Benzo-seven-membered nitrogen heterocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a benzo-seven-membered nitrogen heterocyclic compound as well as a preparation method and application thereof, and particularly discloses a compound as shown in a formula I or pharmaceutically acceptable salt thereof, the compound has high affinity and high selectivity to GluN2B, can be used as a GluN2B inhibitor, is used for diagnosing and treating NMDA change related diseases, and can be used for preparing a compound for treating NMDA change related diseases. Especially diagnosis and treatment of pancreatic cancer related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of small molecule therapeutic drugs, and specifically relates to a benzo seven-membered nitrogen heterocyclic compound, a preparation method thereof and an application thereof. Background Art

[0002] Pancreatic cancer, especially pancreatic adenocarcinoma, is a common cancer with a poor prognosis. Studies have shown that N-methyl-D-aspartate (NMDA) receptors are very important for pancreatic cancer growth and survival. Immunohistochemistry with antibodies against GluN1 and GluN2B showed that all invasive pancreatic adenocarcinomas and pancreatic neuroendocrine tumors may express these two NMDA receptor proteins. These proteins were found to be membrane components of pancreatic cancer cell lines, and both channel blocker antagonists and GluN2B antagonists significantly reduced the viability of cells in vitro. Both types of antagonists cause internalization of the receptor. Dizocilpine maleate (MK-801) and ifenprodil hemitartrate both significantly inhibited the growth of pancreatic tumors transplanted in mice. These findings predict that pancreatic cancer can be successfully treated with NMDA receptor antagonists or other receptor inhibitor blockers alone or in combination.

[0003] Ifenprodil is a first-generation GluN2B antagonist, but it and its analogs do not completely bind only to GluN2B, and even bind more strongly to sigma receptors. In order to overcome the shortcomings of ifenprodil, it is urgent to develop compounds with higher affinity and selectivity for GluN2B. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the disadvantages of low affinity and selectivity of existing GluN2B antagonists, thereby providing a benzo seven-membered nitrogen heterocyclic compound, a preparation method thereof and its application. The compound of the present invention has high affinity and high selectivity for GluN2B, and can be used as a GluN2B antagonist for the diagnosis and treatment of diseases related to NMDA changes, especially the diagnosis and treatment of pancreatic cancer-related diseases.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R 6 is H or C1-C6 alkyl;

[0010] R1 , R 2 , R 3 , R 4 and R 5 Each is independently H, halogen, C1-C6 alkoxy or C1-C6 alkylthio.

[0011] In certain preferred embodiments of the present invention, certain groups in the compound of formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment").

[0012] In one scenario, R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, halogen or C1-C6 alkylthio, and R 1 , R 2 , R 3 , R 4 and R 5 1, 2, 3, 4 or 5 are not H.

[0013] In one scenario, R 1 , R 2 , R 3 , R 4 and R 5 One of them is halogen or C1-C6 alkylthio, and the rest are H.

[0014] In one scenario, R 6 In the above, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0015] In one scenario, R 1 , R 2 , R 3 , R 4 and R 5 In the above, the halogen is independently fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine.

[0016] In one scenario, R 1 , R 2 , R 3 , R 4 and R 5 In the above, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0017] In one scenario, R 1 , R 2, R 3 , R 4 and R 5 In the above, the C1-C6 alkylthio groups are independently methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio, preferably methylthio.

[0018] In one scenario, R 6 It is H or methyl.

[0019] In one scenario, R 1 , R 2 , R 3 , R 4 and R 5 One of them is chloro, bromo, iodo or methylthio; the rest are H.

[0020] In one embodiment, the compound represented by Formula I is as represented by IA, IB or IC:

[0021]

[0022] Among them, R 1 , R 2 , R 3 and R 6 is defined as in any of the above schemes.

[0023] In one embodiment, in the compound shown in IA, IB or IC, R 1 , R 2 and R 3 Each is independently halogen, C1-C6 alkoxy or C1-C6 alkylthio; for example halogen or C1-C6 alkylthio.

[0024] In one embodiment, the compound represented by formula I is selected from any of the following compounds:

[0025]

[0026] The present invention also provides a method for preparing the compound represented by the above formula I, which comprises method 1 or method 2;

[0027] Method 1 comprises the following steps: in a solvent, in the presence of a catalyst, the compound of formula II-1 and the compound of formula II-2 undergo the following reaction to obtain the compound of formula I; in method 1, R 6 is a C1-C6 alkyl group;

[0028]

[0029] Method 2 comprises the following steps: in a solvent, in the presence of a catalyst, the compound of formula III-1 undergoes a deprotection reaction as shown below to obtain the compound of formula I; in method 2, R 6 is H;

[0030]

[0031] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 The definitions are as described in any embodiment of the present invention.

