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

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, pharmaceutical combinations comprising said pyrimidine derivatives, and their use in the preparation of medicaments for JNK-related diseases. Background Art

[0002] c-Jun N-terminal kinase (JNK) is a serine / threonine kinase. As a member of the MAPK family, JNK is the kinase that interacts with the ultimate effector in the MAPK signaling cascade. There are three subtypes of JNK, JNK1 and JNK2 are ubiquitously expressed, while JNK3 is mainly expressed in the brain and at low levels in the heart and testis.

[0003] The JNK pathway regulates various physiological processes such as inflammatory responses, cell differentiation, cell proliferation, cell death, cell survival, and protein expression. Therefore, JNK is involved in a variety of pathological conditions, including fibrosis, neurodegenerative diseases, cancer, and inflammation. In terms of the fibrosis mechanism, JNK is associated with injuries such as oxidative stress, activator protein 1-mediated pro-inflammatory gene expression, macrophage activation, epithelial-mesenchymal transition, transforming growth factor β signaling, collagen secretion, and MMP-directed remodeling. Additionally, there is some evidence suggesting that JNK3 may be a target for the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Increased phosphorylated JNKs have been found in postmortem brain tissue samples of AD patients, especially JNK3 is significantly expressed and phosphorylated in the brains and cerebrospinal fluid of AD patients.

[0004] Currently, there are no drugs on the market for treating pulmonary fibrosis and other diseases related to this pathway, such as neurodegenerative diseases, diabetes, inflammatory diseases, etc. through the JNK inhibition pathway. Therefore, the development of new JNK inhibitor compounds is of great significance for the treatment of the above diseases. Summary of the Invention

[0005] The object of the present invention is to provide a compound having JNK inhibitory activity.

[0006] Another object of the present invention is to provide a pharmaceutical composition comprising said compound.

[0007] Another object of the present invention is to provide the use of said compound in the preparation of a medicament for treating JNK-related diseases and a method for treating JNK-related diseases using said compound or pharmaceutical composition.

[0008] In a first aspect, the present invention provides a compound of formula 1, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0009]

[0010] In the formula,

[0011] R1 is selected from: H, halogen, cyano, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, optionally substituted phenyl or heteroaryl, optionally substituted acyl, optionally substituted sulfonyl; 1-10 1-10

[0012] R2 and R3 are independently selected from: H, halogen, cyano, nitro, optionally substituted C 1-10 alkyl, optionally substituted C 1-10 alkoxy, optionally substituted 3- to 10-membered saturated or unsaturated carbocyclic group, optionally substituted 3- to 10-membered saturated or unsaturated heterocyclic group, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted phosphonous group,

[0013] Or, two adjacent R2 or R3 together with the carbon atom to which they are attached form a 3- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, O or S;

[0014] X is -O-, -S-, -NR N -, R N is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted acyl;

[0015] L is an optionally substituted C 1-10 hydrocarbon chain, in which one or more atoms may be independently replaced by -O-, -S-, -C(O)-, -NR N -, -N=, =N-, optionally substituted saturated or unsaturated carbocyclic group or heterocyclic group, where R N is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted acyl;

[0016] R4 and R5 are independently selected from: H, optionally substituted C 1-3 acyl, optionally substituted sulfonyl, optionally substituted C 1-10 alkyl, optionally substituted 3- to 10-membered saturated or unsaturated carbocyclic group, optionally substituted 3- to 10-membered saturated or unsaturated heterocyclic group;

[0017] Or, R4 and R5 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycle;

[0018] n and m are independently selected from 0, 1, 2, 3 or 4.

[0019] In a preferred embodiment, the "optionally substituted" means optionally substituted with one or more substituents selected from the following: cyano, halogen, hydroxy, optionally substituted amino, nitro, carboxy, ester, oxo, deuterium, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted C 1-3 acyloxy, optionally substituted C 5-10 aryl, optionally substituted 3- to 7-membered cycloalkyl or heterocyclic group, optionally substituted sulfonyl, optionally substituted acyl.

[0020] In a specific embodiment, R1 is selected from: H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted aminoacyl;

[0021] R2 is selected from: H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted 3- to 10-membered saturated or unsaturated heterocyclic group, optionally substituted aminoacyl;

[0022] R3 is selected from: H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted 3- to 10-membered saturated or unsaturated heterocyclic group;

[0023] X is -NH-;

[0024] L is an optionally substituted C 1-6 hydrocarbon chain, wherein one or more atoms may be independently replaced by -O-, -S-, -C(O)-, -NR N -, R N is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted acyl;

[0025] m and n are independently selected from 0, 1 or 2.

[0026] In a specific embodiment, R1 is selected from: fluorine, chlorine, bromine, iodine, methyl, optionally substituted aminoacyl;

[0027] R2 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted aminoacyl;

[0028] R3 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy;

[0029] L is selected from:

[0030]

[0031] m and n are independently selected from 0, 1 or 2.

[0032] In a specific embodiment, the compound is selected from the group consisting of:

[0033]

[0034]

[0035]

[0036]

[0037] In a specific embodiment, the compound is selected from the group consisting of:

[0038]

[0039]

[0040]

[0041]

[0042] In a specific embodiment, R1 is selected from: fluorine, chlorine, bromine, optionally substituted aminoacyl;

[0043] R2 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted aminoacyl;

[0044] R3 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy;

[0045] L is selected from:

[0046] m and n are independently selected from 0, 1 or 2.

[0047] In a specific embodiment, the compound is selected from the group consisting of:

[0048]

[0049]

[0050]

[0051] In a second aspect, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the compound described in the first aspect or its tautomer, meso form, racemate, enantiomer, diastereoisomer, a mixture form thereof or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0052] In a third aspect, the present invention provides the use of the compound described in the first aspect or its tautomer, meso form, racemate, enantiomer, diastereoisomer, a mixture form thereof or a pharmaceutically acceptable salt thereof in the preparation of a JNK inhibitor.

[0053] In a specific embodiment, the JNK inhibitor is a drug for treating and / or preventing JNK-related diseases.

[0054] In a specific embodiment, the JNK-related diseases are fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, central nervous system diseases, etc.

[0055] In a specific embodiment, the fibrosis includes but is not limited to pulmonary fibrosis;

[0056] The neurodegenerative diseases include but are not limited to Alzheimer's disease, Parkinson's syndrome;

[0057] The inflammatory diseases include but are not limited to arthritis, cardiac inflammation;

[0058] The tumors include but are not limited to lung cancer, liver cancer;

[0059] The central nervous system diseases include but are not limited to cerebral ischemia-reperfusion.

[0060] 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, meso form, racemate, enantiomer, diastereoisomer, a mixture form thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect, to a subject in need thereof.

[0061] In a preferred embodiment, the JNK-related diseases are fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, central nervous system diseases, etc.

[0062] In a preferred embodiment, the fibrosis includes but is not limited to pulmonary fibrosis;

[0063] The neurodegenerative diseases include but are not limited to Alzheimer's disease;

[0064] The inflammatory diseases include but are not limited to arthritis, cardiac inflammation;

[0065] The tumors include, but are not limited to, lung cancer and liver cancer;

[0066] The central nervous system diseases include, but are not limited to, cerebral ischemia-reperfusion.

[0067] 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 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 elaborated one by one here. Detailed implementation manners

[0068] Through extensive and in-depth research, the inventors unexpectedly found a series of compounds with JNK inhibitory activity, so that the compounds can be used in the preparation of drugs for treating JNK-related diseases, and further treat JNK-related diseases. On this basis, the present invention was completed.

[0069] Term definitions

[0070] The terms used herein for groups, substituents or structures of compounds have the same meanings understood by those skilled in the art. For clarity, the terms used in this specification are defined as follows.

[0071] As used in the present invention, "a", "one kind" or "one category" means at least one / kind / category or one / kind / category or more than one / kind / category.

[0072] In this article, expressions such as "C 1-n " etc. mean that the group has 1 - n carbon atoms. For example, the expression "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 carbon atom number range in this article also includes each sub-range therein. For example, when it is mentioned in this article that there are 1 - 10 carbon atoms, it also includes the cases of 1 - 9, 1 - 8, 1 - 7, 1 - 6, 1 - 5, 1 - 4, 1 - 3 carbon atoms.

[0073] The term "hydrocarbon chain" used herein has the meaning commonly understood by those of ordinary skill in the art, and it refers to various saturated or unsaturated straight-chain, branched-chain or cyclic hydrocarbon groups. Those skilled in the art know that if the hydrocarbon chain is a saturated hydrocarbon group, the number of carbon atoms it contains can be 1; if the hydrocarbon chain is an unsaturated hydrocarbon group, the number of carbon atoms it contains is at least 2. Therefore, the term "C 1-10 hydrocarbon chain" used herein includes C 1-10 saturated hydrocarbon chains or hydrocarbon groups, and C 2-10 unsaturated hydrocarbon chains or hydrocarbon groups. Similarly, the term "C 1-6The "hydrocarbon chain" includes C 1-6 saturated hydrocarbon chains or hydrocarbon groups, and C 2-6 unsaturated hydrocarbon chains or hydrocarbon groups.

[0074] As used herein, the term "alkyl" has the same meaning as commonly understood by those of ordinary skill in the art, and refers to various saturated straight-chain, branched-chain or cyclic hydrocarbon groups. For example, the alkyl groups described herein refer to lower alkyl groups having 1 to 10 carbon atoms; preferably lower alkyl groups having 1 to 8 carbon atoms; more preferably lower alkyl groups having 1 to 6 carbon atoms. In specific embodiments, the alkyl groups described herein include, but are 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, branched-chain or cyclic hydrocarbon groups containing a carbon-carbon double bond or a carbon-carbon triple bond.

[0075] As used herein, the terms "aryl" or "aromatic ring" have the same meaning, which is the same as commonly understood by those of ordinary skill 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 without heteroatoms in the ring, such as phenyl, naphthyl, etc. And 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, pyrazinyl.

[0076] As used herein, the term "halogen" has the same meaning as commonly understood by those of ordinary skill in the art. In specific embodiments, halogen refers to fluorine, chlorine, bromine or iodine.

[0077] As used herein, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent can be the substituent described in the corresponding description above, or the specific substituent that appears in each embodiment. Therefore, in the present invention, the substituents in General Formula 1 can each independently be the corresponding groups in the specific compounds in the embodiments; that is, the present invention includes the combinations of the substituents in the above General Formula 1, and also includes the combinations of some of the substituents shown in General Formula 1 and other specific substituents that appear in the embodiments.

[0078] Unless otherwise specified, a substituted group can have a specific substituent at any substitutable site of the group, and the substituents at each position can be the same or different. Cyclic substituents, such as heterocyclic groups, can be linked to another ring, such as a cycloalkyl group, to form a spirobicyclic system. For example, the two rings have a common carbon atom.

[0079] In particular, the various substituents defined above also include groups formed by their further substitution, and these new substituents may also contain other groups. For example, when the hydrogen atoms on an alkyl group and an aryl group are substituted by an amino group, a halogen, or other groups, they become groups falling within the above definitions.

