1,2,4,5-tetrasubstituted pyrimidinone compound, and preparation method therefor and use thereof

Abstract

Provided are a 1,2,4,5-substituted pyrimidinone compound as represented by formula (I) which has an agonistic effect on Homo sapiens caseinolytic protease P (HsClpP), or a stereoisomer, tautomer or deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, and a preparation method therefor and a pharmaceutical composition containing the compound. The compound can be used in the preparation of an HsClpP agonist or a drug for treating and / or preventing HsClpP-mediated diseases.

Description

A 1,2,4,5-tetrasubstituted pyrimidinone compound, its preparation method and application

[0001] Related applications

[0002] This application claims priority to Chinese invention patent application No. 202510063036.2, entitled "A 1,2,4,5-tetrasubstituted pyrimidinone compound and its preparation method and application", filed with the China National Intellectual Property Administration on January 15, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the field of medicinal chemistry, and in particular to a 1,2,4,5-substituted pyrimidinone compound that has an agonistic effect on human casein hydrolase P, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and its preparation method and application. Background Technology

[0004] Mitochondria are the energy production centers within cells. Tumor cells typically exhibit high metabolic activity, thus requiring more energy than normal cells, leading to a high dependence on mitochondrial function. Human sapiens caseinolytic protease P (HsClpP) is a folding peptidase in the mitochondrial matrix responsible for regulating mitochondrial protein homeostasis, controlling protein quality, regulating mitochondrial metabolism, maintaining the integrity of the respiratory chain, and controlling enzyme activity. It plays a crucial role in maintaining mitochondrial function. Abnormal expression of HsClpP can lead to mitochondrial dysfunction, thereby contributing to various human diseases, including cancer. Clinically, HsClpP has been found to be overexpressed in patients with multiple myeloma, various lymphomas, chronic myeloid leukemia, and certain solid tumors (Nat. Rev. Mol. Cell Biol. 2018, 19, 109–120.; Biochem. Biophys. Res. Commun. 2017, 491, 85–90.; Cell Chem. Biol. 2018, 25, 1017–1030.). Therefore, regulating HsClpP activity may provide new treatment options for these cancer patients.

[0005] HsClpP agonists can enhance the protease activity of HsClpP, selectively degrading mitochondrial substrates, including various respiratory chain proteins, thereby affecting intracellular oxidative phosphorylation and leading to mitochondrial dysfunction. When mitochondrial function is impaired, cancer cells cannot maintain their high energy demands and metabolic activities, ultimately leading to apoptosis. Therefore, activating HsClpP holds promise for providing a new intervention for cancer treatment, making the development of HsClpP-targeting agonists as anti-tumor drugs particularly important. Summary of the Invention

[0006] The present invention aims to provide a 1,2,4,5-tetrasubstituted pyrimidinone compound, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, its preparation method and application, wherein such compound can be used as an HsClpP agonist.

[0007] Therefore, in a first aspect, the present invention provides a 1,2,4,5-tetrasubstituted pyrimidinone compound, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which have a significant agonistic effect on HsClpP.

[0008] A second aspect of the present invention also provides a method for preparing 1,2,4,5-tetrasubstituted pyrimidinone compounds.

[0009] A third aspect of the present invention also provides the application of 1,2,4,5-tetrasubstituted pyrimidinone compounds.

[0010] This invention provides the following technical solution:

[0011] A compound of Formula I, its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0012] R 1 Selected from substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted five- to ten-membered heterocycloalkyl groups containing one to three heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, wherein "substituted" means that the group can be selected from one to six atoms selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 3-6 Substituents of cycloalkyl groups;

[0013] R 2 Selected from hydrogen, C 1-6 Alkyl, carbonyl, halogen, cyano, amino, carboxyl, hydroxyl;

[0014] Z is selected from either straight chain or branched chain C. 1-6 Alkylene, deuterated straight-chain or branched C1-6 Alkylene, -NRaC 1-6 Alkylene, wherein the substituent Ra is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 1-6 Alkyl carbonyl;

[0015] L is selected from single bonds and methylene groups;

[0016] X is selected from methylene, carbonyl, and ethylene;

[0017] Y is selected from C and N;

[0018] R 3 Selected from substituted or unsubstituted C 6-14 C of aryl linear or branched chains 1-6 Alkylene, substituted or unsubstituted C 3-10 Cycloalkyl straight-chain or branched C 1-6 Alkylene, substituted or unsubstituted, five- to ten-membered heterocyclic alkyl groups containing one to three heteroatoms selected from N, O, and S, either straight-chain or branched. 1-6 Alkylene, substituted or unsubstituted, five- to fourteen-membered heteroaryl straight-chain or branched C-type compounds containing one to three heteroatoms selected from N, O, and S. 1-6 Alkylene, wherein "substituted" means that the group can be selected from 1 to 6 groups selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 3-6 Substitution with cycloalkyl groups or -NRbRb', wherein Rb and Rb' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl;

[0019] R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxyl, carboxyl, amino, cyano, hydrazine (-NHNH2), amino C 1-6 Alkylene, C 1-6 Alkylamino, thiocyl C 1-6 Alkyl (-SC) 1-6 Alkyl), C 1-6 alkylsulfinyl (-SOC) 1-6 Alkyl), C1-6 alkylsulfonyl (-SO2C) 1-6 alkyl).

[0020] Preferably, R 1 Selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 5-8 Cycloalkyl, substituted or unsubstituted five- to eight-membered heterocycloalkyl groups containing one to three heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to ten-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, wherein "substituted" means that the group can be substituted with one to three atoms selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-4 alkylsulfonyl (-SO2C) 1-4 Alkyl), C 3-6 Substitution of cycloalkyl groups.

[0021] Preferably, R 1 Selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 5-6 Cycloalkyl, substituted or unsubstituted five- to eight-membered heterocycloalkyl groups containing one to three heteroatoms selected from N and O, or substituted or unsubstituted five- to ten-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, wherein "substituted" means that the group can be substituted with one to three atoms selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 Alkyl), C 3-6 Substitution of cycloalkyl groups.

[0022] Preferably, R 2 Selected from hydrogen atoms, C 1-4 Alkyl, carbonyl.

[0023] More preferably, R 2 Selected from hydrogen atoms, methyl, ethyl, n-propyl, isopropyl, and carbonyl.

[0024] Preferably, Z is selected from linear or branched C.1-3 Alkylene, deuterated straight-chain or branched C 1-3 Alkylene, -NRaC 1-3 Alkylene, wherein the substituent Ra is selected from hydrogen atom, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 alkyl).

[0025] Preferably, Z is selected from methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), deuterated methylene (-CH2-), deuterated ethylene (-CH2CH2-), deuterated propylene (-CH2CH2CH2-), -CH(CH3)-, -NRa(CH2)-, -NRa(CH2CH2)-, -NRa(CH2CH2CH2)-, wherein the substituent Ra is selected from hydrogen atom, -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl.

[0026] Preferably, R 3 Selected from substituted or unsubstituted C 6-10 C of aryl linear or branched chains 1-4 Alkylene, substituted or unsubstituted C 3-8 Cycloalkyl straight-chain or branched C 1-4 Alkylene, substituted or unsubstituted, five- to ten-membered heterocyclic alkyl groups containing one to three heteroatoms selected from N, O, and S, either straight-chain or branched. 1-4 Alkylene, substituted or unsubstituted, five- to ten-membered heteroaryl straight-chain or branched C-type compounds containing one to three heteroatoms selected from N, O, and S. 1-4 Alkylene, wherein "substituted" means that the group can be selected from 1 to 3 groups selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 Substitution of alkyl groups and -NRbRb', wherein Rb and Rb' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl.

[0027] Preferably, R 3 Selected from substituted or unsubstituted C 6-10 C of aryl linear or branched chains 1-3 Alkylene, substituted or unsubstituted C 5-6Cycloalkyl straight-chain or branched C 1-3 Alkylene, substituted or unsubstituted, five- to ten-membered heterocyclic alkyl groups containing one to two heteroatoms selected from N and O, either straight-chain or branched. 1-3 Alkylene, substituted or unsubstituted, five- to ten-membered heteroaryl straight-chain or branched C-type compounds containing one to two heteroatoms selected from N and O. 1-3 Alkylene, wherein "substituted" means that the group can be selected from 1 to 3 groups selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 Substitution of alkyl groups and -NRbRb', wherein Rb and Rb' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl.

[0028] Preferably, R 4 Selected from hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, hydroxyl, carboxyl, amino, cyano, hydrazine (-NHNH2), amino C 1-4 Alkylene, C 1-4 Alkylamino, thiocyl C 1-4 Alkyl (-SC) 1-4 Alkyl), C 1-4 alkylsulfinyl (-SOC) 1-4 Alkyl), C 1-4 alkylsulfonyl (-SO2C) 1-4 alkyl).

[0029] Preferably, R 4 Selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxy, carboxyl, amino, cyano, hydrazine (-NHNH2), aminomethylene (-CH2NH2), aminoethylidene (-CH2 CH2NH2), aminon-propylidene (-CH2CH2CH2NH2), aminoisopropylidene (-C(CH3)2NH2), methylamino (-NHCH3), ethylamino (-NHCH2CH3), n-propylamino (-NHCH2CH2CH3), isopropylamino (-NHCH(CH3)2)

[0030] Preferably, the compound represented by Formula I according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof are represented by the following Formula I-1:

[0031] Among them, the substituents Z, Y, X, L, R 2 R 3 and R 4 The definition is the same as in Equation I above.

[0032] Ring A is a saturated or unsaturated six-membered ring, selected from C. 6-14 Aryl, C 3-10 Cycloalkyl groups, five- to ten-membered heterocycloalkyl groups containing one to three heteroatoms selected from N, O, and S, and five- to fourteen-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S.

[0033] R 11 Selected from hydrogen atom, halogen, cyano group, amino group, carboxyl group, hydroxyl group, carbonyl group, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 3-6 cycloalkyl;

[0034] n1 is an integer selected from 0 to 4, preferably an integer of 0, 1, 2 or 3.

[0035] Preferably, ring A is a saturated or unsaturated six-membered ring A, selected from C 6-10 Aryl, C 5-8 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one to three heteroatoms selected from N and O.

[0036] Preferably, ring A is a saturated or unsaturated six-membered ring A, selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, five- to ten-membered heterocyclic alkyl containing one or two heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one or two heteroatoms selected from N and O.

[0037] Preferably, R 11 Selected from hydrogen atom, halogen, cyano group, C 1-4 Alkyl, C 1-4 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-4 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-4 Alkoxy, C 1-4 alkylsulfonyl (-SO2C) 1-4 alkyl).

[0038] Preferably, R 11Selected from hydrogen atom, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, pentafluoropropoxy, hexafluoropropoxy, perfluoropropoxy, methylsulfonyl (-SO2CH3), ethylsulfonyl (-SO2CH2CH3), n-propylsulfonyl (-SO2CH2CH2CH3), isopropylsulfonyl (-SO2CH(CH3)2).

[0039] Preferably, the compound represented by Formula I according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof are represented by the following Formulas I-2:

[0040] Among them, the substituents Z, Y, X, L, R 1 R 2 and R 4 The definition is the same as in Equation I above;

[0041] Z1 is selected from C of either straight chain or branched chain. 1-6 Alkylene;

[0042] Ring B is selected from C 6-14 Aryl, C 3-10 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N, O and S, and five- to fourteen-membered heteroaryl containing one to three heteroatoms selected from N, O and S;

[0043] R 33 Selected from hydrogen atom, halogen, cyano group, amino group, carboxyl group, hydroxyl group, carbonyl group, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Substitution with alkoxy groups or -NRcRc', wherein Rc and Rc' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl;

[0044] n3 is an integer selected from 0 to 4, preferably an integer of 0, 1, 2 or 3.

[0045] Preferably, Z1 is selected from linear or branched C. 1-4 Alkylene.

[0046] Preferably, Z1 is selected from methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2-).

[0047] Preferably, ring B is selected from C. 6-10 Aryl, C 5-8 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one to three heteroatoms selected from N and O.

[0048] Preferably, ring B is selected from phenyl, naphthyl, five- to ten-membered heterocyclic alkyl containing one or two heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one or two heteroatoms selected from N and O.

[0049] Preferably, R 33 Selected from hydrogen atom, halogen, cyano group, amino group, carboxyl group, hydroxyl group, carbonyl group, C 1-4 Alkyl, C 1-4 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-4 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-4 Substitution with alkoxy groups or -NRcRc', wherein Rc and Rc' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl.

