4, 4-disubstituted piperidine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a 4, 4-disubstituted piperidine OGA inhibitor with a new structure, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention relates to a 4, 4-disubstituted piperidine compound with a new structure as shown in a formula I, a pharmaceutically acceptable salt and a preparation method thereof, a composition containing one or more of the compounds, and applications of the compounds in inhibition of OGA and treatment of OGA-related diseases, such as OGA-related diseases, OGA-related diseases, OGA-related diseases, OGA-related diseases, OGA-related diseases, OGA-related diseases and OGA-related diseases. The invention further discloses application of the compound in preparation of drugs for preventing and / or treating neurodegenerative diseases, metabolic diseases, cancers, immune system diseases, cardiovascular and cerebrovascular diseases and eye diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to 4,4-disubstituted piperidine compounds of a novel structure represented by Formula I, pharmaceutically acceptable salts thereof and methods for preparing the same, compositions containing one or more such compounds, and uses of such compounds in inhibiting OGA and treating OGA-related diseases, and in preparing, preventing and / or treating drugs for neurodegenerative diseases, metabolic diseases, cancer, immune system diseases, cardiovascular and cerebrovascular diseases, and eye diseases.

[0002] Background Art

[0003] O-linked β-N-acetylglucosamine modification (O-GlcNAc) is a post-translational modification (PTM) of proteins that reversibly binds N-acetylglucosamine (GlcNAc) to serine (Ser) or threonine (Thr) residues on proteins. This process is regulated by two enzymes: O-GlcNAc transferase (OGT), which transfers GlcNAc to Ser or Thr residues on proteins, and the corresponding O-GlcNAc glycoside hydrolase (O-GlcNAcase, OGA), which hydrolyzes GlcNAc from proteins (Nature Reviews Molecular Cell Biology 2017, 18(7), 452-465).

[0004] O-GlcNAc-modified substrates are numerous and widely distributed, playing an important role in various cellular life activities such as participating in the cell cycle, regulating signal pathways, and regulating protein function. Maintaining the homeostasis of O-GlcNAc is crucial for maintaining the body's life and health. When O-GlcNAc regulation is out of balance, it will cause a variety of diseases such as neurodegenerative diseases, diabetes, cancer, immune system diseases, cardiovascular and cerebrovascular diseases (PhysiologicalReviews 2021, 101(2), 427-493).

[0005] Neurodegenerative diseases (NDs) are characterized by delayed declines in cognition, memory, or motor function. Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are common NDs. The growing number of NDs has brought serious social and economic pressures, but there is no effective treatment for NDs, which is a huge challenge that the scientific community is working to overcome (Cell 2023, 186(4), 693-714).

[0006] Although O-GlcNAc is ubiquitous in different cell types, the enrichment level of O-GlcNAc in the brain is much higher than in the periphery, and the expression levels and enzyme activities of OGT and OGA are increased in the brain. In the past decade, with the gradual deepening of biological research, researchers have found that O-GlcNAc modifies many NDs-related proteins such as tau, α-synuclein, and neurofilament protein, and participates in cellular mechanisms such as autophagy and necrosis, proving that O-GlcNAc plays a key protective role in the brain and is considered to be a brain neuroprotective mechanism. In many NDs models, increasing the level of O-GlcNAc in the brain has a therapeutic effect, and regulating the level of O-GlcNAc in the brain has become a potential NDs treatment strategy. Therefore, OGA has become a potential drug target for the treatment of NDs, and the development of OGA inhibitors has also become a very attractive NDs drug research and development direction (Biochemical Journal 2021, 478 (14), 2733-2758).

[0007] Currently reported OGA inhibitors are mainly divided into two categories: carbohydrate small molecule inhibitors and non-carbohydrate small molecule inhibitors. PUGNAc has a strong inhibitory activity against OGA (hOGA K i =46 nM), but with low selectivity (hHex K i =36nM). NAG-thiazoline also has poor selectivity (hOGA K i =180nM,hHexA&BK i =70nM), and after structural optimization, NButGT (hOGA K i =230nM,hHexB K i =340μM) was increased to 1500 times (Journal of Biological Chemistry 2005, 280(27), 25313-25322). Further optimization resulted in the compound thiamet-G (hOGA K i =21nM,hHexBK i=750μM), the selectivity was increased to 37000 times (Nature Chemical Biology 2008, 4(8), 483-490). Thiamet-G has been used in a variety of disease model studies and has become a very important tool for O-GlcNAc biological research. Thiamet-G has the problems of high polarity and low membrane permeability. In order to improve its physical and chemical properties, researchers have developed its difluoromethyl substituted MK-8719 (hOGA K i =7.9nM), MK-8719 has entered Phase I clinical trials for the treatment of tauopathies (Journal of Medicinal Chemistry 2019, 62(22), 10062-10097).

[0008] Jassen reported a class of spirocyclic OGA non-carbohydrate small molecule inhibitors, among which the preferred compound (+)-56 has good inhibitory activity and pharmacokinetic properties (hOGA IC 50 =9nM,cell IC 50 =39nM)(Journal of Medicinal Chemistry 2020, 63(22), 14017-14044). Takeda Pharmaceutical Company obtained aminopyrimidine skeleton OGA inhibitors based on virtual screening, and preferred compound 5i (hOGAIC 50 =46nM,cell IC 50 =450nM) has good membrane permeability and can penetrate the blood-brain barrier (Journal of Medicinal Chemistry 2021, 64(2), 1103-1115). Cho et al. reported a class of OGA inhibitors based on receptor design with piperidine or piperazine as the skeleton, among which compound 39 (IC 50 =40nM) has therapeutic effects in AD mouse models (European Journal of Medicinal Chemistry 2022, 238). Asceneuron Company obtained OGA inhibitors with 1,4-substituted piperazine as the skeleton through high-throughput screening and structural design modification, among which the preferred compound ASN90 (hOGA IC 50 =10.2nM,cellIC 50 =320nM) has become a candidate drug for the treatment of AD and PD and has entered Phase I clinical trials (ACS Chemical Neuroscience 2022, 13(8), 1296-1314). LY3372689 (hOGA IC) developed by Eli Lilly 50=2.36nM,cell IC 50 =21.9nM) has entered Phase II clinical trials (WO2022020663). Other non-carbohydrate small molecule OGA inhibitors are disclosed in patents, such as the pyrrolidine-based OGA inhibitor reported in WO2020061150 and the 1,3-substituted piperidine-based OGA inhibitor reported in WO2019178191.

[0009] Although various structural types of OGA inhibitors have been reported, only MK-8719, ASN90, and LY3372689 have entered clinical development, and no officially marketed drugs have yet been developed. Therefore, the development of novel, highly effective, and druggable non-carbohydrate small molecule OGA inhibitors with favorable pharmacokinetic properties, blood-brain barrier penetration, and potential for druggability is of great clinical significance.

[0010] The present invention designs and synthesizes a novel 4,4-disubstituted piperidine OGA inhibitor, which has significant inhibitory activity against OGA and provides a new material basis for treating diseases associated with OGA. Summary of the Invention

[0011] The technical problem solved by the present invention is to provide 4,4-disubstituted piperidine compounds and physiologically acceptable salts of formula I, preparation methods and pharmaceutical compositions thereof, and their use in preparing OGA inhibitors and potential drugs thereof, and in preparing drugs for treating neurodegenerative diseases, metabolic diseases, cancer, immune system diseases, cardiovascular and cerebrovascular diseases, and eye diseases.

[0012] In order to solve the technical problems of the invention, the present invention provides the following technical solutions:

[0013] The first aspect of the technical solution of the present invention is to provide a 4,4-disubstituted piperidine derivative or a physiologically acceptable salt thereof as shown in the general formula I:

[0014]

[0015] In Formula 1,

[0016] Chiral carbon atoms can be in R or S configuration;

[0017] A is selected from CH2CH2, a cis double bond, and a trans double bond;

[0018] Y1 is selected from CH, CF, N; Y2 is selected from CH, N;

[0019] R3 is selected from CH3;

[0020] R2 is selected from:

[0021] (1)F, Cl, Br, ORa1 , where the R a1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl, CH2Ar1, CH2CH2Ar1, wherein the Ar1 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0022] (2) substituted or unsubstituted C1, C2, C3, C4 straight chain or branched alkyl, wherein the substituent is selected from F, OR b1 , R b1 Selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl;

[0023] (3) CH2Ar2, CH2CH2Ar2, wherein Ar2 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0024] Ar is selected from:

[0025] (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures:

[0026]

[0027] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0028] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures:

[0029]

[0030] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、Re11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0031] The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

[0032] The second aspect of the technical solution of the present invention is to provide a general formula I A The 4,4-disubstituted piperidine derivatives or physiologically acceptable salts thereof are shown:

[0033]

[0034] In Formula I A middle,

[0035] Chiral carbon atoms can be in R or S configuration;

[0036] R3 is selected from CH3;

[0037] R2 is selected from:

[0038] (1)F, Cl, Br, OR a1 , where the R a1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl, CH2Ar1, CH2CH2Ar1, wherein the Ar1 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NRc9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0039] (2) substituted or unsubstituted C1, C2, C3, C4 straight chain or branched alkyl, wherein the substituent is selected from F, OR b1 , R b1 Selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl;

[0040] (3) CH2Ar2, CH2CH2Ar2, wherein Ar2 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 Rd5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0041] Ar is selected from:

[0042] (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures:

[0043]

[0044] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COORc7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0045] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures:

[0046]

[0047] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0048] The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

[0049] The third aspect of the technical solution of the present invention is to provide a compound of formula I A -1 or a physiologically acceptable salt thereof:

[0050]

[0051] In Formula I A -1 in,

[0052] Chiral carbon atoms can be in R or S configuration;

[0053] R3 is selected from CH3;

[0054] Ar is selected from:

[0055] (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures:

[0056]

[0057] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0058] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures:

[0059]

[0060] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0061] The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

