Pyrimidine derivative with JNK inhibitory activity and application thereof

Abstract

The invention discloses a compound as shown in a formula 1, or a tautomer, a meso-mer, a raceme, an enantiomer, a diastereoisomer, a mixture form or a pharmaceutically acceptable salt thereof. The compound has excellent JNK inhibitory activity, and shows selective inhibitory activity on JNK. Therefore, the compound provided by the invention lays a new material foundation for development of treatment drugs for JNK-related diseases. # imgabs0 #

Description

Pyrimidine derivatives with JNK inhibitory activity and applications thereof Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to pyrimidine derivatives having JNK inhibitory activity, especially JNK1 inhibitory activity, a drug combination comprising the pyrimidine derivatives, and their use in anti-fibrosis (including lung, liver, kidney, heart, and skin fibrosis) drugs. Background Art

[0002] c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family that bind to and phosphorylate c-Jun at Ser-63 and Ser-73. JNKs function within a protein kinase cascade. JNKs themselves are activated through dual phosphorylation (threonine Thr and tyrosine Tyr) by the MAPK kinases MKK4 and MKK7. Both MKK4 and MKK7 can simultaneously phosphorylate tyrosine 185 and threonine 183, with MKK4 preferentially phosphorylating tyrosine and MKK7 preferentially phosphorylating threonine. Both MKK4 and MKK7 are activated by various MAPKK kinases, including mixed lineage protein kinases (MLKs), apoptosis signal-regulating kinases (ASKs), and dual leucine zipper kinases (DLKs). Upon phosphorylation, JNKs undergo nuclear translocation, activating proteins within the cell nucleus, including transcription factors AP-1, ATF-2, c-Myc, p53, ELK1, and NFAR, as well as the apoptosis-related gene Bcl-2 within mitochondria. This control leads to the expression and transcription of a range of nuclear genes. This pathway is implicated in a variety of physiological processes, including neurodegenerative diseases, cancer, and inflammation. In summary, the JNK pathway regulates a variety of physiological processes, including inflammatory responses, cell differentiation, cell proliferation, cell death, cell survival, and protein expression.

[0003] In mammalian genomes, three genes, JNK1, JNK2, and JNK3, encode the three proteins of the JNK protein kinase family, JNK1, JNK2, and JNK3, respectively. JNK proteins have up to 10 different splice isoforms, with molecular weights ranging from 46 kDa to 55 kDa. In most cases, the JNK1 gene produces a 46 kDa protein (four splice isoforms), while the JNK2 gene produces a 55 kDa protein (four splice isoforms), and the JNK3 gene produces 48 and 57 kDa proteins (two splice isoforms). Sequence alignments of these different protein products reveal >80% homology. JNK1 and JNK2 proteins are ubiquitously expressed in all cells and tissues, while JNK3 expression is primarily restricted to the brain, with additional expression in the heart and testes.

[0004] Pulmonary fibrosis (PF) is a terminal disease characterized by fibroblast proliferation and accumulation of extracellular matrix, accompanied by inflammatory damage and tissue structural destruction. This refers to the abnormal repair of damaged alveolar tissue, leading to structural abnormalities (scarring). Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease that can lead to progressive loss of lung function. It has the highest incidence rate and an extremely poor prognosis, manifested by epithelial cell proliferation, exposed basement membrane, alveolar consolidation, and the appearance of fibroblast foci. Pharmacological treatment options are limited. Currently, the internationally approved drugs pirfenidone and nintedanib can only delay the progression of IPF but cannot prevent or reverse the disease.

[0005] Numerous studies have demonstrated that JNKs play an important role in pulmonary fibrosis and allergic airway diseases. JNK1, but not JNK2, has been reported to play a causal role in TGF-β1-induced epithelial-to-mesenchymal transition and profibrotic gene expression. In a mouse model of interstitial pulmonary fibrosis induced by TGF-β1 and bleomycin, mice with JNK1 disruption showed reduced profibrotic gene expression and subepithelial collagen accumulation. In a model of house dust mite pulmonary fibrosis, JNK inhibitors reduced ECM (extracellular matrix) accumulation and fibrosis. Therefore, selective JNK1 inhibitors hold promise for the treatment of pulmonary fibrosis.

[0006] In addition, the JNK pathway regulates a variety of physiological processes such as inflammatory response, cell differentiation, cell proliferation, cell death, cell survival and protein expression. Therefore, JNK is involved in a variety of pathological conditions, including neurodegenerative diseases, cancer and inflammation. Regarding the relationship between JNK and cancer, many experiments have obtained contradictory results: on the one hand, JNK has a pro-cancer function and participates in oncogenic transformation, while JNK-mediated pro-survival autophagy also promotes cancer cells' resistance to chemotherapy; but other studies have also shown that JNK can act as a tumor suppressor. There is some evidence that JNK3 may be a target for the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. An increase in phosphorylated JNKs was found in brain tissue samples from postmortem patients with AD, especially JNK3, which was significantly expressed and phosphorylated in the brain and cerebrospinal fluid of AD patients. Yoon et al. found that JNK3 is responsible for the phosphorylation of β-amyloid precursor protein, thereby stimulating Aβ 42The production of JNK3 gene knockout in familial AD mice can lead to a significant decrease in Aβ42 levels and neuritic plaques and improve cognition. The JNK signaling pathway is believed to be involved in many inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. Several studies have shown that: inflammatory cell infiltration and joint damage in mice with genetic deletion of JNK1 are significantly reduced. In addition, JNK can also be used as a potential target for intervention in ischemic brain and cardiac damage, for the treatment and prevention of ischemia-reperfusion. It has been shown that JNK / SAPKs are significantly involved in ischemia-induced cell death and reperfusion injury in several different tissues, and control insulin sensitivity in metabolic regulation. At the same time, there is also increasing evidence that JNK1 and JNK2 promote the development of insulin resistance and obesity, and JNK3 appears to be able to induce the loss of β-cell function.