[0080] In a specific embodiment, the "optionally substituted" means optionally substituted by one or more substituents selected from the following: cyano, halogen, hydroxyl, optionally substituted amino, nitro, carboxyl, ester group, oxo, deuterium, 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- to 7-membered cycloalkyl or heterocyclic group, optionally substituted sulfonyl, optionally substituted acyl.

[0081] The compounds of the present invention

[0082] To overcome the deficiencies in the prior art, the present invention provides pyrimidine derivatives, their pharmaceutical combinations and their applications that can be used for JNK-related diseases.

[0083] For this purpose, the present invention provides a pyrimidine derivative, and the structural formula of the pyrimidine derivative is shown in Formula 1:

[0084] The substituents in the formula are as described above respectively.

[0085] Based on the compounds of the present invention, the present invention further provides a pharmaceutical composition, which comprises the above-mentioned compound or its tautomer, mesomer, racemate, enantiomer, diastereomer, their mixture form or their pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier.

[0086] 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. In a specific embodiment, the JNK inhibitors of the present invention are drugs for treating and / or preventing JNK-related diseases.

[0087] Those skilled in the art are aware of specific JNK-related diseases, such as neurodegenerative diseases, diabetes, inflammatory diseases, central nervous system diseases, fibrosis and other diseases.

[0088] Advantages of the present invention:

[0089] 1. The compounds of the present invention have excellent JNK inhibitory activity;

[0090] 2. The compounds of the present invention have excellent selective inhibitory activity against JNK;

[0091] 3. The compounds of the present invention lay a new material foundation for the development of therapeutic drugs for JNK-related diseases.

[0092] The technical solutions of the present invention are further described below in conjunction with specific implementation cases. However, the following implementation cases do not constitute a limitation to the present invention. All application methods adopted based on the principles and technical means of the present invention belong to the scope of the present invention. For the experimental methods without specific conditions noted in the following examples, they are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0093] There are no special restrictions on the sources of all raw materials of the present invention. They can be purchased on the market or prepared according to the conventional methods well-known to those skilled in the art.

[0094] Example

[0095] I. Preparation of Ring Compounds Cy1 - Cy29

[0096] Example 1: Cy1

[0097]

[0098] The synthesis route is as follows:

[0099]

[0100] Step 1. Synthesis of Cy1 1-1

[0101] Weigh 3-(Boc-amino)phenol (1.00 g, 4.78 mmol), methyl bromoacetate (0.96 g, 5.74 mmol) and potassium carbonate (2.00 g, 14.34 mmol) in a 100 mL round-bottom flask. After dissolving in DMF (15 mL), stir at room temperature for 6 h, and monitor the reaction progress by TLC. After the reaction is completed, quench with water, extract with EA (3 × 50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (PE / EA = 10:1) with 200 - 300 mesh silica gel to obtain 1.24 g of colorless oily compound Cy1 1-1 (yield: 87.86%).

[0102] 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.10–7.06 (m, 2H), 6.51 (d, J = 8.1 Hz, 1H), 4.73 (s, 2H), 3.70 (s, 3H), 1.47 (s, 9H).

[0103] Step 2. Synthesis of Cy1 1-2

[0104] Weigh Cy1 1-1 (1.24 g, 4.41 mmol) in a 100 mL single-necked flask, dissolve it in DCM (10 mL), add 3.0 mL of trifluoroacetic acid, and react at room temperature for 2 h. Monitor the reaction progress by TLC. After the reaction is completed, remove the solvent by rotary evaporation to obtain a light yellow oily substance, which is directly used for the next reaction without purification.

[0105] Step 3. Synthesis of Cy1 1-3

[0106] Add 2,4-dichloro-5-pyrimidinecarboxamide (0.50 g, 2.60 mmol) and N,N-diisopropylethylamine (DIPEA, 1.36 mL, 7.81 mmol) to a 100 mL single-necked flask. Dissolve them in DMF (10 mL). After stirring at room temperature for 10 min, add Cy1 1-2 (0.56 g, 3.13 mmol), and continue to react at room temperature. Monitor the reaction progress by TLC. After the reaction is completed, add water (30 mL). A large amount of solid precipitates. Filter by suction and wash with water to obtain 0.71 g of yellow solid (yield: 81.20%).

[0107] 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 8.01 (s, 1H), 7.41 (s, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 4.83 (s, 2H), 3.71 (s, 3H).

[0108] Step 4. Synthesis of Cy1 1-4

[0109] Weigh Cy1 1-3 (0.70 g, 2.09 mmol) and N-Boc-m-phenylenediamine (0.87 g, 4.17 mmol) in a 100 mL single-necked flask. Add a small amount of DMF (4 mL) to dissolve them, then add isopropanol (10 mL) and trifluoroacetic acid (0.8 mL). Reflux at 90 °C for 2 h. Monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature. A solid precipitates. Filter by suction to obtain 0.38 g of purple solid (yield: 35.84%).

[0110] 11H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.07 (s, 1H), 9.34 (s, 1H), 8.77 (s, 1H), 8.27 (s, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.32 (t, J = 9.4 Hz, 2H), 7.26 (s, 1H), 7.23 - 7.16 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 4.75 (s, 2H), 3.69 (s, 3H), 1.46 (s, 9H).

[0111] Step 5. Synthesis of Cy1 1-5

[0112] Weighed compound CyN1 1-4 (0.38 g, 0.75 mmol) in a 100 mL single-necked flask, dissolved in THF (3 mL), added 15 mL of 20% aqueous KOH solution, and reacted at room temperature overnight. The reaction progress was monitored by TLC. After the reaction was completed, 5 mol / L hydrochloric acid was added to adjust the pH to 2, and a large amount of solid precipitated. The purple solid Cy1 1-5 (0.28 g, yield: 75.77%) was obtained by suction filtration.

[0113] 1 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.63 (s, 1H), 9.27 (s, 1H), 8.73 (s, 1H), 8.13 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 7.40 - 7.35 (m, 2H), 7.25 - 7.11 (m, 3H), 7.05 (d, J = 8.5 Hz, 1H), 6.60 (dd, J = 8.2, 2.5 Hz, 1H), 4.66 (s, 2H), 1.46 (s, 9H).

[0114] Step 6. Synthesis of Cy1 1-6

[0115] Weighed Cy1 1-5 (0.20 g, 0.41 mmol) in a 50 mL single-necked flask, dissolved in DCM (3 mL), added 3.0 mL of trifluoroacetic acid, and reacted at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation to obtain 0.16 g of purple solid, which was used directly in the next step without purification.

[0116] 11H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 9.96 (s, 1H), 8.77 (s, 1H), 8.22 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.55 (s, 2H), 7.36 - 7.22 (m, 4H), 6.90 (d, J = 7.2 Hz, 1H), 6.67 - 6.64 (m, 1H), 4.70 (s, 2H). MS (ESI): m / z 395.15 [M+H] + .

[0117] Step 7. Synthesis of Cy1

[0118] Weigh TBTU (0.16 g, 0.50 mmol) and DIPEA (0.20 mL, 1.14 mmol) in a 50 mL single-necked flask, dissolve them in DMF (10 mL), slowly add dropwise a DMF (5 mL) solution of Cy1 1-6 (0.15 g, 0.38 mmol), stir at room temperature overnight, and monitor the reaction progress by TLC. After the reaction is completed, quench with water, extract with EA (3 × 50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (DCM / CH3OH = 20:1) with 200 - 300 mesh silica gel to obtain 0.05 g of purple solid Cy1 (yield: 34.93%).

[0119] 1 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 9.99 (s, 1H), 9.66 (s, 1H), 8.76 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.90 (s, 1H), 7.49 (s, 1H), 7.23 - 7.30 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.92–6.87 (m, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.68 (s, 2H). MS (ESI): m / z 377.14 [M+H] + .

[0120] Example 2: Cy2

[0121]

[0122] The synthesis route is as follows:

[0123]

[0124] Step 1. Synthesis of Cy2 1-1

[0125] Weigh 3-(Boc-amino)phenol (1.00 g, 4.78 mmol), methyl acrylate (4.94 g, 57.35 mmol) and DMAP (0.038 g, 0.96 mmol) in a 100 mL single-necked flask. Heat the mixture to 100 °C and react for 24 h. Monitor the reaction progress by TLC. After the reaction is completed, quench with water, expand the volume with EA, extract with EA (3×50 mL) and water (3×50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (200-300 mesh, PE / EA = 7:1) to obtain 0.35 g of colorless oily compound Cy2 1-1 (yield: 24.80%).

[0126] 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.17 - 7.09 (m, 2H), 7.00 (dd, J = 8.2, 1.7 Hz, 1H), 6.56 - 6.50 (m, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 2.78 (t, J = 6.0 Hz, 2H), 1.47 (s, 9H).

[0127] Step 2. Synthesis of Cy2 1-2

[0128] Refer to the synthesis method of intermediate (Cy1 1-2). It is a light yellow oil and can be directly used for the next step without purification.

[0129] Step 3. Synthesis of Cy2 1-3

[0130] Refer to the synthesis method of intermediate (Cy1 1-3). The yield is 76.63% and it is a white solid.

[0131] Step 4. Synthesis of Cy2 1-4

[0132] Refer to the synthesis method of intermediate (Cy1 1-4). The yield is 76.71% and it is a purple solid.

[0133] 11H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 9.72 (s, 1H), 9.25 (s, 1H), 8.69 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.35 (dt, J = 7.9, 1.7 Hz, 1H), 7.27–7.25 (m, 2H), 7.19 (t, J = 8.1 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.67–6.61 (m, 1H), 4.12 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H), 1.46 (s, 9H).

[0134] Step 5. Synthesis of Cy2 1-5

[0135] Refer to the synthesis method of intermediate (Cy1 1-5), with a yield of 58.23%, purple solid.

[0136] 1 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.12 (s, 1H), 9.34 (s, 1H), 8.73–8.55 (m, 1H), 8.25 (s, 1H), 7.66 (s, 2H), 7.41–7.06 (m, 6H), 6.69 (d, J = 7.2 Hz, 1H), 4.09 (d, J = 6.5 Hz, 2H), 2.66 (d, J = 6.3 Hz, 2H), 1.46 (s, 9H).

[0137] Step 6. Synthesis of Cy2 1-6

[0138] Refer to the synthesis method of intermediate (Cy1 1-6), purple solid, without purification, directly used for the next step.

[0139] 1 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 10.00 (s, 1H), 8.71 (d, J = 6.3 Hz, 1H), 8.14 (s, 2H), 7.67 (s, 1H), 7.31–7.13 (m, 5H), 6.99 (t, J = 2.1 Hz, 1H), 6.84 (t, J = 6.4 Hz, 1H), 6.73–6.66 (m, 1H), 6.55 (dt, J = 8.5, 1.6 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H). MS (ESI): m / z 409.16 [M+H] + .

[0140] Step 7. Synthesis of Cy2

[0141] Refer to the synthesis method of reference compound (Cy1), with a yield of 41.85%, a white solid.

