Application of aromatic compound in preparation of USP7 agonist

Abstract

The invention relates to an application of aromatic compounds in preparation of USP7 agonists, in particular to an application of a compound shown as a formula I or pharmaceutically acceptable salts thereof in preparation of USP7 agonists.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of ubiquitin-specific protease 7 (USP7) agonists, and particularly relates to application of an aromatic compound or a pharmaceutically acceptable salt thereof in preparation of a USP7 agonist. BACKGROUND

[0002] The function execution of proteins in vivo is regulated by various post-translational modifications, and ubiquitination modification is an important part of the post-translational modification system of proteins.

[0003] Ubiquitination modification of proteins is a reversible biochemical process, and the forward ubiquitination modification is catalyzed by ubiquitin-activating enzyme, ubiquitin-conjugating enzyme and ubiquitin ligase, while the reverse deubiquitination modification process is mediated by deubiquitinating enzymes (DUBs) to achieve.

[0004] The human genome encodes about 100 deubiquitinating enzymes, which are divided into 7 subfamilies according to sequence homology and structural similarity, namely: ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), OTU catalytic domain-containing proteases (OTUs), Josephin catalytic domain-containing proteases (MJDs), JAB1 / MPN / MOV34 metalloproteases (JAMMs), monocyte chemotactic protein-induced protein family (MCPIPs), and zinc finger with UFM1-specific peptidase domain protein (ZUFSP / ZUP proteases) (Cell 2009, 138(2), 389-403; Nature Reviews Molecular Cell Biology 2019, 20(6), 338-352). Among them, ubiquitin-specific proteases (USPs) are the largest deubiquitinating enzyme subfamily, containing more than 50 members.

[0005] USP7 is one of the most concerned members in the ubiquitin-specific protease subfamily, and there is a considerable amount of data accumulated in the research of its structure, function and chemical intervention. USP7 is also known as Herpes-Associated Ubiquitin Specific Protease (HAUSP), which was first discovered and reported in 1997 (The EMBO Journal 1997, 16(7), 1519-1530).

[0006] Because a large number of research data show that USP7 can promote the occurrence and development of tumors through the regulation of MDM2-p53 and other pathways, the development of USP7 inhibitors has become a research hotspot in the field of anti-tumor, and a large number of USP7 inhibitors have been developed.

[0007] In addition to playing an important role in the pathological process of tumors by functional up-regulation, the loss of function of USP7 is found to be closely related to children's neurodevelopmental disorders. In 2015, scientists Yi-Heng Hao and Michael D. Fountain et al. found that the MAGE-L2-TRIM27 ubiquitin ligase functional complex and the WASH protein, which play a key role in the endosomal protein recycling process, are the substrate proteins of USP7. USP7 can form a stable complex with MAGE-L2-TRIM27 and at the same time inhibit the auto-ubiquitination modification of TRIM27 to improve its intracellular stability. The improved stability of TRIM27 will further promote the K63-coupled ubiquitination modification of WASH protein and the functional activation associated therewith (Molecular Cell 2015, 59(6), 956-969). In addition, since WASH protein is also the substrate of USP7, USP7 can directly act on WASH protein to avoid its excessive activation. Haploinsufficiency (single allele loss or functional loss of gene change) of USP7 will lead to the inhibition of the function of WASH protein and hinder the subsequent recycling of F-actin and other proteins through endosomal retrograde transport, ultimately leading to children's neurodevelopmental abnormalities such as developmental delay, autism spectrum disorder, etc. (Molecular Cell 2015, 59(6), 956-969).

[0008] So far, scientists and clinicians such as Yi-Heng Hao and Michael D. Fountain have found dozens of cases of neurodevelopmental disorders caused by haploinsufficiency (single allele loss or loss-of-function genetic alteration) of USP7 through comprehensive analysis of clinical big data (Molecular Cell 2015, 59(6), 956-969; Genetics in Medicine 2019, 21(8), 1797-1807; Genetics in Medicine 2021, 23(2), 421-422; Clinical Genetics 2024, 105(5), 499-509), and this disease is named Hao-Fountain Syndrome.

[0009] The pathological mechanism of Hao-Fountain Syndrome suggests that USP7 is a potential target protein for therapeutic intervention of the disease, and small molecule compounds (agonists) with positive intervention effects on the enzymatic activity of USP7 pathogenic mutant can be expected to alleviate the pathological process of Hao-Fountain Syndrome.

[0010] Currently, there is no report on agonists targeting USP7 protein, and the research on USP7 agonists has high innovativeness. SUMMARY

[0011] The inventors have unexpectedly found that a class of aromatic compounds have USP7 agonistic activity and can be used to prepare USP7 agonists, thereby completing the present application.

[0012] The present application provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a USP7 agonist,

[0013]

[0014] wherein,

[0015] X 1 , X 2 , X 3 , X 4 are each independently selected from CR a or N; in particular CR a ;

[0016] L is selected from CR b R c or is absent; in particular CH2;

[0017] Y is selected from NH, O, S, NHCR b R c, OCR b R c or SCR b R c ;

[0018] ring Cy is selected from C3-C10cycloalkyl, 4-8 membered heterocyclic ring, 7-15 membered spirocyclic ring, 7-15 membered bridged cyclic ring, 7-15 membered fused cyclic ring, wherein the above rings are optionally further substituted by one or more R d ;

[0019] R 1 is selected from C6-C10aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, preferably from phenyl, naphthyl, quinolinyl, naphthrydine, pyridyl, indolyl; the above groups are optionally substituted by one or more R e ;

[0020] R 2 is selected from H, C6-C10aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -(C1-C4alkyl)-(C6-C10)aryl, -(C1-C4alkyl)-(5-10 membered)heteroaryl, -(C1-C4alkyl)-(3-10 membered)heterocyclyl, -(C3-C6cycloalkyl)-(C6-C10)aryl, -(C3-C6cycloalkyl)-(5-10 membered)heteroaryl, -(C3-C6cycloalkyl)-(5-10 membered)heterocyclyl, wherein the above aryl, heteroaryl, heterocyclyl, alkyl, cycloalkyl groups are optionally substituted by one or more R f ;

[0021] each R a is independently selected from H, deuterium (D), halogen, C1-C6alkyl, C1-C6alkoxy, -OH, -COOH, -NH2, NO2, -CN, wherein the above C1-C6alkyl, C1-C6alkoxy groups are optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, -NH2, nitro, COOH;

[0022] R b , R c are each independently selected from H, D, C1-C4alkyl, in particular H, D, C1-C2alkyl;

[0023] R d , R e and R feach independently selected from the group consisting of D, -OH, -COOH, -NH2, -NO2, -CN, =0, =S, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, wherein the aforementioned alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, halogen, -CN, -OH, -NO2, -COOH, =0.

[0024] In some embodiments, the compound of formula I is selected from the following compounds of formula I-1:

[0025]

[0026] wherein,

[0027] R a1 and R a2 are independently selected from the group consisting of H, deuterium (D), halogen, C1-C6alkyl, C1-C6alkoxy, -OH, -COOH, -NH2, NO2, -CN, wherein the aforementioned C1-C6alkyl, C1-C6alkoxy are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -NH2, nitro, COOH; in particular, R a1 and R a2 are independently selected from the group consisting of H, deuterium (D), halogen, C1-C4alkyl, C1-C4alkoxy; more particularly, R a1 and R a2 are identical and selected from the group consisting of H, Cl, F, C1-C2alkyl;

[0028] Z1is CR e5 or N; preferably CR e5 ;

[0029] R e1 , R e2 , R e3 , R e4 and R e5 are independently selected from the group consisting of H, D, halogen, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy, nitro, amino, hydroxyl; in particular, R e1 , R e2 , R e3 , R e4 and R e5Independently selected from H, D, F, Cl, Br, C1-C2 alkyl, fluoroC1-C2 alkyl, chloroC1-C2 alkyl, C1-C2 alkoxy, fluoroC1-C2 alkoxy, nitro, amino, hydroxyl; more particularly, R e1 R e2 R e3 R e4 and R e5 Independently selected from H, D, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro; or

[0030] R e1 R e2 R e3 R e4 and R e5 The two adjacent groups and the carbon atoms attached to them together form a benzene ring or a 5-6 membered heteroaromatic ring, preferably a benzene ring or a pyridine ring; the benzene ring or heteroaromatic ring is optionally surrounded by 1-4 R groups. e6 replace;

[0031] Z2 is either O(CH2)m or NH(CH2)m;

[0032] m, p, and q are independently 0, 1, 2, 3, or 4; and p + q is at least 2; in particular, m is 0 or 1; p and q are independently 1, 2, or 3;

[0033] Z3 is CHR 2 or NR 2 ;

[0034] R 2 The definition is the same as above, in particular, R 2 Selected from H, -NH2, -(C1-C4 alkyl)phenyl, -(C1-C4 alkyl)5-6 heteroaryl, particularly R 2 Selected from H, -NH2, -(C1-C2 alkyl)phenyl, -(C1-C2 alkyl)pyridyl, wherein the phenyl group and the 5-6 heteroaryl group are optionally surrounded by 1-4 R groups. e6 replace;

[0035] The R e6 Independently selected from D, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, nitro, amino, hydroxyl; particularly independently selected from D, F, Cl, Br, C1-C2 alkyl, fluoro-C1-C2 alkyl, chloro-C1-C2 alkyl, C1-C2 alkoxy, fluoro-C1-C2 alkoxy, nitro, amino, hydroxyl; even more particularly independently selected from D, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro.

