Saturated heterocyclic compound as well as preparation method and application thereof

Abstract

The invention provides a saturated heterocyclic compound as well as a preparation method and application thereof. Specifically, the method provided by the invention provides a compound as shown in a formula I, and an isomer, hydrate or solvate or pharmaceutically acceptable salt or ester thereof, the compound has a structure as shown in the following formula, and X, Y, Z, m, n, R1 and R2 are defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and in particular, relates to a saturated heterocyclic compound and a preparation method and use thereof. Background Art

[0002] ClpP is a highly conserved serine protease that is widely present in prokaryotes and eukaryotes. Human serine hydrolase ClpP is strictly localized in the mitochondrial matrix, promptly removing erroneous or abnormal proteins produced by stress in the mitochondria, and plays an important role in maintaining mitochondrial protein homeostasis. Disrupting the function of ClpP through small molecule regulators can cause homeostasis disorders of the respiratory chain complex, inhibit OXPHOS function, and thus cause protein toxicity stress and cell death. Bacterial ClpP is usually associated with AAA + The family's molecular chaperone ClpX binds to form the ClpXP protease complex, which unfolds abnormal or misfolded protein substrates in bacteria and then transfers the substrate molecules to the hydrolysis cavity of the ClpP protease for degradation, regulating the stability and activity of protein functions in bacteria, thereby affecting a variety of bacterial biological functions.

[0003] ClpP regulators can be divided into ClpP small molecule inhibitors and agonists. ClpP inhibitors can occupy the binding pocket of ClpP and the chaperone protein ClpX, thereby inhibiting ClpXP from performing normal biological functions. Studies have shown that ClpP small molecule inhibitors can affect the formation of bacterial biofilms and change the sensitivity of bacteria to temperature and oxygen content. ClpP small molecule agonists can trigger the remodeling of the ClpP protease complex structure, rearrange the core structure of the ClpP protease, deviate the protein from the regulation of the normal mechanism, and degrade certain functional proteins in the cell in large quantities. Studies have shown that ClpP small molecule agonists can inhibit bacterial growth. ClpP regulators can effectively kill acute myeloid leukemia cells under the premise of maintaining normal cell homeostasis. It also has application value for pancreatic cancer, leukemia, intestinal cancer and other tumors as well as bacterial infections.

[0004] Therefore, there is an urgent need in the art to develop novel small molecule regulators of ClpP. Summary of the invention

[0005] The purpose of the present invention is to provide a novel ClpP small molecule regulator.

[0006] In the first aspect of the present invention, there is provided a compound of formula I, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, having the following structure:

[0007]

[0008] in,

[0009] X is selected from the following group: O, S, Se, CH 2 or NH;

[0010] Y is selected from the group consisting of N or CH;

[0011] Z is selected from the following group: -CH 2 -CH 2 -、-CH(NHFmoc)-CH 2 -、-CH=CH-、-CH 2 -CH 2 -NH-

[0012] (Methylene end and R 2 Connected), -CH 2 -NH-(methylene end and R 2 Connected), -CH 2 -O-(O terminal and R 2 connected);

[0013] m, n are each independently selected from the following group: 0, 1, 2, 3, 4 or 5; and is a 4-9 membered ring;

[0014] R 1 Selected from the following group: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-4 heteroatoms selected from N, O, S and C6-C10 aryl; substituted or unsubstituted C4-C14 heterocycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 cycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S and C5-C10 cycloalkyl;

[0015] R 2is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, C1-C10 alkyl having 1-4 heteroatoms selected from N, S and O, C2-C6 alkenyl having 1-4 heteroatoms selected from N, S and O, 5-C10 alkyl having 1-3 heteroatoms selected from N, S and O -10-membered heterocyclic group, 5-8-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 4-8-membered heterocyclic group having 1-3 heteroatoms selected from N, O, and S and C6-C10 aryl, substituted or unsubstituted 4-8-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S and C6-C10 aryl, -NRbRc, wherein Rb and Rc are each independently H, C1-C4 alkyl, or Rb, Rc and the nitrogen atom to which they are connected together form a 5-10-membered heterocyclic ring;

[0016] Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3 or 4) substituents selected from the following groups: halogen, deuterated, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, amino, nitro, hydroxyl.

[0017] In another preferred embodiment, the C1-C4 haloalkyl group is a C1-C4 fluoroalkyl group.

[0018] In another preferred embodiment, R 1 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, wherein the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, nitro, C1-C6 alkyl, C1-C4 alkoxy.

[0019] In another preferred embodiment, R 1 Select from the following group:

[0020]

[0021] In another preferred embodiment, R 1 The term "substituted" refers to substituted or unsubstituted C6-C14 aryl, wherein the aryl is substituted by one or more (eg, 2, 3 or 4) substituents selected from the group consisting of halogen, C1-C4 haloalkyl.

[0022] In another preferred embodiment, R 2 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, cyano, nitro.

[0023] In another preferred embodiment, R 2 Select from the following group:

[0024]

[0025] In another preferred embodiment, R 2 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following groups: halogen, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, cyano.

[0026] In another preferred embodiment, the compound of formula I is selected from the following group:

[0027]

[0028]

[0029] The second aspect of the present invention provides a compound of formula II, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, having the following structure:

[0030]

[0031] Wherein, X is selected from the following group: O, S, Se, CH 2 or NH;

[0032] Y is selected from the group consisting of: -NH- or -CH 2 -;

[0033] Z is selected from the following group: -CH 2 -, -NH-, -CH=CH-;

[0034] m, n are each independently selected from the following group: 0, 1, 2, 3, 4 or 5; and is a 4-9 membered ring;

[0035] R 1 Selected from the following group: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-4 heteroatoms selected from N, O, S and C6-C10 aryl; substituted or unsubstituted C4-C14 heterocycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 cycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S and C5-C10 cycloalkyl;

[0036] R 2 is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, C1-C10 alkyl having 1-4 heteroatoms selected from N, S and O, C2-C6 alkenyl having 1-4 heteroatoms selected from N, S and O, 5-C10 alkyl having 1-3 heteroatoms selected from N, S and O -10-membered heterocyclic group, 5-8-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 4-8-membered heterocyclic group having 1-3 heteroatoms selected from N, O, and S and C6-C10 aryl, substituted or unsubstituted 4-8-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S and C6-C10 aryl, -NRbRc, wherein Rb and Rc are each independently H, C1-C4 alkyl, or Rb, Rc and the nitrogen atom to which they are connected together form a 5-10-membered heterocyclic ring;

[0037] Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3 or 4) substituents selected from the following groups: halogen, deuterated, oxo (=O), carboxyl, phenyl, N,N-dimethylamino, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C8 cycloalkyl, a 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, cyano, amino, nitro, hydroxyl, thiol, and C1-C6 sulfone.

[0038] In another preferred embodiment, the C1-C4 haloalkyl group is a C1-C4 fluoroalkyl group.

[0039] In another preferred embodiment, R 1Selected from the following groups: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, wherein the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, nitro, C1-C6 alkyl, C1-C4 alkoxy.

[0040] In another preferred embodiment, R 1 Select from the following group:

[0041]

[0042] In another preferred embodiment, R 1 The term "substituted" refers to substituted or unsubstituted C6-C14 aryl, wherein the aryl is substituted by one or more (eg, 2, 3 or 4) substituents selected from the group consisting of halogen, C1-C4 haloalkyl.

[0043] In another preferred embodiment, R 2 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, cyano, nitro.

[0044] In another preferred embodiment, R 2 Select from the following group:

[0045]

[0046] In another preferred embodiment, R 2 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, wherein the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, cyano.

[0047] In another preferred embodiment, the compound of formula II is selected from the following group:

[0048]

[0049]

[0050] The third aspect of the present invention provides a compound of formula III, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, having the following structure:

[0051]

[0052] in,

[0053] Y is selected from the group consisting of N or CH;

[0054] Z is selected from the following group: -CH 2 -O-CH 2 -、-NH-CH 2 -CH 2 -(methylene end and R 2 connected);

[0055] m, n are each independently selected from the following group: 0, 1, 2, 3, 4 or 5; and is a 4-9 membered ring;

[0056] R 1 Selected from the following group: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-4 heteroatoms selected from N, O, S and C6-C10 aryl; substituted or unsubstituted C4-C14 heterocycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 cycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S and C5-C10 cycloalkyl;

[0057] R 2is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, C1-C10 alkyl having 1-4 heteroatoms selected from N, S and O, C2-C6 alkenyl having 1-4 heteroatoms selected from N, S and O, 5-C10 alkyl having 1-3 heteroatoms selected from N, S and O -10-membered heterocyclic group, 5-8-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 4-8-membered heterocyclic group having 1-3 heteroatoms selected from N, O, and S and C6-C10 aryl, substituted or unsubstituted 4-8-membered heteroaryl having 1-3 heteroatoms selected from N, O, and S and C6-C10 aryl, -NRbRc, wherein Rb and Rc are each independently H, C1-C4 alkyl, or Rb, Rc and the nitrogen atom to which they are connected together form a 5-10-membered heterocyclic ring;

[0058] Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3 or 4) substituents selected from the following groups: halogen, deuterated, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, amino, nitro, hydroxyl.