[0032] The present invention also provides a compound as shown in formula II-2 or formula III-1:

[0033]

[0034] Among them, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The definitions of are as described in any embodiment of the present invention, R 7 is a leaving group (e.g., Ms (methylsulfonyl) or Ts (p-toluenesulfonyl)), R 8 is a hydroxyl protecting group (eg, Bn(benzyl)).

[0035] In one embodiment, the compound represented by formula II-2 is selected from any of the following compounds:

[0036]

[0037] In one embodiment, the compound represented by formula III-1 is selected from any of the following compounds:

[0038]

[0039]

[0040] The present invention also provides a pharmaceutical composition, which comprises the above-mentioned (therapeutically effective amount) of the compound represented by formula I or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0041] The present invention also provides the use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a GluN2B inhibitor.

[0042] In the application, the GluN2B inhibitor can be used in mammals in vivo; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of GluN2B inhibitory effects.

[0043] The present invention also provides the use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating pancreatic cancer.

[0044] The pancreatic cancer may be invasive pancreatic adenocarcinoma or pancreatic neuroendocrine tumor.

[0045] the term

[0046] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0047] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0048] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0049] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0050] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0051] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., 1-6 The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0052] The term "alkoxy" refers to the group RO-, where R is defined as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0053] The term "alkylthio" refers to the group RS-, where R is defined as the term "alkyl". Alkylthio includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like.

[0054] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0055] The term "treating" refers to removing the cause or alleviating the symptoms.

[0056] The term "prevention" refers to reducing the risk of developing a disease.

[0057] The term "patient" refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0058] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0059] The reagents and raw materials used in the present invention are commercially available.

[0060] The positive and progressive effect of the present invention is that the benzo seven-membered nitrogen heterocyclic compound of the present invention has high affinity and high selectivity for GluN2B, and can be used as a GluN2B inhibitor for the diagnosis and treatment of diseases related to NMDA changes, especially the diagnosis and treatment of pancreatic cancer-related diseases. DETAILED DESCRIPTION

[0061] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0062] The preparation method of the benzo seven-membered nitrogen heterocyclic compound provided by the present invention is as follows:

[0063] Example 1 Preparation of Compound IP1

[0064]

[0065] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0066] Compound IP1, yield 94%,

[0067] 1 H NMR (400MHz; CDCl3), δ7.62(d, 3 J HH =8.6Hz,2H,Ar-H),7.07(d, 3 J HH =8.6Hz,2H),3.91(t, 3 J HH =6.0Hz,2H),3.14(s,3H),2.61(t, 3 J HH =6.0Hz,2H),1.50-1.61(m,4H).

[0068] Example 2 Preparation of Compound IM1

[0069]

[0070] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0071] Compound IM1, yield 89%,

[0072] 1 H NMR (400MHz; CDCl3), δ7.70-7.75(m,2H,Ar-H),7.20-7.30(m,2H),3.89(t, 3 J HH =6.0Hz,2H),3.13(s,3H),2.59(t, 3 J HH =6.0Hz,2H),1.50-1.63(m,4H).

[0073] Example 3 Preparation of Compound IO1

[0074]

[0075] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0076] Compound IO1, yield 92%,

[0077] 1 H NMR (400MHz; CDCl3), δ7.81(d, 3 J HH =8.6Hz,2H,Ar-H),7.27(t, 3 J HH =8.6Hz,1H,Ar-H),6.90-7.00(m,2H,Ar-H),3.95(t, 3 J HH =6.0Hz,2H),3.12(s,3H),2.67(t, 3 J HH =6.0Hz,2H),1.50-1.64(m,4H).

[0078] Example 4 Preparation of Compound BP1

[0079]

[0080] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0081] Compound BP1, yield 87%,

[0082] 1 H NMR(400MHz; CDCl3), δ7.85(d, 3 J HH =8.6Hz,2H,Ar-H),7.13(d, 3 J HH =8.6Hz,2H),4.05(t, 3 J HH =6.0Hz,2H),3.19(s,3H),2.65(t, 3 J HH =6.0Hz,2H),1.50-1.61(m,4H).

[0083] Example 5 Preparation of Compound BM1

[0084]

[0085] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0086] Compound BM1, yield 90%,

[0087] 1 H NMR (400MHz; CDCl3), δ7.49(d, 3 J HH =8.6Hz,1H,Ar-H),7.35(s,1H),7.25(t, 3 J HH =8.6Hz,1H,Ar-H),7.13(d, 3 J HH =8.6Hz,1H,Ar-H),3.92(t, 3 J HH =6.0Hz,2H),3.17(s,3H),2.54(t, 3 J HH =6.0Hz,2H),1.53-1.60(m,4H).

[0088] Example 6 Preparation of Compound BO1

[0089]

[0090] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0091] Compound BO1, yield 84%,

[0092] 1 H NMR (400MHz; CDCl3), δ7.57(d, 3 J HH =8.6Hz,2H,Ar-H),7.24(t, 3 J HH =8.6Hz,1H,Ar-H),6.97-7.09(m,2H,Ar-H),3.90(t, 3 J HH =6.0Hz,2H),3.19(s,3H),2.60(t, 3 JHH =6.0Hz,2H),1.54-1.61(m,4H).