[0142] 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.79 (s, 1H), 9.46 (s, 1H), 8.71 (s, 1H), 8.07–8.05 (m, 2H), 7.63 (t, J = 2.2 Hz, 1H), 7.44 (s, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.19 (dd, J = 3.0, 1.4 Hz, 2H), 6.90 (dd, J = 6.1, 2.7 Hz, 1H), 6.83 (dd, J = 8.2, 2.4 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 4.37 (t, J = 5.5 Hz, 2H), 2.60 (t, J = 5.5 Hz, 2H). MS (ESI): m / z 391.15 [M+H] + .

[0143] Example 3: Cy3

[0144]

[0145] The synthesis route is as follows:

[0146]

[0147] Step 1. Synthesis of Cy3 1-1

[0148] Refer to the synthesis method of intermediate (Cy1 1-1), with a yield of 66.86%, a colorless oil.

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.74 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.14 (d, J = 8.1 Hz, 1H), 6.02 (t, J = 6.4 Hz, 1H), 3.83 (d, J = 6.4 Hz, 2H), 3.64 (d, J = 1.2 Hz, 3H), 1.45 (d, J = 1.1 Hz, 9H).

[0150] Step 2. Synthesis of Cy3 1-2

[0151] Refer to the synthesis method of intermediate (Cy1 1-2), a light yellow oil, without purification, directly used for the next step.

[0152] Step 3. Synthesis of Cy3 1-3

[0153] Referring to the synthesis method of intermediate (Cy1 1-3), the yield was 81.20%, yellow solid.

[0154] 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.81 (s, 1H), 8.52 (s, 1H), 7.96 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.90–6.79 (m, 2H), 6.36 (dd, J = 8.0, 2.2 Hz, 1H), 3.92 (s, 2H), 3.65 (s, 3H).

[0155] Step 4. Synthesis of Cy3 1-4

[0156] Referring to the synthesis method of intermediate (Cy1 1-4), the yield was 35.84%, brown solid.

[0157] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 10.57 (s, 1H), 9.42 (s, 1H), 8.81 (s, 1H), 8.47 (s, 1H), 7.82 (s, 1H), 7.61 (s, 1H), 7.31 (q, J = 3.3, 2.3 Hz, 1H), 7.21 (d, J = 5.2 Hz, 2H), 7.02 (d, J = 6.1 Hz, 2H), 6.70 (s, 1H), 6.38 (dt, J = 6.1, 2.5 Hz, 1H), 3.89 (s, 2H), 3.64 (s, 3H), 1.47 (s, 9H).

[0158] Step 5. Synthesis of Cy3 1-5

[0159] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 75.78%, brown solid.

[0160] 11H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.77 (s, 1H), 9.28 (s, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.12–6.99 (m, 3H), 6.80 (s, 1H), 6.31 (d, J = 7.5 Hz, 1H), 3.80 (s, 2H), 1.47 (s, 9H).

[0161] Step 6. Synthesis of Cy3 1-6

[0162] Referring to the synthesis method of the intermediate (Cy1 1-6), a brown solid, without purification, was directly used in the next step.

[0163] 1 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.20 (s, 1H), 8.76 (s, 1H), 8.24 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.61 (s, 2H), 7.34 (t, J = 8.1 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.05–6.92 (m, 2H), 6.88 (s, 1H), 6.37 (d, J = 8.0 Hz, 1H), 3.82 (s, 2H). MS (ESI): m / z 394.16 [M+H] + .

[0164] Step 7. Synthesis of Cy3

[0165] Referring to the synthesis method of the compound (Cy1), the yield was 34.93%, a white solid.

[0166] 1 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.97 (s, 1H), 9.53 (s, 1H), 8.74 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.22 (d, J = 7.9 Hz, 1H), 6.03 (s, 1H), 3.71 (d, J = 7.1 Hz, 2H). MS (ESI): m / z 376.15 [M+H] +.

[0167] Example 4: Cy4

[0168]

[0169] The synthesis route is as follows:

[0170]

[0171] Step 1. Synthesis of Cy4 1-1

[0172] Referring to the synthesis method of intermediate (Cy2 1-1), the yield is 25.65%, colorless oil.

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.22–6.16 (m, 1H), 5.61 (t, J = 5.8 Hz, 1H), 3.61 (s, 3H), 3.22 (q, J = 6.5 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 1.46 (s, 9H).

[0174] Step 2. Synthesis of Cy4 1-2

[0175] Referring to the synthesis method of intermediate (Cy1 1-2), light yellow oil, without purification, directly used for the next step.

[0176] Step 3. Synthesis of Cy4 1-3

[0177] Referring to the synthesis method of intermediate (Cy1 1-3), the yield is 73.19%, yellow solid.

[0178] Step 4. Synthesis of Cy4 1-4

[0179] Referring to the synthesis method of intermediate (Cy1 1-4), the yield is 93.89%, brown solid.

[0180] 11H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.65 (s, 1H), 9.22 (s, 1H), 8.65 (s, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.09–7.08 (m, 3H), 7.02 (t, J = 8.0 Hz, 1H), 6.72 (s, 1H), 6.33 (d, J = 7.9 Hz, 1H), 3.61 (s, 3H), 3.26 (t, J = 6.8 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H), 1.47 (s, 9H).

[0181] Step 5. Synthesis of Cy4 1-5

[0182] Refer to the synthesis method of intermediate (Cy1 1-5), with a yield of 55.05%, brown solid.

[0183] Step 6. Synthesis of Cy4 1-6

[0184] Refer to the synthesis method of intermediate (Cy1 1-6), brown solid, no purification required, directly used for the next step.

[0185] 1 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.34 (s, 1H), 8.66 (s, 1H), 8.01 (s, 1H), 7.36 (s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 7.02 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.93–6.90 (m, 2H), 6.87 (s, 1H), 6.34–6.27 (m, 3H), 5.52 (s, 2H), 3.24 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H). MS (ESI): m / z 408.18 [M+H] + .

[0186] Step 7. Synthesis of Cy4

[0187] Refer to the synthesis method of compound (Cy1), with a yield of 21.80%, white solid.

[0188] 11H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.74 (s, 1H), 8.90 (s, 1H), 8.67 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.38 (s, 1H), 7.18–7.02 (m, 4H), 6.89 (d, J = 8.0 Hz, 1H), 6.53–6.45 (m, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.63 (t, J = 6.8 Hz, 1H), 3.46 (q, J = 6.0 Hz, 2H), 2.44 (t, J = 5.7 Hz, 2H). MS (ESI): m / z 390.17 [M+H] + .

[0189] Example 5: Cy5

[0190]

[0191] The synthetic route is as follows:

[0192]

[0193] Step 1. Synthesis of Cy5 1-1

[0194] Referring to the synthesis method of intermediate (Cy1 1-3), the yield was 60.96%, a yellow solid.

[0195] 1 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.82 (s, 1H), 8.47 (s, 1H), 8.07–7.96 (m, 2H), 7.58–7.52 (m, 1H), 7.36–7.32 (m, 2H).

[0196] Step 2. Synthesis of Cy5 1-2

[0197] Referring to the synthesis method of intermediate (Cy1 1-4), the yield was 83.03%, a brown solid.

[0198] 11H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.45 (s, 1H), 8.80 (s, 1H), 8.36 (s, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.64–7.47 (m, 3H), 7.40–7.31 (m, 2H), 7.27 (t, J = 8.0 Hz, 2H), 6.66 (dd, J = 17.6, 10.9 Hz, 1H), 5.73 (d, J = 17.6 Hz, 1H), 5.25 (d, J = 10.9 Hz, 1H). MS (ESI): m / z 410.06 [M+H] + .

[0199] Step 3. Synthesis of Cy5

[0200] Weigh compound Cy5 1-2 (0.30 g, 0.73 mmol), palladium acetate (0.07 g, 0.40 mmol), and tris(ortho-methylphenyl)phosphine (0.50 g, 1.46 mmol) in a two-necked flask. Under nitrogen protection, dissolve them in ultradry DMF (5 mL). Add TEA (0.56 mL, 4.02 mmol) under stirring at room temperature, and react at 120 °C overnight. Monitor the reaction progress by TLC. After the reaction is completed, quench with water, expand the volume with EA, extract with EA (3 × 50 mL) and water (3 × 50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (DCM / CH3OH = 20:1) with 200-300 mesh silica gel to obtain 0.19 g of white solid Cy5 (yield: 78.89%).

[0201] 1 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.74 (s, 1H), 8.98 (dt, J = 16.2, 2.0 Hz, 2H), 8.72 (s, 1H), 8.05 (s, 1H), 7.44 (s, 1H), 7.27 (dt, J = 16.8, 7.8 Hz, 2H), 7.13–7.06 (m, 1H), 7.06–7.01 (m, 1H), 7.00–6.91 (m, 2H), 6.59 (s, 2H). MS (ESI): m / z 330.14 [M+H] + .

[0202] Example 6: Cy6

[0203]

[0204] The synthesis route is as follows:

[0205]

[0206] Step 2. Synthesis of Cy6

[0207] Weigh Cy5 (0.04 g, 0.12 mmol) in a 100 mL two-necked flask, dissolve it in dry THF (10 mL), add Pd / C (65 mg, 0.06 mmol), and react overnight under a hydrogen atmosphere. Monitor the reaction progress by TLC. After the reaction is completed, remove the solvent by rotary evaporation, redissolve it in EA, extract with EA (3×50 mL) and water (3×50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (200 - 300 mesh, DCM / CH3OH = 20:1) to obtain 35 mg of white solid Cy6 (yield: 86.97%)

[0208] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.60 (s, 1H), 8.69 (s, 1H), 8.05 (dt, J = 6.2, 2.0 Hz, 2H), 7.99 (s, 1H), 7.37 (s, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.01–6.93 (m, 2H), 6.88 (t, J = 7.3 Hz, 2H), 2.85 (s, 4H). MS (ESI): m / z 332.15 [M+H] + .

[0209] Example 7: Cy7

[0210]

[0211] The synthesis route is as follows:

[0212]

[0213] Step 1. Synthesis of Cy7 1-1

[0214] Refer to the synthesis method of intermediate (Cy1 1-3), with a yield of 81.31%, yellow solid.

[0215] Step 2. Synthesis of Cy7 1-2

[0216] Refer to the synthesis method of intermediate (Cy1 1-4), with a yield of 42.11%, white solid.

[0217] 11H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 11.65 (s, 1H), 9.86 (s, 1H), 8.75 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.40 (td, J = 7.6, 4.0 Hz, 2H), 7.30 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 4.12 (d, J = 6.2 Hz, 2H), 1.39 (s, 9H).

[0218] Step 3. Synthesis of Cy7 1-3

[0219] Refer to the synthesis method of intermediate (Cy1 1-6), white solid, directly used for the next step without purification.