[0007] Currently, there are no drugs on the market that inhibit the JNK pathway to treat pulmonary fibrosis and other diseases related to this pathway, such as neurodegenerative diseases, diabetes, inflammatory diseases, etc. Therefore, the development of new JNK inhibitor compounds is of great significance for the treatment of the above diseases, especially pulmonary fibrosis.

[0008] Summary of the Invention

[0009] The object of the present invention is to provide a compound having JNK inhibitory activity, particularly JNK1 inhibitory activity.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising the compound.

[0011] Another object of the present invention is to provide a use of the compound in preparing a drug for treating JNK-related diseases and a method for treating JNK-related diseases using the compound or pharmaceutical composition.

[0012] In a first aspect, the present invention provides a compound of Formula 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof,

[0013] Where,

[0014] R1 is selected from: H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, halogen, cyano, optionally substituted 5-6 membered aryl or heteroaryl,

[0015] R2 is selected from the group consisting of: H, hydroxy, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 Aryl, halogen, cyano, nitro, optionally substituted sulfonamido, optionally substituted sulfonyl, optionally substituted phosphinyl, optionally substituted 5-7 membered heterocyclic group;

[0016] Alternatively, two adjacent R2 together with the carbon atom to which they are attached form a 3-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S;

[0017] x is 0, 1, 2, 3, 4, or 5;

[0018] R3 is selected from: H, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 1-10 Alkoxy, optionally substituted C 5-10 Aryl, optionally substituted C 3-10 cycloalkyl, an optionally substituted 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S;

[0019] R 41 and R 42 are independently selected from: H, optionally substituted hydroxy, optionally substituted amino, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optionally substituted C 5-10 Aryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclic group;

[0020] R5 is H, optionally substituted C 1-3 Acyl, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 Aryl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O or S;

[0021] R6 and R7 are independently selected from: H, optionally substituted C 1-3 Acyl, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted C 3-10 cycloalkyl, an optionally substituted 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S;

[0022] n and m are independently selected from 0, 1, 2, 3, 4, 5 or 6; preferably, n and m are independently selected from 0, 1, or 2; more preferably, n and m are 0.

[0023] In a preferred embodiment, the "optionally substituted" refers to being optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, hydroxy, optionally substituted amino, nitro, carboxyl, ester, oxo, deuterated, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 1-3 Acyloxy, optionally substituted C 5-10 aryl or heteroaryl, optionally substituted 3-7 membered cycloalkyl or heterocyclic group, optionally substituted sulfonyl, optionally substituted acyl.

[0024] In a specific embodiment, R1 is selected from: halogen, cyano, optionally substituted C 1-6 Alkyl, -C(O)R 41 ;

[0025] R2 is selected from: -OR5, -NR6R7, halogen, optionally substituted C 1-6 alkyl, optionally substituted phosphinyl;

[0026] R3 is selected from: optionally substituted C 1-6 alkyl, optionally substituted 5-7 membered cycloalkyl or heterocyclic group, optionally substituted C 5-10 Aryl; or

[0027] R3 is phenyl, which is optionally substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, amino, carboxyl, ester, sulfonamide, sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted 5-7 membered heteroaryl, -C 0-3 -C(O)-NR 61 R 71 ;

[0028] R 41 is an optionally substituted amino group, an optionally substituted C 1-6 alkoxy;

[0029] R 42 Selected from: hydroxy, optionally substituted amino, optionally substituted C 1-6 alkoxy;

[0030] R5 is H, optionally substituted C 1-6 alkyl;

[0031] R6 and R7 are each H, optionally substituted C 1-6 Alkyl; or

[0032] R6 and R7 together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring;

[0033] R 61 and R 71 Each is H, an optionally substituted 3-7 membered cycloalkyl or heterocyclic group, a spiro ring, or a bridged ring; or

[0034] or R 61 and R 71 Together with the nitrogen atom to which it is bound, it forms an optionally substituted 3-7 membered cycloalkyl or heterocyclic group, a spirocyclic ring, or a bridged ring;

[0035] n is 0, 1, 2, or 3;

[0036] x is 1, 2, or 3.

[0037] In a specific embodiment, R5 is H, C optionally substituted with one or more groups independently selected from the following 1-6 Alkyl: halogen, hydroxyl, carboxyl, C 1-3 Acyloxy, -NR 62 R 72 ;

[0038] R 62 and R 72 Each is H, optionally substituted C 1-6 Alkyl; or

[0039] R 62 and R 72 Together with the nitrogen atom to which it is bound, it forms an optionally substituted 3-7 membered heterocyclic ring.