[0093] Example 7 Preparation of Compound CP1

[0094]

[0095] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0096] Compound CP1, yield 97%,

[0097] 1 H NMR (400MHz; CDCl3), δ7.31(d, 3 J HH =8.6Hz,2H,Ar-H),7.10(d, 3 J HH =8.6Hz,2H),4.08(t, 3 J HH =6.0Hz,2H),3.14(s,3H),2.57(t, 3 J HH =6.0Hz,2H),1.50-1.65(m,4H).

[0098] Example 8 Preparation of Compound CM1

[0099]

[0100] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0101] Compound CM1, yield 88%,

[0102] 1 H NMR(400MHz; CDCl3), δ7.25-7.40(m,3H,Ar-H),7.01(d, 3 J HH =8.6Hz,1H,Ar-H),3.89(t, 3 J HH=6.0Hz,2H),3.10(s,3H),2.49(t, 3 J HH =6.0Hz,2H),1.50-1.59(m,4H).

[0103] Example 9 Preparation of Compound CO1

[0104]

[0105] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0106] Compound CO1, yield 86%,

[0107] 1 H NMR (400MHz; CDCl3), δ7.67(d, 3 J HH =8.6Hz,2H,Ar-H),7.10-7.29(m,3H,Ar-H),3.97(t, 3 J HH =6.0Hz,2H),3.21(s,3H),2.68(t, 3 J HH =6.0Hz,2H),1.56-1.66(m,4H).

[0108] Example 10 Preparation of Compound SP1

[0109]

[0110] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0111] Compound SP1, yield 74%,

[0112] 1 H NMR (400MHz; CDCl3), δ7.25(d, 3 J HH =8.6Hz,2H,Ar-H),7.04(d, 3 JHH =8.6Hz,2H),3.96(t, 3 J HH =6.0Hz,2H),3.11(s,3H),2.51(t, 3 J HH =6.0Hz,2H),2.31(s,3H),1.48-1.56(m,4H).

[0113] Example 11 Preparation of Compound SM1

[0114]

[0115] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0116] Compound SM1, yield 77%,

[0117] 1 H NMR (400MHz; CDCl3), δ7.21-7.32(m,2H,Ar-H),7.11(s,1H),6.91(d, 3 J HH =8.6Hz,1H,Ar-H),3.87(t, 3 J HH =6.0Hz,2H),3.09(s,3H),2.47(t, 3 J HH =6.0Hz,2H),2.41(s,3H),1.49-1.55(m,4H).

[0118] Example 12 Preparation of Compound SO1

[0119]

[0120] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, chloroform as solvent, the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0121] Compound SO1, yield 69%,

[0122] 1H NMR (400MHz; CDCl3), δ7.34(d, 3 J HH =8.6Hz,2H,Ar-H),7.20(t, 3 J HH =8.6Hz,1H,Ar-H),7.00-7.10(m,2H,Ar-H),3.92(t, 3 J HH =6.0Hz,2H),3.12(s,3H),2.57(t, 3 J HH =6.0Hz,2H),2.39(s,3H),1.46-1.53(m,4H).

[0123] Example 13 Preparation of compounds IP2, BP2, CP2 and SP2

[0124]

[0125] General synthesis steps: 1.0 mmol 1.5 equivalent 3.0 equivalents of K2CO3, CH3CN as solvent, the reaction mixture was stirred at 80°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0126] Compound IP2 (X = I), yield 64%,

[0127] 1 H NMR (400MHz; CDCl3), δ7.52(d, 3 J HH =8.6Hz,2H,Ar-H),7.26(d, 3 J HH =8.6Hz,1H),6.90-6.95(m,2H),6.75(d, 3 J HH =8.6Hz,1H,Ar-H),6.10(brs,1H),4.79(t, 3 J HH =6.0Hz,1H),3.61(s,3H,OCH3),2.60-3.00(m,8H),2.41(t, 3 J HH =6.0Hz,2H),1.52(m,2H),1.31(m,2H).

[0128] Compound BP2 (X = Br), yield 83%,

[0129] 1 H NMR(400MHz; CDCl3), δ7.80(d, 3 J HH =8.6Hz,2H,Ar-H),7.24(d, 3 J HH =8.6Hz,1H),7.04(d, 3 J HH =8.6Hz,2H),6.89(s,1H),6.72(d, 3 J HH =8.6Hz,1H,Ar-H),6.21(brs,1H),4.81(t, 3 J HH =6.0Hz,1H),3.65(s,3H,OCH3),2.60-3.00(m,8H),2.39(t, 3 J HH =6.0Hz,2H),1.55(m,2H),1.37(m,2H).