[0059] In another preferred embodiment, the C1-C4 haloalkyl group is a C1-C4 fluoroalkyl group.

[0060] In another preferred embodiment, R 1 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, wherein the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, nitro, C1-C6 alkyl, C1-C4 alkoxy.

[0061] In another preferred embodiment, R 1 Select from the following group:

[0062]

[0063] In another preferred embodiment, R 1 The term "substituted" refers to substituted or unsubstituted C6-C14 aryl, wherein the aryl is substituted by one or more (eg, 2, 3 or 4) substituents selected from the group consisting of halogen, C1-C4 haloalkyl.

[0064] In another preferred embodiment, R 2 Selected from the following groups: substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, nitro.

[0065] In another preferred embodiment, R 2 Select from the following group:

[0066]

[0067] In another preferred embodiment, R 2 Selected from the following group: substituted or unsubstituted C6-C14 aryl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, wherein the "substituted" refers to replacement by one or more (e.g. 2, 3 or 4) substituents selected from the following group: halogen, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 haloalkoxy.

[0068] In another preferred embodiment, the compound of formula III is selected from the following group:

[0069]

[0070] The fourth aspect of the present invention provides a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of one or more compounds as described in the first aspect, the second aspect, or the third aspect of the present invention, their isomers, hydrates, or solvates, or pharmaceutically acceptable salts or esters; (2) a pharmaceutically acceptable carrier or excipient; and (3) a second therapeutic agent, wherein the second therapeutic agent is an anti-tumor drug or an anti-infective drug.

[0071] In another preferred embodiment, the second therapeutic agent is selected from the following group: bortezomib, gemcitabine, kinase inhibitors, mitochondrial respiratory chain inhibitors, quinolone antibiotics, penicillin antibiotics, cephalosporin antibiotics, cephamycin antibiotics, monocyclic β-lactam antibiotics, oxycephalosporin antibiotics, β-lactamase inhibitors and combined preparations of β-lactam antibiotics and β-lactamase inhibitors, carbapenem antibiotics, aminoglycoside antibiotics, fluoroquinolone antibiotics, macrolide antibiotics, vancomycin and other glycopeptide antibiotics, tetracycline and chloramphenicol antibiotics, lincomycin and clindamycin, polypeptide antibiotics, rifamycin antibiotics, sulfonamides, nitroimidazoles, furan antibiotics and other commonly used antibiotics, or a combination thereof.

[0072] The fifth aspect of the present invention provides a pharmaceutical composition, which comprises: (1) a therapeutically effective amount of one or more compounds as described in the first aspect, the second aspect, or the third aspect of the present invention, or their isomers, hydrates, or solvates, or pharmaceutically acceptable salts or esters.

[0073] The sixth aspect of the present invention provides a compound as described in the first aspect, the second aspect, or the third aspect of the present invention, and its isomers, hydrates or solvates, or pharmaceutically acceptable salts or esters for use in preparing a pharmaceutical composition for preventing and / or treating diseases or conditions associated with ClpP protease activity or expression.

[0074] In another preferred embodiment, the disease or condition related to the activity or expression of ClpP protease is a disease or condition caused by infection.

[0075] In another preferred embodiment, the disease or disorder is a disease associated with abnormal proliferation, including but not limited to hyperproliferation, carcinoma in situ, tumor and metastasis.

[0076] In another preferred embodiment, the disease or condition is cancer.

[0077] In another preferred embodiment, the cancer is selected from glioma, solid tumor, leukemia, or a combination thereof.

[0078] In another preferred embodiment, the solid tumor is selected from the group consisting of renal cancer, liver cancer, prostate cancer, melanoma, colon cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, gastric cancer, brain cancer, rectal cancer, melanoma, ovarian cancer, or a combination thereof.

[0079] In another preferred embodiment, the infection is a bacterial infection.

[0080] In another preferred embodiment, the bacterial infection is a Gram-positive bacterial infection.

[0081] In another preferred embodiment, the bacteria are Gram-positive bacteria: preferably, the bacteria are selected from the following group: Staphylococcus, methicillin-resistant Staphylococcus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Streptococcus pyogenes.

[0082] In another preferred embodiment, the bacterial infection is a Gram-negative bacterial infection.

[0083] In another preferred embodiment, the bacteria are Gram-positive bacteria: preferably, the bacteria are selected from the following group: Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella dysenteriae, Klebsiella pneumoniae, Brucella, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella, Pasteurella, Vibrio cholerae, and Vibrio parahaemolyticus.

[0084] In another preferred embodiment, the infection can be caused by one or more bacteria simultaneously.

[0085] In another preferred embodiment, the treatment comprises using the pharmaceutical composition alone or in combination with commonly used antibacterial drugs.

[0086] The seventh aspect of the present invention provides a method for preparing the compound as described in the first aspect, the second aspect, or the third aspect of the present invention, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, comprising the steps of:

[0087] (A-3) Compound I3 undergoes an isocyanate reaction with an isocyanate reagent or a condensation reaction with a carboxylic acid derivative to obtain Compound I:

[0088]

[0089] Where Y is N, R 1 , R 2 , m, n, X, and Z are as defined in the first aspect of the present invention;

[0090] or,

[0091] (B-3) Compound II3 undergoes an isocyanate reaction with an isocyanate reagent or a condensation reaction with a carboxylic acid derivative to obtain Compound II:

[0092]

[0093] Where Y is NH, R 1 , R 2 , m, n, X, and Z are as defined in the second aspect of the present invention;

[0094] or,

[0095] (C-3) Compound III3' or III2" undergoes nucleophilic substitution reaction with a halogenated alkane reagent to obtain compound III:

[0096]

[0097] Wherein, Y is CH and Z is -CH 2 -O-CH 2 - or -NH-CH 2 -CH 2 -(methylene end and R 2 connected), R 1 , R 2 The definitions of , m, and n are as described in the third aspect of the present invention.

[0098] In another preferred embodiment, the I3 compound is prepared by deprotecting the I2 compound:

[0099]

[0100] In another preferred embodiment, the I2 compound is prepared by a nucleophilic substitution reaction between the I1 compound and a halogenated alkane:

[0101]

[0102] In another preferred embodiment, the II3 compound is prepared by deprotecting the II2 compound:

[0103]

[0104] In another preferred embodiment, the II2 compound is prepared by a nucleophilic substitution reaction between the II1 compound and a halogenated alkane:

[0105]

[0106] In another preferred embodiment, the III3' compound is prepared by deprotecting the III2' compound:

[0107]

[0108] In another preferred embodiment, the III2' compound is prepared by substitution of the III1' compound:

[0109]

[0110] In another preferred embodiment, the III2" compound is prepared by substitution of the III1" compound:

[0111]

[0112] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0113] The inventors have conducted extensive and in-depth research and developed a novel ClpP regulator for the first time through a large number of screenings. Based on the molecular recognition mechanism between small molecules and ClpP protein, the inventors have discovered a class of ClpP regulators that are completely different in structure from existing ClpP regulating small molecules and have excellent regulatory effects. On this basis, the present invention was completed.

[0114] the term

[0115] As used herein, the term "alkyl" includes straight or branched alkyl groups. For example, C1-C6 alkyl groups represent straight or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0116] As used herein, the term "alkylene" refers to a linear or branched alkane with two bonds substituted, for example, C1-C4 alkylene represents a linear or branched C1-C4 alkane with two bonds substituted, such as methylene, ethylene, n-propylene, isopropylene, butylene, etc.

[0117] As used herein, the term "alkenyl" includes straight or branched alkenyls. For example, C2-C6 alkenyl refers to a straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

[0118] As used herein, the term "alkynyl" includes straight or branched alkynyl groups. For example, C2-C6 alkynyl refers to a straight or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0119] As used herein, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.

[0120] As used herein, the term "C1-C6 alkylthio" refers to -S-(straight or branched alkyl having 1 to 6 carbon atoms); for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio and the like.

[0121] As used herein, the term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3-8 carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a similar group. It can also be a bicyclic form, such as a bridged ring or a spirocyclic form.

[0122] As used herein, the term "heterocyclyl" refers to a saturated or partially saturated cyclic group having 1-3 heteroatoms selected from N, S and O as the ring skeleton, which may have any number of ring atoms, such as 3-8 members, 5-10 members, etc. It may be a monocyclic ring or a bicyclic ring, such as a bridged ring or a spirocyclic ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, etc.