[0050] Preferably, R 33 Selected from hydrogen atom, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monomethylamino, dimethylamino, monoethylamino, diethylamino.

[0051] Preferably, the compound represented by Formula I according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof are represented by the following Formula II:

[0052] Among them, the substituents Z, Z1, Y, X, L, R 1 R 2 R 3 R 4 R 11 and R 33 The definitions of subscripts n1 and n3 are the same as those in Equations I, I-1 and I-2 above.

[0053] Preferably, the compounds represented by Formula I, Formula I-1, Formula I-2 and Formula II according to the present invention, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof are selected from the following structures:

[0054] According to another aspect of the invention, another object of the invention is to provide a method for preparing compounds of Formula I, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, wherein when Formula I is represented by the following general structural formula Ia, the synthetic route is as follows:

[0055] Includes the following steps:

[0056] Step a. Compound 1 is reacted with different guanidine salts in methanol solvent, with sodium methoxide as base, at 80°C to prepare compound 2;

[0057] Step b. Compound 2 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to give compound of general formula Ia.

[0058] Among them, substituent R 1 R 3 and R 4 The definition is the same as in Equation I above.

[0059] When equation I is expressed as the following structural formulas Ib, Ic, or Id, where R 4 The compounds are hydroxyl, methoxy, and ethoxy; the synthetic route is shown in reaction formula 2 below:

[0060] Step a. Compound 1 and thiourea are reacted in methanol solvent, with sodium methoxide as the base, at 80°C to prepare compound 3;

[0061] Step b. Compound 3 is reacted with iodomethane in methanol solvent, with sodium hydroxide as the base, at 35°C to prepare compound 4;

[0062] Step c. Compound 4 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to give compound 5;

[0063] Step d. Compound 5 is reacted with m-chloroperoxybenzoic acid in dichloromethane solvent at room temperature to prepare general formulas Ib and Ic;

[0064] Step e. Compound Ib or compound Ic reacts with the corresponding nucleophile to prepare general formula Id.

[0065] When formula I is represented by the following general structural formula Ie, the synthetic route is as shown in reaction formula 3:

[0066] Step a. Compound 6 is reductively amination with different amines in dichloromethane solvent, with N,N-diisopropylethylamine as a base, to obtain compound 7;

[0067] Step b. Compound 7 and di-tert-butyl dicarbonate were reacted in dichloromethane solvent with triethylamine as base at 40°C to prepare compound 8;

[0068] Step c. Compound 8 and potassium tert-butoxide undergo Dieckmann condensation in tetrahydrofuran solvent at -70°C to give compound 9;

[0069] Step d. Compound 9 reacts with different guanidine salts in methanol solvent, with sodium methoxide as a base, at 80°C to give compound 10;

[0070] Step e. Compound 10 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to undergo a substitution reaction to prepare compound 11;

[0071] Step f. Compound 11 is deprotected under acid to obtain compound 12;

[0072] Step g. Compound 12 reacts with different haloalkanes, acyl chlorides, and sulfonyl chlorides to give compounds of general formula Ie.

[0073] When equation I is expressed as the following general structural formula If, the synthetic route is as shown in reaction 4:

[0074] Step a. Compound 13 is reductively amination with different amines in dichloromethane solvent, with N,N-diisopropylethylamine as a base, to give compound 14;

[0075] Step b. Compound 14 and di-tert-butyl dicarbonate were reacted in dichloromethane solvent with triethylamine as a base at 40°C to give compound 15;

[0076] Step c. Compound 15 and potassium tert-butoxide undergo Dieckmann condensation in tetrahydrofuran solvent at -70°C to give compound 16;

[0077] Step d. Compound 16 reacts with different guanidine salts in methanol solvent, with sodium methoxide as a base, at 80 °C to give compound 17;

[0078] Step e. Compound 17 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, and undergoes a substitution reaction at 80°C to prepare compound 18;

[0079] Step f. Compound 18 is deprotected by the Boc protecting group under acid to obtain compound 19;

[0080] Step g. Compound 19 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to give compounds of the general formula If.

[0081] When formula I is represented by the following general structural formula Ig, the synthetic route is as shown in reaction formula 5:

[0082] Step a. Compound 20 was reacted with different guanidine salts in methanol solvent, with sodium methoxide as the base, at 80°C to prepare compound 21;

[0083] Step b. Compound 21 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to give compound Ig.

[0084] When formula I is represented by the following general structural formula Ih, the synthetic route is as shown in reaction formula 6:

[0085] Step a. Compound 22 and methyl malonate chloride 23 were reacted in dichloromethane solvent with triethylamine as base at 0°C to give compound 24;

[0086] Step b. Compound 24 and potassium tert-butoxide undergo Dieckmann condensation in tetrahydrofuran solvent at -70°C to give compound 25;

[0087] Step c. Compound 25 is reacted with guanidine hydrochloride in methanol solvent, with sodium methoxide as base, at 80°C to prepare compound 26;

[0088] Step d. Compound 26 undergoes a substitution reaction with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80 °C to prepare compound Ih.

[0089] When formula I is represented by the following general structural formula Ii, the synthetic route is as shown in reaction formula 7:

[0090] Step a. Compound 27 reacts with diethyl oxalate in an ethanol solvent with sodium ethoxide as a base at room temperature to give compound 28;

[0091] Step b. Compound 28 reacts with ammonium acetate in ethanol solvent at 78°C to give compound 29;

[0092] Step c. Compound 29 reacts with guanidine hydrochloride in methanol solvent, with sodium methoxide as the base, at 80°C to give compound 30;

[0093] Step d. Compound 30 reacts with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to prepare compound Ii.

[0094] When equation I is represented by the following general structural formulas Ij and Ik, the synthetic route is as shown in reaction formula 8:

[0095] Step a. Compound 27 reacts with methyl malonate chloride in dichloromethane solvent, with triethylamine as a base, at room temperature to give compound 31;

[0096] Step b. Compound 31 undergoes Dieckmann condensation with potassium tert-butoxide in tetrahydrofuran solvent at -70°C to give compounds 32a and 32b;

[0097] Step c. Compounds 32a and 32b react with guanidine hydrochloride in methanol solvent, with sodium methoxide as base, at 80°C to give compounds 33a and 33b through cyclization.

[0098] Step d. Compounds 33a and 33b react with different haloalkanes in tetrahydrofuran solvent, with cesium carbonate as a base, at 80°C to prepare compounds Ij and Ik.

[0099] According to another aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising compounds represented by Formula I, Formula I-1, Formula I-2 and Formula II, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0100] According to another aspect of the invention, another object of the invention is to provide the use of compounds of formula I, formula I-1, formula I-2 and formula II, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof or said pharmaceutical compositions in the preparation of HsClpP agonists.

[0101] According to another aspect of the invention, another object of the invention is to provide the use of compounds of formula I, formula I-1, formula I-2 and formula II, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof or said pharmaceutical compositions in the preparation of medicaments for treating and / or preventing diseases mediated by HsClpP.

[0102] Preferably, the diseases mediated by HsClpP include HsClpP-mediated neurological diseases, metabolic syndromes, and tumors, such as acute myeloid leukemia, diffuse large B-cell lymphoma, and glioma.

[0103] According to another aspect of the invention, another object of the invention is to provide a method for treating a disease mediated by HsClpP, the method comprising administering to a subject in need a compound represented by Formula I, Formula I-1, Formula I-2 and Formula II, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or said pharmaceutical composition. Detailed Implementation

[0104] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0105] definition

[0106] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0107] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0108] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0109] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0110] In this document, when Markush groups or alternative terms are used to describe features or instances of the invention, those skilled in the art will understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that claims of X being X1 and claims of X being X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or instances of the invention, those skilled in the art will understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that claims of X being X1 or X2 or X3 and Y being Y1 or Y2 or Y3 have been fully described. When a range of values ​​is listed, it is intended to include every value and subrange within that range. For example, “C” 1–6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 .

[0111] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may exist as hydrates, solvates, or prodrugs. Therefore, hydrates, solvates, or prodrugs of the compounds of the present invention, or pharmaceutically acceptable salts thereof, are also included within the scope of this invention.

[0112] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0113] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a specific substituent, as discovered in this invention, with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and the organic acids include, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid. Propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucohepose, gluconic acid, hydroxyethanesulfonic acid, lactic acid, lactose, dodecyl sulfonic acid, dihydroxynaphthyl acid, salicylic acid, succinic acid, phosphorous acid, etc.; acetic acid, edetate, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and similar acids; also including salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and can thus be converted into any base or acid addition salt. The parent form of a compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0114] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0115] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0116] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups.

[0117] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0118] As used herein, the term “treatment” means the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treating a disease or condition does not require the complete elimination of its associated symptoms. As used herein, the term “treatment” and similar terms can include “preventive treatment,” which refers to reducing the likelihood of the recurrence of a disease or condition or the relapse of a previously controlled disease or condition in subjects who are not at risk or are at risk of developing or being at risk of developing or experiencing a disease or condition or its recurrence. The term “treatment” and its synonyms are considered in relation to the administration of a therapeutically effective amount of the compound described herein to a subject who requires such treatment.

[0119] As used herein, the term “therapeutic effective amount” refers to an amount of a therapeutic agent (e.g., any one or more compounds described herein) sufficient to relieve symptoms of one or more conditions or ailments (e.g., gout, hyperuricemia), or to prevent the onset or development of a disease or ailment, or to cause the remission or cure of a disease or ailment.

[0120] As used herein, the term "subject" (which may be alternatively referred to as "patient") means an animal, preferably a mammal, and most preferably a human, that has become the subject of treatment, observation, or experimentation. In any of the embodiments described herein, the subject may be a human.

[0121] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, refer to the corresponding unsubstituted or substituted group. Generally, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is substituted by a permitted substituent (e.g., the substitution of the substituent results in a stable compound, e.g., a compound that does not spontaneously transform, for example, through rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent at each position may be the same or different. Typically, when substituted, the optionally substituted group herein may be substituted by 1 to 5 substituents. Substituents may be carbon, nitrogen, oxygen, or sulfur substituents, if applicable.

[0122] Unless otherwise expressly stated, combinations of substituents and / or variables are permitted only if they are chemically permissible and produce stable compounds. A “stable” compound is one that can be prepared and isolated and whose structure and properties remain or substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0123] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms ("C..."). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., halogens, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-10 Alkyl (e.g., unsubstituted C) 1-6 Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-10 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0124] "Cycloalkyl" or "saturated or unsaturated cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C10"). 3-10 The cycloalkyl group comprises a non-aromatic cycloalkyl group with 3 to 8 carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Cycloalkyl). Exemplary C 3-6Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C... 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C 3-10 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C… 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0125] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the linkage of a heterocycle as defined above with one or more cycloalkyl groups is on the cycloalkyl or heterocycle, or ring systems in which a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of the heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group.

[0126] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0127] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0128] "Aryl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group that is optionally substituted with an aryl group. In some embodiments, the aryl group is an optionally substituted benzyl group. In some embodiments, the aryl group is a benzyl group. In some embodiments, the aryl group is an optionally substituted phenethyl group. In some embodiments, the aryl group is a phenethyl group.

[0129] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0130] "Unsaturated" or "partially unsaturated" refers to a group containing at least one double or triple bond. The term "partially unsaturated" ring systems also aims to encompass rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" means a group containing no double or triple bonds, i.e., entirely composed of single bonds.

[0131] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0132] The term "tautomer" or "tautomerizing" refers to a compound in which two or more interconvert to each other, resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions. It should also be understood that compounds having the same molecular formula but different properties, or different bonding sequences of their atoms, or different spatial arrangements of their atoms are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers."

[0133] Unless otherwise specified, the reagents, methods, and equipment used in this invention are all conventional reagents, methods, and equipment in this technical field. The analytical data of the samples were determined by the following instruments: nuclear magnetic resonance (NMR) was measured using a BRUKER AVANCE NEO 500 or BRUKER AVANCE NEO 600 NMR spectrometer, with TMS (tetramethylsilane) as an internal standard; chemical shift units were in ppm, and coupling constant units were in Hz; mass spectrometry was performed using a G6125C mass spectrometer.