[0040] In a specific embodiment, x is 2 or 3, and at least one R2 is -C(O)R 42 , and substituted at the ortho-position of -NH-.

[0041] In a specific embodiment, the compound has a structure shown in Formula 2:

[0042] In the formula

[0043] R1 is selected from: halogen, cyano, C 1-6 Alkyl, -C(O)R 41 ;

[0044] R2 is selected from: -C(O)R 42 、-OR5、-NR6R7、halogen、C 1-6 alkyl;

[0045] R 31 Selected from: halogen, hydroxyl, amino, carboxyl, ester, sulfonamide, sulfonyl, C 1-6 Alkyl, C 1-6 Alkoxy, 5-7 membered heteroaryl, -C 0-3 -C(O)-NR61 R 71 ;

[0046] Among them C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, amino, carboxyl, sulfonamide, and 5-7 membered heteroaryl;

[0047] R 43 Selected from: hydroxyl, unsubstituted or C 1-6 Alkyl-substituted amino, wherein C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from the group consisting of halogen, sulfonamide, ester, amide, carboxyl, sulfonyl, hydroxy, and oxo;

[0048] R 41 is amino, or C 1-6 alkoxy;

[0049] R 42 Hydroxyl, or C 1-6 alkoxy;

[0050] R5 is selected from: H, C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxyl, C 1-3 Acyloxy, -NR 62 R 72 ;

[0051] R6 and R7 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring optionally substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl, C 1-6 alkoxy;

[0052] R 61 and R 71 Each is H, 3-7 membered cycloalkyl or heterocyclic group, spiro ring, bridged ring, or R 61 and R 71 Together with the nitrogen atom to which it is bound, it forms a spiro ring, a bridged ring, or a 3-7 membered heterocycle;

[0053] The above spiro ring, bridged ring, 3-7 membered cycloalkyl or heterocyclic group are optionally substituted by one or more groups independently selected from the following: amino protecting group, sulfonyl group, 3-5 membered cycloalkyl or heterocyclic group, 3-5 membered cycloalkyl formyl group, 3-5 membered heterocyclic formyl group, wherein the cycloalkyl and heterocyclic groups may be further substituted by halogen or amino protecting group;

[0054] R 62 and R 72 H, C respectively 1-6 Alkyl; or

[0055] or R 62 and R 72 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic ring optionally substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkyl-C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy-OH, -C 1-6 Alkyl-NR 62 R 72 ;

[0056] y is 0, 1, 2, or 3;

[0057] x is 1 or 2.

[0058] In a specific embodiment, the -C 0-3 -C(O)-NR 61 R 71 mid-C(O)-NR 61 R 71 Selected from the following structures:

[0059] In a specific embodiment, R 62 and R 72 Together with the nitrogen atom to which it is bound, it forms a group selected from the group consisting of:

[0060] In a specific embodiment, the compound is a compound selected from the group consisting of: a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0061] In a specific embodiment, the compound is a compound with the compound number shown below:

[0062] In a second aspect, the present invention provides a pharmaceutical combination, characterized in that the pharmaceutical composition comprises the compound described in the first aspect or its tautomer, mesomer, racemate, enantiomer, diastereomer, a mixture thereof or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0063] In a third aspect, the present invention provides use of the compound of the first aspect or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt in the preparation of a JNK inhibitor.

[0064] In a preferred embodiment, the JNK inhibitor is a JNK1 inhibitor.

[0065] In a specific embodiment, the JNK inhibitor is a drug for treating and / or preventing JNK-related diseases.

[0066] In a specific embodiment, the JNK-related disease is fibrosis, neurodegenerative disease, diabetes, inflammatory disease, tumor, central nervous system disease, etc.

[0067] In a specific embodiment, said fibrosis includes but is not limited to pulmonary fibrosis;

[0068] The neurodegenerative diseases include, but are not limited to, Alzheimer's disease;

[0069] The inflammatory diseases include but are not limited to arthritis and heart inflammation;

[0070] The tumors include but are not limited to lung cancer and liver cancer;

[0071] The central nervous system diseases include but are not limited to cerebral ischemia-reperfusion.

[0072] In a fourth aspect, the present invention provides a method for treating a JNK-related disease, comprising the step of administering a therapeutically effective amount of the compound described in the first aspect or its tautomer, mesomer, racemate, enantiomer, diastereomer, a mixture thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect to a subject in need thereof.

[0073] In a preferred embodiment, the JNK-related diseases are fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, central nervous system diseases, etc.

[0074] In a preferred embodiment, the fibrosis includes but is not limited to pulmonary fibrosis;

[0075] The neurodegenerative diseases include, but are not limited to, Alzheimer's disease;

[0076] The inflammatory diseases include but are not limited to arthritis and heart inflammation;

[0077] The tumors include but are not limited to lung cancer and liver cancer;

[0078] The central nervous system diseases include but are not limited to cerebral ischemia-reperfusion.

[0079] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail 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 listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] FIG1 shows the effects of compound Q63 (JZ088) on lung function indicators in mice with bleomycin-induced pulmonary fibrosis. DETAILED DESCRIPTION

[0081] After extensive and in-depth research, the inventors unexpectedly discovered a series of compounds with JNK inhibitory activity, particularly JNK1 inhibitory activity. These compounds can be used to prepare drugs for treating JNK-related diseases, thereby treating JNK-related diseases. This is the basis for the completion of the present invention.