[0123] As used herein, the term "C6-C14 aryl group" refers to an aryl group having 6 to 14 carbon atoms, for example, a phenyl group or a naphthyl group or the like.

[0124] As used herein, the term "5-14 membered heteroaryl" refers to a cyclic aromatic group having 5-14 atoms, of which 1-3 atoms are heteroatoms selected from N, S and O. It may be a monocyclic ring or a condensed ring. Specific examples may include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

[0125] Unless otherwise specified as being "substituted or unsubstituted", the groups described in the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0126] As used herein, "halogen" refers to F, Cl, Br, and I.

[0127] As used herein, the term "haloalkyl" refers to a C1-C4 alkyl group substituted by a halogen. Preferably, the haloalkyl group is trifluoromethyl, difluoromethyl, or trifluoromethoxy. Here, "C1-C4 alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl.

[0128] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0129] As used herein, the term "enantiomer" refers to isomers of compounds with the same molecular formula that are caused by different spatial configurations of atoms, and enantiomers are mirror images of each other, for example, R and S configurations containing an asymmetric center.

[0130] Compounds of formula I, formula II and formula III of the present invention

[0131] The structure of the compound of the present invention is obtained by designing the recognition mechanism based on the crystal structure of the complex of small molecules and ClpP. Specifically, the compound of the present invention adopts a "compound skeleton" and a two-part "side arm" structure. Under the support of the skeleton, the small molecule binds to the two hydrophobic pockets of the ClpP protein respectively, regulates the activity of ClpP, and affects a variety of biological functions. This part of the skeleton structure is different from the skeleton of the ClpP-related regulator reported in the existing literature, and by optimizing the "skeleton" and "side arm" structures, the present invention further obtains small molecule compounds with different regulatory activities on the ClpP protein.

[0132] As used herein, "compounds of the present invention" refer to compounds of formula I, II and III, and also include various pharmaceutically acceptable salts or esters, various crystal forms, stereoisomers, solvates and hydrates thereof of the above compounds. The compounds of the present invention include stereoisomers of various R configurations and / or S configurations of each compound, and / or cis-trans isomers of E- / Z-.

[0133] In another preferred embodiment, the pharmaceutically acceptable salts include salts formed by combining with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases that can provide physiologically acceptable cations, and ammonium salts.

[0134] In another preferred embodiment, the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ion is selected from lithium ion, sodium ion, potassium ion; the alkaline earth metal ion is selected from calcium ion and magnesium ion; the organic base capable of providing physiologically acceptable cations is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[0135] All such salts within the scope of the present invention may be prepared by conventional methods.

[0136] The starting materials and intermediates used in the preparation of the compounds of the present invention are easily available, and each step of the reaction can be easily synthesized according to the reported literature or by conventional methods in organic synthesis for those skilled in the art. The compounds described in general formulas I, II and III may exist in the form of solvates or unsolvates, and different solvates may be obtained by crystallization using different solvents.

[0137] Preparation method of the compound of formula I, formula II and formula III of the present invention

[0138] The preparation methods of the compounds of formula I, formula II and formula III are described in more detail below.

[0139] The preparation method of the compound of formula I is shown in the following figure:

[0140]

[0141] Typically, the following steps are involved:

[0142] (A-1) The compound of formula I1 undergoes a nucleophilic substitution reaction with a halogenated alkane to obtain a compound I2;

[0143] (A-2) Compound I2 is deprotected to obtain compound I3;

[0144] (A-3) Compound I3 undergoes an isocyanate reaction with an isocyanate reagent or a condensation reaction with a carboxylic acid derivative to obtain Compound I;

[0145] Among them, R 1 , R 2 , m, n, X, and Z are defined as described in the first aspect of the present invention.

[0146] In step (A-1), typically, the halogenated alkane can undergo a nucleophilic substitution reaction with a nucleophilic reagent because the carbon-halogen bond in the molecule is a polar covalent bond and is relatively easy to break. Due to the special properties of the carbon-fluorine bond, in the present invention, the halogenated alkane is preferably an iodide, a bromide, and a chloride. Examples of the application of halogenated alkanes include, but are not limited to, 1-bromomethylnaphthalene, 2-bromomethylnaphthalene, substituted or unsubstituted benzyl bromide, and the like.

[0147] In step (A-1), as the reaction proceeds, the reaction system gradually becomes acidic, and an alkaline agent needs to be added for neutralization. Common bases in halogenated alkane nucleophilic reactions include, but are not limited to, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, etc., preferably N,N-diisopropylethylamine.

[0148] The method can be carried out in any suitable solvent system, such as acetonitrile, toluene, xylene, n-hexane, n-heptane, n-pentane, cyclohexane, cyclopentane, methyl tert-butyl ether, isopropyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), or a combination thereof. In the most preferred case, the solvent is dichloromethane.

[0149] In step (A-2), the deprotection reaction of the amino group is carried out in an acidic environment. Common acids include, but are not limited to, hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like.

[0150] In step (A-3), the I3 compound reacts with a carboxylic acid derivative or an isocyanate reagent. Carboxylic acid derivatives include but are not limited to acyl chlorides and carboxylic acids, wherein the specific types of acyl chlorides and carboxylic acids are determined according to the substituents of the compound.

[0151] The compound I synthesized in step (A-3) retains the carbonyl group of the carboxylic acid derivative, and can thus be further reacted with a Wittig reagent or an amine compound to prepare an imine or an olefin.

[0152] The preparation method of the compound of formula II is shown in the figure below:

[0153]

[0154] Typically, the following steps are involved:

[0155] (B-1) The compound of formula II1 undergoes a nucleophilic substitution reaction with a halogenated alkane to obtain a compound II2;

[0156] (B-2) Compound II2 is deprotected to obtain compound II3;

[0157] (B-3) Compound II3 undergoes an isocyanate reaction with an isocyanate reagent or a condensation reaction with a carboxylic acid derivative to obtain Compound II;

[0158] Among them, R 1 , R 2 , m, n, X, and Z are defined as described in the second aspect of the present invention.

[0159] In step (B-1), typically, the halogenated alkane can undergo a nucleophilic substitution reaction with a nucleophilic reagent because the carbon-halogen bond in the molecule is a polar covalent bond and is relatively easy to break. Due to the special properties of the carbon-fluorine bond, in the present invention, the halogenated alkane is preferably an iodoalkane, a bromide, and a chloroalkane. Examples of the application of halogenated alkanes include, but are not limited to, 1-bromomethylnaphthalene, 2-bromomethylnaphthalene, substituted or unsubstituted benzyl bromide, and the like.

[0160] In step (B-1), as the reaction proceeds, the reaction system gradually becomes acidic, and an alkaline agent needs to be added for neutralization. Common bases in halogenated alkane nucleophilic reactions include, but are not limited to, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, etc., preferably N,N-diisopropylethylamine.

[0161] The method can be carried out in any suitable solvent system, such as acetonitrile, toluene, xylene, n-hexane, n-heptane, n-pentane, cyclohexane, cyclopentane, methyl tert-butyl ether, isopropyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), or a combination thereof. In the most preferred case, the solvent is dichloromethane.

[0162] In step (B-2), the deprotection reaction of the amino group is carried out in an acidic environment. Common acids include but are not limited to: hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, etc. Preferably, the deprotection reaction of the amino group is carried out in a hydrochloric acid environment.

[0163] In step (B-3), the II3 compound reacts with a carboxylic acid derivative or an isocyanate reagent. Carboxylic acid derivatives include but are not limited to acyl chlorides and carboxylic acids, wherein the specific types of acyl chlorides and carboxylic acids are determined according to the substituents of the compound.

[0164] The II compound synthesized in step (B-3) retains the carbonyl group of the carboxylic acid derivative, and can thus be further reacted with a Wittig reagent or an amine compound to prepare an imine or an olefin.

[0165] The preparation of the compound of formula II has the same mechanism and structurally similar reaction substrates as the preparation of the compound of formula I, so the preparation method of the compound of formula I can be referred to to prepare the compound of formula II.

[0166] The preparation method of the compound of formula III is shown in the figure below:

[0167]

[0168] Typically, the following steps are involved:

[0169] (C-1) The compound of formula III1' or III1" undergoes a nucleophilic substitution reaction with a halogenated alkane to obtain a compound III2' or III2";

[0170] (C-2) Compound III2' is deprotected to obtain compound III3';

[0171] (C-3) Compound III3' or III2" undergoes nucleophilic substitution with a halogenated alkane to obtain compound III;

[0172] Among them, R 1 , R 2, m, n, Y, and Z are defined as described in the third aspect of the present invention.