[0036] In some embodiments, the compound of formula I is selected from the group consisting of the following compounds I-1-1 and I-1-2:

[0037]

[0038] wherein R a1 , R a2 are the same as defined above, in particular R a1 and R a2 are the same and are selected from the group consisting of H, Cl, methyl;

[0039] R e1 , R e2 , R e3 and R e4 are the same as defined above, in particular R e1 , R e2 , R e3 and R e4 are independently selected from the group consisting of H, D, F, Cl, methyl, trifluoromethyl, methoxy, nitro; and R e1 , R e2 , R e3 and R e4 are at least two H;

[0040] or R e1 and R e2 together with the carbon atom to which they are attached form a benzene or pyridine ring, R e3 , R e4 are the same as defined above, preferably both are H;

[0041] Z1is CH or N, preferably CH;

[0042] Z2is O, OCH2, NH, or NHCH2;

[0043] p and q are independently 1, 2 or 3;

[0044] R 2 is selected from the group consisting of H, -(C1-C2 alkyl)phenyl, -(C1-C2 alkyl)pyridyl, said phenyl and pyridyl being optionally substituted with 1-4 R e6 ;

[0045] R e6 are the same as defined above, in particular said R e6 are independently selected from the group consisting of D, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0046] In some embodiments, the compound of formula I is selected from the group consisting of the following compounds I-1-1-1 and I-1-1-2:

[0047]

[0048] wherein R a1 , R a2 are the same as defined above, in particular R a1 and R a2 are selected from H, CI, methyl;

[0049] R e2 , R e3 and R e4 are the same as defined above, in particular R e2 , R e3 and R e4 are independently selected from H, D, F, CI, methyl, trifluoromethyl, methoxy, nitro; and R e2 , R e3 and R e4 are at least one H;

[0050] Z1is CH or N, preferably CH;

[0051] Z2is O, OCH2, NH, or NHCH2.

[0052] In some embodiments, the compound of formula I is selected from the following compounds I-1-1-3 and I-1-1-4:

[0053]

[0054] wherein R a1 , R a2 are the same as defined above, in particular R a1 and R a2 are selected from H, CI, methyl;

[0055] R e3 and R e4 are the same as defined above, in particular R e3 and R e4 are H;

[0056] Z1is CH or N, preferably CH;

[0057] Z4is CH or N;

[0058] Z2is O, OCH2, NH, or NHCH2.

[0059] In some embodiments, the compound of formula I is selected from the following compounds:

[0060]

[0061]

[0062]

[0063] The above-mentioned compounds of the present application can contain asymmetric or chiral centers, and as such can exist in different stereoisomeric forms. All stereoisomeric forms of the above-mentioned compounds of the present application, including but not limited to, optical isomers (including diastereomeric and enantiomeric), atropisomers, geometric isomers (cis / trans isomers), conformational isomers, and mixtures thereof (e.g., racemic mixtures), are included in the scope of the present application.

[0064] The above-mentioned compounds of the present application can also exist in different tautomeric forms and all such forms are embraced within the scope of the present application. The term "tautomers" or "tautomeric forms" refers to different energy structures which interconvert via a low energy barrier.

[0065] The above-mentioned compounds of the present application can exist in unsolvated as well as in solvated forms, including hydrated forms, and the present application encompasses all such forms. The compounds of the present application include solvates and unsolvated forms.

[0066] The above-mentioned compounds of the present application can also exist as prodrugs, which are converted to compounds of the present application in vivo, and as such are included within the scope of the compounds of the present application.

[0067] The compounds of Formula I have basic groups and thus can form pharmaceutically acceptable salts (i.e., pharmaceutically acceptable salts) with inorganic or organic acids, including pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable salts can be obtained by treating the free base of the compounds of Formula (I) with a suitable inorganic or organic acid. The inorganic acids are, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, carbonic acid, and sulfuric acid, and the organic acids are, for example, ascorbic acid, nicotinic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, oxalic acid, malic acid, glycolic acid, hydroxyacetic acid, cinnamic acid, mandelic acid, pyruvic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, and the like, but are not limited thereto.

[0068] The above-mentioned compounds of the present application, pharmaceutically acceptable salts, solvates, prodrugs thereof can also exist in one or more crystalline forms, having similar or improved properties, and as such are included within the scope of the compounds of the present application.

[0069] The present application also embraces the above-mentioned compounds labeled with a radioactive isotope in place of one or more non- radioactive atoms. Examples of isotopes that can be incorporated into a compound of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as: 2 hydrogen, 3 hydrogen,11 carbon, 13 carbon, 14 carbon, 13 nitrogen, 15 nitrogen, 15 oxygen, 17 oxygen, 18 oxygen, 18 fluorine, and 36 chlorine.

[0070] In the present application, the terms used in the present application have the meanings defined below, unless explicitly stated otherwise. The terms not defined in the present application have the general meanings as commonly understood by a person skilled in the art.

[0071] The term "optionally" as used herein means that the substitution pattern, event or circumstance described subsequently can or can not occur, and the description includes the situation where the substitution pattern occurs as well as the situation where the substitution pattern does not occur.

[0072] As used herein, "halogen" can be fluorine, chlorine, bromine or iodine. Preferred halogen is fluorine or chlorine.

[0073] As used herein, "C1-C6 alkyl" means a fully saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms; specific examples thereof can include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, t-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethyl-butyl, and the like, but are not limited thereto. The meaning of C1-C4 alkyl is construed similarly.

[0074] As used herein, "C1-C6 alkoxy" means a RO- group, wherein R is C1-C6 alkyl as described above. Specific examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, and the like. The meaning of C1-C4 alkoxy is construed similarly.

[0075] As used herein, "C3-C10 cycloalkyl" means a fully saturated cyclic hydrocarbon compound group containing 3 to 10 ring carbon atoms; specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The meaning of C3-C6 cycloalkyl is construed similarly.

[0076] As used herein, "3-10 membered heterocycle" means a 3-8 membered non-aromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur in the ring; specific examples thereof include azetidine, oxetane, thietane, tetrahydroimidazole, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine. The meaning of 4-8 membered heterocycle, 5-10 membered heterocycle is construed similarly.

[0077] As used herein, C6-C10 aryl refers to an aromatic carbocyclic radical having from 6 to 10 carbon atoms in the ring, specific examples of which include phenyl, naphthyl.

[0078] As used herein, "5-10 membered heteroaryl" refers to a 5-10 membered aromatic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur in the ring, specific examples of which include imidazolyl, furanyl, thiophenyl, pyridyl, pyranyl, pyrazinyl, indazolyl, indolyl, quinolinyl, isoquinolinyl, cinnolinyl. The meaning of 4-8 membered heterocycle, 5-10 membered heterocycle is by analogy.

[0079] The above-mentioned compounds of the present application can be commercially available compounds, or can be synthesized according to known methods in the art. Alternatively, based on the specific structure of the above-mentioned compounds of the present application, those skilled in the art can design and synthesize the above-mentioned compounds of the present application in combination with the synthesis knowledge in the art and the prior art, or can refer to the examples of the present application to synthesize the above-mentioned compounds of the present application.

[0080] The USP7 agonist comprises a therapeutically effective amount of one or more selected from the above-mentioned compounds of the present application and pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

[0081] In certain embodiments of the USP7 agonist, the USP7 agonist is formulated for intravenous administration, intramuscular administration, oral administration, rectal administration, inhalation administration, nasal administration, topical administration, ocular administration, or aural administration. In other embodiments of the USP7 agonist, the USP7 agonist is a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a solution, an emulsion, an ointment, an eye drop, or an ear drop.

[0082] In other embodiments of the USP7 agonist, it can further comprise one or more additional therapeutic agents. The additional therapeutic agent can be another USP7 agonist other than the above-mentioned compounds of the present application and pharmaceutically acceptable salts thereof, or a compound having other activity.