[0082] Definition of terms

[0083] The terms used herein with respect to the groups, substituents or structures of the compounds have the same meanings as understood by those skilled in the art. For the sake of clarity, the terms used in this specification are defined as follows.

[0084] As used herein, “a” or “an” or “a type” means at least one / kind / type or one / kind / type or more than one / kind / type.

[0085] In this article, the form "C 1-n " means that the group has 1-n carbon atoms, for example, "C 1-10 " means that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; similarly, "C6-C10" means that the group has 6, 7, 8, 9 or 10 carbon atoms. At the same time, the description of the range of carbon atoms herein also includes the sub-ranges therein. For example, when 1-10 carbon atoms are mentioned herein, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, and 1-3 carbon atoms are also included.

[0086] The term "alkyl" as used herein has the same meaning as commonly understood by those of ordinary skill in the art, and refers to various saturated or unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups. For example, the alkyl group described herein refers to a lower alkyl group having 1 to 10 carbon atoms; preferably a lower alkyl group having 1 to 8 carbon atoms; more preferably a lower alkyl group having 1 to 6 carbon atoms. In specific embodiments, the alkyl group described herein includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like. Similarly, the terms "alkenyl" or "alkynyl" as used herein refer to various unsaturated straight-chain, side-chain, or cyclic hydrocarbon groups containing a carbon-carbon double bond or a carbon-carbon triple bond.

[0087] As used herein, the terms "aryl" and "aromatic ring" have the same meaning as commonly understood by those skilled in the art, and refer to a cyclic conjugated aromatic system. For example, the term "C6-C10 aryl" refers to an aromatic ring group having 6 to 10 carbon atoms, such as phenyl and naphthyl, that does not contain heteroatoms in the ring. The term "heteroaryl" as used herein refers to a cyclic conjugated aromatic system that contains one or more heteroatoms, such as N, O, or S, in the ring; for example, pyridyl and pyrazinyl.

[0088] The term "halogen" as used herein has the meaning commonly understood by those skilled in the art. In specific embodiments, halogen refers to fluorine, chlorine, bromine or iodine.

[0089] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent may be the substituent described above or the specific substituents described in the Examples. Therefore, in the present invention, the substituents in Formula 1 may each independently be the corresponding groups described in the specific compounds described in the Examples; that is, the present invention includes combinations of the substituents in Formula 1, as well as combinations of some of the substituents shown in Formula 1 with other specific substituents described in the Examples.

[0090] Unless otherwise specified, a substituted group may have a specific substituent at any substitutable position on the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocyclyl, may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, e.g., where the two rings share a common carbon atom.

[0091] In particular, the various substituents defined above also include groups formed by further substitutions thereof, wherein these new substituents may also contain other groups. For example, hydrogen atoms on alkyl and aryl groups replaced by amino, halogen or other groups become groups within the above definitions.

[0092] In a specific embodiment, the "optionally substituted" refers to being optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, hydroxy, optionally substituted amino, nitro, carboxyl, ester, oxo, deuterated, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy, optionally substituted C 1-3 Acyloxy, optionally substituted C 5-10 aryl or heteroaryl, optionally substituted 3-7 membered cycloalkyl or heterocyclic group, optionally substituted sulfonyl, optionally substituted acyl.

[0093] Compounds of the present invention

[0094] To overcome the deficiencies in the prior art, the present invention provides pyrimidine derivatives, drug combinations thereof, and applications thereof that can be used for JNK-related diseases.

[0095] To this end, the present invention provides a pyrimidine derivative, the structural formula of the pyrimidine derivative is shown in Formula 1:

[0096] The substituents in the formula are each as described above.

[0097] Based on the compounds of the present invention, the present invention also provides a pharmaceutical composition comprising the above-mentioned compound or its tautomers, mesomers, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

[0098] Based on the teachings of the present invention, those skilled in the art will understand that the compounds of the present invention can be used to prepare JNK inhibitors, particularly JNK1 inhibitors. In a specific embodiment, the JNK inhibitors of the present invention are drugs for treating and / or preventing JNK-related diseases.

[0099] Those skilled in the art are aware of specific JNK-related diseases, such as neurodegenerative diseases, diabetes, inflammatory diseases, central nervous system diseases, fibrosis, etc. The present invention is particularly concerned with fibrosis, especially pulmonary fibrosis.

[0100] Advantages of the present invention:

[0101] 1. The compounds of the present invention have excellent JNK inhibitory activity;

[0102] 2. The compounds of the present invention have excellent selective inhibitory activity against JNK;

[0103] 3. The compounds of the present invention lay a new material foundation for the development of therapeutic drugs for JNK-related diseases.

[0104] The technical solutions of the present invention are further described below with reference to specific examples. However, the following examples do not constitute a limitation of the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following examples, where specific conditions are not specified, are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0105] All raw materials of the present invention are not particularly limited in their sources and can be purchased from the market or prepared according to conventional methods well known to those skilled in the art.