[0173] In step (C-1), typically, the halogenated alkane can undergo a nucleophilic substitution reaction with a nucleophilic reagent because the carbon-halogen bond in the molecule is a polar covalent bond and is relatively easy to break. Due to the special properties of the carbon-fluorine bond, in the present invention, the halogenated alkane is preferably an iodoalkane, a bromide, and a chloroalkane. Examples of the application of halogenated alkanes include, but are not limited to, 1-bromomethylnaphthalene, 2-bromomethylnaphthalene, substituted or unsubstituted benzyl bromide, and the like.

[0174] In step (C-1), as the reaction proceeds, the reaction system gradually becomes acidic, and an alkaline agent needs to be added for neutralization. Common bases in halogenated alkane nucleophilic reactions include, but are not limited to, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, etc., preferably N,N-diisopropylethylamine.

[0175] The method can be carried out in any suitable solvent system, such as acetonitrile, toluene, xylene, n-hexane, n-heptane, n-pentane, cyclohexane, cyclopentane, methyl tert-butyl ether, isopropyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), or a combination thereof. In the most preferred case, the solvent is dichloromethane.

[0176] In step (C-2), the deprotection reaction of the amino group is carried out in an acidic environment. Common acids include but are not limited to: hydrobromic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, etc. Preferably, the deprotection reaction of the amino group is carried out in a hydrochloric acid environment.

[0177] In step (C-3), compound III3' or III2" undergoes nucleophilic substitution with a halogenated alkane. In the present invention, the halogenated alkane is preferably an iodide, a bromide and a chloride. Application examples of halogenated alkanes include, but are not limited to, 1-bromomethylnaphthalene, 2-bromomethylnaphthalene, substituted or unsubstituted benzyl bromide, and the like. In step (C-3), a common base in a nucleophilic reaction can be used, including, but not limited to, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, sodium hydride, and the like, preferably sodium hydride. The preparation of the compound of formula III has the same mechanism and structurally similar reaction substrates as those of the compounds of formula I and II, and thus the compound of formula III can be prepared with reference to the preparation methods of the compounds of formula I and II.

[0178] Pharmaceutical compositions and methods of administration

[0179] Since the compounds of the present invention have excellent ClpP regulating activity, the compounds of the present invention and their pharmaceutically acceptable inorganic or organic salts, or stereoisomers, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) ClpP-related diseases (e.g., cancer).

[0180] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0181] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0182] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration).

[0183] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0184] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0185] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0186] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0187] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0188] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0189] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, other therapeutic agents).

[0190] When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention to prevent and / or treat ClpP-related diseases.

[0191] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0192] Combination therapy

[0193] As used herein, the term "combination therapy" means that a compound of the present invention is administered sequentially or simultaneously with at least one additional drug or agent (eg, an anticancer agent).

[0194] As mentioned above, the compounds of the present invention can potentially be used in combination with one or more other anticancer agents as described below. When using combination therapy, one or more other anticancer agents can be administered sequentially or simultaneously with the compounds of the present invention. In one embodiment, the other anticancer agent is administered to a mammal (object, patient) before administering the compounds of the present invention. In another embodiment, the other anticancer agent is administered to a mammal after administering the compounds of the present invention. In another embodiment, the other anticancer agent is administered to a mammal while administering the compounds of the present invention.

[0195] The present invention also relates to a pharmaceutical composition for treating abnormal cell growth in mammals, including humans, comprising an amount of a compound of the present invention as defined herein, in combination with one or more (preferably one to three) anticancer agents selected from anti-angiogenesis agents and signal transduction inhibitors and a pharmaceutically acceptable carrier, wherein the amount of active agent and combined anticancer agent, when taken as a whole, is therapeutically effective for treating said abnormal cell growth.

[0196] In one embodiment of the invention, the anticancer agent used in combination with the compounds and pharmaceutical compositions of the invention described herein is an anti-angiogenic agent (e.g., an agent that prevents a tumor from developing new blood vessels). Examples of anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiogenin inhibitors, PKCβ inhibitors, COX-2 inhibitors, integrins, MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors.

[0197] Preferred anti-angiogenic agents include sunitinib, bevacizumab, axitinib (AG 13736), SU 14813 (Pfizer) and AG13958 (Pfizer).

[0198] Additional anti-angiogenic agents include vatalanib (CGP 79787), sorafenib, pegaptanib octasodium, vandetanib, PF-0337210 (Pfizer), SU14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (AE 941), tetrathiomolyb-data AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer).

[0199] Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone, and UCN 01 (Kyowa Hakko).

[0200] Other examples of anti-angiogenic agents that can be used in combination with the compounds and pharmaceutical compositions of the invention described herein include celecoxib, parecoxib, deracoxib (SC59046), lumiracoxib (Preige™), valdecoxic (Bextra™), rofecoxib (Vioxx™), iguratimod IP 751 (Invedus), SC-58125 (Pharmacia), and etoricoxib

[0201] Other anti-angiogenic agents include exisulind, salsalate, diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac, and promazine.

[0202] Other anti-angiogenic agents include ABT 510 (abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide, and PCK 3145 (Procyon).

[0203] Other anti-angiogenic agents include acitretin, plitidepsin, cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4HPR), rebimastat (BMS 275291), catumaxomab lenalidomide, squalamine, thalidomide, NSC 631570, MEDI 522, and zoledronic acid.

[0204] In another embodiment, the anticancer agent is a so-called signal transduction inhibitor (e.g., a method for inhibiting the communication of regulatory molecules that control the basic processes of cell growth, differentiation and survival in cells). Signal transduction inhibitors include small molecules, antibodies and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EgF inhibitors, ErbB-1 (EGFR) inhibitors, ErbB-2 inhibitors, pan-erb inhibitors, IGF1R inhibitors, MEK (1, 2) inhibitors, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, CDK inhibitors, CDK4 / 6 inhibitors, BTK inhibitors of WNT pathway inhibitors and so-called multi-target kinase inhibitors.

[0205] Preferred signal transduction inhibitors include gefitinib, cetuximab, erlotinib, trastuzmab, sunitinib, imatinib (GSK1120212), abemaciclib, palbociclib, ibrutinib, acalabrutinib, LOXO-305 and XL518.

[0206] Additional examples of signal transduction inhibitors that can be used in conjunction with the compounds and pharmaceutical compositions of the invention described herein include BMS 214662, lonafamib, pelitrexol (AG2037), matuzumab (EMD 7200), nimotuzumab, panitumumab, vandetanib, pazopanib (SB 786034), BIBW 2992 (Boehringer Ingelheim), and TP 38.

[0207] Other examples of signal transduction inhibitors include Canertinib (CI 1033), pertuzumab, Lapatinib, pelitinib (EKB569), miltefosine, BMS 599626, Lapuleucel-T, IDM 1, mubritinib (TAK-165), Panitumumab, lapatinib, pelitinib (EKB 569), erbafitinib (Balversa), and pertuzumab.

[0208] Other examples of signal transduction inhibitors include ARRY142886, everolimus, zotarolimus, temsirolimus, and VX 680 (Vertex).

[0209] The present invention contemplates the use of the compounds of the present invention with antineoplastic agents. Antineoplastic agents include, but are not limited to, hormones, anti-estrogen therapeutics, histone deacetylase (HDAC) inhibitors, gene silencing agents or gene activators, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly (ADP-ribose), polymerase-1 (PARP-1) inhibitors, tubulin inhibitors, antibiotics, spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTA) and statins.

[0210] Examples of antineoplastic agents useful in combination therapy with the compounds of the invention include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostance, and CHF 4227 (Cheisi), selective estrogen receptor downregulators (SERDs, such as fulvestrant), exemestane, anastrozole, atamestane, fadrozole, letrozole (Femara), gonadotropin-releasing hormone (GnRH, also commonly called luteinizing hormone-releasing hormone [LHRH]) agonists, such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (leuprorelin), and luteinizing hormone-releasing hormone (LHRH) agonists. prorelin) (Lupron), and triptorelin, abarelix, bicalutamide, cyproterone, flutamide, megestrol, nilutamide, and osaterone, dutasteride, epristeride, finasteride, abarelix, goserelin, leuprolide, triptorelin, bicalutamide, tamoxifen, exemestane, anastrozole, fadrozole, fromestane, letrozole, and combinations thereof.

[0211] Other examples of anti-tumor agents for use in combination with the compounds of the invention include, but are not limited to, suberolanilide hydroxamic acid (Merck), ester peptide (FR901228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101 / (ranpimase), PS-341, (bortezomib), 9-aminocamptothecin, belotecan, BN-80915, camptothecin, diflomotecan, edotecarin, exatecan, gimatecan, 10-hydroxycamptothecin, irinotecan hydrochloride, HCl) lurtotecan, mbitecan, SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, aclarubicin, doxorubicin, amifide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamicin, epirubicin, etoposide, idarubicin, galarubicin, hydroxyurea, nemorubicin, novantrone, pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane ), tafluposide, valrubicin, dexrazoxane, nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, Ap-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquinone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, nitrogen mustard, melphalan, dibromomannitol, dibromodulcitol, mitomycin C, mitoxantrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating agents such as cisplatin. Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, oxaliplatin, streptozocin, satmlatin, and combinations thereof.