[0083] The USP7 agonist of the present application can be selected to comprise at least one pharmaceutically acceptable carrier selected from the group consisting of diluents, adjuvants, excipients, preservatives, fillers, binders, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, flavorants, lubricants, dispersants, temperature-sensitive materials, temperature-regulating agents, adhesion agents, stabilizers, suspending agents, and the like, depending on the nature of the mode of administration and the dosage form.

[0084] In embodiments, the USP7 agonist is a medicament for preventing and / or treating a disease that is improved by agonizing USP7.

[0085] Another aspect of the present application provides a method of preventing and / or treating a disease ameliorated by agonizing USP7, comprising administering to an individual in need of such treatment a therapeutically effective amount of one or several selected from the compounds of the present application and pharmaceutically acceptable salts thereof, or the pharmaceutical composition.

[0086] In some embodiments of the present application, the disease ameliorated by agonizing USP7 includes, but is not limited to, childhood neurodevelopmental disorders, Hao-Fountain syndrome.

[0087] In some embodiments of the present application, the childhood neurodevelopmental disorders include, but are not limited to, developmental delay, autism spectrum disorder.

[0088] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of the present application that elicits the biological or medical response that is being sought in a subject, alleviates the symptoms, slows down or delays the worsening of the disease, or prevents the disease, and the like.

[0089] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In a preferred embodiment, the subject is a human.

[0090] As used herein, in one embodiment, the term "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or slowing down the development of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" refers to ameliorating at least one physical parameter including possible subjective improvement in which no alteration in disease status is subjectively perceptible to the patient, in still another embodiment, "treatment" refers to modulating the disease or disorder physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. BRIEF DESCRIPTION OF DRAWINGS

[0091] Figure 1 A graph showing that Astemizole is able to significantly activate the deubiquitinase activity of USP7 disease mutants USP7 I-575, USP7 L757P, USP7 I766T and USP7 D1080N. DETAILED DESCRIPTION

[0092] The present application is further illustrated by the following examples, which in no way should be construed as limiting the scope of the present application. The experimental methods in the following examples, where no specific conditions are mentioned, are in accordance with the conventional methods and conditions, or are selected according to the commercial instructions.

[0093] In the present application, room temperature refers to ambient temperature, which is 10-35 °C. Overnight refers to 8-15 hours. Reflux refers to the solvent reflux temperature under normal pressure.

[0094] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in 10-6 (ppm) units. NMR measurements are performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard. MS measurements are performed on a Finnigan LCQ / Deca (ESI) mass spectrometer. High performance liquid chromatography (HPLC) analysis is performed on a Gilson-215 high pressure liquid chromatograph.

[0095] Thin layer chromatography (TLC) is performed on silica gel plates of Yantai Huanghai HSGF 254 or Qingdao GF 254. The silica gel plates used in TLC have a thickness of 0.15 mm-0.2 mm, and the silica gel plates used in the separation and purification of products by thin layer chromatography have a thickness of 0.4 mm-0.5 mm. Silica gel column chromatography is generally performed using Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0096] The known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from Shanghai Haohong Biomedicine Technology Co., Ltd., Bide Pharmaceutical Co., Ltd., etc. Unless otherwise specified in the examples, the reactions can be performed under an argon or nitrogen atmosphere.

[0097] The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing agents used in the reactions, the eluent systems used in the column chromatography for the purification of compounds, and the developing agent systems used in the thin layer chromatography include dichloromethane / methanol systems and petroleum ether / ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine and basic or acidic reagents such as acetic acid can also be added for adjustment.

[0098] Example 1: Synthesis of Compound 1

[0099]

[0100] Take 10 mL single-mouth bottle, in turn compound A1B1 (500 mg, 1.92 mmol) and compound C1 (1-tert-butoxycarbonyl-3-hydroxypyrrolidine, 334.8 mg, 3.85 mmol) are dissolved in 1.5 mL of N-methylpyrrolidone, heated to 170 DEG C under nitrogen protection and stirred overnight, and the reaction is monitored by TLC plate. After the reaction is completed, the organic phase is diluted with 45 mL of methanol / dichloromethane 8:1 (volume ratio) mixed solvent, washed with 5 mL of saturated sodium bicarbonate solution three times, dried with anhydrous sodium sulfate, and filtered under suction. The organic phase after concentration under reduced pressure is mixed with silica gel and purified by column chromatography, eluted with methanol / dichloromethane = 1-5% gradient, and the obtained crude product is subjected to reverse phase preparation purification to obtain compound 1 as a white solid with a yield of about 22% and a purity of more than 98%.

[0101] 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 7.7 Hz, 1H), 7.14 (m, 5H), 7.02 (m, 1H), 6.95-6.89 (m, 1H), 5.45-5.29 (m, 2H), 4.31 (s, 1H), 3.69 (ddd, J = 13.6, 10.0, 5.7 Hz, 2H), 3.51 (td, J = 8.8, 3.6 Hz, 1H), 3.31 (dd, J = 10.9, 2.0 Hz, 1H), 1.93 (dtd, J = 13.1, 8.5, 4.6 Hz, 1H), 1.81 (ddt, J = 12.9, 6.8, 3.3 Hz, 1H);

[0102] MS-ESI m / z: [M+H] + :312.25.

[0103] Example 2: Synthesis of compound 2

[0104]

[0105] Compound C1 in the synthesis of compound 1 is replaced by 1-tert-butoxycarbonyl-4-hydroxypiperidine to obtain compound 2 as a white solid with a yield of about 18% and a purity of more than 98%.

[0106] 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.7 Hz, 1H), 7.23 - 7.11 (m, 5H), 7.10 - 6.99 (m, 2H), 5.25 (s, 2H), 3.67 (tq, J = 8.2, 3.9 Hz, 1H), 3.39 (d, J = 6.7 Hz, 2H), 2.98 (ddd, J = 12.7, 9.9, 2.9 Hz, 2H), 1.83 (dq, J = 12.7, 3.9 Hz, 2H), 1.56 (dtd, J = 12.8, 9.3, 3.6 Hz, 2H);

[0107] MS-ESI m / z: [M+H] + : 326.25.

[0108] Example 3: Synthesis of compound 3

[0109]

[0110] Compound 1 synthesis step, compound C1 is replaced by 1-Boc-3-hydroxymethylpyrrolidine to obtain compound 3, white solid, yield about 20%, purity greater than 98%.

[0111] 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.7 Hz, 1H), 7.23 - 7.11 (m, 5H), 7.10 - 6.99 (m, 2H), 5.25 (s, 2H), 3.67 (tq, J = 8.2, 3.9 Hz, 1H), 3.39 (d, J = 6.7 Hz, 2H), 2.98 (ddd, J = 12.7, 9.9, 2.9 Hz, 2H), 1.83 (dq, J = 12.7, 3.9 Hz, 2H), 1.56 (dtd, J = 12.8, 9.3, 3.6 Hz, 2H);

[0112] MS-ESI m / z: [M+H] + : 326.26.

[0113] Example 4: Synthesis of compound 4

[0114]

[0115] Compound 1 synthesis step, compound C1 is replaced by 1-Boc-4-piperidinemethanol to obtain compound 4, white solid, yield about 15%, purity greater than 98%.

[0116] 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.7 Hz, 1H), 7.23 - 7.11 (m, 5H), 7.10 - 6.99 (m, 2H), 5.25 (s, 2H), 3.67 (tq, J = 8.2, 3.9 Hz, 1H), 3.39 (d, J = 6.7 Hz, 2H), 2.98 (ddd, J = 12.7, 9.9, 2.9 Hz, 2H), 1.83 (dq, J = 12.7, 3.9 Hz, 2H), 1.56 (dtd, J = 12.8, 9.3, 3.6 Hz, 2H);

[0117] MS-ESI m / z: [M+H] + : 340.27.

[0118] Example 5: Synthesis of compound 5

[0119]

[0120] Compound 1 synthesis step, compound C1 is replaced by 3-amino-N-Boc-pyrrolidine to obtain compound 5, white solid, yield about 25%, purity greater than 98%.

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.7 Hz, 1H), 7.23 - 7.11 (m, 5H), 7.10 - 6.99 (m, 2H), 5.25 (s, 2H), 3.67 (tq, J = 8.2, 3.9 Hz, 1H), 3.39 (d, J = 6.7 Hz, 2H), 2.98 (ddd, J = 12.7, 9.9, 2.9 Hz, 2H), 1.83 (dq, J = 12.7, 3.9 Hz, 2H), 1.56 (dtd, J = 12.8, 9.3, 3.6 Hz, 2H);

[0122] MS-ESI m / z: [M+H] + : 311.30.

[0123] Example 6: Synthesis of compound 6

[0124]

[0125] Compound 1 synthesis step, compound C1 is replaced by N-Boc-trans-1,4- cyclohexyl diamine to obtain compound 6, white solid, yield about 23%, purity greater than 98%.