[0062] The fourth aspect of the technical solution of the present invention is to provide a general formula I B The 4,4-disubstituted piperidine derivatives or physiologically acceptable salts thereof are shown:

[0063]

[0064] In Formula I B middle,

[0065] A is selected from a cis double bond and a trans double bond;

[0066] R2 is selected from:

[0067] (1)F, Cl, Br, OR a1 , where the R a1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl, CH2Ar1, CH2CH2Ar1, wherein the Ar1 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、Rc8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0068] (2) substituted or unsubstituted C1, C2, C3, C4 straight chain or branched alkyl, wherein the substituent is selected from F, OR b1 , R b1 Selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl;

[0069] (3) CH2Ar2, CH2CH2Ar2, wherein Ar2 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、Rc6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0070] Ar is selected from:

[0071] (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures:

[0072]

[0073] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、Rd5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0074] (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures:

[0075]

[0076] wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F;

[0077] The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

[0078] In the fifth aspect of the technical solution of the present invention, in order to achieve the purpose of the present invention, preferred compounds include but are not limited to:

[0079]

[0080]

[0081] The sixth aspect of the technical solution of the present invention provides a method for preparing the compounds described in aspects 1 to 5, wherein the technical solution adopted comprises the following steps:

[0082] i. Using 2-aminothiazole-5-carboxylic acid ethyl thiazole (1) as a raw material, an acylation reaction is performed to obtain an intermediate (2);

[0083] ii. intermediate (2) undergoes reduction reaction to obtain intermediate (3);

[0084] iii. Intermediate (3) undergoes substitution reaction to obtain key intermediate (4);

[0085] iv. Using substituted N-Boc-4-piperidone (5) as a raw material, an addition reaction is carried out with trimethylsilyl acetylene to obtain an intermediate (6);

[0086] v. Removing the silicon protecting group from the intermediate (6) to obtain the intermediate (7);

[0087] vi. Intermediate (7) is subjected to Sonogashira coupling reaction to obtain intermediate (8);

[0088] vii. Intermediate (8) undergoes substitution reaction to obtain intermediate (9);

[0089] viii. Intermediate (9) is subjected to reduction reaction to obtain intermediate (10);

[0090] ix. Removal of the Boc protecting group from intermediate (10) to obtain the key intermediate (11);

[0091] x, intermediate (11) and intermediate (4) undergo substitution reaction under alkaline conditions to obtain a compound represented by general formula I (Scheme 1);

[0092] Scheme 1

[0093]

[0094] Scheme 1. Reagents and conditions: (i) Acetyl chloride, TEA, DCM, 0℃; (ii) Li(Et)3BH, Toluene, -15℃; (iii) SOCl2, DCM, 0℃; (iv) Ethynyltrimethylsilane, n-BuLi, THF, Argon, -78℃; (v) TABF, THF, 0℃; (vi) ArX(X=Cl, Br, I), PdCl2(PPh3)2, CuI, TEA, Argon, 60℃; (vii) RX(X=F, Cl, Br, I), THF / DMF / DCM, Argon, 0℃; (viii) Pd-C, H2, MeOH, rt; (ix) TFA, DCM, rt; (x) TEA, MeCN, rt wherein the definitions of Y1, Y2, A, R2, R3, and Ar are consistent with those described in any one of claims 1-4.

[0095] The starting materials and intermediates in the above reactions are readily available, and each step can be readily synthesized using conventional methods in organic synthesis, according to published literature or known to those skilled in the art. The compound of Formula I may exist as a solvate or an unsolvate, and different solvates may be obtained by crystallization using different solvents. Pharmaceutically acceptable salts of Formula I include salts of various acids, such as the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, and lactic acid. Pharmaceutically acceptable salts of Formula I also include various alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts), and ammonium salts, as well as salts of organic bases that provide physiologically acceptable cations, such as salts of methylamine, dimethylamine, trimethylamine, piperidine, morpholine, and tris(2-hydroxyethyl)amine. All of these salts within the scope of the present invention can be prepared using conventional methods.

[0096] The seventh aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises the compound or pharmaceutically acceptable salt thereof as described in the first to fifth aspects of the technical solution of the present invention and a commonly used pharmaceutical carrier.

[0097] The composition comprises at least one compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release formulations, controlled-release formulations, or various microparticle delivery systems. The pharmaceutical composition can be prepared according to methods well known in the art. The compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form suitable for human or animal use. The content of the compound of the present invention in the pharmaceutical composition is generally 0.1-95% by weight.

[0098] The compounds of the present invention or pharmaceutical compositions containing the same can be administered in unit dosage forms, and the routes of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc. The dosage form can be a liquid dosage form, a solid dosage form, or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types, and multiple emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc.

[0099] The compounds of the present invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems. These formulations are prepared according to methods well known to those skilled in the art. Excipients used in the manufacture of tablets, capsules, and coatings are conventional adjuvants, such as starch, gelatin, gum arabic, silica, and polyethylene glycol. Solvents used in liquid dosage forms include, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Formulations containing the compounds of the present invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and pigments.

[0100] In order to prepare the compound of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropyl alcohol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, etc.; lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0101] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0102] To prepare the dosing unit as a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard or soft capsule. Alternatively, the active ingredient compound of the present invention can be first mixed with a diluent, a binder, and a disintegrant to form granules or pellets, which are then placed in a hard or soft capsule. The diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0103] To prepare the compounds of the present invention as injections, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of solubilizers, cosolvents, pH adjusters, and osmotic pressure regulators commonly used in the art can be added. Examples of solubilizers or cosolvents include poloxamer, lecithin, and hydroxypropyl-β-cyclodextrin; pH adjusters include phosphates, acetates, hydrochloric acid, and sodium hydroxide; and osmotic pressure regulators include sodium chloride, mannitol, glucose, phosphates, and acetates. For lyophilized powder injections, mannitol, glucose, and the like can also be added as support agents.

[0104] Furthermore, if necessary, colorants, preservatives, perfumes, flavorings or other additives may be added to the pharmaceutical preparations.

[0105] To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known method of administration.

[0106] The dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally speaking, a suitable daily dosage range of the compound of the present invention is 0.1-1000 mg / kg body weight, preferably 1-500 mg / kg body weight. The above dosage can be administered as a single dosage unit or divided into several dosage units, depending on the clinician's clinical experience and the dosage regimen including the use of other therapeutic means.

[0107] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0108] The eighth aspect of the technical solution of the present invention provides the use of the compounds or pharmaceutically acceptable salts thereof described in aspects 1 to 5 of the present invention in preparing OGA inhibitors, in preparing medicaments for preventing and / or treating diseases related to OGA, in preparing medicaments for treating neurodegenerative diseases, metabolic diseases, cancer, immune system diseases, cardiovascular and cerebrovascular diseases, and eye diseases, especially in preparing medicaments related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, frontotemporal lobar degeneration, Lewy body dementia, multiple system atrophy, Down syndrome, and epilepsy.

[0109] Beneficial technical effects

[0110] The 4,4-disubstituted piperidine compounds in this patent application are OGA inhibitors with a completely new structure, have significant inhibitory activity against OGA, and are potential therapeutic drugs for OGA-related diseases. DETAILED DESCRIPTION

[0111] The invention will be further described below with reference to the following embodiments, but the scope of the invention is not limited thereto.

[0112] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) or high-resolution mass spectrometry (HRMS). NMR measurements were performed on a JEOL ECZ-400S or Quantum-IPlus 500 MHz instrument, using CDCl₃, DMSO-d₆, and MeOH-d₄ as the solvents, TMS as the internal standard, and chemical shifts (δ) in ppm. HRMS measurements were performed on a Thermo Exactive Plus instrument. Melting points (mp) are reported in °C using a Yanaco micro-melting point apparatus, and temperatures are uncorrected. Silica gel column chromatography was performed using 200-300 mesh silica gel as the support.

[0113] List of abbreviations:

[0114] DCM: dichloromethane; EA: ethyl acetate; MeOH: methanol; THF: tetrahydrofuran; PE: petroleum ether;

[0115] DMF: N,N-dimethylformamide; MeCN: acetonitrile;

[0116] TEA: triethylamine; DIEA: N,N-diisopropylethylamine; NaH: sodium hydrogen; TFA: trifluoroacetic acid;

[0117] SOCl2: thionyl chloride; TABF: tetrabutylammonium fluoride; DAST: diethylaminosulfur trifluoride; LiAlH4: lithium aluminum hydride; LDA: lithium diisopropylamide; Li(Et)3BH: lithium triethylborohydride;

[0118] NaBH3CN: sodium cyanoborohydride; PdCl2(PPh3)2: bis(triphenylphosphine)palladium dichloride;

[0119] CuI: copper iodide; NH4Cl: ammonium chloride; NaCl: sodium chloride; NaHCO3: sodium bicarbonate;

[0120] K2CO3: potassium carbonate; Na2S2SO3: sodium thiosulfate; NaOAc: sodium acetate;

[0121] E:P: ethyl acetate: petroleum ether; M:D: methanol: dichloromethane; SiO2: chromatography silica gel;

[0122] Ar: argon; min: minute; h: hour;

[0123] CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; MeOH-d4: deuterated methanol TLC: thin-layer chromatography

[0124] Preparation of intermediates:

[0125] 1.(1) Synthesis of N-(5-(chloromethyl)thiazol-2-yl)acetamide (Intermediate 1-1)

[0126]

[0127] a. Ethyl 2-acetylaminothiazole-5-carboxylate

[0128]

[0129] Ethyl 2-aminothiazole-5-carboxylate (10 g, 58.07 mmol) was placed in a dry reaction flask, and ultra-dry DCM (150 mL) was added. TEA (16.14 mL, 116.14 mmol) was added under an ice-water bath. After stirring for 10 minutes, acetyl chloride (4.96 mL, 69.69 mmol) was slowly added dropwise using a constant pressure dropping funnel. The reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was poured into a Buchner funnel and filtered with suction. The filter cake was washed with water and dried to obtain 10.70 g of a white solid with a yield of 86%.