[0220] 1 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 9.95 (s, 1H), 8.78 (s, 1H), 8.29–8.09 (m, 2H), 8.02–7.93 (m, 2H), 7.61 (dt, J = 7.7, 1.4 Hz, 2H), 7.42 (t, J = 7.9 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 7.7 Hz, 2H), 4.02 (q, J = 5.8 Hz, 2H). MS (ESI): m / z 379.15 [M+H] +

[0221] Step 4. Synthesis of Cy7

[0222] Refer to the synthesis method of compound (Cy1), yield 9.69%, white solid.

[0223] 1 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.04 (s, 1H), 9.35 (s, 1H), 8.78 (s, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.47 (s, 1H), 7.30–7.22 (m, 3H), 7.11 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H). MS (ESI): m / z 361.14 [M+H] +

[0224] Example 8: Cy8

[0225]

[0226] The synthesis route is as follows:

[0227]

[0228] Step 1. Synthesis of Cy8 1-1

[0229] Referring to the synthesis method of intermediate (Cy1 1-3), the yield is 54.77%, and it is a yellow solid.

[0230] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.87 (s, 1H), 7.69–7.59 (m, 1H), 7.32–7.24 (m, 1H), 3.85 (s, 3H).

[0231] Step 2. Synthesis of Cy8 1-2

[0232] Referring to the synthesis method of intermediate (Cy1 1-4), the yield is 84.08%, and it is a yellow solid.

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.35 (s, 1H), 8.73 (s, 1H), 8.32–8.12 (m, 2H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.67 (s, 1H), 7.65–7.55 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.54 (d, J = 7.7 Hz, 2H), 3.85 (s, 3H).

[0234] Step 3. Synthesis of Cy8 1-3

[0235] Referring to the synthesis method of intermediate (Cy1 1-5), the yield is 62.30%, and it is a light yellow solid.

[0236] 11H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 12.13 (s, 1H), 9.69 (s, 1H), 9.36 (s, 1H), 8.70 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.89 (dd, J = 7.8, 1.7 Hz, 1H), 7.58–7.51 (m, 1H), 7.33 (s, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.98 (t, J = 8.1 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H). MS (ESI): m / z 366.12 [M+H] + .

[0237] Step 4. Synthesis of Cy8

[0238] Weigh EDCI (55 mg, 0.28 mmol), HOBt (43 mg, 0.32 mmol) and ammonium chloride (33 mg, 0.62 mmol) in a 50 mL single-necked flask. After dissolving in 5 mL of DMSO, add DIPEA (0.22 mL, 1.25 mmol). Stir at room temperature for 5 min, then slowly add a DMSO solution (5 mL) of Cy8 1-3 (70 mg, 0.19 mmol). Stir at room temperature overnight and monitor the reaction progress by TLC. After the reaction is completed, quench with water, extract with EA (3×50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (DCM / CH3OH = 15:1) with 200-300 mesh silica gel to obtain 25 mg of yellow solid Cy8 (yield: 37.57%).

[0239] 1 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.70–9.54 (m, 2H), 8.53 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 4.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H). MS (ESI): m / z 348.11 [M+H] + .

[0240] Example 9: Cy9

[0241]

[0242] The synthetic route is as follows:

[0243]

[0244] Step 1. Synthesis of Cy9 1-1

[0245] Referring to the synthetic method of intermediate (Cy1 1-4), the yield is 79.48%, and it is a yellow solid.

[0246] 1 H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 9.94 (s, 1H), 9.32 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.65 (s, 1H), 7.51 (t, J = 7.9 Hz, 2H), 7.25 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (dt, J = 14.4, 8.1 Hz, 2H), 3.85 (s, 3H), 1.47 (s, 9H).

[0247] Step 2. Synthesis of Cy9 1-2

[0248] Referring to the synthetic method of intermediate (Cy1 1-5), the yield is 62.25%, and it is a brown solid.

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 12.08 (s, 1H), 9.60 (s, 1H), 9.24 (s, 1H), 8.66 (s, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.17–7.01 (m, 3H), 1.47 (s, 9H).

[0250] Step 3. Synthesis of Cy9 1-3

[0251] Referring to the synthetic method of intermediate (Cy1 1-6), it is a brown solid and can be directly used in the next step without purification.

[0252] 11H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 9.75 (s, 1H), 8.68 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.29 (s, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H). MS (ESI): m / z 365.14 [M+H] +

[0253] Step 4. Synthesis of Cy9

[0254] Referring to the synthesis method of the reference compound (Cy1), the yield was 29.46%, and it was a yellow solid.

[0255] 1 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.65 (d, J = 4.3 Hz, 1H), 8.52 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 4.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.96 (s, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H), 5.26 (s, 1H). MS (ESI): m / z 347.13 [M+H] + .

[0256] Example 10: Cy10

[0257]

[0258] The synthesis route is as follows:

[0259]

[0260] Step 1. Synthesis of Cy10 1-1

[0261] Add 2,4-dichloropyrimidine (0.20 g, 1.34 mmol) and anthranilic acid (0.22 g, 1.61 mmol) to a 50 mL single-necked flask. After dissolving in 0.1 M HCl (5 mL), react at 50 °C for 1 h and then react overnight at room temperature. Monitor the reaction progress by TLC. After the reaction is completed, a white solid precipitates. Filter by suction and wash 3 times with water to obtain 0.17 g of solid (yield: 50.92%).

[0262] Step 2. Synthesis of Cy10 1-2

[0263] Weigh Cy10 1-1 (0.17 g, 0.68 mmol) and m-aminophenol (0.09 g, 0.82 mmol) in a 35 mL sealed tube. Dissolve in 5 mL of ethanol, seal, and react at 110 °C for 1 h. Monitor the reaction progress by TLC. After the reaction is completed, a solid precipitates. Filter by suction and wash with ethanol to obtain 0.10 g of off-white solid (yield: 45.38%).

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.33 (s, 2H), 8.73 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 5.7 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.27–7.21 (m, 1H), 7.15–7.01 (m, 3H), 6.40 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 5.6 Hz, 1H). MS (ESI): m / z 323.11 [M+H] + .

[0265] Step 3. Synthesis of Cy10

[0266] Refer to the synthesis method of the reference compound (Cy8), with a yield of 15.05%, a yellow solid.

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.66 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 6.3 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 2.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.63–6.55 (m, 2H). MS (ESI): m / z 305.10 [M+H] + .

[0268] Example 11: Cy11

[0269]

[0270] The synthesis route is as follows:

[0271]

[0272] Step 1. Synthesis of Cy11 1-1

[0273] Add 2,4-dichloro-5-bromopyrimidine (0.60 g, 2.63 mmol) and methyl anthranilate (0.48 g, 3.16 mmol) into a 100 mL round-bottom flask. After dissolving in 10 mL of isopropanol, add DIPEA (1.38 mL, 7.90 mmol). Stir evenly at room temperature and then reflux at 90 °C overnight. Monitor the reaction process by TLC. After the reaction is completed, cool to room temperature, and a solid precipitates. Filter by suction and wash with isopropanol three times to obtain 0.55 g of off-white solid (yield: 60.97%).

[0274] 1 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.62 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 3.90 (s, 3H).

[0275] Step 2. Synthesis of Cy11 1-2

[0276] Weigh Cy11 1-1 (0.30 g, 0.88 mmol) and m-aminophenol (0.19 g, 1.75 mmol) in a 35 mL sealed tube. After dissolving in 10 mL of sec-butanol, add 200 μL of trifluoroacetic acid, seal it, and react at 100 °C overnight. Monitor the reaction process by TLC. After the reaction is completed, a solid precipitates. Filter by suction and wash with sec-butanol to obtain 0.20 g of off-white solid (yield: 55.00%).

[0277] 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.61 (s, 1H), 8.90 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.04 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.09–7.03 (m, 2H), 6.45 (dt, J = 5.8, 2.5 Hz, 1H), 3.91 (s, 3H).

[0278] Step 3. Synthesis of Cy11 1-3

[0279] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 75.90%, off-white solid.

[0280] 1 1H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 11.34 (s, 1H), 9.44 (s, 1H), 9.31 (s, 1H), 8.99 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.21–7.01 (m, 4H), 6.43 (d, J = 7.3 Hz, 1H). MS (ESI): m / z 401.02 [M+H] + .

[0281] Step 4. Synthesis of Cy11

[0282] Referring to the synthesis method of compound (Cy8), the yield was 45.02%, yellow solid.

[0283] 1 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.60 (s, 1H), 8.26 (dd, J = 8.1, 1.5 Hz, 1H), 8.01 (s, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 2.2 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.61–6.57 (m, 1H). MS (ESI): m / z 383.01 [M+H] + .

[0284] Example 12: Cy12

[0285]

[0286] The synthetic route is as follows:

[0287]

[0288] Step 1. Synthesis of Cy12 1-1

[0289] Referring to the synthesis method of intermediate (Cy11 1-2), the yield is 49.95%, a brown solid.

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.52 (s, 1H), 9.30 (s, 1H), 8.98 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J = 8.0, 1.8 Hz, 1H), 7.74 (t, J = 2.1 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.9 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 1.46 (s, 9H).

[0291] Step 2. Synthesis of Cy12 1-2

[0292] Referring to the synthesis method of intermediate (Cy1 1-5), the yield is 75.39%, a brown solid.

[0293] 1 H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 11.37 (s, 1H), 9.52 (s, 1H), 9.31 (s, 1H), 8.99 (d, J = 8.6 Hz, 1H), 8.32 (s, 1H), 8.03 (dd, J = 7.9, 1.7 Hz, 1H), 7.75 (s, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.20–7.08 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 1.46 (s, 9H).

[0294] Step 2. Synthesis of Cy12 1-3

[0295] Referring to the synthesis method of intermediate (Cy1 1-6), a light brown solid, which is directly used for the next step without purification.

[0296] 11H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 9.83 (s, 1H), 8.96 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H), 8.06 (dd, J = 7.9, 1.7 Hz, 1H), 7.74–7.62 (m, 3H), 7.37 (t, J = 8.1 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H). MS (ESI): m / z 400.04 [M+H] + .

[0297] Step 3. Synthesis of Cy12

[0298] Referring to the synthesis method of the reference compound (Cy1), the yield was 47.70%, and it was a yellow solid.

[0299] 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.24 (dd, J = 8.1, 1.5 Hz, 1H), 7.97 (s, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.89 (t, J = 2.1 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.39 (dd, J = 8.1, 2.2 Hz, 1H), 5.33–5.19 (m, 2H). MS (ESI): m / z 382.03 [M+H] + .

[0300] Example 13: Cy13

[0301]

[0302] The synthesis route is as follows:

[0303]

[0304] Step 1. Synthesis of Cy13 1-1

[0305] Weigh methyl 3-amino-4-carboxybenzoate (0.50 g, 2.56 mmol), EDCI (0.74 g, 3.84 mmol), HOBt (0.57 g, 4.23 mmol) and ammonium chloride (0.45 g, 8.33 mmol) in a 50 mL single-necked flask. After dissolving in DMSO (15 mL), add DIPEA (2.90 mL, 16.65 mmol), stir at room temperature for 6 h, and monitor the reaction progress by TLC. After the reaction is completed, quench with water, extract with EA (3×50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (PE / EA = 5:1) with 200-300 mesh silica gel to obtain 0.40 g of white solid Cy13 1-1 (yield: 80.40%).