[0126] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 5.1 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 8.5, 5.4 Hz, 2H), 7.27 - 7.19 (m, 3H), 5.46 (s, 2H), 3.67 (d, J = 11.2 Hz, 1H), 3.14 - 3.00 (m, 1H), 2.13 - 1.98 (m, 4H), 1.49 (dd, J = 11.4, 6.7 Hz, 4H);

[0127] MS-ESI m / z: [M+H] + : 339.30.

[0128] Example 7: Synthesis of compound 7

[0129]

[0130] Take 100 mL single mouth bottle, compound 7a (2 g, 13.15 mmol), compound 7b (3.7 g, 19.74 mmol), potassium carbonate (3.6 g, 26.31 mmol) were added into the single mouth bottle in turn, dissolved in 30 mL of N, N-dimethylformamide, heated to 75 °C under nitrogen protection, stirred overnight. After the reaction was completed, the reaction liquid was poured into a conical flask containing 90 mL ice water, white solid was precipitated, suction filtration, oven dried to constant weight, to obtain white solid intermediate 7c, which was directly used in the next step.

[0131] The raw materials A1B1, C1 in the synthesis of compound 1 were replaced by 7c, 7d respectively, to obtain compound 7, which was white solid, with a yield of about 22% and a purity of more than 98%.

[0132] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.50 (m, 1H), 7.45 - 7.34 (m, 2H), 7.27 (dtd, J = 22.0, 7.6, 1.2 Hz, 2H), 7.16 (td, J = 10.0, 2.2 Hz, 2H), 7.10 (d, J = 7.7 Hz, 1H), 5.49 (s, 2H), 3.98 (dt, J = 7.6, 3.7 Hz, 1H), 3.45 (s, 2H), 3.05 - 2.90 (m, 2H), 2.23 - 2.13 (m, 2H), 1.81 (dt, J = 13.2, 9.7 Hz, 2H);

[0133] MS-ESI m / z: [M+H] + : 325.28.

[0134] Example 8: Synthesis of compound 8

[0135]

[0136] The starting material 3-fluorobenzyl bromide (7b) in the synthesis of compound 7 was replaced by 3-methylbenzyl bromide, and other steps were the same to obtain compound 8, white solid, yield about 26%, purity greater than 98%.

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 7.44-7.39 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.14-6.97 (m, 5H), 6.92 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 3.42 (dd, J = 12.9, 4.1 Hz, 2H), 2.98-2.86 (m, 2H), 2.73 (tt, J = 10.1, 4.1 Hz, 1H), 2.25 (s, 3H), 1.75 (dd, J = 12.6, 4.1 Hz, 2H), 1.46-1.35 (m, 2H);

[0138] MS-ESI m / z: [M+H] + : 321.29.

[0139] Example 9: Synthesis of compound 9

[0140]

[0141] The starting material 3-fluorobenzyl bromide (7b) in the synthesis of compound 7 was replaced by 3,5-dimethylbenzyl bromide, and other steps were the same to obtain compound 9, white solid, yield about 21%, purity greater than 98%.

[0142] 1 H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J = 7.7 Hz, 1H), 7.04-6.98 (m, 1H), 6.92 (td, J = 7.6, 1.3 Hz, 1H), 6.87 (s, 1H), 6.85-6.76 (m, 3H), 5.19 (s, 2H), 3.95-3.89 (m, 1H), 3.11 (dt, J = 12.9, 3.7 Hz, 2H), 2.74 (td, J = 12.2, 2.7 Hz, 2H), 2.19 (s, 6H), 2.05-1.97 (m, 2H), 1.59-1.49 (m, 2H);

[0143] MS-ESI m / z: [M+H] + : 335.32.

[0144] Example 10: Synthesis of Compound 10

[0145]

[0146] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3,5-bis(trifluoromethyl)benzyl bromide, and the other steps were the same, to obtain compound 10, a white solid with a yield of about 11% and a purity greater than 98%.

[0147] 1 H NMR (400MHz, DMSO-d6) δ8.03 (s, 1H), 7.83 (d, J = 1.7Hz, 2H), 7.25-7.15 (m, 2H),6.95(td,J=7.5,1.2Hz,1H),6.86(td,J=7.5,1.2Hz,1H),5.50(s,2H), 3.86(dtt,J=11.4,7.5,4.2Hz,1H),2.99(dt,J=12.9,3.6Hz,2H),2.57(td, J=12.1,2.5Hz,2H),1.95-1.86(m,2H),1.39(qd,J=13.2,12.5,4.7Hz,2H);

[0148] MS-ESI m / z:[M+H] + :443.28.

[0149] Example 11: Synthesis of Compound 11

[0150]

[0151] By replacing the starting material 3-fluorobenzyl bromide (7b) in the synthesis step of compound 7 with 1-bromomethylnaphthalene, and keeping the other steps the same, compound 11 was obtained as a white solid with a yield of approximately 19% and a purity greater than 98%.

[0152] 1H NMR (400MHz, DMSO-d6) δ8.16(d,J=8.3Hz,1H),7.92(dd,J=8.1,1.6Hz,1H),7.76(d,J=8.2Hz,1H),7.56(dddd,J= 20.4,8.0,6.8,1.4Hz,2H),7.27(dd,J=8.2,7.2Hz,1H),7.20(d,J=7.8Hz,1H),6.88(td,J=7.5,1.2Hz,1H),6.82( d,J=8.2Hz,1H),6.70(td,J=7.6,1.1Hz,1H),6.59(d,J=7.6Hz,1H),5.72(s,2H),3.82(tdt,J=11.2,7.6,4.1Hz, 1H),2.92(dt,J=12.9,3.6Hz,2H),2.52(td,J=12.2,2.5Hz,2H),1.92-1.83(m,2H),1.27(td,J=12.3,4.2Hz,2H);

[0153] MS-ESI m / z:[M+H] + :357.30.

[0154] Example 12: Synthesis of Compound 12

[0155]

[0156] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3-methoxybenzyl bromide, and the other steps were the same, to obtain compound 12, a white solid with a yield of about 21% and a purity greater than 98%.

[0157] 1 H NMR (400MHz, DMSO-d6) δ7.24-7.16 (m, 2H), 7.02 (dd, J=7.9, 1.2Hz, 1H), 6.91 (td, J=7. 5,1.2Hz,1H),6.84-6.77(m,2H),6.75(t,J=2.0Hz,1H),6.71(dt,J=7.7,1.2Hz,1H),5. 25(s,2H),3.83(dtd,J=11.1,7.2,6.6,3.1Hz,1H),3.69(s,3H),2.98(dt,J=12.4,3.6 Hz,2H),2.56(td,J=12.2,2.5Hz,2H),1.93(dd,J=13.1,3.7Hz,2H),1.45-1.34(m,2H);

[0158] MS-ESI m / z:[M+H] +:337.31.

[0159] Example 13: Synthesis of Compound 13

[0160]

[0161] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 4-trifluoromethylbenzyl bromide, and the other steps were the same, to obtain compound 13, a white solid with a yield of about 22% and a purity greater than 98%.

[0162] 1 H NMR (400MHz, DMSO-d6) δ7.70(d,J=8.0Hz,2H),7.32(d,J=8.1Hz,2H),7.22(d,J= 7.7Hz,1H),7.02(d,J=7.7Hz,1H),6.95(t,J=7.5Hz,1H),6.83(t,J=7.5Hz,1H),5 .43(s,2H),3.89(dp,J=11.1,3.5Hz,1H),3.06(dt,J=12.7,3.6Hz,2H),2.68(td ,J=12.2,2.6Hz,2H),1.98(dd,J=12.9,3.9Hz,2H),1.48(tt,J=11.9,6.0Hz,2H);

[0163] MS-ESI m / z:[M+H] + 375.29.

[0164] Example 14: Synthesis of Compound 14

[0165]

[0166] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3,5-bis(trifluoromethyl)benzyl bromide, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-Boc-4-piperidinemethanol, to obtain compound 14, a white solid with a yield of approximately 23% and a purity greater than 98%.

[0167] 1H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.85(d,J=1.7Hz,2H),7.48-7.43(m,1H),7.38-7.32(m,1H),7.09(pd,J=7.3,1.4Hz,2H),5. 50(s,2H),3.43(dt,J=12.8,3.3Hz,2H),3.27(t,J=5.7Hz,2H),2.90(td,J=12.4,2.4Hz,2H),1.71(dd,J=13.5,3.5Hz,2H),1.60-

[0168] 1.49 (m, 1H), 1.28-1.21 (m, 2H);

[0169] MS-ESI m / z:[M+H] + :458.30.

[0170] Example 15: Synthesis of Compound 15

[0171]

[0172] In the synthesis of compound 7, the starting material 3-fluorobromobenzyl (7b) was replaced with 1-bromomethylnaphthalene, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-Boc-4-piperidinemethanol, to obtain compound 15, a white solid with a yield of approximately 21% and a purity greater than 98%.