[0130] 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 12.56 (s, 1H), 8.12 (s, 1H), 4.27 (q, J = 7.5Hz, 2H), 2.19 (s, 3H), 1.29 (t, J = 7.5Hz, 3H).

[0131] bN-(5-(Hydroxymethyl)thiazol-2-yl)acetamide

[0132]

[0133] The compound ethyl 2-acetylaminothiazole-5-carboxylate (10 g, 46.68 mmol) was placed in a dry reaction flask, anhydrous toluene (130 mL) was added, and the reaction solution was cooled to -15°C. A 1M Li(Et)3BH solution in THF (186.7 mL, 186.71 mmol) was slowly added dropwise using a constant pressure dropping funnel. The reaction was allowed to proceed at -15°C for 15 min. The reaction solution was slowly poured into ice water in batches to quench the reaction. After extraction with water, the aqueous phases were combined and glacial acetic acid was added dropwise to the aqueous phases to precipitate a white solid. The solid was filtered, the filter cake was washed with water, and dried to obtain 7.23 g of a white solid with a yield of 90%.

[0134] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.94 (s, 1H), 7.25 (s, 1H), 5.34 (t, J = 5.6Hz, 1H), 4.57 (dd, J1 = 6.0Hz, J2 = 0.8Hz, 2H), 2.12 (s, 3H).

[0135] cN-(5-(Chloromethyl)thiazol-2-yl)acetamide

[0136]

[0137] The compound N-(5-(Hydroxymethyl)thiazol-2-yl)acetamide (2 g, 11.61 mmol) was placed in a dry reaction flask, and ultra-dry DCM (30 mL) was added. SOCl₂ (1.7 mL, 23.23 mmol) was slowly added dropwise under an ice-water bath. The reaction was allowed to react at room temperature for 2 h. The reaction solution was repeatedly added to DCM and rotary evaporated to remove the SOCl₂, yielding a white solid. The solid was slurried with anhydrous ether, filtered, and dried to obtain 2.13 g of a white solid in a 97% yield.

[0138] 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 12.18 (s, 1H), 7.50 (s, 1H), 5.03 (s, 2H), 2.14 (s, 3H).

[0139] (2) Synthesis of N-(5-formylthiazol-2-yl)acetamide (Intermediate 1-2)

[0140]

[0141] 2-Amino-5-formylthiazole hydrochloride (5 g, 30.37 mmol) was placed in a dry reaction flask, and ultra-dry DCM (50 mL) was added. DIEA (21.16 mL, 121.50 mmol) was added under an ice-water bath. After stirring for 10 minutes, acetyl chloride (2.4 mL, 33.41 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was poured into a Buchner funnel and filtered with suction. The filter cake was washed with water and dried to obtain 3.9 g of a yellow solid in a 76% yield.

[0142] 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 12.70 (s, 1H), 9.95 (s, 1H), 8.40 (s, 1H), 2.21 (s, 3H).

[0143] 2. (1) Synthesis of tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (Intermediate 2-1)

[0144]

[0145] a. Synthesis of tert-butyl 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate (2-1-a)

[0146]

[0147] Ultra-dry THF (100 mL) was added to a dry reaction flask. At -78°C, under Ar protection, ethynyltrimethylsilane (5.2 mL, 36.14 mmol) was added dropwise to the THF. The mixture was stirred for 5 minutes, followed by the dropwise addition of a 1.6 M solution of n-butyllithium in hexane (16.9 mL, 42.16 mmol). After reacting at -78°C for 2 hours, a solution of N-Boc-4-piperidone (6 g, 30.11 mmol) in THF (30 mL) was added dropwise to the reaction flask. The reaction was continued at -78°C for 5 hours. EA (30 mL) was added to dilute the reaction solution, which was then washed with NH4Cl solution (20 mL x 3) and saturated NaCl solution (20 mL). The aqueous phase was extracted with EA (30 mL), and the organic phase was concentrated and separated by column chromatography (SiO2, E:P = 2% to 15%, 10%) to afford 8.05 g of a white solid in a 90% yield.

[0148] 1 H-NMR (400 MHz, CDCl3) δ (ppm): 3.80 (ddd, J1 = 13.6 Hz, J2 = 6.4 Hz, J3 = 4.4 Hz, 1H), 3.22 (ddd, J1 = 13.6 Hz, J2 = 10.0 Hz, J3 = 3.2 Hz, 2H), 2.04-1.83 (m, 3H), 1.67 (ddd, J1 = 13.6 Hz, J2 = 10.0 Hz, J3 = 4.0 Hz, 2H), 1.46 (s, 9H), 0.17 (s, 9H). Intermediate 2-2-a was synthesized using (R)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate as raw material according to the preparation method of intermediate 2-1-a.

[0149] The specific structure is as follows:

[0150]

[0151]

[0152] b. tert-Butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (intermediate 2-1)

[0153]

[0154] tert-Butyl 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate (8 g, 26.89 mmol) was placed in a reaction flask, THF (90 mL) was added, and a 1M TABF solution in THF (35 mL, 34.96 mmol) was added dropwise under an ice-water bath. The reaction was allowed to react at room temperature for 2 h. The reaction solution was concentrated, diluted with EA (40 mL), washed with water (15 mL x 3), and then washed with saturated NaCl solution (15 mL). The aqueous phase was extracted with EA (20 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 6% to 25%, 15%) afforded 5.34 g of a white solid in an 88% yield.

[0155] 1 H-NMR (400MHz, CDCl3) δ (ppm): 3.78 (ddd, J1=14.0Hz, J2=6.4Hz, J3=4.4Hz, 1H), 3.27 (ddd, J1=13.2Hz, J2=9.2Hz, J3=3. 2Hz,2H),2.54(s,1H),2.04(brs,1H),1.93-1.86(m,2H),1.71(ddd,J1=13.2Hz,J2=9.2Hz,J3=4.0Hz,2H),1.46(s,9H).

[0156] Intermediate 2-2 was synthesized using intermediate 2-2-a as the raw material according to the preparation method of intermediate 2-1.

[0157] The specific structure is as follows:

[0158]

[0159] (2) Synthesis of tert-butyl 4-ethynyl-4-phenylethylpiperidine-1-carboxylate (Intermediate 2-3)

[0160]

[0161] a. Synthesis of 1-(tert-butyl)-4-ethyl-4-phenylethylpiperidine-1,4-dicarboxylic acid

[0162]

[0163] Ethyl N-Boc-4-piperidinylcarboxylate (2g, 7.77mmol) was placed in a dry reaction flask and THF (15mL) was added. 2M LDA solution (5.8mL, 11.66mmol) was added dropwise at -78°C under Ar protection. The reaction was incubated at -78°C for 1h. Beta-bromophenylethane (1.3mL, 9.33mmol) was then added dropwise. The reaction was continued at -78°C for 20min before being brought to room temperature and allowed to react overnight. The reaction was quenched with water, diluted with EA (15mL), and washed with NH4Cl solution (15mL x 3) and saturated NaCl solution (15mL). The aqueous phase was extracted with EA (15mL), and the organic phase was concentrated and separated by column chromatography (SiO2, E:P = 2%-10%, 8%) to afford 2.39g of a yellow oil (85% yield).

[0164] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.30-7.24 (m, 2H), 7.207.11 (m, 3H), 4.19 (q, J = 7.2Hz, 2H), 3.89 (dt, J1 = 14.0Hz, J2 = 4.0Hz, 2H), 2.92 (ddd, J1 = 14 .0Hz, J2=11.6Hz, J3=2.8Hz,2H),2.57-2.48(m,2H),2.21-2.12(m,2H),1 .86-1.79(m,2H),1.45(s,9H),1.44-1.37(m,2H),1.29(t,J=7.2Hz,3H).

[0165] b. Synthesis of tert-butyl 4-(hydroxymethyl)-4-phenylethylpiperidine-1-carboxylate

[0166]

[0167] 1-(tert-Butyl)-4-ethyl-4-phenethylpiperidine-1,4-dicarboxylic acid (500 mg, 1.38 mmol) was placed in a dry reaction flask, and THF (5 mL) was added. Under Ar protection, a 4M LiAlH₄ solution in THF (0.4 mL, 1.52 mmol) was added dropwise at -10°C. The reaction was allowed to proceed for 30 min at -10°C. The reaction was quenched with water, diluted with EA (20 mL), and filtered through Celite to remove the gel. The filtrate was washed with water (10 mL x 2), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO₂, E:P = 6% to 25%, 24%) afforded 403 mg of a white solid in a 91% yield.

[0168] 1H-NMR (400MHz, CDCl3) δ (ppm): 7.31-7.25 (m, 2H), 7.22-7.15 (m, 3H), 3.55 (s, 2H), 3.54-3.46 (m, 2H), 3.33 (ddd, J 1=13.6Hz, J2=7.6Hz, J3=4.4Hz,2H),2.61-2.53(m,2H),1.76-1.68(m,2H),1.58-1.53(m,1H),1.51-1.42(m,13H).

[0169] c. Synthesis of tert-butyl 4-formyl-4-phenethylpiperidine-1-carboxylate

[0170]

[0171] tert-Butyl 4-(hydroxymethyl)-4-phenethylpiperidine-1-carboxylate (650 mg, 2.04 mmol) was placed in a reaction flask, and DCM (20 mL) was added. Dess-Martin reagent (949 mg, 2.24 mmol) was added under an ice-water bath and allowed to react at room temperature for 3 h. The reaction solution was filtered through celite, and the filtrate was washed with saturated NaHCO₃ solution (10 mL x 2) and saturated Na₂S₂SO₃ solution (10 mL x 2). The aqueous phase was extracted with DCM (15 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO₂, E:P = 2% to 10%, 10%) afforded 331 mg of a white solid in a 51% yield.