[0106] Example

[0107] Example 1. Preparation of pyrimidine compounds JZ001-JZ080 and S1-1-S1-11

[0108] Dissolve 2,4-dichloro-5-substituted pyrimidine (1 eq), substituted aniline (1.2 eq), and DIPEA (3 eq) in DMF and stir at room temperature for 1-3 hours. After TLC, quench the reaction and extract with ethyl acetate three times (30 mL x 3). Combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain the intermediate. Dissolve the intermediate (1 eq) obtained in the first step, the substituted fatty amine (2 eq), and DIPEA (3 eq) in DMF and react at room temperature overnight. After TLC, quench the reaction and extract with ethyl acetate three times (30 mL x 3). Combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography to obtain the final product. Alternatively, dissolve the intermediate (1 eq) obtained in the first step, the substituted aromatic amine (2 eq), and TFA (3 eq) in IPA / DMF and react at 90°C for 2 hours. After TLC detection, the reaction was quenched and extracted with ethyl acetate three times (30 mL*3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the final product.

[0109] Example 2. Preparation of pyrimidine compounds JZ081-JZ085

[0110] 2,4-Dichloro-5-carbonylchloropyrimidine (1 eq) was placed in a 50 mL round-bottom flask and dissolved in ultra-dry DMF. A substituted amine (1.1 eq) and triethylamine (3 eq) were added at -10°C and the reaction was continued for 1-3 hours. After TLC analysis, the reaction was quenched and extracted three times with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the intermediate. The intermediate was further reacted (as in Example 1) to obtain the final product.

[0111] Example 3. Preparation of pyrimidine compounds JZ086-JZ120 and S2-1-S2-91

[0112] 2,4-Dichloro-5-substituted pyrimidine (1 eq), substituted aniline (2 eq), and DIPEA (3 eq) were dissolved in isopropanol and reacted at 90°C overnight. After the reaction was monitored by TLC, the mixture was filtered and the residue was washed three times with isopropanol to obtain the intermediate. The intermediate (1 eq), substituted aniline (2 eq), and TFA (3 eq) were dissolved in sec-butanol and reacted at 100°C overnight. After the reaction was monitored by TLC, the mixture was filtered and the residue was washed three times with sec-butanol to obtain the final product. Alternatively, the intermediate (1 eq), alkylamine (2 eq), and DIPEA (3 eq) were dissolved in NMP and reacted at 140°C overnight. After the reaction was monitored by TLC, the mixture was extracted three times with EA / water and passed through a silica gel column to obtain the final product.

[0113] Example 4. Preparation of pyrimidine compounds S2-92-S2-94

[0114] Compound JZ091 (1 eq), substituted phenylboronic acid (2 eq), tetrakis(triphenylphosphine)palladium, and potassium carbonate were dissolved in DMF under nitrogen and reacted at 100°C for 16 h. After TLC, the reaction was quenched and extracted three times with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the final product.

[0115] Example 5. Preparation of pyrimidine compounds S2-95-S2-149

[0116] Compound JZ099 / S2-51 / S2-48 / S2-49 / S2-50 (1 eq), a substituted amine or N-Boc-substituted amine (2 eq), HATU (1.3 eq), and DIPEA (3 eq) were dissolved in DMF under nitrogen and reacted at room temperature for 2 h. After TLC, the reaction was quenched and extracted three times with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The final product or product containing an N-Boc protecting group was obtained by column chromatography. Each product containing an N-Boc protecting group was further deprotected to obtain the corresponding final product.

[0117] Example 6. Preparation of pyrimidine compounds S2-150-S2-159

[0118] Compound S2-96 / S2-132 (1 eq), the substituted acid (2 eq), HATU (1.3 eq), and DIPEA (3 eq) were dissolved in DMF under nitrogen and reacted at room temperature for 2 h. After TLC, the reaction was quenched and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the final product or product containing an N-Boc protecting group. Each product containing an N-Boc protecting group was further deprotected to obtain the corresponding final product.

[0119] Example 7. Preparation of pyrimidine compounds S2-160-S2-173

[0120] Compound S2-62 was removed from the ester group to obtain a carboxyl-containing intermediate. This intermediate (1 eq), a substituted amine (2 eq), HATU, and DIPEA were dissolved in DMF under nitrogen and allowed to react at room temperature for 2 h. After TLC, the reaction was quenched and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the final product.

[0121] Example 8. Preparation of pyrimidine compounds S2-174-S2-243

[0122] 1) Synthesis of intermediate Int-A

[0123] 2-tert-Butoxycarbonylamino-5-hydroxybenzoic acid (1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.5 eq), 1-hydroxybenzotriazole (HOBT, 1.65 eq), and ammonium chloride (3.25 eq) were dissolved in dimethyl sulfoxide (DMSO). N,N-diisopropylethylamine (DIPEA, 6.5 eq) was added with stirring at room temperature. The reaction was allowed to react overnight at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water, extracted with EA, and then extracted with saturated brine. The EA layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The mixture was then purified by silica gel column chromatography (PE / EA = 1:1) to obtain the intermediate Int-A.

[0124] 2) Synthesis of intermediates Int-B1 / Int-B2

[0125] Intermediate Int-A (1 eq), 1,2-dichloroethane (2 eq) or 1,3-dichloropropane (2 eq), and potassium carbonate (3 eq) were dissolved in DMF, stirred at room temperature, and reacted overnight at 80°C. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was quenched with water, extracted with EA, and then extracted with saturated brine. The EA layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The mixture was then purified by silica gel column chromatography (PE / EA = 5:1) to obtain intermediates Int-B1 / Int-B2.