[0134] Column chromatography used 200-300 mesh silica gel (produced by Titan); TLC silica gel plates were HSGF-254 pre-prepared thin-layer chromatography plates manufactured by Yantai Chemical Plant; petroleum ether had a boiling range of 60-90℃; UV lamp and iodine bath were used for color development. Unless otherwise specified, all conventional reagents and chemicals used in the following examples were purchased from Bidex Group, Antech Group, and Titan Group. Reagents and solvents used in the experiments were handled according to the specific reaction conditions.

[0135] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0136] Example 1

[0137] Synthesis route:

[0138] (1) Dissolve 34 (606 mg, 2.0 mmol) and formamidin acetate 35 (270 mg, 2.6 mmol) in methanol (10 mL), add sodium methoxide (540 mg, 10 mmol), and stir the mixture at 80 °C for 12 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 36 (362 mg, yield 71%).

[0139] (2) 36 (127 mg, 0.5 mmol) and 4-trifluoromethylbenzyl bromide 37 (167 mg, 0.7 mmol) were dissolved in THF, and cesium carbonate (278 mg, 0.7 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-1 (74 mg, yield 36%). MS (ESI) m / z: 414.3 [M+H] +

[0140] Example 2

[0141] The preparation method of compound I-1 in Example 1 is the same, except that compound 36 and 4-chlorobenzyl bromide are used as raw materials. MS (ESI) m / z: 380.2 [M+H] +

[0142] Example 3

[0143] The preparation method of compound I-1 in Example 1 is the same, except that compound 34 and acetamiprid hydrochloride are used as raw materials. 1H NMR(600MHz,Chloroform-d)δ7.57(d,J=8.1Hz,2H),7.36(d,J=7.0Hz,2H),7.31(t,J=7.5Hz,2H),7. 25–7.22(m,2H),5.36(d,J=15.0Hz,1H),5.26(d,J=16.1Hz,1H),3.88(d,J=13.1Hz,1H),3.61(d,J=1 3.1Hz,1H),3.53(s,2H),3.16(h,J=6.4Hz,1H),2.93(dd,J=17.9,5.4Hz,1H),2.63(q,J=7.5Hz,2H), 2.46(dd,J=17.9,4.5Hz,1H),1.22(t,J=7.4Hz,3H),1.14(d,J=6.5Hz,3H).MS(ESI)m / z:428.2[M+H] +

[0144] Example 4

[0145] The preparation method of compound I-1 in Example 1 is the same, except that compound 34 and propanediol hydrochloride are used as raw materials. 1 H NMR(600MHz,Chloroform-d)δ7.60(d,J=8.1Hz,2H),7.39(d,J=7.0Hz,2H),7.33(t,J=7.5Hz,2H),7.28– 7.24(m,3H),5.39(d,J=14.9Hz,1H),5.29(d,J=15.8Hz,1H),3.90(d,J=13.1Hz,1H),3.64(d,J=13.1Hz, 1H),3.55(s,2H),3.18(hept,J=6.1,5.4Hz,1H),2.95(ddd,J=18.1,5.2,2.4Hz,1H),2.65(q,J=7.5Hz,2 H),2.49(dd,J=18.0,4.5Hz,1H),1.25(t,J=7.4Hz,3H),1.17(d,J=6.5Hz,3H).MS(ESI)m / z:442.6[M+H] +

[0146] Example 5

[0147] The preparation method of compound I-1 in Example 1 is the same, except that compound 34 and cyclopropylformamidin hydrochloride are used as raw materials. MS (ESI) m / z: 454.5 [M+H] +

[0148] Example 6

[0149] Synthesis route:

[0150] (1) Dissolve 34 (606 mg, 2 mmol) and (2-amino-2-iminoethyl)carbamate tert-butyl hydrochloride 38 (545 mg, 2.6 mmol) in methanol (10 mL), add sodium methoxide (540 mg, 10 mmol), and stir the mixture at 80 °C for 12 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 39 (507 mg, yield 66%).

[0151] (2) 39 (384 mg, 1 mmol) and 4-trifluoromethylbenzyl bromide 37 (310 mg, 1.3 mmol) were dissolved in THF, and cesium carbonate (432 mg, 1.3 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 10:1) was used to purify 40 (124 mg, yield 22%).

[0152] (3) Dissolve 40 in ethyl acetate, add 5 mL of ethyl acetate solution containing 2 M hydrochloric acid, and purify by column chromatography (dichloromethane:methanol = 10:1) to obtain I-6 (84 mg, yield 86%). MS (ESI) m / z: 443.4 [M+H) +

[0153] Example 7

[0154] Synthesis route:

[0155] (1) Dissolve 34 (6060 mg, 20 mmol) and guanidine hydrochloride 41 (2700 mg, 26 mmol) in methanol (100 mL), add sodium methoxide (5400 mg, 100 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 42 (4050 mg, yield 75%).

[0156] (2) 42 (270 mg, 1 mmol) and 4-trifluoromethylbenzyl bromide 37 (310 mg, 1.3 mmol) were dissolved in THF, and cesium carbonate (423 mg, 1.3 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-7 (132 mg, 31%). 1 H NMR(500MHz,Chloroform-d)δ7.61(d,J=8.1Hz,2H),7.39–7.34(m,4H),7.31(t,J=7.6Hz,2H),7 .24(d,J=7.3Hz,1H),5.32(d,J=16.3Hz,1H),5.15(d,J=16.2Hz,1H),4.97(s,2H),3.87(d,J=13 .2Hz,1H),3.61(d,J=13.1Hz,1H),3.47(d,J=4.3Hz,2H),3.12(h,J=6.1,5.5Hz,1H),2.77(dd,J =17.6,5.1Hz,1H),2.27(dd,J=17.7,4.4Hz,1H),1.13(d,J=6.5Hz,3H).MS(ESI)m / z:429.4[M+H] +

[0157] Example 8

[0158] The preparation method of compound I-7 in Example 7 is the same, except that compound 34 and 1-methylguanidine hydrochloride are used as raw materials. 1 H NMR(600MHz,Chloroform-d)δ7.59(d,J=8.1Hz,2H),7.36(d,J=7.5Hz,2H),7.31(t,J=7.5Hz,2 H),7.28(d,J=8.0Hz,2H),7.24(d,J=7.3Hz,1H),5.37(d,J=16.1Hz,1H),5.23(d,J=16.0Hz,1H ),3.87(d,J=13.2Hz,1H),3.62(d,J=13.1Hz,1H),3.58–3.45(m,2H),3.16(h,J=5.9Hz,1H),2. 91(dd,J=18.0,5.8Hz,1H),2.45–2.39(m,4H),1.13(d,J=6.5Hz,3H).MS(ESI)m / z:443.2[M+H] +

[0159] Example 9

[0160] The preparation method of compound I-7 in Example 7 is the same, except that compound 34 and 1-ethylguanidine hemisulfate are used as raw materials. 1 H NMR(600MHz,Chloroform-d)δ7.60(d,J=8.0Hz,1H),7.38(d,J=7.2Hz,2H),7.35–7.29(m,4H),7.24(t,J =7.3Hz,1H),5.29(d,J=16.5Hz,1H),5.11(d,J=16.5Hz,1H),4.21–4.08(m,1H),3.88(d,J=13.1Hz,1H), 3.60(d,J=13.1Hz,1H),3.48(s,2H),3.37–3.27(m,2H),3.11(h,J=6.3Hz,1H),2.81(dd,J=17.8,5.1Hz, 1H),2.34(dd,J=17.8,4.6Hz,1H),1.14(d,J=6.5Hz,3H),1.04(t,J=7.2Hz,3H).MS(ESI)m / z:457.3[M+H] +

[0161] Example 10

[0162] The preparation method of compound I-7 in Example 7 is the same, except that compound 34 and aminoguanidine hydrochloride are used as raw materials. 1 H NMR (600MHz, CDCl3) δ7.62(d,J=7.9Hz,2H),7.48(d,J=7.8Hz,2H),7.39(s,2H),7.33(t,J=7.4H z,2H),7.26(t,J=7.3Hz,1H),6.61(t,J=6.1Hz,1H),4.69(qd,J=15.2,6.1Hz,2H),4.47(s,2H), 3.86(d,J=13.2Hz,1H),3.61(d,J=13.2Hz,1H),3.46(s,2H),3.12(h,J=6.1Hz,1H),2.80(dd,J= 17.9,5.2Hz,1H),2.34(dd,J=17.7,4.5Hz,1H),1.13(d,J=6.5Hz,3H).MS(ESI)m / z:444.1[M+H] +

[0163] Example 11

[0164] The preparation method of compound I-7 in Example 7 is the same, except that compound 34 and o-methylisourea hydrochloride are used as raw materials. 1 H NMR(600MHz,Chloroform-d)δ7.57(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),7.38(d,J=7.4H z,2H),7.33(t,J=7.5Hz,2H),7.26(d,J=7.3Hz,1H),5.26–5.14(m,2H),3.98(s,3H),3.88(d ,J=13.2Hz,1H),3.62(d,J=13.2Hz,1H),3.48(s,2H),3.14(h,J=5.9Hz,1H),2.85(dd,J=18. 1,5.3Hz,1H),2.37(dd,J=17.9,4.4Hz,1H),1.14(d,J=6.5Hz,3H).MS(ESI)m / z:444.5[M+H] +

[0165] Example 12

[0166] The preparation method of compounds I-7 in Example 7 is the same, except that compound 34 and o-ethylisourea hydrochloride are used as raw materials. MS (ESI) m / z: 458.2 [M+H] +

[0167] Example 13

[0168] Synthesis route:

[0169] (1) 34 (3030 mg, 10 mmol) and thiourea 43 (988 mg, 13 mmol) were dissolved in methanol (50 mL), and sodium methoxide (2700 mg, 50 mmol) was added. The mixture was stirred at 80 °C for 24 h, and the reaction was monitored by LCMS. After the reaction was completed, the reaction solution was diluted with dichloromethane and extracted with water, and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (dichloromethane:methanol = 20:1) was used to purify 44 (1833 mg, yield 64%).

[0170] (2) 44 (1833 mg, 6.4 mmol) and 4-trifluoromethylbenzyl bromide 37 (1980 mg, 9.3 mmol) were dissolved in THF, and cesium carbonate (3030 mg, 9.3 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify 45 (1253 mg, 44%).

[0171] (3) 45 (1253 mg, 2.8 mmol) was dissolved in MeOH (10 mL), and 2.0 M sodium hydroxide solution (8.0 eq) was added, followed by iodomethane (1190 mg, 8.4 mmol). The reaction was carried out overnight at 36 °C. After the reaction was complete, the solvent was removed and water was added. The mixture was extracted with dichloromethane, and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-13 (989 mg, 77%). MS (ESI) m / z: 460.6 [M+H] +

[0172] Example 14

[0173] Synthesis route:

[0174] I-13 (920 mg, 2 mmol) and m-chloroperoxybenzoic acid (516 mg, 3 mmol) were dissolved in DCM (10 mL), and potassium carbonate (414 mg, 4 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. I-14 (466 mg, 51% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 1:1). MS (ESI) m / z: 476.2 [M+H] +

[0175] Example 15

[0176] Synthesis route:

[0177] I-13 (920 mg, 2 mmol) and m-chloroperoxybenzoic acid (516 mg, 3 mmol) were dissolved in DCM (10 mL), and potassium carbonate (414 mg, 4 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. I-15 (245 mg, 25% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 1:2). MS (ESI) m / z: 492.3 [M+H] +

[0178] Example 16

[0179] Synthesis route:

[0180] I-15 (100 mg, 0.2 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (2 mL / 2 mL) and stirred overnight under reflux. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. I-16 (54 mg, 63% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 2:1). MS (ESI) m / z: 430 [M+H] +

[0181] Example 17

[0182] The preparation method of compounds I-7 in Example 7 is the same, except that compound 42 and bromomethylcyclohexane are used as raw materials. MS (ESI) m / z: 366.3 [M+H] +

[0183] Example 18

[0184] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 3-bromomethylpyridine are used as raw materials. MS (ESI) m / z: 362.5 [M+H] +

[0185] Example 19

[0186] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 2-bromomethylpyridine are used as raw materials. MS (ESI) m / z: 362.2 [M+H] +

[0187] Example 20

[0188] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 4-bromomethylpyridine are used as raw materials. MS (ESI) m / z: 362.4 [M+H] +

[0189] Example 21

[0190] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 4-fluorobenzaldehyde are used as raw materials. MS (ESI) m / z: 3792 [M+H] +

[0191] Example 22

[0192] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 4-chlorobenzaldehyde are used as raw materials. MS (ESI) m / z: 395.6 [M+H] +

[0193] Example 23

[0194] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 4-bromobenzaldehyde are used as raw materials. MS (ESI) m / z: 439.1 [M+H] +

[0195] Example 24

[0196] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 4-(bromomethyl)-N,N-dimethylaniline are used as raw materials. MS (ESI) m / z: 404.4 [M+H] +

[0197] Example 25

[0198] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 2-bromo-4-fluorobenzyl bromide are used as raw materials. MS (ESI) m / z: 357.5 [M+H] +

[0199] Example 26

[0200] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 2-fluoro-4-bromobenzyl bromide are used as raw materials. MS (ESI) m / z: 457.8 [M+H] +

[0201] Example 27

[0202] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 2-methoxy-4-fluorobenzyl bromide are used as raw materials. MS (ESI) m / z: 409.2 [M+H] +

[0203] Example 28

[0204] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane were used as raw materials. MS (ESI) m / z: 419.4 [M+H] +

[0205] Example 29

[0206] The preparation method of compounds I-7 in Example 7 is the same, except that compounds 42 and 5-(bromomethyl)benzo[d][1,3]dioxane are used as raw materials. MS (ESI) m / z: 405.2 [M+H] +

[0207] Example 30

[0208] Synthesis route:

[0209] (1) Dissolve 46 (9390 mg, 30 mmol) and guanidine hydrochloride 41 (4297 mg, 45 mmol) in methanol (100 mL), add sodium methoxide (3600 mg, 150 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction progress by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by slurrying with ethyl acetate to obtain 47 (4704 mg, yield 56%).