[0172] d. Synthesis of tert-butyl 4-ethynyl-4-phenylethylpiperidine-1-carboxylate

[0173]

[0174] tert-Butyl 4-formyl-4-phenethylpiperidine-1-carboxylate (490 mg, 1.54 mmol) was placed in a reaction flask, and MeOH (10 mL) was added. KCO (427 mg, 3.09 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (326 mg, 1.70 mmol) were added under an ice-water bath. The reaction was allowed to react at room temperature for 12 h. EA (20 mL) was added to dilute the reaction solution, which was then washed with NH4Cl solution (10 mL x 3) and saturated NaCl solution (15 mL). The aqueous phase was extracted with EA (10 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 2% to 10%, 6%) afforded 353 mg of a white solid in a 73% yield.

[0175] 1H-NMR (400MHz, CDCl3) δ (ppm): 7.31-7.26 (m, 2H), 7.22-7.16 (m, 3H), 4.06-3.98 (m, 2H), 3.15-3.06 (m, 2 H),2.84-2.76(m,2H),2.29(s,1H),1.79-1.70(m,4H),1.46(s,9H),1.37(td,J1=12.8Hz,J2=7.6Hz,2H).

[0176] 3. Synthesis of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2,2,2-trifluoroethane-1-one (Intermediate 3)

[0177]

[0178] 6-Bromo-1,2,3,4-tetrahydroquinoline (1 g, 4.72 mmol) was placed in a reaction flask, and DCM (20 mL) was added. TEA (2.6 mL, 18.86 mmol) and trifluoroacetic anhydride (1.31 mL, 9.43 mmol) were added dropwise under an ice-water bath. The reaction was allowed to react at room temperature for 15 min. The reaction solution was diluted with EA (15 mL) and washed with NH4Cl solution (10 mL x 3) and saturated NaCl solution (15 mL). The aqueous phase was extracted with EA (10 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 2% to 10%, 2%) afforded 1.27 g of a white solid in an 88% yield.

[0179] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 7.73-7.54 (m, 1H), 7.50 (s, 1H), 7.42 (d, J = 8. 4Hz,1H),3.78(t,J=6.0Hz,2H),2.94-2.72(m,2H),1.98(quint,J=6.4Hz,2H).

[0180] 4. Synthesis of tert-butyl 4-hydroxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 4-1)

[0181]

[0182] The compound tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (Intermediate 2-1) (2 g, 8.88 mmol), 2-methoxy-6-bromopyridine (2 g, 10.65 mmol), PdCl2(PPh3)2 (312 mg, 0.44 mmol), and CuI (85 mg, 0.44 mmol) were placed in a reaction flask. Diethylamine (15 mL) was added. Under Ar protection, the temperature was raised to 55°C and the reaction was refluxed for 1 h to stop. EA (25 mL) was added to dilute the reaction solution, and the mixture was washed with NH4Cl solution (15 mL × 3) and saturated NaCl solution (15 mL). The aqueous phase was extracted with EA (15 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 6% to 25%, 21%) afforded 3.05 g of a yellow solid in an 86% yield.

[0183] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.54 (dd, J1 = 8.4Hz, J2 = 7.2Hz, 1H), 7.04 (dd, J1 =7.2Hz, J2=0.8Hz, 1H), 6.73(dd, J1=8.4Hz, J2=0.8Hz, 1H), 3.96(s, 3H), 3.83- 3.74(m,2H),3.39(ddd,J1=13.6Hz,J2=8.8Hz,J3=3.2Hz,2H),2.27(brs,1H),2 .07-1.99(m,2H),1.82(ddd,J1=12.8Hz,J2=8.8Hz,J3=3.6Hz,2H),1.47(s,9H).

[0184] Intermediates 4-2 to 4-7 were prepared by coupling different aryl halides with intermediate 2-1 according to the preparation method of intermediate 4-1;

[0185] Intermediate 4-8 was prepared by coupling 2-methoxy-6-bromopyridine with intermediate 2-2 according to the preparation method of intermediate 4-1;

[0186] Intermediate 4-9 was prepared by coupling 2-methoxy-6-bromopyridine with Intermediate 2-3 according to the preparation method of Intermediate 4-1.

[0187] The specific structure is as follows:

[0188]

[0189]

[0190]

[0191]

[0192] 5. Synthesis of tert-butyl 4-fluoro-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 5-1)

[0193]

[0194] The compound tert-butyl 4-hydroxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 4-1) (400 mg, 1.26 mmol) was placed in a reaction flask, DCM (10 mL) was added, and DAST (0.33 mL, 2.53 mmol) was added dropwise under an ice-water bath. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was diluted with DCM (10 mL) and washed with saturated NaHCO3 solution (10 mL x 3). The aqueous phase was extracted with DCM (10 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 6% to 25%, 18%) afforded 202 mg of a white solid in a 50% yield.

[0195] 1 H-NMR (500MHz, CDCl3) δ (ppm): 7.52 (t, J = 8.0Hz, 1H), 7.06 (d, J = 7.5Hz, 1H), 6.73 (d,J=8.5Hz,1H),3.94(s,3H),3.67-3.51(m,4H),2.17-2.02(m,4H),1.47(s,9H).

[0196] Intermediate 5-2 was synthesized using intermediate 4-2 as the raw material according to the preparation method of intermediate 5-1;

[0197] Intermediate 5-3 was synthesized using intermediate 4-3 as the raw material according to the preparation method of intermediate 5-1;

[0198] Intermediate 5-4 was synthesized using intermediate 4-4 as the raw material according to the preparation method of intermediate 5-1;

[0199] Intermediate 5-5 was synthesized using intermediate 4-5 as the raw material according to the preparation method of intermediate 5-1;

[0200] Intermediate 5-6 was synthesized using intermediate 4-6 as the raw material according to the preparation method of intermediate 5-1;

[0201] Intermediate 5-7 was synthesized using intermediate 4-7 as the raw material according to the preparation method of intermediate 5-1;

[0202] Intermediate 5-8 was synthesized using intermediate 4-8 as the raw material according to the preparation method of intermediate 5-1.

[0203] The specific structure is as follows:

[0204]

[0205]

[0206]

[0207] 6. Synthesis of tert-butyl 4-methoxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 6-1)

[0208]

[0209] NaH (60%, dispersed in liquid paraffin) (120 mg, 3.01 mmol) was placed in a dry reaction flask, and THF (5 mL) was added. At -20°C, under Ar protection, a THF solution (4 mL) of tert-butyl 4-hydroxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 4-1) (500 mg, 1.50 mmol) was added dropwise. After 1 hour of reaction, a THF solution (2 mL) of iodomethane (320 mg, 2.26 mmol) was added dropwise. After 1 hour of reaction, the mixture was allowed to react at room temperature for 3 hours, then raised to 50°C and stopped for 3 hours. The reaction was quenched with water, diluted with EA (20 mL), washed with water (10 mL × 3), and the aqueous phase was extracted with EA (10 mL). The organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 6% to 25%, 12%) gave 348 mg of a yellow solid with a yield of 67%.

[0210] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.51 (dd, J1 = 8.4Hz, J2 = 7.2Hz, 1H), 7.04 (dd, J1 = 7.2Hz, J2 = 0.8Hz, 1H), 6.71 (dd, J1 = 8.4Hz, J2 = 0.8Hz, 1H), 3.94 (s, 3H), 3.79 -3.67(m,2H),3.47(s,3H),3.40(ddd,J1=13.6Hz,J2=8.8Hz,J3=3.6Hz,2H),2. 07-1.99(m,2H),1.81(ddd,J1=12.8Hz,J2=8.8Hz,J3=4.0Hz,2H),1.47(s,9H).

[0211] Intermediate 6-2 was synthesized using 1-bromoethane and intermediate 4-1 as raw materials according to the preparation method of intermediate 6-1;

[0212] Intermediate 6-3 was synthesized using 1-bromopropane and intermediate 4-1 as raw materials according to the preparation method of intermediate 6-1;

[0213] Intermediate 6-4 was synthesized using benzyl bromide and intermediate 4-1 as raw materials according to the preparation method of intermediate 6-1. The specific structure is as follows:

[0214]

[0215]

[0216] 7. Synthesis of tert-butyl 4-hydroxy-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidine-1-carboxylate (Intermediate 7-1)

[0217]

[0218] The compound tert-butyl 4-hydroxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 4-1) (1.44 g, 4.33 mmol) was placed in a reaction flask, and MeOH (15 mL) and 10% palladium on carbon (containing approximately 50-60% water) (432 mg) were added. Catalytic hydrogenation was carried out at room temperature and pressure for 4 hours. The reaction solution was diluted with MeOH (10 mL), filtered through celite, and the filtrate was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 6%-25%, 20%) afforded 1.4 g of a colorless oil, with a yield of 96%.

[0219] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.48 (dd, J1 = 8.4Hz, J2 = 7.2Hz, 1H), 6.74 (dd, J1 = 7.2Hz, J2 = 0.8Hz, 1H), 6.57 (dd, J1 = 8.0Hz, J2 = 0.8Hz, 1H), 4.37-4.20 (m, 1H ),3.90(s,3H),3.88-3.72(m,2H),3.24(t,J=12.4Hz,2H),2.89(t,J=6.8Hz,2 H),1.92(t,J=6.8Hz,2H),1.67-1.59(m,2H),1.56-1.48(m,2H),1.46(s,9H).

[0220] Intermediates 7-2 to 7-17 were synthesized according to the preparation method of intermediate 7-1 using the intermediates in brackets below the numbers as starting materials.

[0221] The specific structure is as follows:

[0222]

[0223]

[0224]

[0225]

[0226]

[0227] (2) Synthesis of tert-butyl (Z)-4-hydroxy-4-(2-(6-methoxypyridin-2-yl)vinyl)piperidine-1-carboxylate (Intermediate 7-18)

[0228]

[0229] The compound tert-butyl 4-hydroxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 4-1) (1 g, 3.01 mmol) was placed in a reaction flask, EA (9 mL) was added, and Lindela's catalyst (100 mg) was added. Catalytic hydrogenation was carried out at room temperature and atmospheric pressure. The reaction was stopped after 4 days. EA (10 mL) was added to dilute the reaction solution, filtered through celite, and the filtrate was concentrated and separated by column chromatography. Column chromatography (SiO2, E:P = 6% to 25%, 18%) afforded 340 mg of a light yellow oil, with a yield of 34%.