[0130] Compound CP2 (X = Cl), yield 78%,

[0131] 1 H NMR (400MHz; CDCl3), δ7.34(d, 3 J HH =8.6Hz,2H,Ar-H),7.26(d, 3 J HH =8.6Hz,1H),7.09(d, 3 J HH =8.6Hz,2H),6.87(s,1H),6.70(d, 3 J HH =8.6Hz,2H,Ar-H),6.25(brs,1H),4.73(t, 3 J HH =6.0Hz,1H),3.59(s,3H,OCH3),2.60-3.00(m,8H),2.35(t, 3 J HH =6.0Hz,2H),1.49(m,2H),1.30(m,2H).

[0132] Compound SP2 (X = SCH3), yield 57%,

[0133] 1 H NMR (400MHz; CDCl3), δ7.27(d, 3 JHH =8.6Hz,3H,Ar-H),7.06(d, 3 J HH =8.6Hz,2H),6.83(s,1H),6.71(d, 3 J HH =8.6Hz,2H,Ar-H),6.18(brs,1H),4.77(t, 3 J HH =6.0Hz,1H),3.64(s,3H,OCH3),2.60-3.00(m,8H),2.45(t, 3 J HH =6.0Hz,2H),2.30(s,3H),1.52(m,2H),1.34(m,2H).

[0134] Example 14 Preparation of compounds IM2, BM2, CM2 and SM2

[0135]

[0136] General synthesis steps: 1.0 mmol 1.5 equivalent 3.0 equivalents of K2CO3, CH3CN as solvent, the reaction mixture was stirred at 80°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0137] Compound IM2 (X = I), yield 69%,

[0138] 1 H NMR (400MHz; CDCl3), δ7.70-7.80(m,2H),7.20-7.30(m,3H),6.87(s,1H),6.77(d, 3 J HH =8.6Hz,1H,Ar-H),6.30(brs,1H),4.74(t, 3 J HH =6.0Hz,1H),3.65(s,3H,OCH3),2.60-3.00(m,8H),2.37(t, 3 J HH =6.0Hz,2H),1.49(m,2H),1.33(m,2H).

[0139] Compound BM2 (X = Br), yield 72%,

[0140] 1H NMR (400MHz; CDCl3), δ7.45(d, 3 J HH =8.6Hz,1H,Ar-H),7.34(s,1H),7.25-7.30(m,2H),7.11(d, 3 J HH =8.6Hz,1H),6.89(s,1H),6.75(d, 3 J HH =8.6Hz,1H,Ar-H),6.35(brs,1H),4.78(t, 3 J HH =6.0Hz,1H),3.62(s,3H,OCH3),2.60-3.00(m,8H),2.43(t, 3 J HH =6.0Hz,2H),1.51(m,2H),1.31(m,2H).

[0141] Compound CM2 (X = Cl), yield 76%,

[0142] 1 H NMR(400MHz; CDCl3), δ7.25-7.40(m,4H),7.05(d, 3 J HH =8.6Hz,2H),6.88(s,1H),6.73(d, 3 J HH =8.6Hz,1H,Ar-H),6.34(brs,1H),4.79(t, 3 J HH =6.0Hz,1H),3.69(s,3H,OCH3),2.60-3.00(m,8H),2.41(t, 3 J HH =6.0Hz,2H),1.53(m,2H),1.37(m,2H).

[0143] Compound SM2 (X = SCH3), yield 54%,

[0144] 1 H NMR (400MHz; CDCl3), δ7.25-7.35(m,4H),7.11(s,1H),6.90-6.98(m,2H),6.74(d, 3 J HH =8.6Hz,2H),6.17(brs,1H),4.85(t, 3 J HH=6.0Hz,1H),3.57(s,3H),2.60-3.00(m,8H),2.40-2.50(m,5H),1.55(m,2H),1.34(m,2H).

[0145] Example 15 Preparation of compounds IO2, BO2, CO2 and SO2

[0146]

[0147] General synthesis steps: 1.0 mmol 1.5 equivalent 3.0 equivalents of K2CO3, CH3CN as solvent, the reaction mixture was stirred at 80°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0148] Compound IO2 (X = I), yield 78%,

[0149] 1 H NMR (400MHz; CDCl3), δ7.81(d, 3 J HH =8.6Hz,1H,Ar-H),7.25-7.28(m,2H),6.90-7.00(m,3H),6.74(d, 3 J HH =8.6Hz,1H,Ar-H),6.22(brs,1H),4.85(t, 3 J HH =6.0Hz,1H),3.68(s,3H),2.60-3.00(m,8H),2.42(t, 3 J HH =6.0Hz,2H),1.52(m,2H),1.38(m,2H).