[0212] The present invention also contemplates the use of the compounds of the present invention with dihydrofolate reductase inhibitors (e.g., methotrexate and trimetresate glucoronate), purine antagonists (e.g., 6-mercaptopurine nucleosides, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar(R)), fludarabine, nelarabine and raltitrexed), pyrimidine antagonists (e.g., 5-fluorouracil (5-FU), (pemetrexed disodium (premetrexed) disodium), capecitabine, cytosine, arabinoside, gemcitabine, UFT or and TS-1 combination including tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release and liposomal forms), enocitabine, 5-azacitidine, decitabine and ethynyl-cytidine) and other antimetabolites such as eflomithine, hydroxyurea, folinic acid, nolatrexed, triapine, trimetrexate, ABT-472, Ino-1001, KU-0687 and GPI18180 and combinations thereof.

[0213] Additional examples of anti-tumor agents for use in combination therapy with the compounds of the invention, optionally with one or more other agents, include, but are not limited to, Genasense (oblimersen), Combretastatin A4P (CA4P), Oxi4503, AVE-8062, ZD-6126, TZT 1027, atorvastatin, pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, pharyngic acid, caduet, and combinations thereof.

[0214] The present invention also contemplates the use of the compounds of the present invention with agents that modulate the immune system, including but not limited to pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, rituximab (Thor-707, and dexamethasone.

[0215] The present invention also contemplates the use of compounds of the present invention with agents that modulate the BCL-2 family of proteins, including but not limited to venetoclax (ABT-199) and AMG176.

[0216] The present invention also contemplates the use of the compounds of the present invention with agents that inhibit the androgen receptor, including but not limited to apalutamide, flutamide, dicalutamide, and enzalutamide.

[0217] The present invention also contemplates the use of the compounds of the present invention with agents that modulate the PARP family of proteins, including but not limited to niraparib, olaparib, rucaparib, and talazoparib.

[0218] Another particularly interesting embodiment of the present invention relates to a method for treating breast cancer in a human in need of such treatment, comprising administering to said human an amount of a compound of the present invention, in combination with one or more (preferably one to three) anticancer agents selected from trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exmestane, letrozole and anastrozole.

[0219] Another embodiment of the invention is directed to a method of treating a neurodegenerative disease in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention in combination with one or more agents selected from the group consisting of anti-tau mAb, anti-β-amyloid mAb, BIIB067 (tofersen), BAN2401, BIIB054 (anti-α-synuclein), BIIB074, BIIB092, BIIB092 (gosuranemab), BIIB104, Natalizumab, BIIB076 (anti-tau mAb), BIIB078 (IONIS-C9RX), BIIB080 (IONIS-MAPTRX), BIIB095 (NAV 1.7), BIIB (XPO1 inhibitor), BIB110, cholinesterase inhibitors, memantine, levodopa, Lodosyn, dopamine agonists (pramipexole, ropinirole, rotigotine, and apomorphine), MAO B inhibitors (selegiline, rasagiline, safinamide), catechol O-methyltransferase (COMT) inhibitors (entacapone and tolcapone), anticholinergics (benzatropine and trihexphenidyl), amantadine, riluzole, edavarone, xenazine, antipsychotics, and benzodiazepines.

[0220] Treatments and uses

[0221] The present invention further provides methods and uses of treatment comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof, alone or in combination with one or more other therapeutic agents or sedative agents.The compositions and methods described herein can be used to treat a variety of disease conditions, including cancer.

[0222] Cancers treated using the methods, compositions and / or agents described herein are characterized by abnormal cell proliferation, including but not limited to pre-neoplastic hyperproliferation, carcinoma in situ, tumors and metastasis. The methods and compositions described herein can be used to prevent and improve the signs and / or symptoms of cancer.

[0223] In one aspect, the compositions and methods described herein are used to treat diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomengial disease, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal or rectal cancer, appendis cancer, astrocytoma, and atypical Teratoid / Rhabdoid tumor.

[0224] In one aspect, the compositions and methods described herein are used to treat diseases such as basal cell carcinoma, basal cell nevus syndrome, Gorlin-Nevus Syndrome, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, and malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt's lymphoma, and spinal cord tumors.

[0225] In one aspect, the compositions and methods described herein are used to treat diseases such as carcinoid tumors, carcinoma of unknown primary site, primary), atypical teratoid / rhabdoma of the central nervous system, leptomeningeal disease, embryonal tumor of the central nervous system, lymphoma of the central nervous system, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor of the central nervous system, endometrial cancer, ependymoma, ependymoma, esophageal cancer, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal stromal tumor, germ cell tumor, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi's sarcoma, renal cancer, Langhans cell histiocytosis, laryngeal cancer, lip cancer, and oral cavity cancer (lipandoral cavity cancer), liver cancer, lung cancer, non-Hodgkin lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone and osteosarcoma, medulloblastoma, medullary epithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, multiple neoplasia syndrome, mouth cancer, multiple / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, neoplasms, multiple myeloma, and myeloproliferative disorders.

[0226] In one aspect, the compositions and methods described herein are used to treat cancer.

[0227] The present invention further provides methods and uses of treatment comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutic agents or sedatives.

[0228] In one aspect, the invention provides a method of treating a disease state in which abnormally high concentrations of a protein that is a ClpP substrate are present in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0229] In one aspect, the invention provides methods for treating disease states, including cancer, wherein a reduction in the concentration of a protein that is a ClpP substrate in a subject results in an improvement in the disease, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0230] In one aspect, the invention provides a method for treating a disease state, including cancer, in which abnormally high concentrations of the protein ClpP are present in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0231] In one aspect, the invention provides a method for treating a disease state in which abnormally low concentrations of the protein ClpP are present in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0232] In one aspect, the present invention provides a method for treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0233] In another aspect, the present invention provides a method for treating abnormal cell growth in a subject, comprising administering to the subject an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an anti-tumor agent, the amounts of which together are effective to treat the abnormal growth. In some embodiments, the anti-tumor agent is selected from mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

[0234] In another aspect, the present invention provides a method for inhibiting the proliferation of cancer cells in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

[0235] On the other hand, the present invention provides a method for treating a cancer selected from a solid tumor, a liquid tumor, a lymphoma, a leukemia or a myeloma. In some embodiments, the treatment of cancer includes preventing tumor growth in a cancer subject, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, to the subject in an amount effective to inhibit cell proliferation.

[0236] In another aspect, the present invention provides a method for inhibiting the invasiveness of cancer cells in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

[0237] In another aspect, the present invention provides a method of inducing apoptosis of cancer cells in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

[0238] In another aspect, the present invention provides a method of inducing apoptosis in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

[0239] In common embodiments of the methods provided herein, the abnormal cell growth is cancer, wherein the cancer is selected from basal cell carcinoma, medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureter cancer, renal cell carcinoma, renal pelvis cancer, a tumor of the central nervous system (CNS), a primary CNS lymphoma, a spinal axis tumor, a brain stem glioma, a pituitary adenoma, or a combination of one or more of the foregoing cancers. In some embodiments, the cell is in a tissue or a tumor, and the tissue or tumor can be in a subject, including a human.

[0240] Cancers treated using the methods and compositions described herein are characterized by abnormal cell proliferation, including but not limited to metastasis, pre-neoplastic hyperproliferation, carcinoma in situ, and tumors. In addition to improving the signs and / or symptoms of cancer, the compounds of the present invention can also be used for prevention. Examples of cancers treated by the compounds of the present invention include but are not limited to breast cancer, CNS cancer, colon cancer, prostate cancer, leukemia, lung cancer, and lymphoma.

[0241] In another aspect, the invention provides a method for treating a leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloproliferative disorder, hairy cell leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and Langhans cell histiocytosis.

[0242] In another aspect, the invention provides a method for treating a lymphoma selected from the group consisting of diffuse large B-cell lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Sesely syndrome, mycosis fungoides (MF), histiocytosis, Burkitt lymphoma, central nervous system lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Hodgkin lymphoma, macroglobulinemia, mycosis fungoides, and lymphoplasmacytic lymphoma.

[0243] In another aspect, the present invention provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0244] In another aspect, the invention provides a method of treating a cancer selected from the group consisting of vaginal cancer, vulvar cancer, endometrial cancer, cancer of unknown primary site, and cancer of unknown primary site.

[0245] In another aspect, the present invention provides a method for treating a bacterial infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0246] In another aspect, the present invention provides a method for treating a Staphylococcus aureus infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0247] In another aspect, the present invention provides a method for treating the following neurodegenerative diseases in a subject, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia, spinal muscular atrophy and motor neuron disease, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0248] On the other hand, other conditions that may be suitable for the methods described herein include, but are not limited to, attention deficit disorder; addiction; epilepsy; viral infection; inflammation; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis; cardiovascular diseases, such as coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, cor pulmonale, cardiac rhythm disorders, inflammatory heart disease, endocarditis, inflammatory cardiac hypertrophy, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, rheumatic heart disease; diabetes and light chain amyloidosis.