[0230] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.60 (dd, J1 = 8.4Hz, J2 = 7.6Hz, 1H), 6.88 (dd, J1 = 7.6Hz, J2 = 0.8Hz, 1H), 6.66 (dd, J1 = 8.4Hz, J2 = 0.8Hz, 1H), 6.30 ( d,J=13.2Hz,1H),5.93(d,J=13.2Hz,1H),3.96(s,3H),3.84-3.67(m,2H ),3.45-3.33(m,2H),1.92-1.81(m,2H),1.77-1.66(m,2H),1.47(s,9H).

[0231] (3) Synthesis of tert-butyl (E)-4-hydroxy-4-(2-(6-methoxypyridin-2-yl)vinyl)piperidine-1-carboxylate (Intermediate 7-19)

[0232]

[0233] The compound tert-butyl 4-hydroxy-4-((6-methoxypyridin-2-yl)ethynyl)piperidine-1-carboxylate (Intermediate 4-1) (500 mg, 2.15 mmol) was placed in a reaction flask. Under Ar protection and an ice-water bath, a 2.4M solution of LiAlH₄ in ether (1.8 mL, 4.31 mmol) was added dropwise. The reaction was allowed to react at room temperature for 4 h. The reaction was quenched with water, diluted with EA (20 mL), and filtered through Celite to remove the gel. The filtrate was washed with water (10 mL), and the aqueous phase was extracted with EA (15 mL). The organic phase was concentrated and separated by column chromatography. Column chromatography (SiO₂, E:P = 10% to 30%, 27%) afforded 230 mg of a brown oil in a 46% yield.

[0234] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.51 (dd, J1 = 8.4, J2 = 7.2Hz, 1H), 6.89 (d, J = 15.6Hz, 1H), 6.80 (dd, J1 = 7.2, J2 = 0.8Hz, 1H), 6.62 (d, J = 15.6Hz, 1H), 6.61 (dd, J1=8.4, J2=0.8Hz, 1H), 3.96 (s, 3H), 3.94-3.80 (m, 2H), 3.27 (t, J=12. 8Hz,2H),1.80(td,J1=13.2,J2=4.4Hz,2H),1.69-1.61(m,2H),1.47(s,9H).

[0235] 8.(1) Synthesis of 4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 8-1)

[0236]

[0237] The compound tert-butyl 4-hydroxy-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidine-1-carboxylate (Intermediate 7-1) (400 mg, 1.19 mmol) was placed in a reaction flask, DCM (10 mL) was added, and TFA (0.9 mL, 11.89 mmol) was added dropwise at room temperature. The reaction was allowed to react for 2 h at room temperature. After concentration, the reaction solution was diluted with DCM (15 mL) and washed with saturated NaHCO3 solution (10 mL × 3). The aqueous phase was extracted with DCM (10 mL), and the organic phase was concentrated to obtain 260 mg of a yellow oil with a yield of 93%, which was used directly in the next reaction.

[0238] 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.82 (brs, 2H), 7.59 (dd, J1 = 8.0 Hz, J2 = 7.2 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.20 (s, 1H), 3.84 (s, 3H), 3.16-3.06 (m, 4H), 2.78-2.69 (m, 2H), 1.86-1.78 (m, 2H), 1.75-1.65 (m, 4H). Intermediates 8-2 to 8-15 were synthesized according to the preparation method of intermediate 8-1 using the intermediates in the brackets below the numbers as raw materials.

[0239] The specific structure is as follows:

[0240]

[0241]

[0242]

[0243]

[0244]

[0245] (2) Synthesis of 2,2,2-trifluoro-1-(6-(2-(4-hydroxypiperidin-4-yl)ethyl)-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one 2,2,2-trifluoroacetate (Intermediate 8-16)

[0246]

[0247] The compound tert-butyl 4-hydroxy-4-(2-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidine-1-carboxylate (Intermediate 7-4) (200 mg, 0.44 mmol) was placed in a reaction flask, DCM (10 mL) was added, and TFA (0.3 mL, 4.38 mmol) was added dropwise at room temperature. The reaction was allowed to proceed for 2 h at room temperature. After concentration, DCM (10 mL × 3) was added and the TFA was partially removed by rotary evaporation. Anhydrous ether was added to precipitate a white solid, which was filtered and dried to obtain 170 mg of a white solid, which was used directly in the next reaction.

[0248] 1H-NMR (400MHz, DMSO-d6) δ (ppm): 8.52 (brs, 1H), 7.65-7.46 (m, 1H), 7.15-7.05 (m, 2H), 4.72 (s, 1H), 3.77 (t, J=6.4Hz,2H),3.17-3.03(m,4H),2.90-2.69(m,2H),2.65-2.58(m,2H),2.06-1.88(m,2H),1.72-1.62(m,6H).

[0249] Intermediates 8-17 to 8-20 were synthesized according to the preparation method of intermediate 8-16, using the intermediates in brackets below the numbers as raw materials.

[0250] The specific structure is as follows:

[0251]

[0252]

[0253] Example 1:

[0254] N-(5-((4-hydroxy-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 1)

[0255]

[0256] Compound 4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 8-1) (296 mg, 0.85 mmol), N-(5-formylthiazol-2-yl)acetamide (Intermediate 1-2) (216 mg, 1.27 mmol), and NaOAc (278 mg, 3.39 mmol) were placed in a reaction flask. MeOH (10 mL) was added and the temperature was raised to 40°C. After reacting for 4 h, NaBH3CN (160 mg, 2.54 mmol) was added and the reaction was stopped at 40°C for 24 h. DCM (20 mL) was added to dilute the reaction solution, and the solution was washed with water (10 mL × 3) and saturated NaCl solution (15 mL). The aqueous phase was extracted with DCM (10 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, M:D = 2% to 10%, 10%) gave 130 mg of a white solid with a yield of 39% and a melting point of 148-150°C.

[0257] 1H-NMR (400MHz, MeOH-d4) δ (ppm): 7.55 (dd, J1=8.4Hz, J2=7.2Hz, 1H), 7.32 (s, 1H), 6.80 (dd, J1=7.2Hz, J2=0.8Hz, 1H), 6.57 (dd, J1= 8.0Hz, J2=0.8Hz,1H),3.89-3.85(m,5H),2.83-2.74(m,4H),2.69-2.58(m,2H),2.20(s,3H),1.90-1.82(m,2H),1.74-1.67(m,4H).

[0258] HRMS(ESI):m / z,Calcd for C 19 H 27 O3N4S[M+H] + :391.1798,Found 391.1809.

[0259] Example 2:

[0260] N-(5-((4-hydroxy-4-(2-(6-methylpyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 2)

[0261]

[0262] Using intermediate 1-2 and intermediate 8-2 as starting materials, the preparation process was the same as that described in Example 1 to obtain 30 mg of a white solid with a yield of 17% and a melting point of 130-132°C.

[0263] 1 H-NMR(400MHz,MeOH-d4)δ(ppm):7.62(t,J=8.0Hz,1H),7.39(s,1H),7.12-7.08(m,2H),4.05(s,2H), 2.98-2.89(m,2H),2.88-2.77(m,4H),2.49(s,3H),2.21(s,3H),1.85-1.79(m,2H),1.78-1.72(m,4H).

[0264] HRMS(ESI):m / z,Calcd for C 19 H 27 O2N4S[M+H] + :375.1849, Found 375.1860. Example 3:

[0265] N-(5-((4-hydroxy-4-(2-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 3)

[0266]

[0267] Compound 4-(2-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperidin-4-ol 2,2,2-trifluoroacetate (Intermediate 8-3) (102 mg, 0.29 mmol) was placed in a reaction flask, and ultra-dry MeCN (10 mL) was added. TEA (0.2 mL, 1.14 mmol) was added dropwise. After the pH of the reaction solution was greater than 7, N-(5-(chloromethyl)thiazol-2-yl)acetamide (Intermediate 1-1) (82 mg, 0.43 mmol) was added and the reaction was stopped at room temperature for 12 h. DCM (15 mL) was added to dilute the reaction solution, and the solution was washed with NH4Cl solution (10 mL × 3) and saturated NaCl solution (15 mL). The aqueous phase was extracted with DCM (15 mL), and the organic phase was concentrated and separated by column chromatography. Column chromatography (SiO2, M:D = 5% to 40%, 32%) gave 71 mg of a white solid with a yield of 62% and a melting point of 185-187°C.

[0268] 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 12.30 (s, 1H), 8.69 (d, J = 7.0Hz, 1H), 8.13 (d, J = 1.5Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7. 19(d,J=7.0Hz,1H),4.90(s,1H),4.49(s,2H),3.15-3.02(m,4H),2.84-2.77(m,2H),2.16(s,3H),1.96-1.86(m,2H),1.84-1.64(m,4H).

[0269] HRMS(ESI):m / z,Calcd for C 20 H 26 O2N5S[M+H] + :400.1802, Found 400.1800. Example 4:

[0270] N-(5-((4-hydroxy-4-(2-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 4)

[0271]

[0272] Using intermediate 1-1 and intermediate 8-16 as starting materials, the preparation process was the same as that described in Example 3 to obtain 105 mg of a white solid with a yield of 61% and a melting point of 180-181°C.

[0273] 1 H-NMR (400MHz, CDCl3) δ (ppm): 11.67 (s, 1H), 7.76-7.58 (m, 1H), 7.26 (s, 1H), 7.06-6.98 (m, 2H), 3.88-3.67 (m, 4 H),2.94-2.62(m,6H),2.57-2.38(m,2H),2.31(s,3H),2.11-2.00(m,2H),1.85-1.71(m,4H),1.70-1.60(m,2H).