[0150] Compound BO2 (X = Br), yield 52%,

[0151] 1 H NMR (400MHz; CDCl3), δ7.51(d, 3 J HH =8.6Hz,1H,Ar-H),7.20-7.30(m,2H),7.00-7.10(m,2H),6.91(s,1H),6.71(d, 3 J HH =8.6Hz,1H,Ar-H),6.25(brs,1H),4.81(t, 3 JHH =6.0Hz,1H),3.67(s,3H),2.60-3.00(m,8H),2.41(t, 3 J HH =6.0Hz,2H),1.57(m,2H),1.41(m,2H).

[0152] Compound CO2 (X = Cl), yield 79%,

[0153] 1 H NMR (400MHz; CDCl3), δ7.66(d, 3 J HH =8.6Hz,1H,Ar-H),7.26(d, 3 J HH =8.6Hz,1H,Ar-H),7.15-7.20(m,3H),6.90(s,1H),6.74(d, 3 J HH =8.6Hz,1H,Ar-H),6.22(brs,1H),4.87(t, 3 J HH =6.0Hz,1H),3.64(s,3H),2.60-3.00(m,8H),2.47(t, 3 J HH =6.0Hz,2H),1.61(m,2H),1.44(m,2H).

[0154] Compound SO2(X=SCH3), yield 48%,

[0155] 1 H NMR (400MHz; CDCl3), δ7.34(d, 3 J HH =8.6Hz,1H,Ar-H),7.20-7.30(m,2H),7.05-7.10(m,2H),6.89(s,1H),6.72(d, 3 J HH =8.6Hz,2H),6.27(brs,1H),4.73(t, 3 J HH =6.0Hz,1H),3.77(s,3H),2.60-3.00(m,8H),2.40-2.45(m,5H),1.52(m,2H),1.42(m,2H).

[0156] Example 16 Preparation of compounds bzIP2, bzBP2, bzCP2 and bzSP2

[0157]

[0158] General synthesis steps: 1.0 mmol 1.5 equivalent 3.0 equivalents of K2CO3, CH3CN as solvent, the reaction mixture was stirred at 80°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0159] Compound bzIP2 (X = I), yield 64%,

[0160] 1 H NMR (400MHz; CDCl3), δ7.55(d, 3 J HH =8.6Hz,2H,Ar-H),7.30-7.50(m,6H),6.90-7.00(m,3H),6.72(d, 3 J HH =8.6Hz,1H,Ar-H),6.17(brs,1H),5.19(s,2H),4.71(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.44(t, 3 J HH =6.0Hz,2H),1.58(m,2H),1.32(m,2H).

[0161] Compound bzBP2 (X = Br), yield 71%,

[0162] 1 H NMR (400MHz; CDCl3), δ7.81(d, 3 J HH =8.6Hz,2H,Ar-H),7.30-7.50(m,6H),7.06(d, 3 J HH =8.6Hz,2H,Ar-H),6.84(s,1H),6.72(d, 3 J HH =8.6Hz,1H,Ar-H),6.27(brs,1H),5.17(s,2H),4.81(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.48(t, 3 J HH=6.0Hz,2H),1.57(m,2H),1.30(m,2H).

[0163] Compound bzCP2 (X = Cl), yield 67%,

[0164] 1 H NMR(400MHz; CDCl3), δ7.30-7.50(m,8H),7.11(d, 3 J HH =8.6Hz,2H,Ar-H),6.90(s,1H),6.77(d, 3 J HH =8.6Hz,1H,Ar-H),6.21(brs,1H),5.09(s,2H),4.88(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.41(t, 3 J HH =6.0Hz,2H),1.62(m,2H),1.38(m,2H).

[0165] Compound bzSP2 (X = SCH3), yield 47%,

[0166] 1 H NMR(400MHz; CDCl3), δ7.30-7.50(m,8H),7.07(d, 3 J HH =8.6Hz,2H,Ar-H),6.92(s,1H),6.73(d, 3 J HH =8.6Hz,1H,Ar-H),6.26(brs,1H),5.18(s,2H),4.84(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.47(t, 3 J HH =6.0Hz,2H),1.52(m,2H),1.31(m,2H).

[0167] Example 17 Preparation of compounds bzIM2, bzBM2, bzCM2 and bzSM2

[0168]

[0169] General synthesis steps: 1.0 mmol 1.5 equivalent 3.0 equivalents of K2CO3, CH3CN as solvent, the reaction mixture was stirred at 80°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0170] Compound bzIM2 (X = I), yield 75%,

[0171] 1 H NMR (400MHz; CDCl3), δ7.70-7.75(m,2H),7.20-7.50(m,8H),6.89(s,1H),6.79(d, 3 J HH =8.6Hz,1H,Ar-H),6.20(brs,1H),5.11(s,2H),4.88(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.47(t, 3 J HH =6.0Hz,2H),1.59(m,2H),1.37(m,2H).