[0249] In another aspect, the invention provides methods for treating cystic fibrosis.

[0250] In another aspect, the present invention provides a method for treating Perrault syndrome.

[0251] In another aspect, the present invention provides a method for treating Perrault syndrome type 3.

[0252] In another aspect, the invention provides methods for treating autoimmune diseases. Autoimmune diseases include, but are not limited to, alopecia areata, antiphospholipids, autoimmune hepatitis, coeliac disease, type 1 diabetes, Graves' disease, Guillain-Barre syndrome, Hasimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory myopathy, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, psoriatic arthritis, Crohn's disease, and vitiligo.

[0253] In another aspect, the invention provides a method for treating allograft rejection. In another aspect, the invention provides a method for treating hereditary spastic paraplegia.

[0254] In another aspect, the invention provides a method for treating the condition Acquired Immune Deficiency Syndrome (AIDS).

[0255] In another aspect, the invention provides methods for treating HIV and the condition, acquired immunodeficiency syndrome (AIDS).

[0256] In another aspect, the invention provides methods for treating a pneumonia disease or condition.

[0257] In another aspect, the present invention provides methods for treating sepsis.

[0258] In another aspect, the invention provides methods for treating viral infections.

[0259] In another aspect, the present invention provides a method for treating hepatitis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0260] In another aspect, the present invention provides a method for treating cryptogenic cirrhosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0261] In another aspect, the present invention provides a method for treating hepatocyte senescence in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0262] In another aspect, the present invention provides a method for treating non-alcoholic fatty liver disease (NAFLD) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0263] In another aspect, the present invention provides a method for treating nonalcoholic steatohepatitis (NASH) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0264] The main advantages of the present invention include:

[0265] (1) The compounds of the present invention are not derived from structural modifications in existing literature, but are obtained through rational design based on the molecular recognition mechanism between ClpP protein and small molecule compounds.

[0266] (2) The compounds of the present invention can effectively regulate ClpP and have both excellent ClpP activation activity and excellent ClpP inhibition activity;

[0267] (3) The compounds of the present invention achieve excellent anti-tumor effects by regulating the ClpP target function.

[0268] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0269] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0270] Example 1. Preparation of Compound ZK2

[0271]

[0272] Step 1. Preparation of compound 2

[0273] Boc-protected piperazine 1 (10.0 mmol), 1-bromomethylnaphthalene (10.0 mmol) and N,N-diisopropylethylamine (15 mmol) were dissolved in dichloromethane (10 mL), stirred at room temperature for 4 hours, washed with saturated brine, extracted with dichloromethane, the organic layer was spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1, v: v) to obtain a colorless oily liquid 2, 2.8 g, with a yield of 86%. LC-MS [M+H] + 327.2.

[0274] Step 2. Preparation of compound 3

[0275] Compound 2 (2.0 g, 6.0 mmol) was dissolved in 10 mL of hydrochloric acid and ethyl acetate solution, stirred at room temperature overnight, and filtered to obtain white solid 3, 1.2 g, with a yield of 75%. LC-MS [M+H] + 227.1.

[0276] Step 3. Preparation of compound 4

[0277] Compound 3 (1.0 g, 3.8 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (576 mg, 5.5 mmol), and chloroacetyl chloride (430 mg, 3.8 mmol) was slowly added dropwise, stirred at room temperature for 2 hours, washed with saturated brine, extracted with dichloromethane, the organic layer was dried by spin drying, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1, v:v) to obtain a white solid 4, 0.8 g, with a yield of 69%. LC-MS [M+H] + 303.1.

[0278] Step 4. Preparation of compound ZK2

[0279] Compound 4 (0.8 g, 2.6 mmol) and p-chlorophenol (0.3 g, 2.6 mmol) were dissolved in DMSO (5 mL), potassium carbonate (0.5 g, 3.9 mmol) was added and stirred at room temperature overnight. The mixture was washed with saturated brine, extracted with dichloromethane, the organic layer was dried by spin drying, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1, v:v) to obtain a white solid ZK2, 0.7 g, with a yield of 67%. 1 H NMR (500 MHz, CDCl 3 )δ7.98(d,J=10.0Hz,2H),7.70(s,1H),7.57(s,1H),7.34(d,J=5.0Hz,3H),7.28(s,1H), 7.01(d,J=20.0Hz,3H),4.82(s,2H),4.10(s,2H),3.40(s,3H),2.48(s,3H).LC-MS[M+H]+ 395.1.

[0280] Example 2-6. Preparation of Compounds ZK6-ZK10

[0281] The method of steps 1-4 of Example 1 was repeated, using benzyl bromide substituted with different substituents instead of 1-bromomethylnaphthalene and phenol substituted with different substituents instead of p-chlorophenol to obtain compounds ZK6-ZK10.

[0282]

[0283]

[0284] Example 7. Preparation of Compound ZK19

[0285]

[0286] Step 1. Preparation of compound 5

[0287] Boc-protected piperazine 1 (10.0 mmol), 3,5-difluorobenzyl bromide (10.0 mmol) and N,N-diisopropylethylamine (15 mmol) were dissolved in dichloromethane (10 mL), stirred at room temperature for 4 hours, washed with saturated brine, extracted with dichloromethane, the organic layer was spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1, v:v) to obtain a colorless oily liquid 5, 2.9 g, with a yield of 93%. LC-MS [M+H] + 313.1.

[0288] Step 2. Preparation of compound 6

[0289] Compound 5 (2.0 g, 6.4 mmol) was dissolved in 10 mL of hydrochloric acid and ethyl acetate solution, stirred at room temperature overnight, and filtered to obtain white solid 6, 1.3 g, with a yield of 82%. LC-MS [M+H] + 213.1.

[0290] Step 3. Preparation of compound ZK19

[0291] Compound 6 (1.0 g, 4.0 mmol), (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (0.9 g, 4.0 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.9 g, 5.0 mmol), and N,N-diisopropylethylamine (0.9 g, 7.0 mmol) were dissolved in DMF (20 mL), stirred at room temperature overnight, washed with saturated brine, extracted with dichloromethane, the organic layer was spin-dried, and purified by column chromatography (petroleum ether:ethyl acetate=3:1, v:v) to obtain white solid ZK19, 1.2 g, with a yield of 73%.1 H NMR (400 MHz, CDCl 3 )δ7.69(d,J=15.5Hz,1H),7.63(s,4H),6.93(m,3H),6.72(t,J=8.9Hz,1H),3.74(d,J=38.2Hz,4H),3.52(s,2H),2.63–2.40(m,4H).LC-MS[M+H] + 411.1.

[0292] Example 8. Preparation of Compound ZK20

[0293] The method of steps 1 to 3 of Example 7 was repeated, using benzyl bromide substituted with different substituents instead of 3,5-difluorobenzyl bromide to obtain compound ZK20.

[0294]

[0295] Example 9. Preparation of compound ZK63

[0296]

[0297] Step 1. Preparation of compound 8

[0298] 4-tert-Butyloxycarbonylaminopiperidine 7 (10.0 mmol), 3,5-difluorobenzyl bromide (10.0 mmol) and N,N-diisopropylethylamine (15 mmol) were dissolved in dichloromethane (10 mL), stirred at room temperature for 4 hours, washed with saturated brine, extracted with dichloromethane, the organic layer was spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1, v: v) to obtain a colorless oily liquid 8, 3.1 g, yield 95%. LC-MS [M+H] + 327.2.

[0299] Step 2. Preparation of compound 9

[0300] Compound 8 (2.0 g, 6.1 mmol) was dissolved in 10 mL of hydrochloric acid and ethyl acetate solution, stirred at room temperature overnight, and filtered to obtain white solid 7, 1.4 g, with a yield of 87%. LC-MS [M+H] + 227.1.

[0301] Step 3. Preparation of compound ZK63

[0302] Compound 9 (1.0 g, 3.8 mmol), (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (0.8 g, 3.8 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.7 g, 4.6 mmol), and N,N-diisopropylethylamine (0.7 g, 5.7 mmol) were dissolved in DMF (20 mL), stirred at room temperature overnight, washed with saturated brine, extracted with dichloromethane, the organic layer was spin-dried, and purified by column chromatography (petroleum ether:ethyl acetate=3:1, v:v) to obtain white solid ZK63, 1.3 g, with a yield of 80%. 1 H NMR (400 MHz, CDCl 3 )δ7.73–7.53(m,5H),6.96–6.82(m,2H),6.71(tt,J=8.9,2.3Hz,1H),6.48(d,J=15.6Hz,1H),5.65(d,J=7.9Hz,1H),4.07–3.90(m, 1H),3.49(s,2H),2.84(d,J=11.9Hz,2H),2.19(t,J=10.7Hz,2H),2.02(d,J=10.9Hz,2H),1.55(qd,J=11.8,3.7Hz,2H).LC-MS[M+H] + 425.1.