[0126] 3) Synthesis of intermediates Int-C1 / Int-C2

[0127] The intermediate Int-B1 / Int-B2 was dissolved in dichloromethane and trifluoroacetic acid (V) was added dropwise under stirring. 二氯甲烷 ∶V 三氟乙酸 =3:1). The reaction was stirred at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation to obtain the intermediate Int-C1 / Int-C2, which was directly carried out to the next step without purification.

[0128] 4) Synthesis of intermediates Int-D1 / Int-D2

[0129] 2,4-Dichloro-5-bromopyrimidine (1 eq), intermediates Int-C1 / Int-C2 (1.2 eq), and DIPEA (3 eq) were dissolved in isopropanol and reacted overnight at 90°C. After completion of the reaction, monitored by TLC, the mixture was filtered and the residue was washed three times with isopropanol to obtain intermediates Int-D1 / Int-D2.

[0130] 5) Synthesis of intermediate Int-E series

[0131] Intermediates Int-D1 / Int-D2 (1 eq), substituted aniline (2 eq), and TFA (3 eq) were dissolved in sec-butanol and reacted overnight at 100°C in a sealed autoclave. The reaction was monitored by TLC. After completion, the reaction was quenched with water, extracted with EA and saturated brine, and the EA layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The mixture was then purified by silica gel column chromatography to obtain the intermediate Int-E series.

[0132] 6) Synthesis of compounds S2-174-S2-243

[0133] The corresponding intermediate Int-E (1 eq), substituted amine (2 eq), potassium iodide (0.1 eq), and potassium carbonate (3 eq) were dissolved in DMF, stirred at room temperature, and reacted overnight at 100°C. The reaction progress was monitored by TLC. After completion of the reaction, the product was quenched with water, extracted with EA and saturated brine, and the EA layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain the corresponding final product.

[0134] Structure and characterization of intermediate Int-E series

[0135] Structure and characterization of compounds S2-174-S2-243

[0136] Example 9. Preparation of pyrimidine compounds S2-244-S2-247

[0137] 1) Synthesis of intermediate Int-A2

[0138] The synthesis of intermediate Int-A was carried out in the same manner as in Example 8, except that ammonium chloride was replaced by methylamine hydrochloride.

[0139] 2) Synthesis of intermediate Int-B3

[0140] The synthesis of intermediate Int-B1 was the same as in Example 8.

[0141] 3) Synthesis of intermediate Int-C3

[0142] The synthesis of intermediate Int-C1 was carried out in the same manner as in Example 8.

[0143] 4) Synthesis of intermediate Int-D3

[0144] The synthesis of intermediate Int-D1 was the same as in Example 8.

[0145] 5) Synthesis of intermediate Int-E series

[0146] The synthesis of the intermediate Int-E series was carried out in the same manner as in Example 8.

[0147] 6) Synthesis of compounds S2-244-S2-247

[0148] The synthesis of compounds S2-174-S2-243 was the same as in Example 8.

[0149] Structure and characterization of intermediate Int-E series

[0150] Structure and characterization of compounds S2-244-S2-247

[0151] Example 10. Determination of the inhibitory activity of the pyrimidine compounds of the present invention on JNK kinase

[0152] (1) Reagent materials: ADP-Glo TM Kinase Assay (Promega, V4071), DMSO (Aladdin, 67-68-5), 384-well white plate (Corning, 3570).

[0153] (2) Experimental instruments: microplate reader (Tecan Group Ltd., Switzerland), microplate shaker (Hangzhou Allsheng Instruments CO., Ltd., MB100-2A).

[0154] (3) Experimental methods:

[0155] 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, maintaining a 2% final DMSO concentration. Add 5 μL of the following reaction mixture to a 384-well plate: 1 μL of 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). Positive and negative controls were set up. The positive control group received 1 μL of 10% DMSO and 2 μL of Reaction Buffer instead of the compound and JNK enzyme, while the negative control group received 1 μL of 10% DMSO instead of the compound. The 384-well plate was placed on a microplate shaker at 25°C for 1 hour (10 ng of JNK enzyme) or 4 hours (2 ng of JNK enzyme). Add 5 μL of ADP-Glo ​​reagent and incubate on a microplate shaker at 25°C for 40 minutes to terminate the reaction and eliminate any excess ATP. Add 10 μL Kinase Detection Reagent and incubate at room temperature at 25°C for 30 minutes to convert ADP into ATP. The luciferase / luciferin reaction with the newly synthesized ATP produces chemiluminescence. Luminescence is detected using a microplate reader and the reading RLU is recorded. According to the formula: Compound inhibition rate (%) = [(RLU 阴 -RLU 样 ) / (RLU 阴 -RLU 阳 )]×100%, RLU 阴 Reading for negative control group, RLU 阳 Reading for the positive control group, RLU 样 The inhibition rate data were imported into GraphPad Prism 8.0 software for fitting, and the experimental results are shown in the table below.