[0172] Compound bzBM2 (X = Br), yield 66%,

[0173] 1 H NMR(400MHz; CDCl3), δ7.20-7.50(m,9H),7.11(d, 3 J HH =8.6Hz,1H,Ar-H),6.91(s,1H),6.74(d, 3 J HH =8.6Hz,1H,Ar-H),6.27(brs,1H),5.18(s,2H),4.81(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.41(t, 3 J HH =6.0Hz,2H),1.51(m,2H),1.32(m,2H).

[0174] Compound bzCM2 (X = Cl), yield 82%,

[0175] 1 H NMR(400MHz; CDCl3), δ7.25-7.50(m,9H),7.07(d, 3 J HH=8.6Hz,1H,Ar-H),6.89(s,1H),6.78(d, 3 J HH =8.6Hz,1H,Ar-H),6.20(brs,1H),5.24(s,2H),4.78(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.37(t, 3 J HH =6.0Hz,2H),1.64(m,2H),1.39(m,2H).

[0176] Compound bzSM2 (X = SCH3), yield 53%,

[0177] 1 H NMR (400MHz; CDCl3), δ7.25-7.50(m,8H),7.10(s,1H,Ar-H),6.90-7.00(m,2H),6.75(d, 3 J HH =8.6Hz,1H,Ar-H),6.24(brs,1H),5.13(s,2H),4.85(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.47(t, 3 J HH =6.0Hz,2H),1.60(m,2H),1.41(m,2H).

[0178] Example 18 Preparation of compounds bzIO2, bzBO2, bzCO2 and bzSO2

[0179]

[0180] General synthesis steps: 1.0 mmol 1.5 equivalent 3.0 equivalents of K2CO3, CH3CN as solvent, the reaction mixture was stirred at 80°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0181] Compound bzIO2 (X = I), yield 82%,

[0182] 1 H NMR (400MHz; CDCl3), δ7.82(d, 3 J HH=8.6Hz,1H,Ar-H),7.30-7.50(m,7H),6.90-7.00(m,3H),6.76(d, 3 J HH =8.6Hz,1H,Ar-H),6.21(brs,1H),5.11(s,2H),4.81(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.44(t, 3 J HH =6.0Hz,2H),1.55(m,2H),1.40(m,2H).

[0183] Compound bzBO2 (X = Br), yield 71%,

[0184] 1 H NMR (400MHz; CDCl3), δ7.30-7.60(m,8H),7.00-7.10(m,2H),6.85(s,1H),6.71(d, 3 J HH =8.6Hz,1H,Ar-H),6.23(brs,1H),5.15(s,2H),4.85(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.37(t, 3 J HH =6.0Hz,2H),1.60(m,2H),1.43(m,2H).

[0185] Compound bzCO2 (X = Cl), yield 68%,

[0186] 1 H NMR (400MHz; CDCl3), δ7.67(d, 3 J HH =8.6Hz,1H,Ar-H),7.30-7.50(m,6H),7.10-7.20(m,3H),6.91(s,1H),6.76(d, 3 J HH =8.6Hz,1H,Ar-H),6.27(brs,1H),5.18(s,2H),4.79(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.47(t, 3 J HH=6.0Hz,2H),1.55(m,2H),1.34(m,2H).

[0187] Compound bzSO2 (X = SCH3), yield 53%,

[0188] 1 H NMR (400MHz; CDCl3), δ7.20-7.50(m,8H),7.00-7.10(m,2H),6.89(s,1H),6.71(d, 3 J HH =8.6Hz,1H,Ar-H),6.22(brs,1H),5.09(s,2H),4.82(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.40-2.50(m,5H),1.51(m,2H),1.29(m,2H).

[0189] Example 19 Preparation of compounds HOIP3, HOBP3, HOCP3 and HOSP3

[0190]

[0191] General synthesis steps: 1.0 mmol 1.5 equivalents of BBr3, CHCl3 as solvent, the reaction mixture was stirred at 0°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0192] Compound HOIP3 (X = I), yield 89%,

[0193] 1 H NMR (400MHz; CDCl3), δ9.30 (brs, 1H), 7.55 (d, 3 J HH =8.6Hz,2H,Ar-H),7.06(d, 3 J HH =8.6Hz,1H),6.91(d, 3 J HH =8.6Hz,2H),6.73(s,1H),6.54(d, 3 J HH =8.6Hz,2H),6.20(brs,1H),4.77(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.44(t,3 J HH =6.0Hz,2H),1.62(m,2H),1.35(m,2H).

[0194] Compound HOBP3 (X = Br), yield 91%,

[0195] 1 H NMR (400MHz; CDCl3), δ9.25 (brs, 1H), 7.80 (d, 3 J HH =8.6Hz,2H,Ar-H),7.08-7.12(m,2H),6.70(s,1H),6.59(d, 3 J HH =8.6Hz,2H),6.24(brs,1H),4.81(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.40(t, 3 J HH =6.0Hz,2H),1.56(m,2H),1.30(m,2H).