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.75 (s, 2H), 3.82 (s, 3H).

[0307] Step 2. Synthesis of Cy13 1-2

[0308] Refer to the synthesis method of intermediate (Cy11 1-1), with a yield of 52.89%, off-white solid.

[0309] 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 9.27–9.18 (m, 1H), 8.60 (d, J = 0.9 Hz, 1H), 8.55 (s, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H).

[0310] Step 2. Synthesis of Cy13 1-3

[0311] Refer to the synthesis method of intermediate (Cy11 1-2), with a yield of 50.49%, light pink solid.

[0312] 11H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.78 (s, 1H), 9.35 (s, 1H), 8.88 (d, J = 1.7 Hz, 1H), 8.49 (s, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.08–6.96 (m, 2H), 6.90 (t, J = 8.0 Hz, 1H), 6.41 (d, J = 7.7 Hz, 1H), 3.72 (s, 3H).

[0313] Step 3. Synthesis of Cy13 1-4

[0314] Refer to the synthesis method of intermediate (Cy1 1-5), with a yield of 82.52%, off-white solid.

[0315] 1 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 10.78 (s, 1H), 9.37 (s, 1H), 9.19 (s, 1H), 8.90 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.67 (dd, J = 8.2, 1.6 Hz, 1H), 7.20 (dd, J = 8.1, 2.0 Hz, 1H), 6.99 (s, 1H), 6.90 (t, J = 8.1 Hz, 1H), 6.34 (dd, J = 8.0, 2.3 Hz, 1H). MS (ESI): m / z 444.03 [M+H] + .

[0316] Step 4. Synthesis of Cy13

[0317] Refer to the synthesis method of compound (Cy8), with a yield of 30.40%, yellow solid.

[0318] 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.59 (s, 1H), 8.37 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 7.25 (s, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H). MS (ESI): m / z 426.02 [M+H] + .

[0319] Example 14: Cy14

[0320]

[0321] The synthetic route is as follows:

[0322]

[0323] Step 1. Synthesis of Cy141-1

[0324] Referring to the synthetic method of intermediate (Cy11 1-2), the yield is 51.33%, and it is a blue solid.

[0325] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.82 (s, 1H), 8.90 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.44 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 3.76 (s, 3H).

[0326] Step 2. Synthesis of Cy14 1-2

[0327] Referring to the synthetic method of intermediate (Cy1 1-5), the yield is 81.06%, and it is a blue solid.

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.17 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.84–6.67 (m, 2H), 6.20–6.14 (m, 1H). MS (ESI): m / z 443.05 [M+H] + .

[0329] Step 4. Synthesis of Cy14

[0330] Referring to the synthetic method of compound (Cy1), the yield is 33.36%, and it is a yellowish-green solid.

[0331] 11H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.94 (s, 1H), 9.42 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.85 (t, J = 2.1 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.14–7.06 (m, 2H), 6.78 (dd, J = 8.1, 1.8 Hz, 1H), 6.73 (dd, J = 7.8, 2.0 Hz, 1H). MS (ESI): m / z 425.04 [M+H] + .

[0332] Example 15: Cy15

[0333]

[0334] The synthetic route is as follows:

[0335]

[0336] Step 1. Synthesis of Cy15 1-1

[0337] Referring to the synthetic method of intermediate (Cy11 1-2), the yield was 47.24%, a brown solid.

[0338] 1 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.53 (s, 1H), 8.89 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.29 (t, J = 6.3 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 3.95 (d, J = 5.9 Hz, 2H), 3.70 (s, 3H), 1.38 (s, 9H).

[0339] Step 2. Synthesis of Cy15 1-2

[0340] Referring to the synthetic method of intermediate (Cy1 1-5), the yield was 87.87%, a brown solid.

[0341] 11H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 11.05 (s, 1H), 9.53 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.09–7.85 (m, 2H), 7.75–7.52 (m, 2H), 7.31 (d, J = 19.3 Hz, 2H), 7.04 (d, J = 9.4 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 3.97 (s, 2H), 1.38 (s, 9H).

[0342] Step 3. Synthesis of Cy15 1-3

[0343] Referring to the synthesis method of intermediate (Cy1 1-6), brown solid, directly used for the next step without purification.

[0344] 1 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.64 (s, 1H), 8.77 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.19 (s, 2H), 7.95 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 3.87–3.78 (m, 2H). MS (ESI): m / z 457.06 [M+H] + .

[0345] Step 4. Synthesis of Cy15

[0346] Referring to the synthesis method of compound (Cy), the yield is 36.44%, light yellow solid.

[0347] 1 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 9.71 (s, 1H), 9.57 (s, 1H), 8.97 (t, J = 6.7 Hz, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.26–7.16 (m, 2H), 6.96 (dd, J = 16.7, 7.8 Hz, 2H), 4.46–4.38 (m, 2H). MS (ESI): m / z 439.05 [M+H] + .

[0348] Example 16: Cy16

[0349]

[0350] The synthetic route is as follows:

[0351]

[0352] Step 1. Synthesis of Cy16 1-1

[0353] Referring to the synthesis method of intermediate (Cy11 1-1), the yield is 66.46%, and it is a white solid.

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.51 (s, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.62 (dt, J = 7.1, 1.9 Hz, 1H), 7.42–7.32 (m, 2H).

[0355] Step 2. Synthesis of Cy16 1-2

[0356] Referring to the synthesis method of intermediate (Cy11 1-2), the yield is 76.03%, and it is an off-white solid.

[0357] 1 H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 7.82 (t, J = 1.9 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.33–7.25 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.56 (dd, J = 17.6, 10.9 Hz, 1H), 5.61 (d, J = 17.6 Hz, 1H), 5.18 (d, J = 11.4 Hz, 1H). MS (ESI): m / z 446.96 [M+H] + .

[0358] Step 3. Synthesis of Cy16

[0359] Referring to the synthesis method of compound (Cy5), the yield is 28.10%, and it is a white solid.

[0360] 11H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.93 (t, J = 1.9 Hz, 1H), 8.88 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.22 (s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.23–7.18 (m, 2H), 7.06–7.01 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 13.1 Hz, 1H), 6.56 (d, J = 13.2 Hz, 1H). MS (ESI): m / z 365.04 [M+H] + .

[0361] Example 17: Cy17

[0362]

[0363] The synthetic route is as follows:

[0364]

[0365] Step 1. Synthesis of Cy17 1-1

[0366] Referring to the synthesis method of intermediate (Cy11 1-2), the yield was 61.87%, a brown solid.

[0367] 1 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.46 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 8.03 (dd, J = 8.0, 1.7 Hz, 1H), 7.54 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.24–7.15 (m, 1H), 6.73 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H).

[0368] Step 2. Synthesis of Cy17 1-2

[0369] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 82.80%, a brown solid.

[0370] 11H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.24 (s, 1H), 9.17 (s, 1H), 8.88 (s, 1H), 8.27 (s, 1H), 8.02 (dd, J = 7.9, 1.7 Hz, 1H), 7.55–7.45 (m, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H).

[0371] Step 3. Synthesis of Cy17

[0372] Refer to the synthesis method of the reference compound (Cy8), with a yield of 36.64%, yellow solid.

[0373] 1 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.51 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.93 (s, 1H), 7.92–7.88 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H). MS (ESI): m / z 383.01 [M+H] + .

[0374] Example 18: Cy18

[0375]

[0376] The synthesis route is as follows:

[0377]

[0378] Step 1. Synthesis of Cy18 1-1

[0379] Refer to the synthesis method of the intermediate (Cy11 1-2), with a yield of 58.61%, blue solid.

[0380] 1 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.50 (s, 1H), 9.24 (s, 1H), 8.83 (s, 1H), 8.33 (s, 1H), 8.04 (dd, J = 8.1, 1.7 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 3.91 (s, 3H), 1.48 (s, 9H).

[0381] Synthesis of Cy18 1-2

[0382] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 71.96%, and it was a blue solid.

[0383] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.41 (s, 1H), 9.22 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 8.03 (dd, J = 8.1, 1.7 Hz, 1H), 7.61–7.47 (m, 3H), 7.37 (d, J = 8.5 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 1.48 (s, 9H).

[0384] Synthesis of Cy18 1-3

[0385] Referring to the synthesis method of intermediate (Cy1 1-6), it was a blue solid. It was directly used for the next step without purification.

[0386] 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.72 (s, 1H), 8.86 (d, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.05 (dd, J = 7.9, 1.7 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H). MS (ESI): m / z 400.04 [M+H] + .

[0387] Synthesis of Cy18

[0388] Referring to the synthesis method of compound (Cy1), the yield was 29.32%, and it was a yellow solid.

[0389] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.22 (dd, J = 8.1, 1.5 Hz, 1H), 7.94–7.87 (m, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.14 (s, 2H). MS (ESI): m / z 382.03 [M+H] + .

[0390] Example 19: Cy19

[0391]

[0392] The synthetic route is as follows:

[0393]

[0394] Step 1. Synthesis of Cy19 1-1

[0395] Referring to the synthesis method of intermediate (Cy11 1-2), the yield was 55.94%, yellow solid.

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.67 (d, J = 8.2 Hz, 3H), 8.31 (s, 1H), 8.00 (dd, J = 8.0, 1.7 Hz, 1H), 7.63–7.52 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.18–7.09 (m, 3H), 3.90 (s, 3H), 1.44 (s, 9H).

[0397] Step 2. Synthesis of Cy19 1-2

[0398] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 71.96%, yellow solid.

[0399] Step 3. Synthesis of Cy19 1-3

[0400] Referring to the synthesis method of intermediate (Cy1 1-6), yellow solid, directly used for the next step without purification.

[0401] 1 H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.78 (d, J = 7.9 Hz, 1H), 8.63 (s, 1H), 8.23 (s, 1H), 7.98 (dd, J = 7.9, 1.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.07–7.01 (m, 1H), 6.97 (td, J = 7.6, 1.5 Hz, 1H), 6.79 (dd, J = 8.0, 1.5 Hz, 1H), 6.61 (td, J = 7.5, 1.5 Hz, 1H). MS (ESI): m / z 400.04 [M+H] + .

[0402] Step 4. Synthesis of Cy19

[0403] Referring to the synthesis method of reference compound (Cy1), the yield was 31.41%, and it was a yellow solid.

[0404] 1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.25 (dd, J = 8.1, 1.5 Hz, 1H), 7.93–7.90 (m, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.21 (dd, J = 7.7, 1.5 Hz, 1H), 7.03–6.96 (m, 1H), 6.75 (dd, J = 8.0, 1.5 Hz, 1H), 6.59 (td, J = 7.5, 1.4 Hz, 1H), 5.14 (s, 2H). MS (ESI): m / z 382.03 [M+H] + .

