Fluoroaryl quinazoline derivative as well as intermediate, preparation method and application thereof

Abstract

The invention relates to a fluoroaryl quinazoline derivative as well as an intermediate, a preparation method and application thereof, and particularly discloses a compound shown as a formula I. In the formula I, X, Y and Z are respectively and independently H, F or CF3, and X, Y and Z are not H at the same time; r is H, and L is 18F; or R is < 18 > F, and L is H; # imgabs0 is an R configuration, an S configuration or a mixture of the R configuration and the S configuration when the connected carbon is chiral carbon; the derivative is high in yield, long in half-life period, simple in marking condition and convenient for long-distance transportation, and can be used for diagnosis, prevention and / or treatment of TSPO change related diseases as an imaging agent. # imgabs1 #

Description

Technical Field

[0001] The invention belongs to the technical field of radiopharmaceutical chemistry and nuclear medicine, and specifically relates to a fluoroarylquinazoline derivative, an intermediate thereof, a preparation method thereof and an application thereof. Background Art

[0002] 18kDa translocator protein (TSPO) is an evolutionarily conserved nuclear gene-encoded membrane protein, which is mainly distributed in tissues related to steroid synthesis, such as testis, ovarian granulosa and corpus luteum cells, placenta, bone marrow, liver, lungs and adrenal cortex. TSPO is related to the activation of glial cells, mitochondrial respiration, opening of mitochondrial permeability transduction pore, immune regulation, cell proliferation and apoptosis, and cholesterol transport from the outer to the inner membrane of mitochondria. Therefore, TSPO is closely related to the occurrence and development of stroke, brain trauma, Alzheimer's disease and brain glioma. For example, TSPO is usually expressed in glial cells in the brain, but under normal physiological conditions, its expression level is low. Under the condition of traumatic brain injury, the expression level of TSPO in microglia and astrocytes will increase significantly. The expression level of TSPO is also increased in the brain of patients with AD, glioma, scabies and HIV encephalitis. Because the upregulation of TSPO may be a reactive response of the body to brain damage, the protein is also considered an important marker of nerve damage or inflammation. Therefore, positron emission tomography (PET) can be used to non-invasively, dynamically, and systemically monitor the expression of TSPO to reflect the occurrence and development of related diseases, thereby providing a reliable imaging basis for the diagnosis and treatment of related diseases.

[0003] The first generation of TSPO-targeting PET probes (imaging agents) is 11C-labeled PK11195. After decades of research, it has become an important probe for studying neuroimmune mechanisms (such as activated microglia). However, this probe has shortcomings such as short half-life, low signal-to-noise ratio, poor brain penetration and low affinity. In order to overcome the shortcomings of PK11195, the second generation of TSPO-targeting probes (imaging agents) were developed, such as: [11C]DPA-713, [11C]PBR-28, [18F]FEPPA, etc. After small animal, primate and clinical verification, the affinity and pharmacokinetics of the second generation probes have been improved. In the clinical application of the second generation probe [11C]PBR-28, it was occasionally found that a small number of patients had low brain uptake. Studies have shown that this is caused by the differences in the expression of the rs6971 gene in patients. To overcome this problem, the third generation probes [18F]GE-180 and [11C]ER-176 were developed. However, in diseases with intact blood-brain barrier, [18F]GE-180 has poor blood-brain barrier permeability and poor signal-to-noise ratio. [11C]ER-176 has a high signal-to-noise ratio in patients with high or low expression of rs6971 gene. Therefore, [11C]ER-176 is the probe with the best properties among those targeting TSPO protein. However, the radioactive half-life of this probe is short, which is not conducive to its practical clinical application. Summary of the invention

[0004] The technical problem solved by the present invention is that the existing imaging agents have a short half-life and complex labeling conditions, thereby providing an 18F-labeled 4-(fluorinated aromatic)quinazoline-2-amide derivative, which has a high yield, a long half-life, simple labeling conditions, and is convenient for long-distance transportation, and can be used for the diagnosis, prevention and / or treatment of diseases related to TSPO changes.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A compound as shown in formula I,