[0196] Compound HOCP3 (X = Cl), yield 85%,

[0197] 1 H NMR(400MHz; CDCl3), δ9.37(brs,1H),7.31(d, 3 J HH =8.6Hz,2H,Ar-H),7.08-7.15(m,2H),6.73(s,1H),6.52(d, 3 J HH =8.6Hz,2H),6.20(brs,1H),4.85(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.45(t, 3 J HH =6.0Hz,2H),1.67(m,2H),1.42(m,2H).

[0198] Compound HOSP3 (X = SCH3), yield 79%,

[0199] 1 H NMR(400MHz; CDCl3), δ9.27(brs,1H),7.25(d, 3 J HH=8.6Hz,2H,Ar-H),7.05-7.15(m,3H),6.76(s,1H),6.50(d, 3 J HH =8.6Hz,2H),6.23(brs,1H),4.75(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.35-2.45(m,5H),1.55(m,2H),1.35(m,2H).

[0200] Example 20 Preparation of compounds HOIM3, HOBM3, HOCM3 and HOSM3

[0201]

[0202] General synthesis steps: 1.0 mmol 1.5 equivalents of BBr3, CHCl3 as solvent, the reaction mixture was stirred at 0°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0203] Compound HOIM3 (X = I), yield 92%,

[0204] 1 H NMR(400MHz; CDCl3), δ9.20(brs,1H),7.70-7.75(m,2H,Ar-H),7.20-7.25(m,2H),7.05(d, 3 J HH =8.6Hz,1H),6.73(s,1H),6.57(d, 3 J HH =8.6Hz,2H),6.19(brs,1H),4.81(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.47(t, 3 J HH =6.0Hz,1H),1.51(m,2H),1.32(m,2H).

[0205] Compound HOBM3 (X = Br), yield 84%,

[0206] 1 H NMR (400MHz; CDCl3), δ9.10 (brs, 1H), 7.45 (d, 3 J HH=8.6Hz,1H),7.34(s,1H),7.21(t, 3 J HH =8.6Hz,1H),7.10-7.15(m,2H,Ar-H),6.73(s,1H),6.51(d, 3 J HH =8.6Hz,2H),6.29(brs,1H),4.80(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.37(t, 3 J HH =6.0Hz,1H),1.57(m,2H),1.30(m,2H).

[0207] Compound HOCM3 (X = Cl), yield 78%,

[0208] 1 H NMR(400MHz; CDCl3), δ9.15(brs,1H),7.30-7.40(m,3H),7.05-7.15(m,2H),6.75(s,1H),6.57(d, 3 J HH =8.6Hz,2H),6.20(brs,1H),4.84(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.48(t, 3 J HH =6.0Hz,1H),1.52(m,2H),1.39(m,2H).

[0209] Compound HOSM3 (X = SCH3), yield 64%,

[0210] 1 H NMR(400MHz; CDCl3), δ9.27(brs,1H),7.25-7.35(m,2H),7.10-7.15(m,2H),6.91(d, 3 J HH =8.6Hz,1H),6.72(s,1H),6.27(brs,1H),4.80(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.44(t, 3 J HH =6.0Hz,1H),1.62(m,2H),1.41(m,2H).

[0211] Example 21 Preparation of compounds HOIO3, HOBO3, HOCO3 and HOSO3

[0212]

[0213] General synthesis steps: 1.0 mmol 1.5 equivalents of BBr3, CHCl3 as solvent, the reaction mixture was stirred at 0°C until the reaction was complete. The reaction mixture was separated between ethyl acetate and saturated brine, and the organic solvent phase was dried over magnesium sulfate. The solvent was drained and the crude product was separated using a silica gel column.

[0214] Compound HOIO3 (X = I), yield 87%,

[0215] 1 H NMR(400MHz; CDCl3), δ9.22(brs,1H),7.81(d, 3 J HH =8.6Hz,1H),7.25(t, 3 J HH =8.6Hz,1H),7.09(d, 3 J HH =8.6Hz,1H),6.90-7.00(m,2H),6.72(s,1H),6.54(d, 3 J HH =8.6Hz,1H),6.72(s,1H),6.10(brs,1H),4.78(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.40(t, 3 J HH =6.0Hz,1H),1.68(m,2H),1.35(m,2H).

[0216] Compound HOBO3 (X = Br), yield 72%,

[0217] 1 H NMR(400MHz; CDCl3), δ9.20(brs,1H),7.52(d, 3 J HH =8.6Hz,1H),7.21(t, 3 J HH =8.6Hz,1H),7.00-7.12(m,3H),6.71(s,1H),6.57(d, 3 J HH=8.6Hz,1H),6.14(brs,1H),4.85(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.47(t, 3 J HH =6.0Hz,1H),1.60(m,2H),1.31(m,2H).