[0156] In this example, the following three compounds with excellent activity in the prior art were used as references to test the inhibitory activity of the new compound on JNK1.

[0157] (4) Experimental results

[0158] The biological activities of the compounds of the present invention were determined by the above experiments. All compounds have a certain inhibitory effect on JNK1. The results are shown in the table below. Among them, the IC values ​​of the compounds designated as "A" for JNK1 inhibitory activity are 50 The value is IC 50 ≤0.01 μM; compounds designated as "B" for activity provided IC 50 The value is 0.01μM<IC 50≤0.1 μM; compounds designated as "C" for activity provided an IC 50 The value is 0.1μM<IC 50 ≤1 μM; compounds designated as "D" for activity provided IC 50 The value is 1μM<IC 50 ≤10 μM; compounds designated as “E” for activity provide IC 50 The value is IC 50 >10 μM;

[0159] Among them, the compounds designated as "A" for JNK1 inhibitory activity have specific JNK1 activity inhibition rates at a concentration of 0.01 μM as shown in the table below.

[0160] As can be seen from the above results, the compounds of the present invention are equally active as, or even superior to, control compounds. Among these control compounds, CC-90001 is currently in Phase II clinical trials for the treatment of IPF. This demonstrates that the compounds of the present invention are valuable for treating JNK-related diseases. They address the shortcomings of existing drugs and their efficacy in treating JNK-related diseases, making them highly significant.

[0161] Example 11. Effects of the pyrimidine compounds of the present invention on lung function in mice with pulmonary fibrosis

[0162] (1) Animals: Male C57 / B6 mice (8 weeks old, ∼25 g / mouse) were purchased from the Laboratory Animal Center of Hangzhou Normal University and housed in a constant temperature and humidity environment. All animal husbandry and experimental use were in accordance with the Guide for the Care and Use of Laboratory Animals.

[0163] (2) Reagents: Bleomycin (purchased from MedChemExpress, dissolved in PBS), compound JZ088 (original number Q63, dissolved in 0.5% CMC / 0.25% Tween 80).

[0164] (3) Experimental instruments: Small animal lung function measurement system (EMMS eSpiratm Forced Manoeuvers System, UK)

[0165] (4) Experimental methods: The mice were adapted for one week and divided into four groups, with 8 mice in each group, specifically: ① control group - CTRL; ② bleomycin-BLE; ③ bleomycin + Q63 (75 mg / kg) group - BLE + Q63 (75); ④ bleomycin + Q63 (25 mg / kg) group - BLE + Q63 (25). On the first day of the experiment, 3 mg / kg bleomycin was administered through tracheal instillation under anesthesia to induce pulmonary fibrosis in mice. Subsequently, for 2-20 days, the mice were gavaged with compound Q63 twice a day, morning and evening, at doses of 25 mg / kg and 75 mg / kg. On the 21st day, the mice were intubated and connected to the small animal pulmonary function measurement system to measure the mouse lung function indicators within 5 minutes, including expiratory volume, tidal volume and minute volume.

[0166] (5) Experimental results:

[0167] The effects of compound Q63 on lung function in mice with bleomycin-induced pulmonary fibrosis are shown in Figure 1: (A) expiratory volume; (B) tidal volume; (C) minute volume. The number of animals in each group was n = 8. *p < 0.05, **p < 0.01.

[0168] The experimental results showed that the expiratory volume, tidal volume, and minute volume of mice in the bleomycin group decreased by approximately 25% compared to the control group, with statistically significant differences. As expected, the mice developed pulmonary fibrosis. Compound JZ088 significantly improved respiratory function indicators, including expiratory volume, tidal volume, and minute volume, at 25 and 75 mg / kg, demonstrating that compound JZ088 can reverse or restore lung function damage in mice with bleomycin-induced pulmonary fibrosis.

[0169] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, In the formula, R1 is selected from: H, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, halogen, cyano, An optionally substituted 5-6 membered aryl or heteroaryl group, R2 is selected from: H, hydroxy, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 Aryl, halogen, cyano, nitro, optionally substituted sulfonyl, optionally substituted sulfonyl, optionally substituted phosphinyl, optionally substituted 5-7 membered heterocyclyl; Alternatively, two adjacent R2 together with the carbon atom to which they are attached form a 3-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S; x is 0, 1, 2, 3, 4, or 5; R3 is selected from: H, optionally substituted C 1-10 Alkyl, optionally substituted C 2-10 Alkenyl, optionally substituted C 2-10 Alkynyl, optionally substituted C 1-10 an alkoxy group, an optionally substituted C 5-10 Aryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O or S; R 41 and R 42 are independently selected from: H, optionally substituted hydroxy, optionally substituted amino, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 an alkoxy group, an optionally substituted C 5-10 Aryl, optionally substituted C 3-10 A cycloalkyl group, an optionally substituted 3-10 membered heterocyclic group; R5 is H, optionally substituted C 1-3 Acyl, optionally substituted C 1-10 Alkyl, optionally substituted C 5-10 Aryl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O or S; R6 and R7 are independently selected from: H, optionally substituted C 1-3Acyl, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O or S; n and m are independently selected from 0, 1, 2, 3, 4, 5 or 6; preferably, n and m are independently selected from 0, 1, or 2; more preferably, n and m are 0.