[0007]

[0008] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0009] R is H, L is 18 F; or R is 18 F, L is H;

[0010] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0011] In a preferred embodiment, the compound shown in formula I is selected from any of the following compounds:

[0012]

[0013] A compound as shown in formula VI,

[0014]

[0015] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 6 For H, L 6 F; or R 6 For F, L 6 is H;

[0016] It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof. In a preferred embodiment, the compound shown in formula VI is selected from any of the following compounds,

[0017]

[0018] A compound as shown in formula V,

[0019]

[0020] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 5 For H, L 5 M; or R 5 For M, L 5 is H;

[0021] L 5 and R 5 In the formula, M is a leaving group and M is It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof. In a preferred embodiment, the compound shown in formula V is selected from any of the following compounds,

[0022]

[0023] A compound as shown in formula IV,

[0024]

[0025] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 4 For H, L 4 OH; or R 4 OH, L 4 is H;

[0026] It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof. In a preferred embodiment, the compound shown in formula IV is selected from any of the following compounds,

[0027]

[0028]

[0029] A compound as shown in formula III

[0030]

[0031] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 3 For H, L 3 M'; or R 3 For M', L 3 is H;

[0032] L 3 and R 3 In the example, M' is a protective group for a hydroxyl group, and M' is

[0033] It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof. In a preferred embodiment, the compound shown in formula III is selected from any of the following compounds,

[0034]

[0035]

[0036] A compound as shown in formula II

[0037]

[0038] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 2 For H, L 2 M'; or R 2 For M', L 2 is H;

[0039] L 2 and R 2 In the example, M' is a protective group for a hydroxyl group, and M' is

[0040] It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof. In a preferred embodiment, the compound shown in formula II is selected from any of the following compounds,

[0041]

[0042]

[0043] A compound as shown in formula I'

[0044]

[0045] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 1 For H, L 1 OH; or R 1 OH, L 1 is H;

[0046] It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof. In a preferred embodiment, the compound shown in formula I' is selected from any of the following compounds,

[0047]

[0048] The present invention also provides a use of the compound shown in formula I in the preparation of an imaging agent.

[0049] In the application, the imaging agent may be a positron emission tomography (PET) imaging agent.

[0050] In the application, the imaging agent may target TSPO receptor.

[0051] In the application, the radiochemical purity of the imaging agent is >99%.

[0052] The present invention also provides an application of a compound as shown in Formula I in the preparation of a drug, wherein the drug is a drug for diagnosing, preventing and / or treating diseases related to changes in TSPO translocation proteins.

[0053] The drug can be used to prepare a kit for diagnosing diseases related to changes in TSPO translocation proteins.

[0054] The diseases associated with changes in the TSPO translocation protein may be stroke, brain trauma, Alzheimer's disease, epilepsy, glioma, ulcers or HIV encephalitis.

[0055] The present invention also provides an application of the compound shown in Formula VI in determining the radioactivity specific activity of the compound shown in Formula I.

[0056] The present invention also provides a method for preparing a compound as shown in formula I, which comprises the following steps: in a solvent, a compound as shown in formula V is subjected to18 F - Fluorination to obtain a compound as shown in Formula I;

[0057]

[0058] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0059] R 5 For H, L 5 is M, R is H, L is 18 F;

[0060] Or, R 5 For M, L 5 is H, R is 18 F, L is H;

[0061] L 5 and R 5 In the formula, M is a leaving group and M is

[0062] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0063] In the method for preparing the compound as shown in Formula I, the method for preparing the compound as shown in Formula I further comprises the following steps:

[0064] (1) QMA column and K 222 / K2CO3 solution elution, evaporation to dryness, preparation 18 F - / K 222 / K2CO3 complex;

[0065] (2) in a solvent, the compound represented by the formula V, the 18 F - / K 222 / K2CO3 complex undergoes a substitution reaction to obtain a compound as shown in formula I.