[0405] Example 20: Cy20

[0406]

[0407] The synthetic route is as follows:

[0408]

[0409] Step 1. Synthesis of Cy20 1-1

[0410] Referring to the synthesis method of intermediate (Cy11 1-1), the yield was 65.19%, and it was an off-white solid.

[0411] 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 3.88 (s, 3H).

[0412] Step 2. Synthesis of Cy20 1-2

[0413] Referring to the synthesis method of intermediate (Cy11 1-2), the yield was 61.87%, and it was a brown solid.

[0414] 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.15 (s, 1H), 8.83 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.30–7.23 (m, 1H), 6.96 (d, J = 4.9 Hz, 2H), 3.82 (s, 3H), 1.45 (s, 9H).

[0415] Step 3. Synthesis of Cy20 1-3

[0416] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 68.54%, a brown solid.

[0417] Step 4. Synthesis of Cy20 1-4

[0418] Referring to the synthesis method of intermediate (Cy1 1-6), a brown solid, directly used in the next step without purification.

[0419] 1 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.98 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.41 (s, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H). MS (ESI): m / z 400.04 [M+H] + .

[0420] Step 5. Synthesis of Cy20

[0421] Referring to the synthesis method of compound (Cy1), the yield was 32.72%, a yellow solid.

[0422] 11H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.31 (s, 1H), 9.06 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H). MS (ESI): m / z 382.03 [M+H] + .

[0423] Example 21: Cy21

[0424]

[0425] The synthetic route is as follows:

[0426]

[0427] Step 1. Synthesis of Cy21 1-1

[0428] Referring to the synthesis method of intermediate (Cy11 1-1), the yield was 88.13%, off-white solid.

[0429] 1 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.45 (s, 1H), 7.47–7.24 (m, 4H), 7.07 (d, J = 6.6 Hz, 1H), 4.13 (s, 2H), 1.39 (s, 9H).

[0430] Step 2. Synthesis of Cy21 1-2

[0431] Referring to the synthesis method of intermediate (Cy11 1-1), the yield was 56.30%, brown solid.

[0432] Step 3. Synthesis of Cy21 1-3

[0433] Referring to the synthesis method of intermediate (Cy11 1-6), brown solid, directly used for the next step without purification.

[0434] 11H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.53 (s, 1H), 8.72 (s, 1H), 8.30 (s, 1H), 8.18 (s, 2H), 8.08 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 4.01 (q, J = 5.8 Hz, 2H). MS (ESI): m / z 414.06 [M+H] + .

[0435] Step 4. Synthesis of Cy21

[0436] Refer to the synthesis method of the reference compound (Cy1), with a yield of 15.68%, a light brown solid.

[0437] 1 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.05 (s, 1H), 8.72–8.63 (m, 2H), 8.27 (s, 1H), 8.09 (s, 1H), 7.29–7.20 (m, 2H), 7.16 (d, J = 6.9 Hz, 2H), 7.10–6.94 (m, 2H), 4.34 (s, 2H). MS (ESI): m / z 396.05 [M+H] + .

[0438] Example 22: Cy22

[0439]

[0440] The synthesis route is as follows:

[0441]

[0442] Step 1. Synthesis of Cy22 1-1

[0443] Refer to the synthesis method of the intermediate (Cy11 1-1), with a yield of 71.44%, an off-white solid.

[0444] 11H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.48 (s, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.24–7.14 (m, 2H), 6.79–6.73 (m, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 2.83 (t, J = 6.0 Hz, 2H).

[0445] Step 2. Synthesis of Cy22 1-2

[0446] Refer to the synthesis method of intermediate (Cy11 1-2), with a yield of 62.31%, brown solid.

[0447] Step 3. Synthesis of Cy22 1-3

[0448] Refer to the synthesis method of intermediate (Cy1 1-5), with a yield of 56.99%, brown solid.

[0449] 1 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.33 (s, 1H), 9.15 (s, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 7.59 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.23–7.18 (m, 2H), 7.04 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.66 (dd, J = 8.2, 2.4 Hz, 1H), 4.12 (t, J = 6.1 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 1.46 (s, 9H).

[0450] Step 4. Synthesis of Cy22 1-4

[0451] Refer to the synthesis method of intermediate (Cy1 1-6), brown solid, directly used for the next step without purification.

[0452] 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 8.1 Hz, 1H), 7.24–7.16 (m, 2H), 6.79–6.69 (m, 2H), 4.16 (t, J = 6.1 Hz, 2H), 2.69 (d, J = 6.2 Hz, 2H). MS (ESI): m / z 446.07 [M+H]+ .

[0453] Step 5. Synthesis of Cy22

[0454] Refer to the synthesis method of reference compound (Cy1), with a yield of 10.42%, white solid.

[0455] 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.33 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 7.88 (s, 1H), 7.36 (s, 1H), 7.27 (t, J = 8.1 Hz, 1H), 7.16–7.07 (m, 2H), 6.89 (dd, J = 8.0, 2.0 Hz, 1H), 6.88–6.78 (m, 2H), 4.38 (t, J = 5.4 Hz, 2H), 2.61 (t, J = 5.4 Hz, 2H). MS (ESI): m / z 426.06 [M+H] + .

[0456] Example 23: Cy23

[0457]

[0458] The synthesis route is as follows:

[0459]

[0460] Step 1. Synthesis of Cy23 1-1

[0461] Refer to the synthesis method of intermediate (Cy1 1-1), with a yield of 66.99%, colorless oil.

[0462] Step 2. Synthesis of Cy23 1-2

[0463] Refer to the synthesis method of intermediate (synthesis method of Cy1 1-2), colorless oil, directly used for the next step without purification.

[0464] Step 3. Synthesis of Cy23 1-3

[0465] Refer to the synthesis method of intermediate (Cy11 1-2), with a yield of 55.94%, brown solid.

[0466] 11H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.56 (s, 1H), 8.89 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.26–7.15 (m, 3H), 6.58 (d, J = 7.9 Hz, 1H), 3.92 (d, J = 3.9 Hz, 5H), 3.71 (t, J = 5.0 Hz, 2H).

[0467] Step 4. Synthesis of Cy23 1-4

[0468] Refer to the synthesis method of intermediate (Cy1 1-5), with a yield of 82.52%, brown solid.

[0469] 1 1H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 11.34 (s, 1H), 9.59 (s, 1H), 8.93 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.04 (dd, J = 7.9, 1.8 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.27–7.11 (m, 3H), 6.58 (d, J = 7.8 Hz, 1H), 3.93 (t, J = 5.0 Hz, 2H), 3.71 (t, J = 5.0 Hz, 2H). MS (ESI): m / z 445.05 [M+H] + .

[0470] Step 4. Synthesis of Cy23

[0471] Refer to the synthesis method of compound (Cy8), with a yield of 29.18%, yellow solid.

[0472] 1 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.94 (t, J = 7.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.46 (s, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 4.92 (t, J = 5.5 Hz, 1H), 4.00 (t, J = 4.9 Hz, 2H), 3.73 (q, J = 5.2 Hz, 2H). MS (ESI): m / z 427.04 [M+H]+ .

[0473] Example 24: Cy24

[0474]

[0475] The synthetic route is as follows:

[0476]

[0477] Step 1. Synthesis of Cy24 1-1

[0478] Add 2-tert-butoxycarbonylamino-5-hydroxybenzoic acid (1 eq), methyl iodide (1 eq) and potassium carbonate (3 eq) into a 100 mL round-bottom flask, dissolve them in 10 mL of DMF, react at room temperature for 3 h, and monitor the reaction progress by TLC. After the reaction is completed, quench with water, extract with EA (3×50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (PE / EA = 7:1) with 200-300 mesh silica gel to obtain a white solid with a yield of 55.87%.

[0479] 1 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.55 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 3.0 Hz, 1H), 7.00 (dd, J = 9.0, 2.9 Hz, 1H), 3.82 (s, 3H), 1.45 (s, 9H).

[0480] Step 2. Synthesis of Cy24 1-2

[0481] Weigh Cy24 1-1 (1 eq), 1,2-dichloroethane (2 eq) and potassium carbonate (3 eq) in a 100 mL round-bottom flask, dissolve them in 10 mL of DMF, stir evenly at room temperature, reflux at 80 °C overnight, and monitor the reaction progress by TLC. After the reaction is completed, quench with water, extract with EA (3×50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (PE / EA = 20:1) with 200-300 mesh silica gel to obtain a colorless oil with a yield of 79.67%.

[0482] 11H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.26 (dd, J = 9.2, 3.1 Hz, 1H), 4.28–4.24 (m, 2H), 3.96–3.91 (m, 2H), 3.84 (s, 3H), 1.46 (s, 9H).

[0483] Step 3. Synthesis of Cy24 1-3

[0484] Refer to the synthesis method of the reference compound (Cy1 1-2), light yellow oil, without purification, directly used for the next step.

[0485] Step 4. Synthesis of Cy24 1-4

[0486] Refer to the synthesis method of the intermediate (Cy11 1-1), yield 78.56%, off-white solid.

[0487] 1 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.55 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 3.1 Hz, 1H), 7.39 (dd, J = 9.2, 3.1 Hz, 1H), 4.37–4.30 (m, 2H), 4.00–3.93 (m, 2H), 3.86 (s, 3H).

[0488] Step 5. Synthesis of Cy24 1-5

[0489] Refer to the synthesis method of the intermediate (Cy11 1-2), yield 71.02%, brown solid.

[0490] Step 6. Synthesis of Cy24 1-6

[0491] Refer to the synthesis method of the intermediate (Cy1 1-5), yield 76.82%, brown solid.

[0492] Step 7. Synthesis of Cy24 1-7

[0493] Refer to the synthesis method of the intermediate (Cy1 1-6), brown solid, without purification, directly used for the next step.

[0494] 11H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.79 (s, 1H), 8.80 (d, J = 9.2 Hz, 1H), 8.34 (s, 1H), 7.67 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 3.1 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.26 (dd, J = 9.2, 3.1 Hz, 1H), 6.88 (dd, J = 7.9, 2.1 Hz, 1H), 4.36–4.29 (m, 2H), 4.01–3.94 (m, 2H). MS (ESI): m / z 480.03 [M+H] + .

[0495] Step 8. Synthesis of Cy24 1-8

[0496] Referring to the synthesis method of the reference compound (Cy1), the yield was 51.95%, and it was a yellow solid.

[0497] 1 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.63–7.55 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 2.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.39 (dd, J = 7.6, 2.1 Hz, 1H), 5.24 (s, 2H), 4.42 (t, J = 5.0 Hz, 2H), 4.02 (t, J = 4.9 Hz, 2H). MS (ESI): m / z 462.02 [M+H] + .

[0498] Step 9. Synthesis of Cy24

[0499] Weigh Cy24 1-8 (1 eq), potassium carbonate (2 eq) and potassium iodide (1 eq) in a 50 mL single-necked flask. After dissolving in 3 mL of DMF, add dimethylamine (2 eq). Stir evenly at room temperature and then react at 100 °C overnight. Monitor the reaction process by TLC. After the reaction is completed, quench with water, extract with EA (3 × 50 mL), combine the EA layers, extract with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent, and perform silica gel column chromatography (DCM / CH3OH = 10:1) with 200-300 mesh silica gel to obtain a white solid with a yield of 43.19%.