[0303] Examples 10-15. Preparation of compounds ZK64, ZK65, ZK66, ZK67, ZK69, and ZK86

[0304] The method of steps 1-3 of Example 9 was repeated, using benzyl bromide or 2-bromomethylnaphthalene substituted with different substituents instead of 3,5-difluorobenzyl bromide, and using acids substituted with different substituents instead of (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid to obtain compounds ZK64, ZK65, ZK66, ZK67, ZK69, and ZK86.

[0305]

[0306]

[0307] Example 16. Preparation of Compound ZK121

[0308]

[0309] Step 1. Preparation of compound 11

[0310] 4-Hydroxymethylpiperidine 10 (10.0 mmol), 3,5-difluorobenzyl bromide (10.0 mmol) and N,N-diisopropylethylamine (15 mmol) were dissolved in dichloromethane (10 mL), stirred at room temperature for 4 hours, washed with saturated brine, extracted with dichloromethane, the organic layer was dried by spin drying, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1, v:v) to obtain a colorless oily liquid 11, 3.1 g, with a yield of 95%. LC-MS [M+H] + 242.1.

[0311] Step 2. Preparation of compound ZK121

[0312] Compound 11 (2.0 g, 6.1 mmol) was dissolved in 10 mL DMF, NaH (0.2 g, 7.3 mmol) was added in batches, and the mixture was stirred at room temperature for 1 hour. 2-Bromomethylnaphthalene (1.6 g, 7.3 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. The mixture was washed with saturated brine, extracted with dichloromethane, and the organic layer was dried by spin drying. The mixture was purified by column chromatography (petroleum ether: ethyl acetate = 4:1, v:v) to obtain a white solid powder ZK121, 2.3 g, with a yield of 73%. NMR(600MHz, CDCl3)δ7.82(d,J=8.1Hz,3H),7.76(s,1H),7.49–7.43(m,3H),6.86 (d,J=6.5Hz,2H),6.67(ddd,J=8.9,5.6,2.2Hz,1H),4.66(s,2H),3.44(s,2H),3.3 6(d,J=6.6Hz,2H),2.85(d,J=11.4Hz,2H),1.98(td,J=11.8,1.8Hz,2H),1.76(d, J=12.8Hz,2H),1.67(ddd,J=11.2,7.7,4.1Hz,1H),1.35–1.25(m,3H).LC-MS[M+H] + 382.2.

[0313] Examples 17-18. Preparation of compounds ZK125 and ZK129

[0314] The method of steps 1-2 of Example 16 was repeated, and benzyl bromide substituted with different substituents was used instead of 2-bromomethylnaphthalene to obtain compounds ZK125 and ZK129.

[0315]

[0316] Example 19. Enzymatic evaluation of the compounds of the present invention for stimulating the function of ClpP protease

[0317] ClpP agonists induce remodeling of the ClpP protease complex structure, rearrange the core structure of the ClpP protease, and decouple the protein from the normal mechanism of regulation, thereby non-specifically degrading a large number of certain functional proteins in the cell and inducing the death of bacteria or cancer cells. For example, agonists of HsClpP (human mitochondrial ClpP) can stimulate HsClpP to non-specifically degrade normal proteins in cells, leading to cancer cell death, thereby treating pancreatic cancer, leukemia and other tumors. In normal organisms, the function of ClpP depends on the interaction with the molecular chaperone protein ClpX. Driven by ATP hydrolysis, ClpX depolymerizes misfolded proteins in cells and transports them into the hydrolysis cavity of ClpP to degrade proteins and regulate the homeostasis of proteins in normal cells.

[0318] Compound enzymatic activity test method: The compound activity test uses α-casein (model protein) as a substrate. When a small molecule agonist binds to ClpP, ClpP can drive ClpX to degrade α-casein independently of ATP hydrolysis. Therefore, the activity can be further determined by SDS-PAGE. The detection system is 50 μL, 10 μg HsClpP protein is first dissolved in PD buffer (25 mM HEPES-KOH (pH 7.6), 200 mM KCl, 5 mM MgCl 2 , 1mM EDTA, 10% glycerol and 2mM DTT (dithiothreitol). Then add the compound, incubate at room temperature for 10 minutes, add 0.6mg / mL α-casein, incubate at 37℃ for 2 hours, immediately add 12.5μL SDS-PAGE loading buffer, and heat at 100℃ for 10 minutes. After SDS-PAGE electrophoresis, Coomassie Brilliant Blue staining was used to decolorize and take pictures. DMSO was used as a negative control, ONC201 and ADEP4 were used as positive controls. The activity of the compound regulating ClpP was judged according to the degradation of α-casein. The results are shown in Table 1 below.

[0319] Table 1 Enzyme activity test results of the compounds of the present invention

[0320] Compound No. <![CDATA[EC 50 (μM)]]> ZK2 0.5 ZK6 0.3 ZK7 0.6 ZK8 0.8 ZK9 1.5 ZK10 1.6 ZK19 3.7 ZK20 0.1 ZK63 0.6 ZK64 1.9 ZK65 2.7 ZK66 0.1 ZK67 0.9 ZK69 0.05 ZK86 3.2 ZK121 5.0 ZK125 6.1 ZK129 2.9 ONC201 9.6 ADEP4 5.2

[0321] The results show that the compounds of the present invention have excellent enzymatic activity against human mitochondrial ClpP, wherein ZK69 has an enzymatic activity that is 192 times higher than that of the positive compound ONC201 and 104 times higher than that of ADEP4.

[0322] Example 20. Cytotoxicity assay (MTT)

[0323] The function of ClpP target protein is related to various biological functions, and studies have shown that the regulation of the function of human mitochondrial ClpP protein can affect the growth of tumor cells. The tumor cell sample provided in the embodiment of the present invention is associated with the ClpP target.

[0324] Compound enzymatic cytotoxicity test method: H520 (lung cancer), H1703 (lung cancer), A549 (lung cancer), BxPC-3 (pancreatic cancer), NB4 (leukemia), H1299 (large cell carcinoma) cells were cultured in 1640 medium containing 10% FBS and 1% penicillin / streptomycin; A498 (renal cancer), U87 (brain cancer), MCF-7 (breast cancer) cells were cultured in DMEM medium containing 2.5% horse serum, 10% FBS, 1mM sodium pyruvate and 1% penicillin / streptomycin. The cells were placed at 37°C and 5% CO 2 cultured in a cell culture incubator.

[0325] In order to detect the effect of the compounds of the present invention on the viability of tumor cells, the cancer cells in the logarithmic culture phase were digested with trypsin and resuspended with culture medium, and inoculated in a 96-well cell culture plate at a density of 3000 cells per well, placed in a 37°C cell culture incubator for overnight culture to allow the cells to adhere to the wall, the cell culture medium was aspirated, and fresh cell culture medium containing different concentrations of compounds (DMSO concentration 5‰) was added for 72 hours. During the test, 10 μL of 5mg / mL MTT solution (PBS dissolved) was added to each well and incubated at 37°C for 4-6 hours. After aspirating the supernatant, 150 μL DMSO was added to dissolve the purple formazan precipitate, and the ultraviolet absorption value at 490nm was detected after shaking and mixing. At least 3 biological replicates were performed for each treatment, and the DMSO group was used as the control, and its cell viability was set to 100%. All data were converted to relative values ​​of the control group, and the data were analyzed and processed using Graphpad 8.0. The results are shown in Table 2 below.

[0326] Table 2 Test results of the tumor cell proliferation inhibition activity of the compounds of the present invention

[0327]

[0328]

[0329] In summary, the compounds of the present invention have excellent enzymatic activity on human mitochondrial ClpP and excellent inhibitory effect on cancer cell activity, indicating that the compounds of the present invention can be used as regulators of ClpP protease and used in drugs for treating cancer, such as pancreatic cancer and leukemia.