[0218] Compound HOCO3 (X = Cl), yield 76%,

[0219] 1 H NMR(400MHz; CDCl3), δ9.24(brs,1H),7.62(d, 3 J HH =8.6Hz,1H),7.10-7.20(m,4H),6.70(s,1H),6.54(d, 3 J HH =8.6Hz,1H),6.19(brs,1H),4.80(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.41(t, 3 J HH =6.0Hz,1H),1.66(m,2H),1.37(m,2H).

[0220] Compound HOSO3 (X = SCH3), yield 61%,

[0221] 1 H NMR(400MHz; CDCl3), δ9.22(brs,1H),7.31(d, 3 J HH =8.6Hz,1H),7.21(t, 3 J HH =8.6Hz,1H),7.05-7.15(m,3H),6.74(s,1H),6.59(d, 3 J HH =8.6Hz,1H),6.28(brs,1H),4.74(t, 3 J HH =6.0Hz,1H),2.60-3.00(m,8H),2.48(t, 3 J HH =6.0Hz,1H),1.61(m,2H),1.27(m,2H).

[0222] Effect Example 1

[0223] In vitro binding assay

[0224] Temporarily infected mouse fibroblasts (purchased from Creative Bioarray, Cat. No.: CSC-C8515W) were homogenized to a concentration of approximately 500,000 cells per ml. The suspension was sonicated and 100 μl of the suspension was added to each tube, for a total of 48 tubes. The [3H]ifenprodil concentration was diluted from 1 mCi / ml stock solution to 1 μCi / 100 μl with ethanol. It was further diluted to 2.7×10 -2 μCi / 100 μL, 100 μL was used in each tube. The test compound (compound of the present invention) was dissolved in dimethyl sulfoxide to obtain 1×10 -3 M solution, prepared with dimethyl sulfoxide to 1×10 -4 Up to 1×10 -10 M solution, using 10 μL in each tube. After assembly, vortex the test tube and react at 37°C for 2 hours. Separate using a cell harvester and wash the filter paper with PBS containing 10% ethanol. Place the filter paper in a 4 ml plastic bottle and add 2 mL of scintillation fluid (purchased from PerkinsElmer, UltimaGold AB). Count the samples. Analyze the data using GraphPad to obtain the binding constant.

[0225] The binding constants Ki of the compounds of the present invention are listed in Table 1:

[0226] Table 1

[0227]

[0228]

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof: in, R 6 is H or C1-C6 alkyl; R 1 , R 2 , R 3 , R 4 and R 5 Each is independently H, halogen, C1-C6 alkoxy or C1-C6 alkylthio.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1)R 6 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (2)R 1 , R 2 , R 3 , R 4 and R 5 wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine; (3)R 1 , R 2 , R 3 , R 4 and R 5 In the above, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy; (4)R 1 , R 2 , R 3 , R 4 and R 5 In the above, the C1-C6 alkylthio groups are independently methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio or tert-butylthio, preferably methylthio.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or two of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, halogen or C1-C6 alkylthio, and R 1 , R 2 , R 3 , R 4 and R 5 1, 2, 3, 4 or 5 are not H; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is halogen or C1-C6 alkylthio, and the rest are H; more preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is chlorine, bromine, iodine or methylthio; the rest are H; (2)R 6 It is H or methyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The compound represented by formula I is as shown in IA, IB or IC: Among them, R 1 , R 2 , R 3 and R 6 The definition as in any one of claims 1 to 3; Preferably, R 1 , R 2 and R 3 and C1-C6 alkylthio and C1-C6 alkylthio are independently halogen, C1-C6 alkoxy or C1-C6 alkylthio; for example halogen or C1-C6 alkylthio.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula I is selected from any of the following compounds:

6. A compound as shown in formula II-2 or formula III-1: in, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The definitions are as described in any one of claims 1 to 5, R 7 is a leaving group (e.g., R 7 is Ms (methylsulfonyl) or Ts (toluenesulfonyl)), R 8 is a hydroxyl protecting group (e.g., R 8 is Bn(benzyl)).

7. The compound according to claim 6, characterized in that The compound as shown in formula II-2 is selected from any of the following compounds: The compound represented by formula III-1 is selected from any of the following compounds:

8. A method for preparing the compound of formula I according to any one of claims 1 to 5, comprising method 1 or method 2; Method 1 comprises the following steps: in a solvent, in the presence of a catalyst, the compound of formula II-1 and the compound of formula II-2 undergo the following reaction to obtain the compound of formula I; in method 1, R 6 is a C1-C6 alkyl group; Method 2 comprises the following steps: in a solvent, in the presence of a catalyst, the compound of formula III-1 undergoes a deprotection reaction as shown below to obtain the compound of formula I; in method 2, R 6 is H; in, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 The definitions are as described in any one of claims 1 to 7.

9. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, and a pharmaceutical excipient.

10. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 9 in the preparation of a GluN2B inhibitor.

11. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating pancreatic cancer.

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