[0210] (2) 47 (4704 mg, 16.8 mmol) and 4-trifluoromethylbenzyl bromide 37 (5220 mg, 21.8 mmol) were dissolved in THF, and cesium carbonate (6950 mg, 21.8 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 10:1) was used to purify 48 (3017 mg, yield 42%).

[0211] (3) Dissolve 48 (3017 mg) in ethyl acetate solution of hydrochloric acid (2.0 M, 30 mL), stir at room temperature, and monitor the reaction by LCMS. After the reaction is complete, remove the solvent by rotary evaporation to obtain 49, which can be used directly in the next step.

[0212] (4) Dissolve 49 (374 mg, 1 mmol), m-fluorobenzaldehyde (186 mg, 1.5 mmol), and DIPEA (261 μL, 1.5 mmol) in DCM and stir at room temperature for 2 h. Then, slowly add NaBH(OAc)3 (423 mg, 2 mmol) to the system and continue stirring for 8 h. After the reaction is complete, quench with water, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain I-30 (330 mg, yield 75%). 1 H NMR(600MHz,Chloroform-d)δ7.62(d,J=8.0Hz,2H),7.37(d,J=7.9Hz,2H),7.30–7.26(m,1H),7.14(d,J= 6.3Hz,1H),7.12(s,1H),6.95(td,J=8.5,2.6Hz,1H),5.32(d,J=16.3Hz,1H),5.16(d,J=16.3Hz,1H),5.1 4(s,2H),3.85(d,J=13.5Hz,1H),3.61(d,J=13.5Hz,1H),3.46(d,J=4.1Hz,2H),3.12(h,J=5.9Hz,1H),2. 75(dd,J=17.7,5.3Hz,1H),2.26(dd,J=17.6,4.4Hz,1H),1.12(d,J=6.6Hz,3H).MS(ESI)m / z:447.3[M+H] +

[0213] Example 31

[0214] The preparation method of compound I-30 in Example 30 is the same, except that I-31 is obtained by reductive amination of compound 49 and o-fluorobenzaldehyde. 1H NMR(600MHz,Chloroform-d)δ7.61(d,J=8.1Hz,2H),7.44(td,J=7.6,1.8Hz,1H),7.35(d,J=8.0Hz,2H),7.22(tdd,J =7.6,5.2,1.8Hz,1H),7.10(td,J=7.5,1.2Hz,1H),7.02(ddd,J=9.7,8.2,1.2Hz,1H),5.31(d,J=16.1Hz,1H),5.15(d ,J=16.3Hz,1H),4.98(s,2H),3.86(d,J=13.1Hz,1H),3.69(d,J=13.5Hz,1H),3.50(d,J=1.7Hz,2H),3.14(dtd,J=11 .5,6.5,4.9Hz,1H),2.84–2.63(m,1H),2.27(dd,J=17.7,4.7Hz,1H),1.15(d,J=6.6Hz,3H).MS(ESI)m / z:447.2[M+H] +

[0215] Example 32

[0216] The preparation method of compound I-30 in Example 30 is the same, except that I-32 is obtained by reducing and amination of compound 49 and p-fluorobenzaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=8.1Hz,2H),7.35(d,J=8.0Hz,2H),7.32(dd,J=8.4,5.6Hz, 2H),6.99(t,J=8.7Hz,2H),5.31(d,J=16.2Hz,1H),5.15(d,J=16.3Hz,1H),4.92(s,2H),3.82(d,J= 13.1Hz,1H),3.56(d,J=13.1Hz,1H),3.49–3.35(m,2H),3.10(dtd,J=11.5,6.5,4.8Hz,1H),2.75(d d,J=17.5,5.6Hz,1H),2.26(dd,J=17.8,4.5Hz,1H),1.12(d,J=6.6Hz,3H).MS(ESI)m / z:447.4[M+H] +

[0217] Example 33

[0218] The preparation method of compound I-30 in Example 30 is the same, except that I-33 is obtained by reductive amination of compound 49 and m-methylbenzaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=8.1Hz,2H),7.35(d,J=8.0Hz,2H),7.23–7.10(m,3H),7. 06(d,J=7.4Hz,1H),5.44–5.20(d,J=16.3Hz,1H),5.14(d,J=16.3Hz,1H),4.89(s,2H),3.83(d,J= 13.0Hz,1H),3.55(d,J=13.0Hz,1H),3.51–3.41(m,2H),3.18–3.04(m,1H),2.76(dt,J=17.8,3.6H z,1H),2.34(s,3H),2.26(dd,J=17.7,4.5Hz,1H),1.12(d,J=6.5Hz,3H).MS(ESI)m / z:443.7[M+H] +

[0219] Example 34

[0220] The preparation method of compound I-30 in Example 30 is the same, except that I-34 is obtained by reductive amination of compound 49 and p-difluoromethoxybenzaldehyde. MS (ESI) m / z: 458.2 [M+H] +

[0221] Example 35

[0222] The preparation method of compound I-30 in Example 30 is the same, except that I-35 is obtained by reductive amination of compound 49 and m-chlorobenzaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.62(d,J=8.0Hz,2H),7.43–7.30(m,3H),7.25–7.17(m,3 H),5.32(d,J=16.3Hz,1H),5.16(d,J=16.3Hz,1H),4.86(s,2H),3.82(d,J=13.5Hz,1H) ,3.58(d,J=13.5Hz,1H),3.44(d,J=1.5Hz,2H),3.16–3.05(m,1H),2.76(dd,J=17.6,5. 4Hz,1H),2.26(dd,J=17.7,4.0Hz,1H),1.11(d,J=6.5Hz,3H).MS(ESI)m / z:463.4[M+H]+

[0223] Example 36

[0224] The preparation method of compound I-30 in Example 30 is the same, except that I-36 is obtained by reductive amination of compound 49 and m-bromobenzaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=8.1Hz,2H),7.54(s,1H),7.41–7.32(m,3H),7.32–7.27(m,1H ),7.17(t,J=7.8Hz,1H),5.32(d,J=16.4Hz,1H),5.16(d,J=16.4Hz,1H),4.87(s,2H),3.81(d,J=13.4 Hz,1H),3.57(d,J=13.5Hz,1H),3.44(dt,J=3.5,1.6Hz,2H),3.10(dtd,J=11.4,6.5,4.7Hz,1H),2.76 (dd,J=17.6,5.4Hz,1H),2.26(dd,J=17.7,4.2Hz,1H),1.11(d,J=6.6Hz,3H).MS(ESI)m / z:507.5[M+H] +

[0225] Example 37

[0226] The preparation method of compound I-30 in Example 30 is the same, except that I-37 is obtained by reductive amination of compound 49 and m-methylsulfonylbenzaldehyde. MS (ESI) m / z: 507.1 [M+H] +

[0227] Example 38

[0228] The preparation method of compound I-30 in Example 30 is the same, except that I-38 is obtained by reductive amination of compound 49 and m-trifluoromethylbenzaldehyde. 1H NMR(600MHz,Chloroform-d)δ7.67–7.59(m,3H),7.55(d,J=7.6Hz,1H),7.50(d,J=7.8Hz,1H),7. 42(t,J=7.7Hz,1H),7.36(d,J=7.9Hz,2H),5.32(d,J=16.3Hz,1H),5.16(d,J=16.4Hz,1H),4.83(s ,2H),3.89(d,J=13.6Hz,1H),3.66(d,J=13.6Hz,1H),3.11(h,J=11.4,6.5,4.7Hz,1H),2.77(dt, J=17.7,3.5Hz,1H),2.27(dd,J=17.7,4.4Hz,1H),1.12(d,J=6.6Hz,3H).MS(ESI)m / z:497.2[M+H] +

[0229] Example 39

[0230] The preparation method of compound I-30 in Example 30 is the same, except that I-39 is obtained by reductive amination of compound 49 and m-trifluoromethoxybenzaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=7.9Hz,2H),7.36(d,J=8.0Hz,2H),7.32(t,J=7.8Hz,1H),7.28 (d,J=7.7Hz,1H),7.25(s,1H),7.09(d,J=8.0Hz,1H),5.31(d,J=16.3Hz,1H),5.15(d,J=16.3Hz,1H),5. 08(s,2H),3.85(d,J=13.7Hz,1H),3.63(d,J=13.7Hz,1H),3.51–3.39(m,2H),3.10(h,J=6.0Hz,1H),2.7 5(dd,J=17.8,5.3Hz,1H),2.25(dd,J=17.7,4.3Hz,1H),1.10(d,J=6.6Hz,3H).MS(ESI)m / z:513.6[M+H] +

[0231] Example 40

[0232] The preparation method of compound I-30 in Example 30 is the same, except that I-40 is obtained by reductive amination of compound 49 and m-methoxybenzaldehyde. 1H NMR(600MHz,Chloroform-d)δ8.24(s,2H),7.60(d,J=7.9Hz,2H),7.36(d,J=7.9Hz,2H),7.23(t,J=7.6Hz ,1H),6.95–6.92(m,2H),6.81(dd,J=8.9,2.3Hz,1H),5.27(d,J=16.3Hz,1H),5.16(d,J=16.3Hz,1H),3.8 7(d,J=13.2Hz,1H),3.79(d,J=1.7Hz,3H),3.64(d,J=13.1Hz,1H),3.48(q,J=16.2Hz,2H),3.19(p,J=5.8 Hz,1H),2.86–2.80(m,1H),2.34(dd,J=18.0,4.4Hz,1H),1.15(d,J=6.4Hz,3H).MS(ESI)m / z:459.5[M+H] +

[0233] Example 41

[0234] The preparation method of compound I-30 in Example 30 is the same, except that I-41 is obtained by reductive amination of compound 49 and m-difluoromethoxybenzaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.29(t,J=7.9Hz,1H),7.20(d,J=7.6Hz ,1H),7.15(t,J=2.0Hz,1H),6.99(dd,J=8.1,2.4Hz,1H),6.51(t,J=74.2Hz,1H),5.31(d,J=16.3Hz,1H),5.16(d,J =16.3Hz,1H),4.99(s,2H),3.84(d,J=13.5Hz,1H),3.61(d,J=13.6Hz,1H),3.45(dt,J=3.5,1.6Hz,2H),3.14–3.07 (m,1H),2.76(dd,J=17.5,5.4Hz,1H),2.26(dd,J=17.6,4.3Hz,1H),1.11(d,J=6.6Hz,3H).MS(ESI)m / z:495.8[M+H] +

[0235] Example 42

[0236] The preparation method of compound I-30 in Example 30 is the same, except that I-42 is obtained by reductive amination of compound 49 and o-difluoromethoxybenzaldehyde. 1 H NMR(600MHz,Methanol-d4)δ7.65(d,J=8.1Hz,2H),7.58(dd,J=5.9,3.7Hz,2H) ,7.44(d,J=7.9Hz,2H),7.34(td,J=7.5,5.1Hz,2H),7.00(t,J=73.1Hz,1H),5.3 2(q,J=16.8Hz,2H),4.47(s,2H),3.95–4.10(m,3H),3.08(dd,J=18.8,5.8Hz,1H ),2.79(dd,J=18.9,7.1Hz,1H),1.62(d,J=6.7Hz,3H).MS(ESI)m / z:495.2[M+H] +