[0330] Example 21. Minimum inhibitory concentration experiment (MIC)

[0331] Staphylococcus aureus MIC test method: After taking the strain out of the -80℃ refrigerator, streak it on a TSA (tryptic soy agar medium) plate and culture it overnight for more than 12 hours. Pick out 5 clinical drug-resistant bacteria NRS-1 (resistant to aminoglycosides and tetracycline), NRS-70 (resistant to erythromycin), NRS-100 (resistant to oxacillin and tetracycline), NRS-108 (resistant to gentamicin), NRS-271 (resistant to linezolid and ciprofloxacin) obtained from the US Staphylococcus aureus resistance library and the US community-acquired drug-resistant Staphylococcus aureus USA300 (resistant to methicillin), and Staphylococcus aureus Newman (sensitive bacteria) monoclonal clones in 10mL TSB (tryptic soy agar liquid) medium. Culture them at 37℃, 210rpm overnight until the stationary phase. Dilute 1:1000 times to fresh TSB medium the next day. Continue to culture at 37℃, 210rpm until OD 600 The bacterial solution was diluted 400 times with fresh TSB medium. The compound was diluted in fresh TSB medium in advance with equal multiple gradients to a final concentration of 0.39-50 μg / ml. The diluted bacterial solution was added to the diluted compound, and then the 96-well plate was placed in a 37°C incubator for 18 hours. The bacterial growth in each well was observed with the naked eye. The lowest concentration of the compound that did not inhibit bacterial growth was the MIC value of the compound. After the approximate MIC value range of the compound was obtained in the initial experiment, it was continuously optimized under the conditions in the second experiment, and the optimal MIC value was finally obtained.

[0332] Streptococcus pyogenes MIC test method: Take the strain out of the -80℃ freezer and streak it on a TSA plate for more than 12 hours overnight. Pick a single clone of Streptococcus pyogenes Sp12344 (ATCC Streptococcus pyogenes 12344) obtained from the American Type Culture Collection and place it in 10mL THB (Todd Hewitt Broth) medium. Culture overnight at 37℃, 210rpm until the stationary phase. Dilute 1:1000 into fresh THB medium the next day. Continue to culture at 37℃, 210rpm until OD 600 The bacterial solution was diluted 400 times with fresh THB medium. The compound was diluted in fresh THB medium in advance with equal multiple gradients, and the final concentration was 0.39-50 μg / ml. The diluted bacterial solution was added to the diluted compound, and then the 96-well plate was placed in a 37°C incubator for 18 hours. The bacterial growth in each well was observed with the naked eye, and the lowest concentration of the compound that did not inhibit bacterial growth was the MIC value of the compound. The results are shown in Table 3 below:

[0333] Table 3 Minimum inhibitory concentration test results of the compounds of the present invention

[0334]

[0335] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula I, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, characterized in that: Has the following structure: in, X is selected from the group consisting of O, S, Se, CH2 or NH; Y is selected from the group consisting of N or CH; Z is selected from the following group: -CH2-CH2-, -CH(NHFmoc)-CH2-, -CH=CH-, -CH2-CH2-NH- (the methylene end is connected to R2), -CH2-NH- (the methylene end is connected to R2), -CH2-O- (the O end is connected to R2); m, n are each independently selected from the following group: 0, 1, 2, 3, 4 or 5; and is a 4-9 membered ring; R1 is selected from the following groups: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-4 heteroatoms selected from N, O, S and C6-C10 aryl; substituted or unsubstituted C4-C14 heterocycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 cycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S and C5-C10 cycloalkyl; R2 is selected from the following group: H, halogen, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, C1-C10 alkyl having 1-4 heteroatoms selected from N, S and O, C2-C6 alkenyl having 1-4 heteroatoms selected from N, S and O, C1-C6 alkyl having 1-3 heteroatoms selected from N, S and O 5-10 membered heterocyclyl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, -NRbRc, wherein Rb and Rc are each independently H, C1-C4 alkyl, or Rb, Rc and the nitrogen atom to which they are connected together constitute a 5-10 membered heterocyclic ring; Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3 or 4) substituents selected from the group consisting of halogen, deuterated, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, amino, nitro, and hydroxy.

2. The compound of formula I, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester according to claim 1, characterized in that: The compound of formula I is selected from the following group:

3. A compound of formula II, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, characterized in that: Has the following structure: wherein X is selected from the group consisting of O, S, Se, CH2 or NH; Y is selected from the group consisting of -NH- or -CH2-; Z is selected from the group consisting of -CH2-, -NH-, -CH=CH-; m, n are each independently selected from the following group: 0, 1, 2, 3, 4 or 5; and It is a 4-9 membered ring; R1 is selected from the following groups: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-4 heteroatoms selected from N, O, S and C6-C10 aryl; substituted or unsubstituted C4-C14 heterocycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 cycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S and C5-C10 cycloalkyl; R2 is selected from the following group: H, halogen, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, C1-C10 alkyl having 1-4 heteroatoms selected from N, S and O, C2-C6 alkenyl having 1-4 heteroatoms selected from N, S and O, C1-C6 alkyl having 1-3 heteroatoms selected from N, S and O 5-10 membered heterocyclyl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, -NRbRc, wherein Rb and Rc are each independently H, C1-C4 alkyl, or Rb, Rc and the nitrogen atom to which they are connected together constitute a 5-10 membered heterocyclic ring; Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3 or 4) substituents selected from the following groups: halogen, deuterated, oxo (=O), carboxyl, phenyl, N,N-dimethylamino, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C8 cycloalkyl, a 5-10 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, cyano, amino, nitro, hydroxyl, thiol, and C1-C6 sulfone.

4. The compound of formula II, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester as claimed in claim 3, characterized in that: The compound of formula II is selected from the following group:

5. A compound of formula III, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, characterized in that: Has the following structure: in, Y is selected from the group consisting of N or CH; Z is selected from the following group: -CH2-O-CH2-, -NH-CH2-CH2- (the methylene end is connected to R2); m, n are each independently selected from the following group: 0, 1, 2, 3, 4 or 5; and It is a 4-9 membered ring; R1 is selected from the following groups: substituted or unsubstituted C6-C14 aryl, 5-14 membered heteroaryl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 aryl, substituted or unsubstituted 4-8 membered heterocyclyl having 1-4 heteroatoms selected from N, O, S and C6-C10 aryl; substituted or unsubstituted C4-C14 heterocycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S, substituted or unsubstituted C5-C8 cycloalkyl and C6-C10 cycloalkyl, 5-14 membered heterocycloalkyl having 1-4 heteroatoms selected from N, O, S and C5-C10 cycloalkyl; R2 is selected from the following group: H, halogen, substituted or unsubstituted C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C3-C10 cycloalkyl, C1-C10 alkyl having 1-4 heteroatoms selected from N, S and O, C2-C6 alkenyl having 1-4 heteroatoms selected from N, S and O, C1-C6 alkyl having 1-3 heteroatoms selected from N, S and O 5-10 membered heterocyclyl, 5-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted 4-8 membered heterocyclyl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, substituted or unsubstituted 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, O, S and C6-C10 aryl, -NRbRc, wherein Rb and Rc are each independently H, C1-C4 alkyl, or Rb, Rc and the nitrogen atom to which they are connected together constitute a 5-10 membered heterocyclic ring; Unless otherwise specified, the term "substituted" refers to substitution by one or more (e.g., 2, 3 or 4) substituents selected from the group consisting of halogen, deuterated, C1-C4 haloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, amino, nitro, and hydroxy.

6. The compound of formula III, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester according to claim 5, characterized in that: The compound of formula III is selected from the following group:

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more compounds as described in any one of claims 1 to 6, their isomers, hydrates or solvates, or pharmaceutically acceptable salts or esters; (2) a pharmaceutically acceptable carrier or excipient; and (3) a second therapeutic agent, wherein the second therapeutic agent is an anti-tumor drug or an anti-infective drug.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more compounds as described in any one of claims 1 to 6, or an isomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt or ester thereof.

9. A compound according to any one of claims 1 to 6, its isomer, hydrate or solvate, or pharmaceutically acceptable salt or ester, characterized in that: Used for preparing a pharmaceutical composition for preventing and / or treating diseases or conditions associated with ClpP protease activity or expression.

10. The use according to claim 9, wherein The disease or condition is cancer.

11. The use according to claim 9, wherein The disease or condition is a disease or condition caused by infection.

12. A method for preparing a compound as claimed in any one of claims 1 to 6, an isomer, a hydrate or a solvate thereof, or a pharmaceutically acceptable salt or ester thereof, characterized in that: Includes steps: (A-3) Compound I3 undergoes an isocyanate reaction with an isocyanate reagent or a condensation reaction with a carboxylic acid derivative to obtain Compound I: Wherein, Y is N, and R1, R2, m, n, X, and Z are as defined in claim 1; or, (B-3) Compound II3 undergoes an isocyanate reaction with an isocyanate reagent or a condensation reaction with a carboxylic acid derivative to obtain Compound II: Wherein, Y is NH, and R1, R2, m, n, X, and Z are as defined in claim 3; or, (C-3) Compound III3' or III2" undergoes nucleophilic substitution reaction with a halogenated alkane reagent to obtain compound III: Wherein, Y is CH, Z is -CH2-O-CH2- or -NH-CH2-CH2- (the methylene end is connected to R2), and the definitions of R1, R2, m and n are as described in claim 5.

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