[0173] 1 H NMR(400MHz,DMSO-d6)δ8.16(dd,J=8.3,1.5Hz,1H),8.04(dd,J=7.9,1.7Hz,1H),7 .93(d,J=8.3Hz,1H),7.66(dqd,J=8.1,6.9,1.4Hz,2H),7.57(d,J=7.9Hz,1H),7.45 (dd,J=8.3,7.1Hz,1H),7.33(tp,J=8.2,4.3Hz,1H),7.25-7.16(m,3H),5.86(s,2H ),3.71(d,J=13.2Hz,2H),3.27-3.13(m,4H),1.68-1.56(m,3H),1.36-1.26(m,2H);

[0174] MS-ESI m / z:[M+H] + 372.28.

[0175] Example 16: Synthesis of Compound 16

[0176]

[0177] In the synthesis of compound 7, the starting material 3-fluorobromobenzyl (7b) was replaced with 3,5-bis(trifluoromethyl)benzyl bromide, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-Boc-3-aminopyrrolidine, to obtain compound 16, a white solid with a yield of approximately 26% and a purity greater than 98%.

[0178] 1 H NMR (400MHz, DMSO-d6) δ8.04 (s, 1H), 7.82 (s, 2H), 7.30 (d, J = 7.7Hz, 1H), 7.19 (t,J=7.2Hz,2H),7.01(td,J=7.6,1.2Hz,1H),5.51(s,2H),4.52(q,J=6.0Hz, 1H), 3.46 (dd, J=11.8, 6.7Hz, 1H), 3.30 (dt, J=11.4, 7.4Hz, 1H), 3.19 (ddt, J= 19.4,11.7,5.7Hz,2H),2.24(dq,J=14.4,7.3,6.7Hz,1H),2.03-1.93(m,1H);

[0179] MS-ESI m / z:[M+H] + :429.34.

[0180] Example 17: Synthesis of Compound 17

[0181]

[0182] In the synthesis of compound 7, the starting material 3-fluorobromobenzyl (7b) was replaced with 1-bromomethylnaphthalene, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-Boc-3-aminopyrrolidine, to obtain compound 17, a white solid with a yield of approximately 21% and a purity greater than 98%.

[0183] 1H NMR (400MHz, DMSO-d6) δ8.22(d,J=8.3Hz,1H),7.98(dd,J=8.0,1.5Hz,1H),7.82(d,J=8.2Hz,1H ),7.71-7.57(m,2H),7.37-7.24(m,2H),6.99-6.92(m,1H),6.88(d,J=7.7Hz,1H),6.83-6.72(m ,2H),5.79(s,2H),4.38(tq,J=6.9,3.4,2.4Hz,1H),3.05(dd,J=11.3,6.5Hz,1H),2.86(ddd,J= 10.8,8.0,6.2Hz,1H),2.81-2.63(m,2H),2.03(dtd,J=14.0,8.0,6.2Hz,1H),1.71-1.62(m,1H);

[0184] MS-ESI m / z:[M+H] + 343.29.

[0185] Example 18: Synthesis of Compound 18

[0186]

[0187] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3-nitrobenzyl bromide, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-Boc-4-piperidinemethanol, to obtain compound 18, a white solid with a purity greater than 98%.

[0188] 1 H NMR (400MHz, DMSO-d6) δ8.15-8.09(m,2H),7.62(t,J=7.9Hz,1H),7.56(dt,J=7.8,1.5H z,1H),7.48-7.42(m,1H),7.24(dd,J=7.7,1.4Hz,1H),7.07(dtd,J=21.8,7.4,1.3Hz,2H ),5.43(s,2H),3.46(dt,J=12.6,3.2Hz,2H),3.29(t,J=5.6Hz,2H),2.90(td,J=12.3,2 .4Hz,2H),1.71(dd,J=13.4,3.5Hz,2H),1.55(ddt,J=11.1,7.1,3.7Hz,1H),1.32(tt,J=

[0189] 12.2, 6.3 Hz, 2H);

[0190] MS-ESI m / z:[M+H]+ 367.29.

[0191] Example 19: Synthesis of Compound 19

[0192]

[0193] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3-nitrobenzyl bromide, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-Boc-3-aminopyrrolidine, to obtain compound 19, a white solid with a yield of approximately 21% and a purity greater than 98%.

[0194] 1 H NMR (400MHz, DMSO-d6) δ8.15-8.04(m,2H),7.62(t,J=7.9Hz,1H),7.59-7.52(m,1H ),7.24(d,J=7.7Hz,1H),7.09(d,J=7.7Hz,1H),6.95(td,J=7.6,1.2Hz,1H),6.89-

[0195] 6.85(m,1H),5.45(s,2H),4.34(qt,J=6.8,4.3Hz,1H),3.06(dd,J=11.4,6.4Hz,1H),2.92(ddd,J =10.8,8.0,6.4Hz,1H),2.86-2.70(m,2H),2.10-1.96(m,1H),1.70(ddt,J=13.0,7.9,5.2Hz,1H);

[0196] MS-ESI m / z:[M+H] + :338.32.

[0197] Example 20: Synthesis of Compound 20

[0198]

[0199] In the synthesis of compound 7, the starting material 3-fluorobromobenzyl (7b) was replaced with 1-bromomethylnaphthalene, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-tert-butoxycarbonyl-4-aminomethylpiperidine, to obtain compound 20, a white solid with a yield of approximately 16% and a purity greater than 98%.

[0200] 1H NMR (400MHz, DMSO-d6) δ8.16(d,J=8.3Hz,1H),8.03(dd,J=8.1,1.4Hz,1H),7.90(d,J=8.2Hz,1H),7. 68(dddd,J=23.2,8.0,6.9,1.3Hz,2H),7.59(d,J=7.9Hz,1H),7.41-7.29(m,3H),7.22(td,J=7.8,1. 1Hz,1H),6.76-6.66(m,1H),5.96(s,2H),3.38(t,J=6.6Hz,2H),3.29(d,J=12.5Hz,2H),2.84(q,J=1 1.8Hz,2H),1.98(qd,J=8.4,7.8,3.9Hz,1H),1.91-1.81(m,2H),1.32(qd,J=11.4,10.4,6.4Hz,2H);

[0201] MS-ESI m / z:[M+H] + :371.30.

[0202] Example 21: Synthesis of Compound 21

[0203]

[0204] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3,5-bis(trifluoromethyl)benzyl bromide, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-tert-butoxycarbonyl-4-aminomethylpiperidine, to obtain compound 21, a white solid with a yield of approximately 18% and a purity greater than 98%.

[0205] 1 H NMR (400MHz, DMSO-d6) δ8.45(d,J=11.2Hz,1H),8.10(s,1H),8.04(s,2H),7.52(dd,J=7.7,1.4Hz,2H),7.29(pd,J=7.6,1.2Hz,2H),5.62(s,2H),3. 38(t,J=6.6Hz,2H),3.29(d,J=12.6Hz,2H),2.82(q,J=11.8Hz,2H),1.99( ddt,J=14.4,10.2,5.3Hz,1H),1.90-1.82(m,2H),1.34(q,J=10.8Hz,2H);

[0206] MS-ESI m / z:[M+H] + :457.29.

[0207] Example 22: Synthesis of Compound 22

[0208]

[0209] In the synthesis of compound 7, the starting material 3-fluorobenzyl bromide (7b) was replaced with 3-nitrobenzyl bromide, and the starting material 1-Boc-4-aminopiperidine (7d) was replaced with 1-tert-butoxycarbonyl-4-aminomethylpiperidine, to obtain compound 22, a white solid with a yield of approximately 19% and a purity greater than 98%.

[0210] 1 H NMR (400MHz, DMSO-d6) δ8.23-8.13(m,2H),7.73-7.61(m,2H),7.55-7.45(m,2H),7.26(dtd,J=17.9,7.6,1.3Hz,2H),5.61(s,2H),3.40(t,J=6.6H z,2H),3.30(d,J=12.6Hz,2H),2.83(q,J=12.0,11.4Hz,2H),1.99(ddh,J=11.3,7.7,3.7Hz,1H),1.88(dd,J=14.3,3.4Hz,2H),1.42-1.30(m,2H);

[0211] MS-ESI m / z:[M+H] + 366.29.

[0212] Example 23: Synthesis of Compound 23

[0213]

[0214] Take a 10 mL single-necked flask and dissolve compound 23a (1.0 g, 65.61 mmol) and compound 23b (2.6 g, 131.20 mmol) in 5 mL of N-methylpyrrolidone. Heat to 140 °C under nitrogen protection and stir overnight. After the reaction is complete, dilute with 100 mL of a 9:1 (v / v) methanol / dichloromethane mixture. Wash the organic phase three times with 10 mL of saturated sodium bicarbonate solution each time. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography. Elute with a methanol / dichloromethane gradient of 1–5% to obtain intermediate 23c, a white solid with a yield of approximately 28% and a purity greater than 98%. MS-ESI m / z: [M+H]+: 317.30.

