 21 2. Optional substitution of C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S. Or, two R atoms attached to the same carbon atom 17 Together with this carbon atom, it forms an optionally substituted C 3-10 Cycloalkyl or optionally substituted 3- to 10-membered heterocyclic groups containing one, two, or three independent heteroatoms selected from N, O, or S. Or, R6, R 17 and R 18 The two atoms attached to adjacent atoms, together with the atoms they are attached to, form an optionally substituted C atom. 5-10 aryl or optionally substituted C-type compounds containing one, two, or three heteroatoms independently selected from N, O, or S. 5-10 Mixed aromatics; R7, R 11 and R 19 Each is independently selected from: H, optionally substituted hydroxyl group, optionally substituted amino group, optionally substituted C group. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R8, R 12 and R 20 Each is independently selected from: H, and optionally substituted C. 1-3 Acyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; R9, R 13 and R 21 Each is independently selected from: H, and optionally substituted C. 1-3 Acyl group, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 aryl or C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 5-10 heteroaryl, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, or S; Or, two R9s, two Rs 13 Or two Rs 21 Together with the nitrogen atoms attached to them, they form optional substituted 3-10 membered heterocyclic groups; R 10 For substituted or unsubstituted methylene, R 10 The substituents can be halogen, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 cycloalkyl or heterocyclic groups; or, R 10 The two substituents are linked to form an optionally substituted C 3-10 Cycloalkyl or heterocyclic groups.

2. The compound of claim 1, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, Y is or ; R1 is selected from: H, halogen, or optionally substituted C. 1-6 alkyl; R2 is H, or R2 and R1 together with the carbon atoms attached to them form an optionally substituted 3-10 membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S. R3 is H; Ring A is selected from: phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 3-6 membered cycloalkyl or 5-6 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S; Ring B is a phenyl, a 6-membered cycloalkyl, or a heterocyclic group; m can be 0, 1, 2, or 3; n is 0, 1, or 2; R4 is selected from: H, hydroxyl, halogen, cyano, nitro, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, -C 0-6 -C(O)R7、-C 0-6 -OR8、-C 0-6 -N(R9)2; R5 is selected from: H, hydroxyl, halogen, cyano, nitro, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, -C 0-6 -C(O)R 11 -C 0-6 -OR 12 -C 0-6 -N(R 13 )2; for ; X is selected from: N or CR 24 ; R 22 Selected from: hydrogen, C 1-6 Alkyl, 3-6 membered cycloalkyl or heterocyclic, -C 0-6 -C(O)R 25 -C 0-6 -OR 26 -C 0-6 -N(R 27 )2, the C 1-6 Alkyl, 3-6 membered cycloalkyl or heterocyclic groups may be optionally substituted with halogens, hydroxyl groups or amino groups; R 23 Selected from: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 10-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R 24 It is hydrogen, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 10-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R 25 Independently selected from: H, hydroxyl, optionally substituted amino, optionally substituted C 1-6 Alkoxy; R 26 Independently selected from: H, optional substituted C 1-6 alkyl; R 27 Independently selected from: H, optional substituted C 1-6 alkyl.

3. The compound of claim 2, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, R1 is a halogen; preferably bromine.

4. The compound of claim 2, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, When ring B is phenyl, R4 is -C(O)R7 or -OR8; R7 is selected from: H, hydroxyl group, optionally substituted amino group, optionally substituted C group. 1-6 Alkoxy; R8 is selected from: H, C which is optionally substituted by one or more groups independently selected from the following 1-6 Alkyl groups: halogen, hydroxyl, carboxyl, C 1-3 Acyloxy group, -N(R) 28 )2; Each R 28 Each is independently H, and the C can be arbitrarily substituted. 1-6 Alkyl; or, two Rs 28 Together with the nitrogen atom it is bonded to, it forms an optionally substituted 3-7 membered heterocycle, which optionally further contains one or two heteroatoms independently selected from N, O or S; m is 1, 2 or 3, and at least one of the R4s is -C(O)R7 and is substituted at the -NH- ortho position.

5. The compound of claim 2, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, for ; R 22 C is unsubstituted or hydroxylated 1-6 Alkyl groups, unsubstituted or hydroxyl-substituted 3-6 membered cycloalkyl groups; R 29 It is hydrogen or halogen.

6. The compound of claim 1, or its tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that, Y is or ; R1 is selected from: H, halogen; R2 is H, or R2 and R1 together with the carbon atoms attached to them form an optional substituted 5-6 membered heteroaryl group containing an N heteroatom; R3 is H; Ring A is selected from: phenyl, or 3-6 membered cycloalkyl; Ring B is a phenyl, a 6-membered cycloalkyl, or a heterocyclic group; m is 1, 2, or 3; n is 0, 1, or 2; R4 is selected from: H, C 1-6 Alkyl, -C 0-6 -C(O)R7、-C 0-6 -OR8; R5 is selected from: H, hydroxyl, halogen, cyano, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy; for ; X is CR 24 ; R 22 Selected from: C 1-6 Alkyl, 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl groups and 3-6 membered cycloalkyl groups may be optionally substituted with halogens, hydroxyl groups, or amino groups; R 23 Selected from: hydrogen, C 1-6 Alkyl, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 10-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S; R 24 It is hydrogen, or R 23 With R 24 Together with the atoms they are attached to, they form optionally substituted C atoms. 5-8 Aryl (preferably phenyl), optionally substituted 3- to 6-membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S.

7. Compounds selected from the group consisting of, or their tautomers, meso compounds, racemates, enantiomers, diastereomers, mixtures thereof, or pharmaceutically acceptable salts thereof: B29、 B33、 B34、 B36、 B37、 B38、 B39、 B40、 B41ぁ B42ぁ B43ぁ B44、 B45ぁ B46、 B47、 B49、 B48ぁ B50ぁ B51ぁ B52ぁ B55ぁ B56ぁ B57ぁ B59ぁ B60、 B61、 B62ぁ B63、 B64、 B65、 B66、 B67、 B68、 B69、 B70、 B71、 B72ぁ B73、 B74、 B75ぁ B76、 B77ぁ B80、 B81; Preferably, the compound is selected from the group consisting of: B29、 B33、 B38、 B42ぁ B43ぁ B44、 B47、 B48ぁ B50ぁ B51ぁ B59ぁ B64、 B65、 B68、 B73、 B76、 B77.

8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or its tautomers, mesosomes, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable transporter.

9. Use of the compound of any one of claims 1 to 7, or its tautomer, meso compound, racemic compound, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, in the preparation of a JNK inhibitor, an NLRP3 inhibitor, or a JNK & NLRP3 dual-target inhibitor.

10. The use as described in claim 9, characterized in that, The JNK inhibitor, NLRP3 inhibitor, or JNK&NLRP3 dual-target inhibitor is a drug for the treatment and / or prevention of JNK / NLRP3-related diseases.

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