[0274] HRMS(ESI):m / z,Calcd for C 24 H 30 O3N4F3S[M+H] + :511.1985,Found511.1968.

[0275] Example 5:

[0276] N-(5-((4-hydroxy-4-(2-(1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 5)

[0277]

[0278] Compound N-(5-((4-hydroxy-4-(2-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 4) (80 mg, 0.16 mmol) was placed in a reaction flask, MeOH (3 mL) was added, and a solution of K2CO3 (80 mg, 0.16 mmol) in water (1 mL) was added dropwise. The reaction was stopped at room temperature for 1 h. DCM (15 mL) was added to dilute the reaction solution, washed with NH4Cl solution (10 mL×3), and the aqueous phase was extracted with DCM (10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a white solid. The solid was slurried with n-hexane and anhydrous ether and filtered to obtain 41 mg of a white solid with a yield of 63% and a melting point of 205-207°C.

[0279] 1H-NMR (400MHz, CDCl3) δ (ppm): 12.01 (s, 1H), 7.22 (s, 1H), 6.82-6.75 (m, 2H), 6.41 (dd, J1 = 6.0Hz, J2 = 2.4Hz, 1H), 3.71 (s, 2H), 3.27 (t, J = 5.2H) z,2H),2.78-2.62(m,4H),2.59-2.52(m,2H),2.50-2.35(m,2H),2.31(s,3H),1.92(quint,J=6.0Hz,2H),1.81-1.67(m,4H),1.66-1.58(m,2H).

[0280] HRMS(ESI):m / z,Calcd for C 22 H 31 O2N4S[M+H] + :415.2162, Found 415.2182. Example 6:

[0281] N-(5-(((2R,4S)-4-hydroxy-4-(2-(6-methoxypyridin-2-yl)ethyl)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 6)

[0282]

[0283] Using intermediate 1-1 and intermediate 8-4 as starting materials, the preparation process was the same as that described in Example 3 to obtain 95 mg of a white solid with a yield of 49% and a melting point of 72-74°C.

[0284] 1 H-NMR (400MHz, CDCl3) δ (ppm): 11.65 (s, 1H), 7.48 (dd, J1 = 8.0Hz, J2 = 7.2Hz, 1H), 7.32 (s, 1H), 6.74 (d, J = 7.6Hz, 1H), 6.56 (d, J = 8.0Hz ,1H),4.24(brs,1H),3.97-3.78(m,4H),2.98-2.66(m,4H),2.32(s,3H),1.91(t,J=6.8Hz,2H),1.85-1.46(m,5H),1.42-1.23(m,4H).

[0285] HRMS(ESI):m / z,Calcd for C 20 H 29 O3N4S[M+H] + :405.1955,Found 405.1975.Example 7:

[0286] N-(5-((4-fluoro-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 7)

[0287]

[0288] Using intermediate 1-2 and intermediate 8-5 as starting materials, the preparation process was the same as that described in Example 1 to obtain 50 mg of a yellow solid with a yield of 30% and a melting point of 145-147°C.

[0289] 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 11.95 (s, 1H), 7.58 (t, J = 8.0Hz, 1H), 7.26 (s, 1H), 6.85 (d, J = 7.0Hz, 1H), 6.60 (d, J = 8.5Hz, 1H), 3.82 (s, 3H) ,3.65(s,2H),2.76-2.69(m,2H),2.68-2.60(m,2H),2.28-2.17(m,2H) ,2.11(s,3H),2.03-1.92(m,2H),1.85-1.75(m,2H),1.74-1.58(m,2H).

[0290] HRMS(ESI):m / z,Calcd for C 19 H 26 O2N4FS[M+H] + :393.1755,Found393.1746.

[0291] Example 8:

[0292] N-(5-((4-fluoro-4-(2-(6-methylpyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 8)

[0293]

[0294] Using intermediate 1-2 and intermediate 8-6 as starting materials, the preparation process was the same as that described in Example 1 to obtain 60 mg of a yellow solid with a yield of 36% and a melting point of 160-162°C.

[0295] 1H-NMR (400MHz, CDCl3) δ (ppm): 11.95 (s, 1H), 7.51-7.44 (m, 1H), 7.24 (s, 1H), 6.99-6.92 (m, 2H), 3.73 (s, 2H), 2.93-2.84 (m, 2H) ,2.83-2.72(m,1H),2.61-2.49(m,4H),2.47-2.36(m,2H),2.32(s,3H),2.09-1.87(m,2H),1.95-1.86(m,2H),1.85-1.65(m,2H).

[0296] HRMS(ESI):m / z,Calcd for C 19 H 26 ON4FS[M+H] + :377.1806, Found 377.1816. Example 9:

[0297] N-(5-((4-fluoro-4-(2-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 9)

[0298]

[0299] Using intermediate 1-1 and intermediate 8-7 as starting materials, the preparation process was the same as that described in Example 3 to obtain 107 mg of a yellow solid with a yield of 66% and a melting point of 219-220°C.

[0300] 1 H-NMR (400MHz, CDCl3) δ (ppm): 11.94 (s, 1H), 8.08-8.01 (m, 1H), 7.61-7.5 6(m,1H),7.53-7.50(m,1H),7.44-7.39(m,1H),7.24-7.21(m,1H),6.68-6 .61(m,1H),3.73(s,2H),2.83-2.74(m,3H),2.68-2.62(m,0.3H),2.58-2. 50(m,0.7H),2.47-2.27(m,6H),2.20-2.15(m,0.3H),2.00-1.67(m,4.7H).

[0301] HRMS(ESI):m / z,Calcd for C 20 H 25 ON5FS[M+H] + :402.1758, Found 402.1763. Example 10:

[0302] N-(5-((4-fluoro-4-(2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 10)

[0303]

[0304] Using intermediate 1-1 and intermediate 8-17 as starting materials, the preparation process was the same as that described in Example 3 to obtain 90 mg of a white solid with a yield of 63% and a melting point of 219-220°C.

[0305] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.95 (s, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.53 (s, 1H), 7.46 (dd, J1 = 8.0Hz, J2 = 1.2Hz, 1H), 7.26 (s,1H),5.37(s,2H),3.65(s,2H),2.86-2.78(m,2H),2.73-2.60(m,2H),2.30-2.18(m,2H),2.12(s,3H),2.00-1.60(m,6H).

[0306] HRMS(ESI):m / z,Calcd for C 21 H 25 O3N3FS[M+H] + :418.1595, Found 418.1592. Example 11:

[0307] N-(5-((4-fluoro-4-(2-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 11)

[0308]

[0309] Using intermediate 1-1 and intermediate 8-18 as starting materials, the preparation process was the same as that described in Example 3 to obtain 110 mg of a white solid with a yield of 77% and a melting point of 202-203°C.

[0310] 1H-NMR (400MHz, CDCl3) δ (ppm): 12.06 (s, 1H), 7.79-7.53 (m, 1H), 7.24 (s, 1H), 7.07-6.98 (m, 2H), 3.82 (t ,J=6.0Hz,2H),3.73(s,2H),2.98-2.60(m,6H),2.50-2.28(m,5H),2.11-2.00(m,2H),1.95-1.64(m,6H).

[0311] HRMS(ESI):m / z,Calcd for C 24 H 29 O2N4F4S[M+H] + :513.1942,Found513.1943.

[0312] Example 12:

[0313] N-(5-((4-fluoro-4-(2-(1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 12)

[0314]

[0315] Starting from N-(5-((4-fluoro-4-(2-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 11), the preparation process was the same as that described in Example 5 to give 22 mg of a yellow solid with a yield of 39% and a melting point of 209-210°C.

[0316] 1 H-NMR (400MHz, CDCl3) δ (ppm): 11.95 (s, 1H), 7.26 (s, 1H), 6.81-6.75 (m, 2H), 6.44-6.39 (m, 1H), 3.74 (s, 2H), 3 .27(t,J=5.6Hz,2H),2.92-2.66(m,4H),2.61-2.52(m,2H),2.51-2.36(m,2H),2.32(s,3H),1.98-1.61(m,8H).

[0317] HRMS(ESI):m / z,Calcd for C 22 H 30 ON4FS[M+H] + :417.2119, Found 417.2119. Example 13:

[0318] N-(5-((4-fluoro-4-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 13)

[0319]

[0320] Using intermediate 1-1 and intermediate 8-19 as starting materials, the preparation process was the same as that described in Example 3 to obtain 48 mg of a yellow solid with a yield of 52% and a melting point of 217-219°C.

[0321] 1 H-NMR (400MHz, CDCl3) δ (ppm): 11.94 (s, 1H), 8.91 (s, 1H), 7.28 (s, 1H), 7.03-6.97 (m, 2H), 6.70 (d, J = 8.8Hz, 1H), 3.75 ( s,2H),2.94(t,J=7.2Hz,2H),2.88-2.72(m,2H),2.70-2.60(m,4H),2.49-2.35(m,2H),2.31(s,3H),1.95-1.65(m,6H).

[0322] HRMS(ESI):m / z,Calcd for C 22 H 28 O2N4FS[M+H] + :431.1912,Found431.1919.

[0323] Example 14:

[0324] N-(5-((4-fluoro-4-(2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 14)

[0325]

[0326] Using intermediate 1-1 and intermediate 8-20 as starting materials, the preparation process was the same as that described in Example 3 to obtain 110 mg of a white solid with a yield of 89% and a melting point of 209-210°C.

[0327] 1H-NMR (500MHz, DMSO-d6) δ (ppm): 11.97 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.5Hz, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.0Hz, 1H), 7.15 (s, 1 H),3.65(s,2H),3.34-3.30(m,2H),2.86(t,J=6.5Hz,2H),2.73-2.61(m,4H),2.29-2.17(m,2H),2.12(s,3H),1.93-1.60(m,6H).