[0237] Example 43

[0238] The preparation method of compound I-30 in Example 30 is the same, except that I-43 is obtained by reductive amination of compound 49 and 3-cyano-4-fluorobenzaldehyde. 1 H NMR(500MHz,Chloroform-d)δ7.66(dd,J=6.1,2.2Hz,1H),7.63(d,J=8.1Hz,2H),7.59(ddd,J=7.8,5.1,2.2H z,2H),7.37(d,J=8.0Hz,2H),7.15(t,J=8.6Hz,1H),5.32(d,J=16.2Hz,1H),5.18(d,J=16.2Hz,1H),4.94(s, 2H),3.81(d,J=13.8Hz,1H),3.60(d,J=13.8Hz,1H),3.39(d,J=1.7Hz,2H),3.11(dtd,J=11.5,6.5,4.8Hz,1H ),2.78(dd,J=17.6,4.9Hz,1H),2.29(dd,J=17.7,4.6Hz,1H),1.13(d,J=6.5Hz,3H).MS(ESI)m / z:472.6[M+H] +

[0239] Example 44

[0240] The preparation method of compound I-30 in Example 30 is the same, except that I-44 is obtained by reductive amination of compound 49 and 3-fluoro-4-cyanobenzaldehyde.1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=7.9Hz,2H),7.54(t,J=7.2Hz,1H),7.36(d,J=7.9Hz,2H), 7.30(d,J=9.9Hz,1H),7.25(d,J=8.2Hz,1H),5.31(d,J=16.4Hz,1H),5.17(d,J=16.3Hz,1H),4.92( s,2H),3.86(d,J=14.6Hz,1H),3.67(d,J=14.6Hz,1H),3.41(s,2H),3.10(h,J=5.8Hz,1H),2.76(dd ,J=17.7,5.2Hz,1H),2.27(dd,J=17.6,4.6Hz,1H),1.11(d,J=6.5Hz,3H).MS(ESI)m / z:472.7[M+H] +

[0241] Example 45

[0242] The preparation method of compound I-30 in Example 30 is the same, except that I-45 is obtained by reductive amination of compound 49 and cyclohexylformaldehyde. 1 H NMR(600MHz,Chloroform-d)δ7.64–7.58(m,2H),7.37(d,J=7.9Hz,2H),5.34(d,J=16.3Hz,1H),5.17( d,J=16.3Hz,1H),3.46(s,2H),3.03(h,J=5.8Hz,1H),2.69(dd,J=17.7,5.1Hz,1H),2.41(dd,J=12.4,7 .2Hz,1H),2.27–2.18(m,2H),1.79(d,J=13.1Hz,1H),1.73–1.59(m,3H),1.54(dqd,J=10.8,7.3,3.6Hz ,1H),1.31–1.17(m,2H),1.03(d,J=6.5Hz,3H),0.87(qd,J=12.5,3.4Hz,2H).MS(ESI)m / z:435.6[M+H] +

[0243] Example 46

[0244] The preparation method of compound I-30 in Example 30 is the same, except that I-46 is obtained by reductive amination of compound 49 and 3-pyridinecarboxaldehyde. MS (ESI) m / z: 430.1 [M+H]+

[0245] Example 47

[0246] The preparation method of compound I-30 in Example 30 is the same, except that I-47 is obtained by reductive amination of compound 49 and 7-quinoline carbaldehyde. 1 H NMR(600MHz,Chloroform-d)δ9.16(d,J=5.0Hz,1H),8.73(d,J=8.3Hz,1H),8.58(s,1H),8.11(d,J=8.5H z,1H),8.03(d,J=8.5Hz,1H),7.85(dd,J=8.5,4.8Hz,1H),7.64(d,J=8.0Hz,2H),7.44–7.33(m,2H),5.32 (d,J=16.9Hz,1H),5.19(d,J=16.5Hz,1H),4.33(d,J=13.8Hz,1H),4.21(d,J=13.9Hz,1H),4.12(q,J=7. 1Hz,1H),3.70(d,J=16.4Hz,1H),3.59(d,J=15.9Hz,2H),1.26(d,J=3.1Hz,3H).MS(ESI)m / z:480.2[M+H] +

[0247] Example 48

[0248] The preparation method of compound I-30 in Example 30 was followed, except that compound 49 was subjected to reductive amination with acetophenone, followed by chiral separation to obtain I-48. MS (ESI) m / z: 443.4 [M+H] +

[0249] Example 49

[0250] The preparation method of compound I-30 in Example 30 was followed, except that compound 49 was reductively amination with acetophenone, followed by chiral separation to obtain I-48. MS (ESI) m / z: 443.2 [M+H] +

[0251] Example 50

[0252] Synthesis method:

[0253] The preparation method of compound I-30 in Example 30 is the same, except that compound 49 is used as a starting material, and under DIPEA as a base, it undergoes a substitution reaction with deuterated benzyl bromide 50 to obtain I-50. MS (ESI) m / z: 430.2 [M+H] +

[0254] Example 51

[0255] The preparation method of compound I-41 in Example 41 is the same, except that the compound is used in the preparation of compound I-41. It was obtained from raw materials via chiral separation. MS(ESI) m / z: 495.4 [M+H] +

[0256] Example 52

[0257] The preparation method of compound I-41 in Example 41 is the same, except that the compound is used in the preparation of compound I-41. It was obtained from raw materials via chiral separation. MS (ESI) m / z: 495.7 [M+H] +

[0258] Example 53

[0259] Synthesis route:

[0260] (1) Dissolve 6 (4600 mg, 20 mmol) and benzylamine (4360 μL, 40 mmol) in methanol (40 mL), add AcOH (120 mg, 2 mmol), and stir the mixture at room temperature for 2 h. Then, add NaBH(OAc)3 (12700 mg, 60 mmol) at 0 °C and stir at room temperature for 8 h. After the reaction is complete, remove the solvent by rotary evaporation, dilute the reaction system with dichloromethane, and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 42 (3531 mg, yield 55%).

[0261] (2) 52 (3531 mg, 11 mmol) and Boc2O (3120 mg, 14.3 mmol) were dissolved in dichloromethane, and E3N (2000 μL, 14.3 mmol) was added. The mixture was stirred overnight at 40 °C. After the reaction was complete, the reaction solution was added with water and extracted with dichloromethane, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 53.

[0262] (3) Crude product 53 was dissolved in THF (40 mL), and potassium tert-butoxide was slowly added at 0 °C. The reaction was monitored by LCMS until completion. After the reaction was complete, the solvent was removed by rotary evaporation, the reaction solution was added with water and extracted with dichloromethane, and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 10:1) was used to purify 54 (2662 mg, two-step yield 64%).

[0263] (4) Dissolve 54 (2662 mg, 7.1 mmol) and guanidine hydrochloride 41 (1017 mg, 10.7 mmol) in methanol (30 mL), add sodium methoxide (1910 mg, 35.5 mmol), and stir the mixture overnight at 80 °C. Monitor the reaction progress by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by slurrying with ethyl acetate to obtain 55 (1665 mg, yield 63%).

[0264] (5) 55 (1665 mg, 4.5 mmol) and 4-trifluoromethylbenzyl bromide 37 (1400 mg, 5.9 mmol) were dissolved in THF, and cesium carbonate (1930 mg, 5.9 mmol) was added. The mixture was stirred at 80 °C for 6 h, and the reaction was monitored by LCMS to indicate completion. After the reaction was complete, water was added to the reaction solution and the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed three times with saturated NaCl. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify 56 (930 mg, yield 41%).

[0265] (6) I-53 (930 mg) was dissolved in ethyl acetate solution of hydrochloric acid (2.0 M, 20 mL), stirred at room temperature, and the reaction was monitored by LCMS. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to alkaline, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain I-53 (685 mg, yield 91%). MS (ESI) m / z: 429.1 [M+H] +

[0266] Example 54

[0267] Synthesis method:

[0268] I-53 (150 mg, 0.35 mmol) was dissolved in CH3CN (10 mL), and iodomethane (98 mg, 0.7 mmol) and DIPEA (122 μL, 0.7 mmol) were added. The mixture was stirred overnight at 35 °C. After the reaction was complete, water was added and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. I-54 (115 mg, 74% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 1:1). MS (ESI) m / z: 443.2 [M+H] +

[0269] Example 55

[0270] Synthesis method:

[0271] I-53 (150 mg, 0.35 mmol) was dissolved in DCM (10 mL), and acetyl chloride 57 (39 mg, 0.5 mmol) and Et3N (70 μL, 0.5 mmol) were added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, water was added and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. I-55 (144 mg, 88% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 1:1). MS (ESI) m / z: 471.2 [M+H] +

[0272] Example 56

[0273] Synthesis method

[0274] I-53 (150 mg, 0.35 mmol) was dissolved in DCM (10 mL), and methanesulfonyl chloride 58 (57 mg, 0.5 mmol) and Et3N (70 μL, 0.5 mmol) were added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, water was added and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. I-56 (115 mg, 74% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 1:1). MS (ESI) m / z: 507.2 [M+H] +

[0275] Example 57

[0276] Synthesis route:

[0277] (1) 13 (3760 mg, 20 mmol) and benzylamine (4360 μL, 40 mmol) were dissolved in DCM (40 mL), and AcOH (120 mg, 2 mmol) was added. The mixture was stirred at room temperature for 2 h. Subsequently, NaBH(OAc)3 (12700 mg, 60 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 8 h. After the reaction was completed, the solvent was removed by rotary evaporation, the reaction system was diluted with dichloromethane and extracted with water, and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether: ethyl acetate = 1:1) was used to purify 59 (2845 mg, yield 51%).

[0278] (2) Dissolve 59 (2845 mg, 10 mmol) and Boc2O (2837 mg, 13 mmol) in dichloromethane, add Et3N (1800 μL, 13 mmol), and stir the mixture overnight at 40 °C. After the reaction is complete, add water to the reaction solution and extract with dichloromethane, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate to a crude product of 60.

[0279] (3) Crude product 60 was dissolved in THF (40 mL), and potassium tert-butoxide was slowly added at 0 °C. The reaction was monitored by LCMS until completion. After the reaction was complete, the solvent was removed by rotary evaporation, the reaction solution was added with water and extracted with dichloromethane, and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 10:1) was used to purify 61 (1180 mg, two-step yield 34%).

[0280] (4) Dissolve 61 (1180 mg, 3.4 mmol) and guanidine hydrochloride 41 (487 mg, 5.1 mmol) in methanol (20 mL), add sodium methoxide (980 mg, 17 mmol), and stir the mixture overnight at 80 °C. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by slurrying with ethyl acetate to obtain 62 (835 mg, yield 69%).

[0281] (5) Dissolve 62 (835 mg, 2.3 mmol) and 4-trifluoromethylbenzyl bromide 37 (715 mg, 3 mmol) in THF, add cesium carbonate (980 mg, 3 mmol), and stir the mixture at 80 °C for 4 h. Monitor the reaction completion by LCMS. After the reaction is complete, add water to the reaction solution and extract three times with ethyl acetate. Combine the organic phases and wash three times with saturated NaCl. Combine the organic phases, dry them with anhydrous sodium sulfate, filter and concentrate. Purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 63 (472 mg, yield 40%).

[0282] (6) 63 (472 mg, 0.9 mmol) was dissolved in ethyl acetate solution of hydrochloric acid (2.0 M, 10 mL), stirred at room temperature, and the reaction was monitored by LCMS until completion. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to alkaline, and the mixture was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (dichloromethane:methanol = 10:1) to give I-57 (362 mg, yield 94%). MS (ESI) m / z: 415.2 [M+H] +

[0283] Example 58

[0284] Synthesis route:

[0285] I-57 (80 mg, 0.2 mmol) was dissolved in DCM (10 mL), and acetyl chloride 57 (24 mg, 0.3 mmol) and Et3N (42 μL, 0.3 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give I-58 (77 mg, yield 84%). MS (ESI) m / z: 457.2 [M+H] +

[0286] Example 59

[0287] Synthesis route:

[0288] I-53 (80 mg, 0.2 mmol) was dissolved in DCM (10 mL), and methanesulfonyl chloride 58 (34 mg, 0.3 mmol) and Et3N (42 μL, 0.3 mmol) were added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, water was added and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. I-56 (62 mg, 71% yield) was purified by column chromatography (petroleum ether:ethyl acetate = 1:1). MS (ESI) m / z: 493.2 [M+H] +

[0289] Example 60

[0290]

[0291] Synthesis route:

[0292] (1) Dissolve 64 (4940 mg, 20 mmol) and guanidine hydrochloride 41 (2700 mg, 26 mmol) in methanol (100 mL), add sodium methoxide (5400 mg, 100 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain 65 (4150 mg, yield 81%).