[0500] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.55 (s, 1H), 8.15 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.06 (dd, J = 9.0, 3.0 Hz, 1H), 6.98 (d, J = 3.0 Hz, 1H), 6.86–6.78 (m, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.16 (dd, J = 7.7, 2.2 Hz, 1H), 4.83 (s, 2H), 4.11 (t, J = 5.7 Hz, 2H), 2.75 (t, J = 5.8 Hz, 2H), 2.30 (s, 6H). MS (ESI): m / z 469.10 [M+H] + .

[0501] Example 25: Cy25

[0502]

[0503] The synthetic route is as follows:

[0504]

[0505] Step 1. Synthesis of Cy25 1-1

[0506] Referring to the synthetic method of intermediate (Cy11 1-2), the yield was 79.81%, a brown solid.

[0507] Step 2. Synthesis of Cy25 1-2

[0508] Referring to the synthetic method of intermediate (Cy1 1-5), the yield was 77.45%, a brown solid.

[0509] 1 1H NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 11.33 (s, 1H), 9.56 (s, 1H), 8.94 (d, J = 8.3 Hz, 1H), 8.35 (s, 1H), 8.04 (dd, J = 8.0, 1.7 Hz, 1H), 7.64–7.51 (m, 3H), 7.25 (t, J = 7.8 Hz, 1H), 7.19–7.11 (m, 1H), 6.97 (d, J = 7.5 Hz, 1H), 5.17 (s, 1H), 4.46 (s, 2H). MS (ESI): m / z 415.04 [M+H] + .

[0510] Step 3. Synthesis of Cy25

[0511] Referring to the synthetic method of compound (Cy8), the yield was 30.15%, a yellow solid.

[0512] 1 H NMR(400 MHz, DMSO-d6) δ 12.41(s, 1H), 8.25(dd, J=8.1, 1.5 Hz, 1H), 8.01(s, 1H), 7.93(ddd, J=8.5, 7.1, 1.5 Hz, 1H), 7.69(d, J=8.2 Hz, 1H), 7.63(dd, J=8.0, 2.3 Hz, 1H), 7.58(s, 1H), 7.55(t, J=7.5 Hz, 1H), 7.36(t, J=7.8 Hz, 1H), 7.13(d, J=7.6 Hz, 1H), 5.29(s, 1H), 4.53(s, 2H). MS(ESI): m / z 397.03[M + H] + .

[0513] Example 26: Cy26

[0514]

[0515] The synthetic route is as follows:

[0516]

[0517] Step 1. Synthesis of Cy26 1-1

[0518] Referring to the synthesis method of intermediate (Cy11 1-2), the yield was 75.32%, a brown solid.

[0519] 1 H NMR(400 MHz, DMSO-d6) δ 10.86(s, 1H), 9.53(s, 1H), 8.87(s, 1H), 8.37(s, 1H), 8.05(dd, J=8.0, 1.7 Hz, 1H), 7.61(t, J=7.6 Hz, 1H), 7.51(d, J=8.2 Hz, 1H), 7.46(s, 1H), 7.19(t, J=7.7 Hz, 2H), 6.85(d, J=7.5 Hz, 1H), 3.91(s, 3H), 3.57(t, J=7.2 Hz, 2H), 2.67(t, J=7.2 Hz, 2H).

[0520] Step 2. Synthesis of Cy26 1-2

[0521] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 72.45%, a brown solid.

[0522] 11H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.57 (s, 1H), 8.94–8.86 (m, 1H), 8.36 (s, 1H), 8.04 (dd, J = 7.9, 1.7 Hz, 1H), 7.60–7.54 (m, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 3.58 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H). MS (ESI): m / z 429.06 [M+H] + .

[0523] Step 3. Synthesis of Cy26

[0524] Refer to the synthesis method of the reference compound (Cy8), with a yield of 35.15%, yellow solid.

[0525] 1 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.25 (dd, J = 8.1, 1.5 Hz, 1H), 8.01 (s, 1H), 7.94 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 8.1, 2.3 Hz, 1H), 7.55 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.46 (t, J = 2.0 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 4.68 (s, 1H), 3.63 (t, J = 7.0 Hz, 2H), 2.75 (t, J = 7.0 Hz, 2H). MS (ESI): m / z 411.05 [M+H] + .

[0526] Example 27: Cy27

[0527]

[0528] The synthesis route is as follows:

[0529]

[0530] Step 1. Synthesis of Cy27 1-1

[0531] Refer to the synthesis method of the intermediate (Cy11 1-2), with a yield of 81.41%, brown solid.

[0532] Synthesis of Cy27 1-2 in Step 2

[0533] Referring to the synthesis method of intermediate (Cy1 1-5), the yield is 75.39%, and it is a brown solid.

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 13.68 (s, 1H), 11.32 (s, 1H), 9.57 (s, 1H), 8.93 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J = 7.9, 1.7 Hz, 1H), 7.64–7.54 (m, 2H), 7.49 (s, 1H), 7.37 (t, J = 6.3 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.09 (d, J = 5.8 Hz, 2H), 1.40 (s, 9H).

[0535] Synthesis of Cy27 1-3 in Step 2

[0536] Referring to the synthesis method of intermediate (Cy1 1-6), it is a black solid and can be directly used for the next step without purification.

[0537] 1 H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.74 (s, 1H), 8.87 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.17 (s, 3H), 8.05 (dd, J = 7.9, 1.7 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.68–7.63 (m, 1H), 7.62–7.56 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.20–7.14 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 3.97 (q, J = 5.8 Hz, 2H). MS (ESI): m / z 414.06 [M+H] + .

[0538] Synthesis of Cy27 in Step 3

[0539] Referring to the synthesis method of compound (Cy1), the yield is 37.70%, and it is a yellow solid.

[0540] 11H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.07 (t, J = 6.0 Hz, 1H), 8.26 (dd, J = 8.2, 1.5 Hz, 1H), 7.97 (s, 1H), 7.97–7.92 (m, 1H), 7.69 (dd, J = 8.5, 3.7 Hz, 2H), 7.60–7.51 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.43 (d, J = 5.9 Hz, 2H). MS (ESI): m / z 396.05 [M+H] + .

[0541] Example 28: Cy28

[0542]

[0543] The synthetic route is as follows:

[0544]

[0545] Step 1. Synthesis of Cy28 1-1

[0546] Referring to the synthesis method of intermediate (Cy11 1-2), the yield was 76.22%, a brown solid.

[0547] Step 2. Synthesis of Cy28 1-2

[0548] Referring to the synthesis method of intermediate (Cy1 1-5), the yield was 80.15%, a brown solid.

[0549] 1 1H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 11.30 (s, 1H), 9.50 (s, 1H), 8.91 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.04 (dd, J = 8.0, 1.7 Hz, 1H), 7.60–7.54 (m, 2H), 7.46 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 5.7 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 3.11 (q, J = 6.9 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.37 (s, 9H).

[0550] Step 2. Synthesis of Cy28 1-3

[0551] Referring to the synthesis method of intermediate (Cy1 1-6), a black solid, which was directly used in the next step without purification.

[0552] 1 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.59 (s, 1H), 8.90 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.07–8.02 (m, 1H), 7.80 (s, 3H), 7.59 (d, J = 8.9 Hz, 2H), 7.51 (s, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.01 (dt, J = 9.0, 5.4 Hz, 2H), 2.82 (t, J = 8.0 Hz, 2H). MS (ESI): m / z 428.07 [M+H] + .

[0553] Step 3. Synthesis of Cy28

[0554] Referring to the synthesis method of the reference compound (Cy1), the yield was 40.12%, and it was a yellow solid.

[0555] 1 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.55 (t, J = 11.1 Hz, 1H), 8.26 (dd, J = 8.1, 1.5 Hz, 1H), 8.01 (s, 1H), 7.94 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.68–7.64 (m, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 2.0 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 3.45 (q, J = 6.9 Hz, 2H), 2.84 (t, J = 7.3 Hz, 2H). MS (ESI): m / z 410.06 [M+H] + .

[0556] Example 29: Cy29

[0557]

[0558] The synthesis route is as follows:

[0559]

[0560] Step 1. Synthesis of Cy291-1

[0561] Weigh methyl 2-nitrophenylacetate (1 eq) in a two-necked flask. After dissolving it in ultra-dry tetrahydrofuran (10 mL), add Pd / C (0.1 eq) under a hydrogen atmosphere and react at room temperature for 2 h. Monitor the reaction progress by TLC. After the reaction is completed, filter by suction, and concentrate the filtrate directly for the next step.

[0562] 1 H NMR (400 MHz, DMSO-d6) δ 7.01–6.88 (m, 2H), 6.64 (dd, J = 7.9, 1.3 Hz, 1H), 6.51 (td, J = 7.3, 1.3 Hz, 1H), 4.88 (s, 2H), 3.59 (s, 3H), 3.52 (s, 2H).

[0563] Step 2. Synthesis of Cy29 1-2

[0564] Refer to the synthesis method of intermediate (Cy11 1-1), with a yield of 71.28%, a white solid.

[0565] 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.43 (s, 1H), 7.41–7.27 (m, 4H), 3.66 (s, 2H), 3.50 (s, 3H).

[0566] Step 3. Synthesis of Cy29 1-3

[0567] Refer to the synthesis method of intermediate (Cy11 1-2), with a yield of 59.63%, a brown solid.

[0568] Step 4. Synthesis of Cy29 1-4

[0569] Refer to the synthesis method of intermediate (Cy1 1-5), with a yield of 73.25%, a brown solid.

[0570] Step 5. Synthesis of Cy29 1-5

[0571] Refer to the synthesis method of intermediate (Cy1 1-6), a black solid, which can be directly used for the next step without purification.

[0572] 11H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.77–8.71 (m, 1H), 8.26 (s, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 3H), 7.29–7.23 (m, 1H), 7.09 (t, J = 8.6 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.55–6.50 (m, 1H), 3.61 (s, 2H). MS (ESI): m / z 414.06 [M+H] + .

[0573] Step 6. Synthesis of Cy29

[0574] Referring to the synthesis method of the reference compound (Cy1), the yield was 30.16%, and it was a yellow solid.

[0575] 1 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.80 (s, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.94–6.82 (m, 4H), 6.23 (dt, J = 6.6, 2.3 Hz, 1H), 5.04 (s, 2H), 3.87 (s, 2H). MS (ESI): m / z 396.05 [M+H] + .

[0576] Example 30: Preparation of CyD1-CyD29

[0577] The synthesis route is as follows:

[0578]

[0579] Step 1. Synthesis of CyD1-CyD29 1-1

[0580] Add 2,4-dichloro-5-substituted pyrimidine (1 eq) and methyl substituted anthranilate (1.2 eq) into a 100 mL round-bottom flask. After dissolving in isopropanol, add DIPEA (3 eq). Stir evenly at room temperature and then reflux at 90 °C overnight. Monitor the reaction progress by TLC. After the reaction is completed, cool to room temperature, and a solid will precipitate. Filter by suction and wash with isopropanol three times to obtain the intermediate CyD1-CyD29 1-1.