[0328] HRMS(ESI):m / z,Calcd for C 22 H 28 O2N4FS[M+H] + :431.1912,Found431.1914.

[0329] Example 15:

[0330] N-(5-(((2R,4S)-4-fluoro-4-(2-(6-methoxypyridin-2-yl)ethyl)-2-methylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 15)

[0331]

[0332] Using intermediate 1-1 and intermediate 8-8 as starting materials, the preparation process was the same as that described in Example 3 to obtain 20 mg of a white solid with a yield of 50% and a melting point of 209-210°C.

[0333] 1 H-NMR(400MHz,MeOH-d4)δ(ppm):7.57-7.51(m,1H),7.28-7.24(m,1H),6.81-6.73(m,1H),6.59-6.54 (m,1H),4.11(d,J=14.8Hz,0.5H),4.01(d,J=14.4Hz,0.5H),3.90-3.86(m,3H),3.86-3.77(m,1H),3.4 2-3.38(m,0.2H),3.11-3.02(m,0.4H),3.00-2.92(m,0.4H),2.83-2.72(m,2.5H),2.66-2.35(m,2.5H ),2.26-2.12(m,4H),2.09-1.81(m,3H),1.78-1.58(m,0.5H),1.57-1.38(m,0.5H),1.25-1.12(m,3H).

[0334] HRMS(ESI):m / z,Calcd for C 20 H 28 O2N4FS[M+H] + :407.1912,Found407.1897.

[0335] Example 16:

[0336] N-(5-((4-methoxy-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 16)

[0337]

[0338] Using intermediates 1-2 and 8-9 as starting materials, the preparation process was the same as that described in Example 1 to obtain 106 mg of a white solid with a yield of 65% and a melting point of 108-109°C.

[0339] 1 H-NMR (400MHz, MeOH-d4) δ (ppm): 7.54 (dd, J1 = 8.0Hz, J2 = 7.2Hz, 1H), 7.31 (s, 2H), 6.79 (d, J = 7.2Hz, 1H), 6.57 (d, J = 8.4Hz, 1H), 3.88 (s, 3H), 3.87-3. 85(m,2H),3.21(s,3H),2.81-2.73(m,2H),2.69-2.62(m,2H),2.53(td,J1= 12.0Hz, J2=2.4Hz,2H),2.20(s,3H),1.95-1.85(m,4H),1.66-1.56(m,2H).

[0340] HRMS(ESI):m / z,Calcd for C 20 H 29 O3N4S[M+H] + :405.1955,Found 405.1945.

[0341] Example 17:

[0342] N-(5-((4-ethoxy-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 17)

[0343]

[0344] aN-(5-((4-((6-methoxypyridin-2-yl)ethynyl)-4-propoxypiperidin-1-yl)methyl)thiazol-2-yl)acetamide

[0345]

[0346] Using intermediate 1-1 and intermediate 8-15 as starting materials, the preparation process was the same as that described in Example 3 to obtain 590 mg of a white solid with a yield of 53%.

[0347] 1 H-NMR (500MHz, DMSO-d6) δ (ppm): 11.95 (s, 1H), 7.68 (t, J = 8.0Hz, 1H), 7.26 (s, 1H), 7.10 (d, J = 7.5Hz, 1H), 6.83 (d, J = 8.0Hz, 1H), 3.84 (s, 3H), 3. 67(s,2H),3.61(q,J=7.0Hz,2H),2.71-2.54(m,2H),2.46-2.34(m,2H),2 .12(s,3H),2.00-1.91(m,2H),1.86-1.74(m,2H),1.15(t,J=7.0Hz,3H).

[0348] bN-(5-((4-ethoxy-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide

[0349]

[0350] The compound N-(5-((4-((6-methoxypyridin-2-yl)ethynyl)-4-propoxypiperidin-1-yl)methyl)thiazol-2-yl)acetamide (300 mg, 0.72 mmol) was placed in a reaction flask, THF (10 mL) and 10% palladium on carbon (containing approximately 50-60% water) (90 mg) were added, and catalytic hydrogenation was carried out at room temperature and pressure. The reaction was stopped after 3 days. The reaction solution was diluted with MeOH (15 mL), filtered through celite, and the filtrate was concentrated and separated by column chromatography. Column chromatography (SiO2, M:D = 2%-10%, 10%) gave 50 mg of a white solid, with a yield of 17%, melting point: 113-115°C.

[0351] 1H-NMR (500MHz, CDCl3) δ (ppm): 12.10 (s, 1H), 7.45 (t, J = 8.0Hz, 1H), 7.23 (s, 1H), 6.70 (d, J = 7.0Hz, 1H), 6.53 (d, J = 8.0Hz, 1H), 3.90 (s, 3H), 3.7 0(s,2H),3.39(q,J=7.0Hz,2H),2.75-2.58(m,4H),2.47-2.33(m,2H),2 .32(s,3H),1.92-1.80(m,4H),1.68-1.52(m,2H),1.20(t,J=7.0Hz,3H).

[0352] HRMS(ESI):m / z,Calcd for C 21 H 31 O3N4S[M+H] + :419.2111, Found 419.2093. Example 18:

[0353] N-(5-((4-(2-(6-methoxypyridin-2-yl)ethyl)-4-propoxypiperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 18)

[0354]

[0355] Using intermediates 1-2 and 8-10 as starting materials, the preparation process was the same as that described in Example 1 to obtain 110 mg of a white solid with a yield of 71% and a melting point of 98-100°C.

[0356] 1 H-NMR(400MHz,MeOH-d4)δ(ppm):7.48(t,J=7.6Hz,1H),7.22(s,1H),6.72(d,J=7.2Hz,1H),6.52(d,J=8.4Hz,1H),3.83(s,3 H),3.71(s,2H),2.73-2.55(m,4H),2.47-2.34(m,2H),2.16(s,3H),1.91-1.76(m,4H),1.61-1.46(m,4H),1.00-0.75(m,5H).

[0357] HRMS(ESI):m / z,Calcd for C 22 H 33 O3N4S[M+H] + :433.2268, Found 433.2258. Example 19:

[0358] N-(5-((4-(Benzyloxy)-4-(2-(6-methoxypyridin-2-yl)ethyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 19)

[0359]

[0360] Using intermediate 1-1 and intermediate 7-17 as starting materials, the preparation process was the same as that described in Example 3 to obtain 45 mg of a white solid with a yield of 31% and a melting point of 75-76°C.

[0361] 1 H-NMR (400MHz, MeOH-d4) δ (ppm): 7.52 (dd, J1=8.0Hz, J2=7.2Hz, 1H), 7.37-7.21 (m, 6H), 6.76 (dd, J1=7.2Hz, J2=0.8Hz, 1H), 6.56 (dd, J1=8.0Hz, J2=0.8Hz,1H),4.44(s,2H),3.87(s,3H),3.81(s,2H),2.76-2.68(m,4H ),2.60-2.51(m,2H),2.21(s,3H),2.04-1.97(m,4H),1.71-1.61(m,2H).

[0362] HRMS(ESI):m / z,Calcd for C 26 H 33 O3N4S[M+H] + :481.2268, Found 481.2260. Example 20:

[0363] N-(5-((4-(2-(6-methoxypyridin-2-yl)ethyl)-4-phenethylpiperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 20)

[0364]

[0365] Using intermediate 1-1 and intermediate 8-12 as starting materials, the preparation process was the same as that described in Example 3 to obtain 51 mg of a white solid with a yield of 57% and a melting point of 99-100°C.

[0366] 1H-NMR (500MHz, CDCl3) δ (ppm): 11.73 (s, 1H), 7.46 (t, J = 7.5Hz, 1H), 7.32-7.26 (m, 3H), 7.23-7.15 (m, 3H), 6.71 (d, J = 7.0Hz, 1H),6.54(d,J=8.5Hz,1H),3.91(s,3H),3.71(s,2H),2.71-2.42(m,8H),2.31(s,3H),1.84-1.77(m,2H),1.71-1.53(m,6H).

[0367] HRMS(ESI):m / z,Calcd for C 27 H 35 O2N4S[M+H] + :479.2475, Found 479.2487. Example 21:

[0368] (Z)-N-(5-((4-hydroxy-4-(2-(6-methoxypyridin-2-yl)vinyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 21)

[0369]

[0370] Using intermediate 1-1 and intermediate 8-13 as starting materials, the preparation process was the same as that described in Example 3 to obtain 73 mg of a white solid with a yield of 22% and a melting point of 150-152°C.

[0371] 1 H-NMR (400MHz, MeOH-d4) δ (ppm): 7.75 (dd, J1=8.4Hz, J2=7.6Hz, 1H), 7.54 (s, 1H), 7.03 (d, J=7.2Hz, 1H), 6.78 (dd, J1=8.4Hz, J2=0.8Hz, 1H), 6 .46(d,J=13.2Hz,1H),5.95(d,J=12.8Hz,1H),4.39(s,2H),3.94(s,3H) ,3.27-3.17(m,4H),2.22(s,3H),2.13-2.06(m,2H),2.04-1.94(m,2H).

[0372] HRMS(ESI):m / z,Calcd for C 19 H 25 O3N4S[M+H] + :389.1642, Found 389.1628. Example 22:

[0373] (E)-N-(5-((4-hydroxy-4-(2-(6-methoxypyridin-2-yl)vinyl)piperidin-1-yl)methyl)thiazol-2-yl)acetamide (Compound 22)

[0374]

[0375] Using intermediate 1-1 and intermediate 8-14 as starting materials, the preparation process was the same as that described in Example 3 to obtain 92 mg of a white solid with a yield of 55% and a melting point of 175-177°C.

[0376] 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.95 (s, 1H), 7.62 (dd, J1=8.4Hz, J2=7.6Hz, 1H),7.26(s,1H),6.95(d,J=7.6Hz,1H),6.83(d,J=15.6Hz,1H),6.63(d,J=8.0H z,1H),6.56(d,J=15.6Hz,1H),4.63(s,1H),3.86(s,3H),3.66(s,2H),2.65-2.5 3(m,2H),2.46-2.35(m,2H),2.12(s,3H),1.77-1.65(m,2H),1.58-1.48(m,2H).