[0293] (2) 65 (256 mg, 1 mmol) and 4-trifluoromethylbenzyl bromide 37 (310 mg, 1.3 mmol) were dissolved in THF, and cesium carbonate (423 mg, 1.3 mg) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-60 (139 mg, 36%). MS (ESI) m / z: 429.4 [M+H] +

[0294] Example 61

[0295] The preparation method of compound I-60 in Example 60 is the same, except that the compound is used in the preparation of compound I-60. This is the starting material. MS(ESI) m / z: 433.2 [M+H] +

[0296] Example 62

[0297] The preparation method of compound I-60 in Example 60 is the same, except that the compound is used in the preparation of compound I-60. As raw material. MS(ESI) m / z: 481.2 [M+H] +

[0298] Example 63

[0299] The preparation method of compound I-60 in Example 60 is the same, except that the compound is used in the preparation of compound I-60. As raw material. MS(ESI) m / z: 429.2 [M+H] +

[0300] Example 64

[0301] The preparation method of compound I-60 in Example 60 is the same, except that the compound is used in the preparation of compound I-60. As raw material. MS(ESI) m / z: 417.2 [M+H] +

[0302] Example 65

[0303] The preparation method of compound I-60 in Example 60 is the same, except that it is obtained by a substitution reaction between 64 and 2-methyl-4-bromobenzyl bromide. MS (ESI) m / z: 439.1 [M+H] +

[0304] Example 66

[0305] The preparation method of compound I-60 in Example 60 is the same, except that 64 and It is obtained through a substitution reaction. MS (ESI) m / z: 429.1 [M+H] +

[0306] Example 67

[0307] Synthesis route:

[0308] (1) Dissolve 71 (2331 mg, 10 mmol) and guanidine hydrochloride 41 (1350 mg, 13 mmol) in methanol (50 mL), add sodium methoxide (2700 mg, 50 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain 72 (1525 mg, yield 63%).

[0309] (2) 72 (242 mg, 1 mmol) and 4-trifluoromethylbenzyl bromide 37 (310 mg, 1.3 mmol) were dissolved in THF, and cesium carbonate (423 mg, 1.3 mg) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-67 (124 mg, 31%). 1H NMR (600MHz, Acetone-d6) δ7.72–7.66 (m, 4H), 7.50 (d, J = 8.1Hz, 2H), 7.48–7.4 5(m,3H),5.40(s,2H),4.62(s,2H),4.43–4.33(m,4H).MS(ESI)m / z:401.1[M+H] +

[0310] Example 68

[0311] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw materials. 1 ¹H NMR (600 MHz, acetone-d6) δ 7.70 (d, J = 7.9 Hz, 2H), 7.58–7.52 (m, 3H), 7.50 (d, J = 8.1 Hz, 2H), 7.31–7.23 (m, 1H), 5.41 (s, 2H), 4.75 (s, 2H), 4.50 (d, J = 7.2 Hz, 4H). 13 C NMR (151MHz, Acetone-d6) δ162.83 (d, J = 245.5Hz), 160.41, 157.69, 157.29, 139.9 3,133.58(d,J=7.8Hz),131.06(d,J=8.3Hz),129.16(q,J=32.2Hz),127.44,126.65 (d,J=3.0Hz),125.44(q,J=3.8Hz),124.35(q,J=271.3Hz),117.41(d,J=22.5Hz),1 16.51(d,J=21.1Hz),103.48,57.91,57.66,55.26,43.52.MS(ESI)m / z:419.1[M+H] +

[0312] Example 69

[0313] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw material. MS(ESI) m / z: 426.2 [M+H] +

[0314] Example 70

[0315] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw material. MS(ESI) m / z: 467.1 [M+H] +

[0316] Example 71

[0317] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw material. MS(ESI) m / z: 415.2 [M+H] +

[0318] Example 72

[0319] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw material. MS(ESI) m / z: 403.2 [M+H] +

[0320] Example 73

[0321] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw material. MS(ESI) m / z: 435.1 [M+H] +

[0322] Example 74

[0323] The preparation method of compound I-67 in Example 67 is the same, except that the compound is used in the preparation of compound I-67. As raw material. MS(ESI) m / z: 479.1 [M+H] +

[0324] Example 75

[0325] The preparation method of compound I-67 in Example 67 is the same, except that 74 and 4-fluorobenzyl bromide are used as reactants, respectively. MS (ESI) m / z: 417.2 [M+H] +

[0326] Example 76

[0327] The preparation method of compound I-67 in Example 67 is the same, except that 74 and 4-chlorobenzyl bromide are used as raw materials, respectively. MS (ESI) m / z: 433.2 [M+H] +

[0328] Example 77

[0329] The preparation method of compound I-67 in Example 67 is the same, except that 74 and 4-bromobenzyl bromide are used as raw materials, respectively. MS (ESI) m / z: 477.1 [M+H] +

[0330] Example 78

[0331] The preparation method of compound I-67 in Example 67 is the same, except that 74 and 2-methyl-4-bromobenzyl bromide are used as raw materials, respectively. MS (ESI) m / z: 491.1 [M+H] +

[0332] Example 79

[0333] The preparation method of compound I-67 in Example 67 is the same, except that 74 and As raw material. MS(ESI) m / z: 415.2 [M+H] +

[0334] Example 80

[0335] Synthesis route:

[0336] (1) Dissolve 80 (1000 mg, 5 mmol) and 23 (751 mg, 5.5 mmol) in DCM (25 mL), add triethylamine (2 mL, 15 mmol), stir overnight at room temperature, and monitor the reaction by LCMS. After the reaction is complete, concentrate under vacuum to remove the solvent, wash the residue with saturated NaHCO3 / H2O solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 81 (1027 mg, yield 70%).

[0337] (2) Dissolve 81 (1027 mg, 3.5 mmol) in THF (10 mL) and slowly add it. t Buok's THF solution (4.0 mL, 1.0 M THF) was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by vacuum concentration. HCl / H₂O (3 M, 3 mL) was added to the yellow oil to give a yellow solid. The solid was filtered and then washed with water to give a grayish-white solid 82 (741 mg, yield 81%).

[0338] (3) Dissolve 82 (741 mg, 3 mmol) and guanidine hydrochloride 41 (373 mg, 3.9 mmol) in methanol (10 mL), add sodium methoxide (810 mg, 15 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 83 (492 mg, yield 64%).

[0339] (4) I-80 (256 mg, 1 mmol) and 4-trifluoromethylbenzyl bromide 37 (310 mg, 1.3 mmol) were dissolved in THF, and cesium carbonate (423 mg, 1.3 mg) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was completed, the reaction solution was diluted with dichloromethane and extracted with water, and the process was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain I-80 (103 mg, 25%). 1 H NMR (600MHz, DMSO-d6) δ7.90(s,1H),7.71(d,J=8.1Hz,2H),7.41(d,J=8.0Hz,2H),7.35(t,J=7 .5Hz,2H),7.30–7.22(m,3H),5.25(s,2H),4.56(s,2H),4.04(s,2H).MS(ESI)m / z:415.3[M+H] +

[0340] Example 81

[0341] Synthesis route:

[0342] (1) Dissolve 84 (1036 mg, 5 mmol) and diethyl oxalate 85 (804 mg, 5.5 mmol) in a 20% sodium ethoxide / ethanol solution (3 mL) and stir at room temperature for 2 hours. After the reaction is complete, concentrate under vacuum to remove volatiles, add water, stir for 5 minutes, and adjust the pH to 1 with 1N HCl aqueous solution. Filter the mixture under vacuum. Collect the solid, dry under vacuum overnight, and crystallize from ethanol to obtain 86 (980 mg, yield 75%).

[0343] (2) Dissolve 86 (980 mg, 4 mmol) and ammonium acetate (505 mg, 8 mmol) in ethanol (10 mL) and stir overnight at 78 °C. After the reaction is complete, concentrate under vacuum to remove volatiles and filter with ethyl acetate as solvent. Evaporate the filtrate and crystallize the resulting solid from ethanol to obtain 87 (698 mg, yield 67%).

[0344] (3) Dissolve 87 (698 mg, 3 mmol) and guanidine hydrochloride 41 (373 mg, 3.9 mmol) in methanol (10 mL), add sodium methoxide (810 mg, 15 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 88 (407 mg, yield 53%).

[0345] (4) I-81 (83 mg, 20%) was dissolved in THF (256 mg, 1 mmol) and 4-trifluoromethylbenzyl bromide 37 (310 mg, 1.3 mmol). Cesium carbonate (423 mg, 1.3 mg) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-81 (83 mg, 20%). MS (ESI) m / z: 415.7 [M+H] +

[0346] Example 82

[0347] Synthesis route:

[0348] (1) Dissolve 89 (4144 mg, 20 mmol) and triethylamine (3473 μL, 25 mmol) in DCM (50 mL), and slowly add 23 (3005 mg, 22 mmol) dropwise. React at room temperature for 6 hours. After the reaction is complete, concentrate under vacuum to remove volatiles, add water, extract with DCM, and repeat three times. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify by column chromatography (petroleum ether: ethyl acetate = 2:1) to give 90 (3980 mg, yield 62%).

[0349] (2) Dissolve 90 (3900 mg, 12.4 mmol) in tetrahydrofuran (30 mL) and add dropwise slowly. tBuOK's THF solution (14 mL, 1.0 M in THF) was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation and water was added. The mixture was extracted with DCM, and the reaction was repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:2) was used to purify 91a (2088 mg, yield 64%) and 91b (485 mg, yield 15%), respectively.

[0350] (3) Dissolve 91a (331 mg, 1.3 mmol) and guanidine hydrochloride 41 (163 mg, 1.7 mmol) in methanol (10 mL), add sodium methoxide (351 mg, 6.5 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 92 (211 mg, yield 60%).

[0351] (4) I-82 (211 mg, 0.8 mmol) and 4-trifluoromethylbenzyl bromide 37 (239 mg, 1 mmol) were dissolved in THF (5 mL), and cesium carbonate (339 mg, 1.3 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:2) was used to purify I-82 (86 mg, yield 25%). MS (ESI) m / z: 429.4 [M+H] +

[0352] Example 83

[0353] Synthesis route:

[0354] (1) Dissolve 91b (485 mg, 1.9 mmol) and guanidine hydrochloride 41 (238 mg, 2.5 mmol) in methanol (10 mL), add sodium methoxide (513 mg, 9.5 mmol), and stir the mixture at 80 °C for 24 h. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 93 (308 mg, yield 60%).

[0355] (2) I-83 (211 mg, 0.8 mmol) and 4-trifluoromethylbenzyl bromide 37 (239 mg, 1 mmol) were dissolved in THF (5 mL), and cesium carbonate (339 mg, 1.3 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-83 (86 mg, yield 25%). MS (ESI) m / z: 429.4 [M+H] +

[0356] Example 84

[0357] Synthesis route:

[0358] 49 (187 mg, 0.5 mmol) was dissolved in DCM (5 mL), and triethylamine (100 μL, 0.7 mmol) was added at 0 °C. 94 (98 mg, 0.7 mmol) was then slowly added, and the reaction was monitored by LC-MS until completion. After the reaction, the residue was washed with saturated NaHCO3 / H2O solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 2:1) yielded I-83 (163 mg, 77% yield). MS (ESI) m / z: 443.2 [M+H] +

[0359] Example 85

[0360] The preparation method of compound I-30 in Example 30 is the same, except that I-85 is obtained by reductive amination of compound 49 and tetrahydropyran-4-carboxaldehyde. MS (ESI) m / z: 437.2 [M+H] +

[0361] Example 86

[0362] Synthesis route:

[0363] (1) 49 (748 mg, 2 mmol), 95 (372 mg, 3 mmol), and DIPEA (525 μL, 3 mmol) were dissolved in DCM and stirred at room temperature for 2 h. Then, NaBH(OAc)3 (845 mg, 4 mmol) was slowly added to the system, and stirring was continued for 8 h. After the reaction was completed, water was added to quench the reaction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether: ethyl acetate = 1:1) was used to purify 96 (651 mg, yield 61%).