[0581] Step 2. Synthesis of CyD1-CyD29 1-2

[0582] Weigh the intermediate CyD1-CyD29 1-1 (1 eq) and the substituted m-aminophenol (2 eq) in a 35 mL sealed tube. After dissolving in 10 mL of sec-butanol, add 200 μL of trifluoroacetic acid, seal it, and react at 100 °C overnight. Monitor the reaction progress by TLC. After the reaction is completed, if a solid precipitates, filter it by suction, wash it 3 times with sec-butanol, and collect the filter residue; if no solid precipitates, quench it with water, extract it with EA (3 × 50 mL), combine the EA layers, extract with saturated brine, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure to remove the solvent, and perform silica gel column chromatography with 200-300 mesh to obtain the intermediate CyD1-CyD29 1-2.

[0583] Step 3. Synthesis of CyD1-CyD29 1-3

[0584] Weigh the compound CyD1-CyD29 1-2 in a 100 mL single-necked flask, dissolve it in THF (3 mL), add 15 mL of 20% KOH aqueous solution, and react at room temperature overnight. Monitor the reaction progress by TLC. After the reaction is completed, adjust the pH to 2 with 5 mol / L hydrochloric acid, and a large amount of solid precipitates. Filter it by suction to obtain the intermediate CyD1-CyD29 1-3.

[0585] Step 4. Synthesis of CyD1-CyD29

[0586] Weigh EDCI (1.5 eq), HOBt (1.65 eq), and ammonium chloride (3.25 eq) in a 50 mL single-necked flask. After dissolving in DMSO, add DIPEA (6.5 eq), stir at room temperature for 5 min, then slowly dropwise add the DMSO solution of CyD1-CyD29 1-3 (1 eq), and stir at room temperature overnight. Monitor the reaction progress by TLC. After the reaction is completed, quench it with water, extract it with EA (3 × 50 mL), combine the EA layers, extract with saturated brine, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure to remove the solvent, and perform silica gel column chromatography with 200-300 mesh to obtain the final product CyD1-CyD29.

[0587] Example 31: Preparation of CyD30-CyD31

[0588] The synthesis route is as follows:

[0589]

[0590] Step 1. Synthesis of CyD30-CyD31 1-1

[0591] Methyl anthranilate (1 eq) was added to a 50 mL round-bottom flask, dissolved in 5 mL of DMF, and NaH (2 eq) was added under an ice bath. The mixture was stirred at room temperature for 10 min, and then a solution of 2,4-dichloro-5-bromopyrimidine (1.2 eq) in DMF (5 mL) was added. The reaction was carried out overnight at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched with water, extracted with EA (3×50 mL), the EA layers were combined, extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (200 - 300 mesh, PE / EA = 30:1) to obtain the intermediate CyD30-CyD31 1-1.

[0592] Step 2. Synthesis of CyD30-CyD31 1-2

[0593] CyD30-CyD31 1-1 (1 eq) and m-aminophenol (1.2 eq) were added to a 50 mL round-bottom flask, dissolved in 5 mL of IPA, 200 μL of TFA was added, and the reaction was carried out overnight at 80 °C. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, and a solid precipitated. The solid was filtered off and the filter cake was washed 3 times with isopropanol to obtain the intermediate CyD30-CyD31 1-2.

[0594] Step 3. Synthesis of CyD30-CyD31 1-3

[0595] Compound CyD30-CyD31 1-2 was weighed into a 100 mL single-necked flask, dissolved in THF (3 mL), 15 mL of 20% aqueous KOH solution was added, and the reaction was carried out overnight at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, 5 mol / L hydrochloric acid was added to adjust the pH to 2, and a large amount of solid precipitated. The solid was filtered off to obtain the intermediate CyD30-CyD31 1-3.

[0596] Step 4. Synthesis of CyD30-CyD31

[0597] EDCI (1.5 eq), HOBt (1.65 eq) and ammonium chloride (3.25 eq) were weighed into a 50 mL single-necked flask, dissolved in DMSO, and DIPEA (6.5 eq) was added. After stirring at room temperature for 5 min, a solution of CyD30-CyD31 1-3 (1 eq) in DMSO was slowly added dropwise, and the reaction was stirred overnight at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the reaction was quenched with water, extracted with EA (3×50 mL), the EA layers were combined, extracted with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain the final product CyD30-CyD31.

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608] Example 32. Determination of the inhibitory activity of the pyrimidine compounds of the present invention against JNK kinase

[0609] (1) Reagent materials: ADP-Glo TM Kinase Assay (Promega, V4071), DMSO (Aladdin, 67-68-5), 384-well white plate (Corning, 3570).

[0610] (2) Experimental instruments: Microplate reader (Tecan Group Ltd., Swiss), microplate oscillator (Hangzhou Allsheng Instruments CO., Ltd., MB100-2A).

[0611] (3) Experimental method:

[0612] Dissolve the compound in DMSO to prepare a stock solution. Dilute the compound to 8 final concentrations with Reaction Buffer according to the kit instructions, and control the final concentration of DMSO to be 2%. Add 5 μL of reaction system 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). Set up positive and negative control groups for the reaction. In the positive control group, add 1 μL of 10% DMSO and 2 μL of Reaction Buffer instead of the compound and JNK enzyme. In the negative control group, add 1 μL of 10% DMSO instead of the compound. Place the 384-well plate on a microplate shaker at room temperature (25 °C) for 1 h (when the amount of JNK enzyme is 10 ng) or 4 h (when the amount of JNK enzyme is 2 ng). Add 5 μL of ADP-Glo reagent, place it on the microplate shaker at room temperature (25 °C), and incubate for 40 minutes to terminate the reaction and eliminate the remaining ATP. Add 10 μL of Kinase Detection Reagent, incubate at room temperature (25 °C) for 30 minutes to convert ADP to ATP, and generate chemiluminescence through the luciferase / luciferin reaction with the newly synthesized ATP. Detect the Luminescence with a microplate reader and record the reading RLU. According to the formula: Compound inhibition rate (%) = [(RLU 阴 - RLU 样 ) / (RLU 阴 - RLU 阳 )] × 100%, where RLU 阴 is the reading of the negative control group, RLU 阳 is the reading of the positive control group, and RLU 样 is the reading of the experimental group. Import the inhibition rate data into GraphPad Prism 8.0 software for fitting, and the obtained experimental results are shown in the following table.

[0613] (4) Experimental results

[0614] The biological activity of the compounds described in the present invention was determined by the above experiments. All compounds showed certain inhibitory effects on JNK. The results are shown in the following table. Among them, the compounds designated as "A" for JNK inhibitory activity provided an IC 50 value of IC 50 ≤ 0.1 μM; the compounds designated as "B" for activity provided an IC 50 value of 0.1 μM < IC 50 ≤ 1 μM; the compounds designated as "C" for activity provided an IC 50 value of IC 50 value of IC 50 > 1 μM; NT is not tested.

[0615]

[0616] JNK1 is closely related to inflammatory, metabolic and liver diseases. Inhibiting JNK1 can reduce the excessive release of inflammatory mediators and treat chronic inflammatory diseases and other inflammation-related diseases; JNK3 is mainly expressed in the central nervous system and the heart and is closely related to neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease) and ischemic brain injury. Dual inhibitors can act on these two types of diseases simultaneously, especially showing advantages under pathological conditions where inflammation and the nervous system act together. Selective inhibitors can act more precisely on related diseases without affecting other JNK subtypes, reducing side effects. Therefore, the compounds of the present invention are very valuable for treating JNK-related diseases, making up for the deficiencies in the types and efficacy of existing drugs for treating JNK-related diseases, which is very significant.

[0617] All documents mentioned in the present invention are cited herein by reference as if each document was individually cited by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

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, halogen, cyano, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optionally substituted C 1-10 alkylthio, optionally substituted phenyl or heteroaryl, optionally substituted acyl, optionally substituted sulfonyl; R2 and R3 are independently selected from: H, halogen, cyano, nitro, optionally substituted C 1-10 Alkyl, optionally substituted C 1-10 an alkoxy group, an optionally substituted 3-10 membered saturated or unsaturated carbocyclic group, an optionally substituted 3-10 membered saturated or unsaturated heterocyclic group, an optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted phosphinyl group, Alternatively, two adjacent R2 or R3 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 -O-, -S-, or -NR N -, R N is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted acyl; L is an optionally substituted C 1-10 A hydrocarbon chain in which one or more atoms can be independently replaced by -O-, -S-, -C(O)-, -NR N -, -N=, =N-, an optionally substituted saturated or unsaturated carbocyclic or heterocyclic group, wherein R N is H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted acyl; R4 and R5 are independently selected from: H, optionally substituted C 1-3 acyl, optionally substituted sulfonyl, optionally substituted C 1-10 an alkyl group, an optionally substituted 3-10 membered saturated or unsaturated carbocyclic group, or an optionally substituted 3-10 membered saturated or unsaturated heterocyclic group; Alternatively, R4 and R5 together with the nitrogen atom to which they are attached form a 3-10 membered heterocyclic ring; n and m are independently selected from 0, 1, 2, 3 or 4.

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: H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkoxy, optionally substituted aminoacyl; R2 is selected from: H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted 3-10 membered saturated or unsaturated heterocyclic group, optionally substituted aminoacyl; R3 is selected from: H, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted 3-10 membered saturated or unsaturated heterocyclic group; X is -NH-; L is an optionally substituted C 1-6 A hydrocarbon chain in which one or more atoms can be independently replaced by -O-, -S-, -C(O)-, -NR N -, R N is H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted acyl; m and n are independently selected from 0, 1 or 2.

3. The compound according to claim 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from the group consisting of fluorine, chlorine, bromine, iodine, methyl, and optionally substituted aminoacyl; R2 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 alkoxy, optionally substituted aminoacyl; R3 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy; L is selected from: m and n are independently selected from 0, 1 or 2.

4. The compound according to claim 1-3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

5. The compound according to claim 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

6. The compound according to claim 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from: fluorine, chlorine, bromine, optionally substituted aminoacyl; R2 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 alkoxy, optionally substituted aminoacyl; R3 is selected from: H, chlorine, fluorine, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 Alkoxy; L is selected from: m and n are independently selected from 0, 1 or 2.

7. The compound according to claim 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 7 or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or its tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof or pharmaceutically acceptable salt thereof in the preparation of a JNK inhibitor.

10. The use according to claim 6, characterized in that The JNK inhibitor is a drug for treating and / or preventing JNK-related diseases.

11. The use according to claim 10, characterized in that The JNK-related diseases are fibrosis, neurodegenerative diseases, diabetes, inflammatory diseases, tumors, central nervous system diseases, etc.

12. The use according to claim 11, 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 and Parkinson's syndrome; 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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