[0377] HRMS(ESI):m / z,Calcd for C 19 H 25 O3N4S[M+H] + :389.1642,Found 389.1647.Pharmacological Experiment

[0378] 1. Evaluation of In vitro Enzymatic Inhibitory Activity

[0379] (1) Experimental materials

[0380] Human OGA: GST-MGEA5 (NM_012215) plasmid was prepared in the laboratory, purified by shake filtration, and diluted tenfold before use. The purity was approximately 70%;

[0381] Substrate FL-GlcNAc: Purchased from Abcam, prepared as a 10 mM stock solution. Dilute 0.6 μL / 100 μL to a 4× working solution before use.

[0382] FL reaction solution: 10 μM Mcllvaine's Buffer, mixed with 1000 mL of 0.1 M citric acid and 625 mL of 0.1 M Na2HPO4, adjusted to pH 6.5, and stored at 4°C;

[0383] Stop solution: 200 mmol / L glycine, adjust pH to 10.75 with NaOH, store at 4°C;

[0384] Test compounds: Prepare 10 mM stock solution in DMSO;

[0385] Instrument consumables: 0.5-10 μL, 20-200 μL pipettes, pipettes of various ranges, Bio-tek Synergy H1 fluorescence microplate reader (using white low volume 384-well plates, automatic gain, top reading, height 10.5).

[0386] (2) Experimental steps

[0387] Before the experiment, take the aliquoted OGA stock solution and dilute it with the reaction solution at a ratio of 0.25:2.5 to make a 4× working solution. The substrate is prepared with the reaction solution to make a 4× working solution.

[0388] The test compound was diluted with the reaction solution to a series of 2× concentrations. DMSO was diluted and mixed in the corresponding proportions as a control drug for the max and min values.

[0389] To a white 384-well plate, add 2.5 μL of OGA working solution and shake to the bottom of the plate. Then, add 5 μL of the test compound at various concentrations to each well. Set up three replicates per well for each compound and concentration, adding 2.5 μL of OGA working solution to each well. Also set up 3-4 controls as the max, adding 2.5 μL of OGA working solution and 5 μL of DMSO; and 3-4 controls as the min, adding 2.5 μL of reaction solution (without OGA) and 5 μL of DMSO. Add 2.5 μL of substrate working solution to all wells. Centrifuge the solution to the bottom of the plate (1500 rpm x 1 min). Incubate at room temperature in the dark for 60 min. Then, add 10 μL of stop solution to each well and measure fluorescence (excitation: 485 nm, absorbance: 528 nm, top reading, automatic gain, height 10.5 mm).

[0390] (3) Data processing

[0391] Inhibition rate of each compound:

[0392]

[0393] Among them FU max F is the fluorescence value of the control group with no compound added and only DMSO of corresponding dilution multiple added. min is the fluorescence value of the control without OGA.

[0394] (4) Experimental results (as shown in Table 1)

[0395] Table 1 Inhibitory activity of compounds in the examples against OGA

[0396]

[0397]

Claims

1. A compound as represented by general formula I or a pharmaceutically acceptable salt thereof, In Formula 1, Chiral carbon atoms can be in R or S configuration; A is selected from CH2CH2, a cis double bond, and a trans double bond; Y1 is selected from CH, CF, N; Y2 is selected from CH, N; R3 is selected from CH3; R2 is selected from: (1)F, Cl, Br, OR a1 , where the R a1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl, CH2Ar1, CH2CH2Ar1, wherein the Ar1 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) substituted or unsubstituted C1, C2, C3, C4 straight chain or branched alkyl, wherein the substituent is selected from F, OR b1 , R b1 Selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl; (3) CH2Ar2, CH2CH2Ar2, wherein Ar2 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; Ar is selected from: (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is as shown in the general formula I A shown In Formula I A middle, Chiral carbon atoms can be in R or S configuration; R3 is selected from CH3; R2 is selected from: (1)F, Cl, Br, OR a1 , where the R a1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl, CH2Ar1, CH2CH2Ar1, wherein the Ar1 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) substituted or unsubstituted C1, C2, C3, C4 straight chain or branched alkyl, wherein the substituent is selected from F, ORb1, and Rb1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, and cyclopropyl; (3) CH2Ar2, CH2CH2Ar2, wherein Ar2 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; Ar is selected from: (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that The compound is as shown in the general formula I A -1 In Formula I A -1 in, Chiral carbon atoms can be in R or S configuration; R3 is selected from CH3; Ar is selected from: (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is as shown in the general formula I B shown In Formula I B middle, A is selected from a cis double bond and a trans double bond; R2 is selected from: (1)F, Cl, Br, OR a1 , where the R a1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl, CH2Ar1, CH2CH2Ar1, wherein the Ar1 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) substituted or unsubstituted C1, C2, C3, C4 straight chain or branched alkyl, wherein the substituent is selected from F, ORb1, and Rb1 is selected from H, CH3, C2H5, C3H7, CF3, CHF2, and cyclopropyl; (3) CH2Ar2, CH2CH2Ar2, wherein Ar2 is selected from substituted or unsubstituted benzene ring, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent on the benzene ring or heterocycle is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen-substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; Ar is selected from: (1) Substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR c1 NR c2 R d1 NR c3 COR d2 NR c4 COOR d3 NR c5 SO2R d4 、CONR c6 R d5 、COOR c7 、SO2R c8 、SO2NR c9 R d6 、(CH2) n NR c10 R d7 、(CH2) n OR c11 , where the R c1 、R c2 、R d1 、R c3 、R d2 、R c4 、R d3 、R c5 、R d4 、R c6 、R d5 、R c7 、R c8 、R c9 、R d6 、R c10 、R d7 、R c11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; (2) Substituted or unsubstituted aromatic fused rings or fused heterocycles, substituted or unsubstituted non-aromatic fused rings or fused heterocycles, including substituted or unsubstituted benzo six-membered heterocycles, substituted or unsubstituted benzo five-membered heterocycles, substituted or unsubstituted pyrido five-membered heterocycles, preferably selected from the following structures: wherein the substituent R1 is selected from H, C1, C2, C3, C4 straight chain or branched alkyl, halogen substituted C1, C2, C3, C4 straight chain or branched alkyl, F, Cl, Br, NO2, CN, CF3, CHF2, azetidine ring, pyrrolidine ring, OR e1 NR e2 R f1 NR e3 COR f2 NR e4 COOR f3 NR e5 SO2R f4 、CONR e6 R f5 、COOR e7 、SO2R e8 、SO2NR e9 R f6 、(CH2) n NR e10 R f7 、(CH2) n OR e11 , where the R e1 、R e2 、R f1 、R e3 、R f2 、R e4 、R f3 、R e5 、R f4 、R e6 、R f5 、R e7 、R e8 、R e9 、R f6 、R e10 、R f7 、R e11 Independently selected from H, CH3, C2H5, C3H7, CF3, CHF2, cyclopropyl, cyclobutyl, isopropyl; wherein the fused ring or fused heterocyclic ring may be monosubstituted or polysubstituted; the heterocyclic ring may contain one or more heteroatoms, and the heteroatoms are selected from N, O, and S; n is selected from 1, 2, and 3; wherein the halogen is selected from F; The substituent R7 is selected from H, CH3, C2H5, CF3, CHF2, CH2F, COCF3, COCH3, HCO, CH2CF3, methylenecyclopropyl, and cyclopropyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from:

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salts of the compounds are selected from salts formed by combining inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases that can provide physiologically acceptable cations, and ammonium salts.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that The inorganic salt 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 acid, tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ion is selected from lithium ion, sodium ion and 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.

8. A method for preparing a compound according to any one of claims 1 to 7, characterized in that The steps include: i. Using 2-aminothiazole-5-carboxylic acid ethyl thiazole (1) as a raw material, an acylation reaction is performed to obtain an intermediate (2); ii. intermediate (2) undergoes reduction reaction to obtain intermediate (3); iii. Intermediate (3) undergoes substitution reaction to obtain key intermediate (4); iv. Using substituted N-Boc-4-piperidone (5) as a raw material, an addition reaction is carried out with trimethylsilyl acetylene to obtain an intermediate (6); v. Removing the silicon protecting group from the intermediate (6) to obtain the intermediate (7); vi. Intermediate (7) is subjected to Sonogashira coupling reaction to obtain intermediate (8); vii. Intermediate (8) undergoes substitution reaction to obtain intermediate (9); viii. Intermediate (9) is subjected to reduction reaction to obtain intermediate (10); ix. Removal of the Boc protecting group from intermediate (10) to obtain the key intermediate (11); x, intermediate (11) and intermediate (4) undergo substitution reaction under alkaline conditions to obtain a compound represented by general formula I (Scheme 1); The definitions of Y1, Y2, A, R2, R3, and Ar are consistent with those in any one of claims 1-7.

9. A pharmaceutical composition, characterized in that The invention comprises an effective dose of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of an OGA inhibitor.

11. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases associated with OGA.

12. Use according to claim 11, characterized in that Diseases related to OGA include neurodegenerative diseases, metabolic diseases, cancer, immune system diseases, cardiovascular and cerebrovascular diseases, and eye diseases.

13. Use according to claim 12, characterized in that The neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, frontotemporal lobar degeneration, Lewy body dementia, multiple system atrophy, Down syndrome, and epilepsy.

14. Use according to claim 12, characterized in that The cardiovascular and cerebrovascular diseases include ischemic stroke, hemorrhagic stroke, heart failure, myocardial ischemia, and cardiac diastolic dysfunction.

15. Use according to claim 12, characterized in that The metabolic diseases include diabetes and abnormal lipid metabolism.

16. Use according to claim 12, characterized in that The eye diseases include corneal endothelial diseases.

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