[0364] (2) I-86 (260 mg, 0.5 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added at 0 °C. The mixture was stirred for 1 hour. After the reaction was complete, saturated NaHCO3 was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (dichloromethane:methanol = 15:1) was used to purify I-86 (202 mg, yield 94%). MS (ESI) m / z: 436.2 [M+H] +

[0365] Example 87

[0366] Synthesis route:

[0367] I-86 (100 mg, 0.23 mmol), BrCN (53 mg, 0.5 mmol), and K₂CO₃ (83 mg, 0.6 mmol) were dissolved in CH₃CN and stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. I-87 (33 mg, 31% yield) was purified by column chromatography (dichloromethane:methanol = 20:1). MS (ESI) m / z: 461.2 [M+H] +

[0368] Example 88

[0369] The preparation method of compound I-30 in Example 30 is the same, except that I-88 is obtained by reductive amination of compound 49 and 4,4-difluorocyclohexylformaldehyde. 1H NMR (500MHz, Chloroform-d) δ7.66 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 5.37 (d, J = 16. 2Hz,1H),5.22(d,J=16.4Hz,1H),4.79(s,2H),3.49(s,2H),3.04(h,J=6.0Hz,1H),2.77–2. 64(m,1H),2.51(dd,J=12.5,7.0Hz,1H),2.35–2.21(m,2H),2.10(dtt,J=14.7,8.0,3.2Hz, 2H),1.97–1.83(m,2H),1.80–1.61(m,4H),1.07(d,J=6.5Hz,3H).MS(ESI)m / z:471.2[M+H] +

[0370] Example 89

[0371] The preparation method of compound I-30 in Example 30 is the same, except that I-89 is obtained by reductive amination of compound 49 and cyclopentylformaldehyde. 1 H NMR(500MHz,Chloroform-d)δ9.44(s,2H),7.56(d,J=7.9Hz,2H),7.41(d,J= 7.9Hz,2H),5.37–5.24(m,2H),4.42–3.57(m,3H),3.38(d,J=7.1Hz,1H),3.13 –2.61(m,3H),2.25(p,J=7.8Hz,1H),1.92(dp,J=12.2,6.3Hz,2H),1.73–1.5 3(m,4H),1.39(s,3H),1.24(tt,J=15.4,7.3Hz,2H).MS(ESI)m / z:421.3[M+H] +

[0372] Example 90

[0373] The preparation method of compound I-30 in Example 30 was followed, except that I-90 was obtained by reductive amination of compound 49 and cyclobutylformaldehyde. ¹H NMR (500 MHz, Chloroform-d) δ 8.27 (s, 2H), 7.59 (t, J = 6.6 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 5.19 (d, J = 25.3 Hz, 2H), 3.77 (d, J = 15.7 Hz, 1H), 3.62 (d, J = 16.0 Hz, 1H), 3.42 (s, 1H), 3.02–2.88 (m, 2H) ),2.89–2.80(m,1H),2.74(p,J=7.5Hz,1H),2.41(d,J=17.7Hz,1H),2.15(q,J=8.8,8.3Hz,2H) ,1.94(h,J=8.6,7.6Hz,1H),1.86–1.72(m,3H),1.22(d,J=6.2Hz,3H).MS(ESI)m / z:407.1[M+H] +

[0374] Example 91

[0375] The preparation method of compound I-30 in Example 30 is the same, except that I-91 is obtained by reductive amination of compound 49 and cyclopropylformaldehyde. MS (ESI) m / z: 393.2 [M+H] +

[0376] Example 92

[0377] The preparation method of compound I-30 in Example 30 was followed, except that I-92 was obtained by reductive amination of compound 49 with (3,3-difluorocyclobutyl)formaldehyde. MS (ESI) m / z: 443.2 [M+H] +

[0378] Example 93

[0379] The preparation method of compound I-30 in Example 30 was followed, except that I-93 was obtained by reductive amination of compound 49 with (3-fluoro-3'-methylcyclobutyl)formaldehyde. MS (ESI) m / z: 439.3 [M+H] +

[0380] Example 94

[0381] Synthesis route:

[0382] (1) Dissolve 96 (2130 mg, 10 mmol), 97 (1560 mg, 13 mmol), and DIPEA (2620 μL, 15 mmol) in DCM (40 mL) and stir at room temperature for 2 h. Then, slowly add NaBH(OAc)3 (4230 mg, 20 mmol) to the system and continue stirring for 6 h. After the reaction is complete, quench with water, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Purify by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 98 (1740 mg, yield 55%).

[0383] (2) Dissolve 98 (1740 mg, 5.5 mmol) and guanidine hydrochloride 41 (790 mg, 8.0 mmol) in methanol (30 mL), add sodium methoxide (1485 mg, 27 mmol), and stir the mixture overnight at 80 °C. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by slurrying with ethyl acetate to obtain 99 (1126 mg, yield 72%).

[0384] (3) 99 (100 mg, 0.35 mmol) and 100 (135 mg, 0.55 mmol) of 1-(bromomethyl)-4-trifluoromethylcyclohexane were dissolved in DMF, and cesium carbonate (180 mg, 0.55 mmol) was added. The mixture was stirred at 80 °C for 4 h, and the reaction was monitored by LCMS to indicate completion. After the reaction was complete, the reaction solution was diluted with ethyl acetate and extracted with water. The organic phases were combined and washed three times with saturated NaCl solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-94 (39 mg, yield 25%). MS (ESI) m / z: 449.1 [M+H] +

[0385] Example 95

[0386] The preparation method of compound I-94 in Example 94 was followed, except that I-95 was obtained by a substitution reaction between compound 99 and 1-(bromomethyl)-4,4-difluorocyclohexane. MS (ESI) m / z: 417.2 [M+H] +

[0387] Example 96

[0388] The preparation method of compound I-95 in Example 95 is the same, except that I-96 is obtained by a substitution reaction between compound 99 and 1-(bromomethyl)-4-fluorocyclohexane. MS (ESI) m / z: 339.2 [M+H] +

[0389] Example 97

[0390] The preparation method of compound I-95 in Example 95 was followed, except that I-97 was obtained by a substitution reaction between compound 99 and 4-fluorobenzyl bromide. MS (ESI) m / z: 393.0 [M+H] +

[0391] Example 98

[0392] The preparation method of compound I-95 in Example 95 is the same, except that I-98 is obtained by a substitution reaction between compound 99 and 4-chlorobenzyl bromide. 1 H NMR(500MHz,Chloroform-d)δ7.37(d,J=8.5Hz,2H),7.23(d,J=8.2Hz,2H),5.25( d,J=16.1Hz,1H),5.13(d,J=16.1Hz,1H),4.24(s,2H),3.51(s,2H),3.11(h,J=6. 2Hz,1H),2.83–2.66(m,4H),2.63(dd,J=12.6,7.4Hz,1H),2.52–2.38(m,1H),2.3 6–2.20(m,3H),1.33–1.24(m,1H),1.12(d,J=6.6Hz,3H).MS(ESI)m / z:409.4[M+H] +

[0393] Example 99

[0394] The preparation method of compound I-95 in Example 95 is the same, except that I-99 is obtained by a substitution reaction between compound 99 and 4-bromobenzyl bromide. MS (ESI) m / z: 453.1 [M+H] +

[0395] Example 99

[0396] Synthesis route:

[0397] (1) Dissolve 101 (2000 mg, 7 mmol) and guanidine hydrochloride 41 (870 mg, 9 mmol) in methanol (30 mL), add sodium methoxide (1890 mg, 35 mmol), and stir the mixture overnight at 80 °C. Monitor the reaction completion by LCMS. After the reaction is complete, dilute the reaction solution with dichloromethane and extract with water, repeating the process three times. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate. Purify by slurrying with ethyl acetate to obtain 102 (1800 mg, yield 92%).

[0398] (2) 102 (840 mg, 3 mmol) and 4-trifluoromethylbenzyl bromide 37 (956 mg, 4 mmol) were dissolved in THF, and cesium carbonate (1300 mg, 4 mmol) was added. The mixture was stirred overnight at 80 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with dichloromethane and extracted with water, repeated three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 3:1) was used to purify 103 (512 mg, yield 39%).

[0399] (3) Dissolve 103 (3017 mg) in ethyl acetate solution of hydrochloric acid (2.0 M, 10 mL), stir at room temperature, and monitor the reaction by LCMS. After the reaction is complete, remove the solvent by rotary evaporation to obtain 104, which can be used directly in the next step.

[0400] (4) 104 (112 mg, 0.3 mmol), benzaldehyde (42 mg, 0.4 mmol), and DIPEA (87 μL, 0.5 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 2 h. Then, NaBH(OAc)3 (127 mg, 0.6 mmol) was slowly added to the system, and stirring was continued for 4 h. After the reaction was complete, water was added to quench the reaction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether:ethyl acetate = 1:1) was used to purify I-100 (85 mg, yield 66%). 1 H NMR (600MHz, DMSO-d6) δ7.72(d,J=8.0Hz,2H),7.40(d,J=7.9Hz,2H),7.34–7.28(m,5H),7.27–7.20(m,1H),6.96(s,2H),5.2 2(s,2H),3.61(s,2H),3.59–3.55(m,1H),2.87–2.83(m,1H),2.69–2.60(m,2H),1.63–1.55(m,1H).MS(ESI)m / z:429.3[M+H] +

[0401] Example 101

[0402] The preparation method of compound I-100 in Example 100 was followed, except that 3-fluorobenzaldehyde was used instead of benzaldehyde in the reductive amination reaction to obtain I-101. MS (ESI) m / z: 447.2 [M+H] +

[0403] Example 102

[0404] The preparation method of compound I-100 in Example 100 was followed, except that 3-cyanobenzaldehyde was used instead of benzaldehyde in the reductive amination reaction to obtain I-102. MS (ESI) m / z: 454.2 [M+H] +

[0405] Example 103

[0406] The preparation method of compound I-100 in Example 100 was followed, except that 4-fluorobenzyl bromide was used instead of 4-trifluoromethylbenzyl bromide in a substitution reaction to obtain I-103. MS (ESI) m / z: 397.3 [M+H] +

[0407] Example 104

[0408] The preparation method of compound I-100 in Example 100 was followed, except that 4-chlorobenzyl bromide was used instead of 4-trifluoromethylbenzyl bromide in a substitution reaction to obtain I-104. MS (ESI) m / z: 413.1 [M+H] +

[0409] Example 105

[0410] The preparation method of compound I-100 in Example 100 was followed, except that 4-bromobenzyl bromide was used instead of 4-trifluoromethylbenzyl bromide in a substitution reaction to obtain I-105. MS (ESI) m / z: 458.3 [M+H] +

[0411] Comparative Example 1

[0412] Comparative Example 1 provides two compounds, ONC201 and ONC212; ONC201 and ONC212 were synthesized according to the method described in CN104860948B.

[0413] Experimental Example 1

[0414] The compound's agonistic activity against HsClpP protease

[0415] The HsClpP protein can recognize and cleave the substrate AC-WLA-AMC, and the cleaved substrate shows detectable AMC signals at 355 nm and 460 nm. HsClpP protein was diluted to a final concentration of 0.7 μM with buffer (50 mM Tris-2HCl pH 8, 10 mM MgCl2, 100 mM KCl, 1 mM DTT, 5% glycerol, 0.02% Triton X-100), and AC-WLA-AMC was diluted to a final concentration of 100 μM. In a 384 black-background plate, 20 μL of HsClpP protein was added first, followed by 10 μL of the compound (final concentration 20 μM, serially diluted 3-fold to 11 concentrations; ONC201 and ONC212 were used as positive controls). After mixing, the mixture was incubated at room temperature for 10 minutes. Finally, 20 μL of AC-WLA-AMC was added. Fluorescence signals were detected at wavelengths of 355 nm and 460 nm using a multi-functional microplate reader. After detection, the plates were sealed and incubated at 37°C. The obtained data were processed using a GraphPad Prism8.

[0416] Experiment Example 2

[0417] The proliferation inhibitory activity of the modified compound was evaluated in the OCI-LY10 cell line.