[0215] Take a 25 mL single-necked flask and dissolve 23c (300 mg, 0.95 mmol), compound 23d (274.1 mg, 1.23 mmol), and potassium carbonate (270.3 mg, 1.90 mmol) in 6 mL of N,N-dimethylformamide. Heat to 70 °C under nitrogen protection and stir overnight. Dilute the reaction solution with 40 mL of ethyl acetate and adjust the pH to 6 with 5 mL of saturated ammonium chloride solution. Wash the organic phase three times with 1 mol / L lithium chloride solution. Collect the organic phase, dry it with anhydrous sodium sulfate, filter it, and purify the concentrated organic phase under reduced pressure by column chromatography using a methanol / dichloromethane gradient of 1–4%. The intermediate 23e is a white solid with a yield of approximately 16% and a purity greater than 98%.

[0216] Take a 10 mL single-necked flask, dissolve 23e (70 mg, 0.95 mmol) in 2 mL of dichloromethane, add 4 mol / L hydrochloric acid-dioxane solution, react at room temperature for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain a white solid compound 23 with a yield of about 90% and a purity greater than 98%.

[0217] 1 H NMR (400MHz, DMSO-d6) δ9.55(d,J=7.9Hz,1H),9.13(dd,J=4.4,1.7Hz,1H),8.56(dd,J =8.3,1.7Hz,1H),8.07-8.00(m,1H),7.72(dd,J=8.3,4.4Hz,1H),7.64-7.58(m,2H),7. 50(d,J=7.8Hz,1H),7.41(d,J=7.9Hz,1H),7.26(td,J=7.7,1.1Hz,1H),6.06(s,2H),4. 28(dtd,J=11.3,7.5,4.0Hz,1H),3.39(d,J=13.0Hz,2H),3.00(q,J=11.8Hz,2H),2.28-

[0218] 2.19(m,2H), 2.08-1.94(m,2H);

[0219] MS-ESI m / z:[M+H] + :358.34.

[0220] Example 24: Synthesis of Compound 24

[0221]

[0222] In the synthesis of compound 23, the starting material 8-bromomethylquinoline (23d) was replaced with 2-bromomethyl-6-methylpyridine, and the other steps were the same, to obtain compound 24, a white solid with a yield of about 17% and a purity greater than 98%.

[0223] 1 H NMR(400MHz, DMSO-d6)δ8.03(t,J=7.9Hz,1H),7.57-7.49(m,2H),7.46(d,J =7.9Hz,1H),7.34(d,J=7.8Hz,1H),7.29(td,J=7.7,1.2Hz,1H),7.22(td,J= 7.7,1.2Hz,1H),5.75(s,2H),4.25(dt,J=7.2,3.6Hz,1H),3.45-3.32(m,2H) ,3.05-2.91(m,2H),2.63(s,3H),2.22-2.12(m,2H),1.97(q,J=10.5Hz,2H);

[0224] MS-ESI m / z:[M+H] + :322.32.

[0225] Example 25: Synthesis of Compound 25

[0226]

[0227] In the synthesis of compound 23, the starting material 8-bromomethylquinoline (23d) was replaced with 3-nitrobenzyl bromide, and the other steps were the same, to obtain compound 25, a white solid with a yield of approximately 89% and a purity greater than 98%.

[0228] 1 H NMR (400MHz, DMSO-d6) δ8.27(t,J=2.0Hz,1H),8.17(dd,J=8.2,2.3Hz,1H),7.73(dt,J=7 .8,1.4Hz,1H),7.65(t,J=7.9Hz,1H),7.54-7.48(m,1H),7.48-7.42(m,1H),7.26(dtd,J =19.7,7.5,1.2Hz,2H),5.81(s,2H),4.20(dtd,J=11.3,7.6,4.5Hz,1H),3.47-3.36(m,2 H),3.05-2.88(m,2H),2.17(dd,J=13.7,3.7Hz,2H),2.01(tdd,J=13.5,11.1,3.8Hz,2H);

[0229] MS-ESI m / z:[M+H]+ :352.28.

[0230] Example 26: Synthesis of Compound 26

[0231]

[0232] By replacing the starting material 8-bromomethylquinoline (23d) in the synthesis step of compound 23 with benzyl bromide, and keeping the other steps the same, compound 26 was obtained as a white solid with a yield of approximately 92% and a purity greater than 98%.

[0233] 1 H NMR (400MHz, DMSO-d6) δ7.52-7.47(m,1H),7.40-7.21(m,8H),5.62(s,2H),4.21(tdt,J=11.4,8.0,3.9H z,1H),3.39(d,J=12.7Hz,2H),2.98(q,J=11.7Hz,2H),2.17(dd,J=13.7,3.7Hz,2H),2.09-1.95(m,2H);

[0234] MS-ESI m / z:[M+H] + :307.30.

[0235] Example 27: Synthesis of Compound 27

[0236]

[0237] In a 250 mL three-necked flask, compound 27a (6.4 g, 35.95 mmol) dissolved in 90 mL of anhydrous acetonitrile was added. After purging with nitrogen, the mixture was cooled to 0–5 °C in an ice-water bath. A solution of 23b (6.0 g, 29.96 mmol) dissolved in 30 mL of anhydrous acetonitrile was then added dropwise. After the addition was complete, the mixture was reacted at room temperature for 4 h. Once the reaction was complete, the reaction solution was evaporated to dryness, stirred with silica gel, and purified by column chromatography using a methanol / dichloromethane gradient of 1–5% to obtain intermediate 27b.

[0238] In a 100 mL single-necked flask, compounds 27b (3 g, 9.68 mmol) and 27c (1.4 g, 11.62 mmol) were added sequentially and dissolved in 60 mL of anhydrous acetonitrile. After purging with nitrogen and protection, the mixture was reacted at 55 °C for 3 h until complete. The reaction solution was concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography using a methanol / dichloromethane gradient of 1–5% to obtain intermediate 27d.

[0239] In a 250 mL single-necked flask, 27d (5 g, 11.97 mmol) and iodomethane (2.3 mL, 35.90 mmol) dissolved in 100 mL of anhydrous ethanol were added sequentially. After nitrogen purging and protection, the reaction was carried out at 75 °C for 3 h until complete. The reaction solution was concentrated under reduced pressure, stirred with silica gel, and purified by column chromatography using a methanol / dichloromethane gradient elution of 1–5%. The crude product was then purified by reverse-phase column chromatography to obtain intermediate 27e, a gray solid, with a yield of 87%. MS-ESI m / z: [M+H]+: 385.08.

[0240] Take a 10 mL single-necked flask and dissolve 27e (150 mg, 0.39 mmol), 4-fluorobenzyl bromide (0.064 mL, 0.51 mmol), and potassium carbonate (110.3 mg, 0.78 mmol) in 3 mL of N,N-dimethylformamide. Heat to 70 °C under nitrogen protection and stir overnight until the reaction is complete. Pour the reaction solution into a conical flask containing 20 mL of ice water. A white solid precipitates. Filter the solution, and purify the crude product using reverse column chromatography to obtain intermediate 27f.

[0241] Take a 10 mL single-necked flask, dissolve 27f (70 mg, 0.14 mmol) in 2 mL of dichloromethane, add 2 mL of 4 mol / L hydrochloric acid-dioxane solution, react at room temperature for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain a white solid compound 27 with a yield of about 97% and a purity greater than 98%.

[0242] 1 H NMR (400MHz, DMSO-d6) δ7.80(s,1H),7.61(s,1H),7.38(dd,J=8.6,5.3Hz,2H),7.23-7.15(m,2H),5.60(s ,2H),4.18-4.07(m,1H),3.38(d,J=12.6Hz,2H),3.03-2.91(m,2H),2.21-2.06(m,2H),2.03-1.95(m,2H);

[0243] MS-ESI m / z:[M+H] + 393.27.

[0244] Example 28: Synthesis of Compound 28

[0245]

[0246] In the synthesis of compound 27, the starting material 4-fluorobenzyl bromide was replaced with 1-bromomethylnaphthalene, and the other steps were the same, to obtain compound 28, a white solid with a purity greater than 98%.

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=8.3Hz,1H),8.02(d,J=8.0Hz,1H),7.89(d,J=8.2Hz,1H),7.77-7.59(m,4H),7.37(t,J=7.7Hz, 1H),6.70(d,J=7.1Hz,1H),6.05(s,2H),4.21(tdt,J=11.6,7.9,3.7Hz,1H),3.35(d,J=12.6Hz,2H),2.96(q,J=11.9Hz,2H),2.23-

[0248] 2.11(m,2H),1.88(qd,J=13.1,3.8Hz,2H);

[0249] MS-ESI m / z:[M+H] + :425.26.