2. The compound according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from: halogen, cyano, optionally substituted C 1-6 Alkyl, -C(O)R 41 ; R2 is selected from: -OR5, -NR6R7, halogen, optionally substituted C 1-6 alkyl, optionally substituted phosphinyl; R3 is selected from: optionally substituted C 1-6 alkyl, optionally substituted 5-7 membered cycloalkyl or heterocyclic group, optionally substituted C 5-10 Aryl; or R3 is phenyl, which is optionally substituted by one or more groups independently selected from the following: halogen, hydroxy, amino, carboxyl, ester, sulfonamide, sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkoxy, optionally substituted 5-7 membered heteroaryl, -C 0-3 -C(O)-NR 61 R 71 ; R 41 is an optionally substituted amino group, an optionally substituted C 1-6 Alkoxy; R 42 Selected from: hydroxy, optionally substituted amino, optionally substituted C 1-6 Alkoxy; R5 is H, optionally substituted C 1-6 alkyl; R6 and R7 are each H, optionally substituted C 1-6 Alkyl; or R6 and R7 together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclic ring; R 61 and R 71 Each is H, an optionally substituted 3-7 membered cycloalkyl or heterocyclic group, a spiro ring, or a bridged ring; or, or R 61 and R 71 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 3-7 membered cycloalkyl or heterocyclic group, a spiro ring, or a bridged ring; n is 0, 1, 2 or 3; x is 1, 2, or 3.

3. The compound according to claim 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: R5 is H, C optionally substituted by one or more groups independently selected from the following 1-6 Alkyl: halogen, hydroxyl, carboxyl, C 1-3 Acyloxy, -NR 62 R 72 ; R 62 and R 72 Each is H, optionally substituted C 1-6 Alkyl; or R 62 and R 72 Together with the nitrogen atom to which it is bound, it forms an optionally substituted 3-7 membered heterocyclic ring.

4. The compound according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: x is 2 or 3, and at least one of the R2 is -C(O)R 42 , and substituted at the ortho-NH-position.

5. The compound according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in Formula 2: In the formula R1 is selected from: halogen, cyano, C 1-6 Alkyl, -C(O)R 41 ; R2 is selected from: -C(O)R 42 、-OR5、-NR6R7、halogen、C 1-6 alkyl; R 31 Selected from: halogen, hydroxyl, amino, carboxyl, ester, sulfonamide, sulfonyl, C 1-6 Alkyl, C 1-6 Alkoxy, 5-7 membered heteroaryl, -C 0-3 -C(O)-NR 61 R 71 ; Among them C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, amino, carboxyl, sulfonamide, 5-7 membered heteroaryl; R 43 Selected from: hydroxyl, unsubstituted or C 1-6 Alkyl-substituted amino, wherein C 1-6 The alkyl group is optionally substituted with one or more groups independently selected from the group consisting of halogen, sulfonamide, ester, amide, carboxyl, sulfonyl, hydroxyl, oxo; R 41 Amino, or C 1-6 Alkoxy; R 42 Hydroxyl, or C 1-6 Alkoxy; R5 is selected from: H, C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by one or more groups independently selected from the group consisting of halogen, hydroxy, carboxyl, C 1-3 Acyloxy, -NR 62 R 72 ; R6 and R7 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring optionally substituted by one or more groups independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; R 61 and R 71 Each is H, a 3-7 membered cycloalkyl or heterocyclic group, a spiro ring, a bridged ring, or R 61 and R 71 Together with the nitrogen atom to which it is bound, it forms a spiro ring, a bridged ring, or a 3-7 membered heterocyclic ring; The above spiro ring, bridged ring, 3-7 membered cycloalkyl or heterocyclic group are optionally substituted by one or more groups independently selected from the following: amino protecting group, sulfonyl group, 3-5 membered cycloalkyl or heterocyclic group, 3-5 membered cycloalkyl formyl group, 3-5 membered heterocyclic formyl group, wherein the cycloalkyl and heterocyclic group can be further substituted by halogen or amino protecting group; R 62 and R 72 H, C 1-6 Alkyl; or or R 62 and R 72 Together with the nitrogen atom to which it is attached, it forms a 3-7 membered heterocyclic ring which is optionally substituted by one or more groups independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy-OH, -C 1-6 Alkyl-NR 62 R 72 ; y is 0, 1, 2, or 3; x is 1 or 2.

6. The compound according to claim 2 or 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: The-C 0-3 -C(O)-NR 61 R 71 Medium-C(O)-NR 61 R 71 Selected from the following structures:

7. The compound according to claim 3 or 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: R 62 and R 72 Together with the nitrogen atom to which it is bound, it forms a group selected from the following:

8. A compound selected from the group consisting of: a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof:

9. The compound according to claim 8, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: The compound is the compound with the compound number shown below:

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 9 or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1 to 9 or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof in the preparation of a JNK inhibitor.

12. The use according to claim 11, characterized in that The JNK inhibitor is a drug for treating and / or preventing JNK-related diseases.

13. The use according to claim 12, characterized in that The JNK-related diseases are fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, central nervous system diseases, etc.

14. The use according to claim 13, characterized in that The fibrosis includes but is not limited to pulmonary fibrosis; The neurodegenerative diseases 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 include but are not limited to cerebral ischemia-reperfusion.

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