[0418] 80 μL of cells (10,000 to 20,000 cells per well) were seeded into 96-well plates. After 0.5 hours of incubation, 20 μL of 0.02% DMSO or different concentrations of the test compound were added to the cells (ONC212 was used as a positive control), and incubation continued for 72 hours. CellTiter was used for analysis. Cell viability was determined using the AQueous non-radioactive cell proliferation assay kit (MTS; Promega, Madison, Wisconsin). 20 μL of MTS mixture (containing tetramethylbenzidine MTT) was added to each well of a 96-well plate and incubated at 37°C for 2 to 4 hours. Optical density at 490 nm was measured using a SpectraMax 340 microplate reader (Molecular Devices, Sunnyvale, CA, USA) (background values ​​were measured at 690 nm and subtracted from the reading). The growth inhibition rate was calculated as: % = [1 - (OD)] Compound –OD blank ) / (OD DMSO –OD blank The resulting data was processed using GraphPad Prism8 and is shown in Table 1. Note: In Table 1, "A" indicates EC. 50 or IC 50Less than 100 nM; "B" indicates EC 50 or IC 50 Between 100-1000 nM; "C" indicates EC 50 or IC 50 Between 1000-5000 nM; "D" indicates EC 50 or IC 50 Greater than 5000 nM.

[0419] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

A compound of Formula I, its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: R 1 Selected from substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted five- to ten-membered heterocycloalkyl groups containing one to three heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to fourteen-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, wherein "substituted" means that the group can be selected from 1 to 6 atoms selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 3-6 Substituents of cycloalkyl groups; R 2 Selected from hydrogen, C 1-6 Alkyl, carbonyl, halogen, cyano, amino, carboxyl, hydroxyl; Z is selected from either straight chain or branched chain C. 1-6 Alkylene, deuterated straight-chain or branched C 1-6 Alkylene, -NRaC 1-6 Alkylene, wherein the substituent Ra is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 1-6 Alkyl carbonyl; L is selected from single bonds and methylene groups; X is selected from methylene, carbonyl, and ethylene; Y is selected from C and N; R 3 Selected from substituted or unsubstituted C 6-14 C of aryl linear or branched chains 1-6 Alkylene, substituted or unsubstituted C 3-10 Cycloalkyl straight-chain or branched C 1-6 Alkylene, substituted or unsubstituted, five- to ten-membered heterocyclic alkyl groups containing one to three heteroatoms selected from N, O, and S, either straight-chain or branched. 1-6 Alkylene, substituted or unsubstituted, five- to fourteen-membered heteroaryl straight-chain or branched C-type compounds containing one to three heteroatoms selected from N, O, and S. 1-6 Alkylene, wherein "substituted" means that the group can be selected from 1 to 6 groups selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 3-6 Substitution with cycloalkyl groups or -NRbRb', wherein Rb and Rb' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl; R 4 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, hydroxyl, carboxyl, amino, cyano, hydrazine (-NHNH2), amino C 1-6 Alkylene, C 1-6 Alkylamino, thiocyl C 1-6 Alkyl (-SC) 1-6 Alkyl), C 1-6 alkylsulfinyl (-SOC) 1-6 Alkyl), C 1-6 alkylsulfonyl (-SO2C) 1-6 alkyl). The compound of Formula I according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, are characterized in that: Preferably, R 1 Selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 5-8 Cycloalkyl, substituted or unsubstituted five- to eight-membered heterocycloalkyl groups containing one to three heteroatoms selected from N, O, and S, or substituted or unsubstituted five- to ten-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, wherein "substituted" means that the group can be selected from one to three atoms selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-4 alkylsulfonyl (-SO2C) 1-4 Alkyl), C 3-6 Substituents of cycloalkyl groups; Preferably, R 1 Selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 5-6 Cycloalkyl, substituted or unsubstituted five- to eight-membered heterocycloalkyl groups containing one to three heteroatoms selected from N and O, or substituted or unsubstituted five- to ten-membered heteroaryl groups containing one to three heteroatoms selected from N, O, and S, wherein "substituted" means that the group can be selected from one to three atoms selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 Alkyl), C 3-6 Substituents of cycloalkyl groups; Preferably, R 2 Selected from hydrogen atoms, C 1-4 Alkyl, carbonyl; More preferably, R 2 Selected from hydrogen atoms, methyl, ethyl, n-propyl, isopropyl, and carbonyl groups; Preferably, Z is selected from linear or branched C. 1-3 Alkylene, deuterated straight-chain or branched C 1-3 Alkylene, -NRaC 1-3 Alkylene, wherein the substituent Ra is selected from hydrogen atom, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 alkyl); Preferably, Z is selected from methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), deuterated methylene (-CH2-), deuterated ethylene (-CH2CH2-), deuterated propylene (-CH2CH2CH2-), -CH(CH3)-, -NRa(CH2)-, -NRa(CH2CH2)-, -NRa(CH2CH2CH2)-, wherein the substituent Ra is selected from hydrogen atom, -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl; Preferably, R 3 Selected from substituted or unsubstituted C 6-10 C of aryl linear or branched chains 1-4 Alkylene, substituted or unsubstituted C 3-8 Cycloalkyl straight-chain or branched C 1-4 Alkylene, substituted or unsubstituted, five- to ten-membered heterocyclic alkyl groups containing one to three heteroatoms selected from N, O, and S, either straight-chain or branched. 1-4 Alkylene, substituted or unsubstituted, five- to ten-membered heteroaryl straight-chain or branched C-type compounds containing one to three heteroatoms selected from N, O, and S. 1-4 Alkylene, wherein "substituted" means that the group can be selected from 1 to 3 groups selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 Substitution of alkyl groups and -NRbRb', wherein Rb and Rb' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl; Preferably, R 3 Selected from substituted or unsubstituted C 6-10 C of aryl linear or branched chains 1-3 Alkylene, substituted or unsubstituted C 5-6 Cycloalkyl straight-chain or branched C 1-3 Alkylene, substituted or unsubstituted, five- to ten-membered heterocyclic alkyl groups containing one to two heteroatoms selected from N and O, either straight-chain or branched. 1-3 Alkylene, substituted or unsubstituted, five- to ten-membered heteroaryl straight-chain or branched C-type compounds containing one to two heteroatoms selected from N and O. 1-3 Alkylene, wherein "substituted" means that the group can be selected from 1 to 3 groups selected from hydrogen, halogen, cyano, amino, carboxyl, hydroxyl, carbonyl, C 1-3 Alkyl, C 1-3 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-3 Alkoxy, C 1-3 alkylsulfonyl (-SO2C) 1-3 Substitution of alkyl groups and -NRbRb', wherein Rb and Rb' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl; Preferably, R 4 Selected from hydrogen atoms, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, hydroxyl, carboxyl, amino, cyano, hydrazine (-NHNH2), amino C 1-4 Alkylene, C 1-4 Alkylamino, thiocyl C 1-4 Alkyl (-SC) 1-4 Alkyl), C 1-4 alkylsulfinyl (-SOC) 1-4 Alkyl), C 1-4 alkylsulfonyl (-SO2C) 1-4 alkyl); Preferably, R 4 Selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxy, carboxyl, amino, cyano, hydrazine (-NHNH2), aminomethylene (-CH2NH2), aminoethylidene (-CH2 CH2NH2), aminon-propylidene (-CH2CH2CH2NH2), aminoisopropylidene (-C(CH3)2NH2), methylamino (-NHCH3), ethylamino (-NHCH2CH3), n-propylamino (-NHCH2CH2CH3), isopropylamino (-NHCH(CH3)2). The compound of Formula I according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, are characterized in that: It is represented by the following equation I-1: Among them, the substituents Z, Y, X, L, R 2 R 3 and R 4 The definition is the same as in Equation I above; Ring A is a saturated or unsaturated six-membered ring, selected from C. 6-14 Aryl, C 3-10 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N, O and S, and five- to fourteen-membered heteroaryl containing one to three heteroatoms selected from N, O and S; R 11 Selected from hydrogen atom, halogen, cyano group, amino group, carboxyl group, hydroxyl group, carbonyl group, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkoxy, C 1-6 alkylsulfonyl (-SO2C) 1-6 Alkyl), C 3-6 cycloalkyl; n1 is an integer selected from 0 to 4, preferably an integer of 0, 1, 2 or 3; Preferably, ring A is a saturated or unsaturated six-membered ring A, selected from C 6-10 Aryl, C 5-8 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one to three heteroatoms selected from N and O; Preferably, ring A is a saturated or unsaturated six-membered ring A, selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, five- to ten-membered heterocyclic alkyl containing one or two heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one or two heteroatoms selected from N and O. Preferably, R 11 Selected from hydrogen atom, halogen, cyano group, C 1-4 Alkyl, C 1-4 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-4 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-4 Alkoxy, C 1-4 alkylsulfonyl (-SO2C) 1-4 alkyl); Preferably, R 11 Selected from hydrogen atom, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, pentafluoropropoxy, hexafluoropropoxy, perfluoropropoxy, methylsulfonyl (-SO2CH3), ethylsulfonyl (-SO2CH2CH3), n-propylsulfonyl (-SO2CH2CH2CH3), isopropylsulfonyl (-SO2CH(CH3)2). The compound of Formula I according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, are characterized in that: It is represented by the following equation I-2: Among them, the substituents Z, Y, X, L, R 1 R 2 and R 4 The definition is the same as in Equation I above; Z1 is selected from C of either straight chain or branched chain. 1-6 Alkylene; Ring B is selected from C 6-14 Aryl, C 3-10 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N, O and S, and five- to fourteen-membered heteroaryl containing one to three heteroatoms selected from N, O and S; R 33 Selected from hydrogen atom, halogen, cyano group, amino group, carboxyl group, hydroxyl group, carbonyl group, C 1-6 Alkyl, C 1-6 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-6 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-6 Substitution with alkoxy groups or -NRcRc', wherein Rc and Rc' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl; n3 is an integer selected from 0 to 4, preferably an integer of 0, 1, 2 or 3; Preferably, Z1 is selected from linear or branched C. 1-4 Alkylene; Preferably, Z1 is selected from methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2-); Preferably, ring B is selected from C. 6-10 Aryl, C 5-8 Cycloalkyl, five- to ten-membered heterocycloalkyl containing one to three heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one to three heteroatoms selected from N and O; Preferably, ring B is selected from phenyl, naphthyl, five- to ten-membered heterocyclic alkyl containing one or two heteroatoms selected from N and O, and five- to ten-membered heteroaryl containing one or two heteroatoms selected from N and O; Preferably, R 33 Selected from hydrogen atom, halogen, cyano group, amino group, carboxyl group, hydroxyl group, carbonyl group, C 1-4 Alkyl, C 1-4 Alkoxy groups, halocarbons containing 1 to 3 halogen atoms 1-4 Alkyl groups, halocarbons containing 1 to 3 halogen atoms 1-4 Substitution with alkoxy groups or -NRcRc', wherein Rc and Rc' are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-3 alkyl; Preferably, R 33 Selected from hydrogen atom, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monomethylamino, dimethylamino, monoethylamino, diethylamino. According to any one of claims 1 to 4, the compounds represented by Formula I, Formula I-1 and Formula I-2, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, are characterized in that: Its origin Equation II represents the following: Among them, the substituents Z, Z1, Y, X, L, R 1 R 2 R 3 R 4 R 11 and R 33 The definitions of subscripts n1 and n3 are the same as those in Equations I, I-1 and I-2 above. The compounds, stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts thereof of Formula I, I-1, I-2, and II according to any one of claims 1 to 5 are characterized in that: It is selected from the following structures: A pharmaceutical composition comprising a compound of any one of formulas I, I-1, I-2 and II according to any one of claims 1 to 6, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. Use of the compounds of Formula I, Formula I-1, Formula I-2 and Formula II, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 7, in the preparation of HsClpP agonists, according to any one of claims 1 to 6. Use of the compounds of Formula I, Formula I-1, Formula I-2 and Formula II, their stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, according to any one of claims 1 to 6, in the preparation of medicaments for treating and / or preventing diseases mediated by HsClpP. Preferably, the diseases mediated by HsClpP include HsClpP-mediated neurological diseases, metabolic syndromes, and tumors, such as acute myeloid leukemia, diffuse large B-cell lymphoma, and glioma. A method for treating a disease mediated by HsClpP, the method comprising administering to a subject in need a compound of formula I, formula I-1, formula I-2 and formula II, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof.

Images