[0250] Example 29: Synthesis of Compound 29

[0251]

[0252] In the synthesis of compound 27, the starting material 4-fluorobenzyl bromide was replaced with 3-nitrobenzyl bromide, and the other steps were the same, to obtain compound 29, a white solid with a purity greater than 98%.

[0253] 1 H NMR (400MHz, DMSO-d6) δ8.26(t,J=2.0Hz,1H),8.17(dd,J=8.2,2.4Hz,1H),7.87(s,1H),7.71(d,J=7.7Hz,1H),7.68-7.61(m,2H),5.77(s ,2H),4.16(dtt,J=11.2,7.7,3.8Hz,1H),3.38(d,J=12.7Hz,2H),3.01-2.91(m,2H),2.15(dd,J=13.8,3.6Hz,2H),1.99(t,J=11.4Hz,2H);

[0254] MS-ESI m / z:[M+H] + :420.26.

[0255] Example 30: Synthesis of Compound 30

[0256]

[0257] In the synthesis of compound 27, the starting material 4-fluorobenzyl bromide was replaced with 3,5-bis(trifluoromethyl)benzyl bromide, and the other steps were the same, to obtain compound 30, a white solid with a purity greater than 98%.

[0258] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,3H),7.88(s,1H),7.61(s,1H),5.76(s,2H),4.16(dtd,J=11.4,7.6,3.8 Hz,1H),3.39(d,J=12.7Hz,2H),2.97(h,J=9.8Hz,2H),2.14(dd,J=13.8,3.7Hz,2H),2.00-1.90(m,2H);

[0259] MS-ESI m / z:[M+H] + :511.27.

[0260] Example 31: Synthesis of Compound 31

[0261]

[0262] In the synthesis of compound 27, the starting material 4-fluorobenzyl bromide was replaced with 8-bromomethylquinoline, and the other steps were the same, to obtain compound 31, a white solid with a purity greater than 98%.

[0263] 1 H NMR(400MHz, DMSO-d6)δ9.06(dd,J=4.2,1.7Hz,1H),8.49(dd,J=8.3,1.8Hz,1H),8.00(dd,J=8.3,1.4Hz,1H),7.68(q,J=4.0Hz,2H),7.64-7.54(m,2H), 7.48(dd,J=7.2,1.4Hz,1H),5.91(s,2H),4.12-3.98(m,1H),3.39(d,J=12. 6Hz,2H),3.02(q,J=11.8Hz,2H),2.22-2.13(m,2H),1.77(q,J=10.3Hz,2H);

[0264] MS-ESI m / z:[M+H] + :426.31.

[0265] Example 32: Synthesis of Compound 32

[0266]

[0267] In the synthesis of compound 27, the starting material 4,5-dichloro-1,2-phenylenediamine (27c) was replaced with 4,5-dimethyl-1,2-phenylenediamine, and the starting material 4-fluorobenzyl bromide was replaced with 1-bromomethylnaphthalene. The other steps were the same, and compound 32 was obtained, a white solid with a purity greater than 98%.

[0268] 1 H NMR (400MHz, DMSO-d6) δ9.09 (d, J = 7.9 Hz, 1H), 8.19-8.12 (m, 1H), 8.02 (dd, J = 8.2, 1. 5Hz,1H),7.88(d,J=8.3Hz,1H),7.67(dddd,J=24.2,8.0,6.8,1.3Hz,2H),7.40-7.33( m,2H),7.11(s,1H),6.00(s,2H),4.21(dp,J=11.1,4.8,3.7Hz,1H),3.36(d,J=12.7Hz ,2H),2.97(q,J=11.9Hz,2H),2.29(s,3H),2.15(d,J=16.9Hz,5H),1.92-1.80(m,2H);

[0269] MS-ESI m / z:[M+H]+:385.34.

[0270] Example 33: Synthesis of Compound 33

[0271]

[0272] In the synthesis of compound 27, the starting material 4,5-dichloro-1,2-phenylenediamine (27c) was replaced with 4,5-dimethyl-1,2-phenylenediamine, and the starting material 4-fluorobenzyl bromide was replaced with 3-nitrobenzyl bromide. The other steps were the same, and compound 33 was obtained, a white solid with a purity greater than 98%.

[0273] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=2.3Hz,1H),8.16(dt,J=6.9,2.3Hz,1H),7.66(d,J=7.0Hz,2H),7.27(s,2H),5.74(s,2H),4.24 -4.13(m,1H),3.39(d,J=12.9Hz,2H),2.98(t,J=11.6Hz,2H),2.26(d,J=16.2Hz,6H),2.17-2.11(m,2H),1.98(t,J=11.5Hz,2H);

[0274] MS-ESI m / z:[M+H] + :380.31.

[0275] Example 34: Synthesis of Compound 34

[0276]

[0277] In the synthesis of compound 27, the starting material 4,5-dichloro-1,2-phenylenediamine (27c) was replaced with 4,5-dimethyl-1,2-phenylenediamine, and the starting material 4-fluorobenzyl bromide was replaced with 3,5-bis(trifluoromethyl)benzyl bromide. The other steps were the same, and compound 34 was obtained, a white solid with a purity greater than 98%.

[0278] 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),8.05(s,2H),7.28(d,J=10.4Hz,2H),5.76(s,2H),4.18(dtd,J=11.1,7.4,3.9Hz,1H) ,3.37(s,2H),3.02-2.91(m,2H),2.26(d,J=16.2Hz,6H),2.14(dd,J=13.1,3.5Hz,2H),1.97(td,J=11.1,10.6,5.3Hz,2H);

[0279] MS-ESI m / z:[M+H] + :471.32.

[0280] Example 35: Synthesis of Compound 35

[0281]

[0282] In the synthesis of compound 27, the starting material 4,5-dichloro-1,2-phenylenediamine (27c) was replaced with 4,5-dimethyl-1,2-phenylenediamine, and the starting material 4-fluorobromobenzyl was replaced with 8-bromomethylquinoline. The other steps were the same, and compound 35 was obtained, a white solid with a purity greater than 98%.

[0283] 1H NMR (400MHz, DMSO-d6) δ9.36(d,J=7.9Hz,1H),9.13(dd,J=4.3,1.7Hz,1H),8.54(dd,J=8.3 ,1.8Hz,1H),8.02(dd,J=8.3,1.4Hz,1H),7.71(dd,J=8.3,4.3Hz,1H),7.59(t,J=7.7Hz,1H) ,7.48(dd,J=7.1,1.3Hz,1H),7.28(s,1H),5.99(s,2H),4.23(dtt,J=11.3,7.9,3.9Hz,1H) ,3.38(d,J=12.9Hz,2H),2.99(q,J=11.9Hz,2H),2.22(d,J=26.7Hz,8H),2.07-1.94(m,2H);

[0284] MS-ESI m / z:[M+H] + 386.37.

[0285] Experimental Example: Activity Test

[0286] The full-length human USP7 coding gene sequence was synthesized by Shanghai Jereh Biotechnology Co., Ltd. and constructed into the pET28a vector. Using the wild-type USP7 plasmid as a template, the USP7 CD-UBL45 protein and the Hao-Fountain syndrome mutant USP7 were obtained through homologous recombination or PCR. 1-575 The mutants USP7 L757P, USP7 I766T, and USP7 D1080N were all confirmed by Sanger sequencing.

[0287] The protein sample and compound were incubated on a 96-well black plate for 15 minutes. Then, the substrate UbAMC of USP7 was added to the wells to initiate the hydrolysis reaction at 37°C. The total reaction volume was 200 μL. USP7... 1-575 The protein concentration was 50 nM, and the concentrations of USP7 L757P, USP7 I766T, and USP7 D1080N proteins were 20 nM. The final concentration of Ub-AMC was 250 nM. The reaction buffer consisted of 22 mM Tris, 220 mM NaCl, 5 mM DTT, 2% DMSO, and pH 7.5. The fluorescence intensity generated during the enzyme activity reaction was recorded in real time using a microplate reader. The excitation wavelength was set to 380 nm, and the emission wavelength was set to 460 nm. The concentration required to activate the enzyme activity of USP7 and its pathogenic mutants to 1.5 times the normal value, EC, was calculated using the following formula. 1.5 .

[0288]

[0289] Where V x / V0 is the enzyme reaction rate of the agonist at concentration X divided by the enzyme reaction rate of the DMSO control group. RV max It is the maximum enzyme reaction rate that an agonist can stimulate.

[0290] Following the experimental method described above, the compound was tested at a concentration of 50 μM to assess its agonistic activity against the USP7 CD-UBL45 protein. The results are shown in Table 1.

[0291] Table 1. Results of the determination of the agonistic activity of the compounds against USP7 protein

[0292]

[0293]

[0294] Astemizole (compound 36) and compounds 17 and 34 were tested to activate the pathogenic USP7 mutant. 1-575 The deubiquitin hydrolase activity of USP7 L757P, USP7 I766T and USP7 D1080N is shown in the figure. Figure 1 And Table 2.

[0295] Table 2. Activation of EC by USP7 pathogenic mutants of compounds 17 and 34 1.5 Value measurement results

[0296]

[0297] Figure 1 This indicates that astemizole can significantly activate the pathogenic USP7 mutant. 1-575 The deubiquitin hydrolase activities of USP7 L757P, USP7 I766T, and USP7 D1080N were measured, and the corresponding EC values ​​were determined. 1.5 The value is between 1 μM and 22 μM.

[0298] Table 2 shows that the compound of Formula I of this invention can significantly activate the pathogenic mutant USP7. 1-575 The deubiquitin hydrolase activities of USP7L757P, USP7I766T and USP7D1080N.

Claims

1. The use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a USP7 agonist. in, X 1 X 2 X 3 X 4 Each independently selected from CR a Or N; especially CR a ; L is selected from CR b R c Or it may not exist; especially CH2; Y is selected from NH, O, S, and NHCR. b R c OCR b R c or SCR b R c ; Cy is selected from C3-C10 cycloalkyl groups, 4-8 membered heterocycles, 7-15 membered spirocycles, 7-15 membered bridged rings, and 7-15 membered fused rings, wherein the above rings are optionally further divided by one or more R groups. d replace; R 1 The groups are selected from C6-C10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups, preferably selected from phenyl, naphthyl, quinolinyl, naphthidyl, pyridyl, and indoleyl; the above groups are optionally surrounded by one or more R groups. e replace; R 2 Selected from H, C6-C10 aryl, 5-10-membered heteroaryl, 3-10-membered heterocyclic, -(C1-C4 alkyl)-(C6-C10)aryl, -(C1-C4 alkyl)-(5-10-membered)heteroaryl, -(C1-C4 alkyl)-(3-10-membered)heterocyclic, -(C3-C6 cycloalkyl)-(C6-C10)aryl, -(C3-C6 cycloalkyl)-(5-10-membered)heteroaryl, -(C3-C6 cycloalkyl)-(5-10-membered)heterocyclic, wherein the above aryl, heteroaryl, heterocyclic, alkyl, and cycloalkyl groups are optionally separated by one or more R groups. f replace; Each R a The group is independently selected from H, deuterium (D), halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -COOH, -NH2, NO2, -CN, wherein the above C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by one or more substituents selected from the group consisting of: halogen, -CN, -NH2, nitro, COOH; R b R c Each is independently selected from H, D, C1-C4 alkyl groups, especially H, D, C1-C2 alkyl groups; R d R e and R f Each of the following groups is independently selected from D, -OH, -COOH, -NH2, -NO2, -CN, =O, =S, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C6-C10 aryl, 5-10 heteroaryl, C3-C8 cycloalkyl, 3-8 heterocyclic, wherein the above alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more substituents selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, halogen, -CN, -OH, -NO2, -COOH, =O.

2. The application according to claim 1, wherein, Compounds of Formula I are selected from compounds of Formula I-1 below: in, R a1 and R a2 Independently selected from H, deuterium (D), halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH, -COOH, -NH2, NO2, -CN, wherein the above-mentioned C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more substituents selected from the group consisting of: halogen, -CN, -NH2, nitro, COOH; particularly, R a1 and R a2 Independently selected from H, deuterium (D), halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups; more particularly, R a1 and R a2 Same, selected from H, Cl, F, C1-C2 alkyl; Z1 is CR e5 Or N; preferably CR e5 ; R e1 R e2 R e3 R e4 and R e5 Independently selected from H, D, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, nitro, amino, hydroxyl; particularly, R e1 R e2 R e3 R e4 and R e5 Independently selected from H, D, F, Cl, Br, C1-C2 alkyl, fluoroC1-C2 alkyl, chloroC1-C2 alkyl, C1-C2 alkoxy, fluoroC1-C2 alkoxy, nitro, amino, hydroxyl; more particularly, R e1 R e2 R e3 R e4 and R e5 Independently selected from H, D, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro; or R e1 R e2 R e3 R e4 and R e5 The two adjacent groups and the carbon atoms attached to them together form a benzene ring or a 5-6 membered heteroaromatic ring, preferably a benzene ring or a pyridine ring; the benzene ring or heteroaromatic ring is optionally surrounded by 1-4 R groups. e6 replace; Z2 is either O(CH2)m or NH(CH2)m; m, p, and q are independently 0, 1, 2, 3, or 4; and p + q is at least 2; in particular, m is 0 or 1; p and q are independently 1, 2, or 3; Z3 is CHR 2 or NR 2 ; R 2 The definition is the same as in claim 1, and in particular, R 2 Selected from H, -NH2, -(C1-C4 alkyl)phenyl, -(C1-C4 alkyl)5-6 heteroaryl, particularly R 2 Selected from H, -NH2, -(C1-C2 alkyl)phenyl, -(C1-C2 alkyl)pyridyl, wherein the phenyl group and the 5-6 heteroaryl group are optionally surrounded by 1-4 R groups. e6 replace; The R e6 Independently selected from D, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, nitro, amino, hydroxyl; particularly independently selected from D, F, Cl, Br, C1-C2 alkyl, fluoro-C1-C2 alkyl, chloro-C1-C2 alkyl, C1-C2 alkoxy, fluoro-C1-C2 alkoxy, nitro, amino, hydroxyl; even more particularly independently selected from D, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro.

3. The application according to claim 1, wherein, Compounds of Formula I are selected from the following compounds I-1-1 and I-1-2: Among them, R a1 R a2 The definition is the same as in claim 1, and in particular, R a1 and R a2 Same, selected from H, Cl, methyl; R e1 R e2 R e3 and R e4 The definition is the same as in claim 1, and in particular, R e1 R e2 R e3 and R e4 Independently selected from H, D, F, Cl, methyl, trifluoromethyl, methoxy, nitro; and R e1 R e2 R e3 and R e4 At least two are H; Or R e1 and R e2 Together with the carbon atoms attached to them, they form a benzene ring or a pyridine ring, R e3 R e4 The definition is the same as in claim 1, and preferably H; Z1 is CH or N, preferably CH; Z2 can be O, OCH2, NH, or NHCH2; p and q are independently 1, 2, or 3; R 2 The group is selected from H, -(C1-C2 alkyl)phenyl, and -(C1-C2 alkyl)pyridyl, wherein the phenyl and pyridyl groups are optionally surrounded by 1-4 R groups. e6 replace; R e6 The definition is the same as in claim 1, and in particular, the R e6 It is independently selected from D, F, Cl, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

4. The application according to claim 1, wherein, Compounds of Formula I are selected from the following compounds I-1-1-1 and I-1-1-2: Among them, R a1 R a2 The definition is the same as in claim 1, and in particular, R a1 and R a2 Same, selected from H, Cl, methyl; R e2 R e3 and R e4 The definition is the same as in claim 1, and in particular, R e2 R e3 and R e4 Independently selected from H, D, F, Cl, methyl, trifluoromethyl, methoxy, nitro; and R e2 R e3 and R e4 At least one is H; Z1 is CH or N, preferably CH; Z2 can be O, OCH2, NH, or NHCH2.

5. The application according to claim 1, wherein, Compounds of Formula I are selected from the following compounds I-1-1-3 and I-1-1-4: Among them, R a1 R a2 The definition is the same as in claim 1, and in particular, R a1 and R a2 Same, selected from H, Cl, methyl; R e3 and R e4 The definition is the same as in claim 1, and in particular, R e3 and R e4 For H; Z1 is CH or N, preferably CH; Z4 is CH or N; Z2 can be O, OCH2, NH, or NHCH2.

6. The application according to claim 1, wherein, Compounds of Formula I are selected from the following compounds:

7. The application according to any one of claims 1-6, wherein, The USP7 agonist comprises a therapeutically effective amount of one or more compounds selected from the formula I compound of any one of claims 1-6 and pharmaceutically acceptable salts thereof, and optionally a pharmaceutically acceptable carrier.

8. The application according to any one of claims 1-6, wherein, The USP7 agonist is a medicine used to prevent and / or treat diseases that are improved by activating USP7.

9. The application according to claim 8, wherein, The conditions that are improved by stimulating USP7 include childhood neurodevelopmental disorders and Hao-Fountain syndrome.

10. The application according to claim 9, wherein, The neurodevelopmental disorders in children include developmental delay and autism spectrum disorder.

Images