[0066] In the method for preparing the compound as shown in Formula I, the K 222 / K2CO3 solution can be 18 F - Conventional K during fluorination 222 / K2CO3 solution, preferably composed of the K 222 , the K2CO3, the solvent and water.

[0067] In the method for preparing the compound as shown in Formula I, the K 222 / K2CO3 solution 222The mass of the K2CO3, the volume of the solvent and the volume ratio of the water can be selected from the group consisting of those in the art. 18 F - The conventional dosage during fluorination is preferably 47:8.5:5.5:1.

[0068] In the method for preparing the compound as shown in Formula I, the solvent can be any 18 F - The conventional solvent for fluorination is acetonitrile, which is preferred.

[0069] In the method for preparing the compound of formula I, the evaporation temperature may be 18 F - The conventional temperature during fluorination is preferably 100-120°C, for example 110°C.

[0070] In the method for preparing the compound of formula I, the reaction temperature of the substitution reaction can be any temperature in the art. 18 F - The conventional reaction temperature during fluorination is preferably 90-110°C, for example 100°C.

[0071] In the method for preparing the compound as shown in formula I, 18 F - After fluorination, post-treatment is also included, and the post-treatment can be 18 F - Conventional post-treatment during fluorination.

[0072] The method for preparing the compound of formula I also includes a method for preparing the compound of formula V, and the method for preparing the compound of formula V includes the following steps: in a solvent, in the presence of an organic base, a compound of formula IV undergoes a substitution reaction with M-Cl or M-Br to obtain a compound of formula V;

[0073]

[0074] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0075] R 4 For H, L 4 For OH, R 5 For H, L 5 is M;

[0076] Or, R 4 OH, L 4 For H, R 5 For M, L 5 is H;

[0077] In L' and R', M is a leaving group, M is

[0078] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0079] In the method for preparing the compound represented by Formula V, the solvent may be a conventional solvent for substitution reactions in the art, preferably acetonitrile.

[0080] In the method for preparing the compound of formula V, the organic base can be a conventional organic base for substitution reactions in the art, preferably triethylamine.

[0081] In the method for preparing the compound of formula V, the molar ratio of the organic base to the compound of formula IV can be the conventional amount used in substitution reactions in the art, preferably 3:1.

[0082] In the method for preparing the compound of formula V, the molar ratio of the M-Cl or M-Br to the compound of formula IV can be the conventional amount used in substitution reactions in the art, preferably 1.5:1.

[0083] In the method for preparing the compound represented by Formula V, the reaction temperature of the substitution reaction can be a conventional reaction temperature of substitution reactions in the art, preferably room temperature.

[0084] In the method for preparing the compound as shown in Formula V, the substitution reaction further includes post-treatment, and the post-treatment can be a conventional post-treatment for substitution reactions in the art.

[0085] In the preparation method of the compound shown in formula I, the preparation method of the compound shown in formula V also includes the preparation method of the compound shown in formula IV, and the preparation method of the compound shown in formula IV includes the following steps: in a solvent, in the presence of TsOH, the compound shown in formula III undergoes a hydrolysis reaction to obtain a compound shown in formula IV;

[0086]

[0087] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0088] R 3 For H, L 3 For M', R 4 For H, L 4 for OH;

[0089] Or, R 3 For M', L 3 For H, R 4 OH, L 4is H;

[0090] L 3 and R 3 In the example, M' is a protective group for a hydroxyl group, and M' is

[0091] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0092] In the method for preparing the compound represented by Formula IV, the solvent may be a conventional solvent for hydrolysis reaction in the art, preferably a mixed solvent of acetonitrile and water; the volume ratio of acetonitrile to water is preferably 1:1.

[0093] In the method for preparing the compound of formula IV, the molar ratio of TsOH to the compound of formula III can be the conventional amount used in hydrolysis reactions in the art, preferably 0.05:1.

[0094] In the method for preparing the compound of formula IV, the reaction temperature of the hydrolysis reaction can be a conventional reaction temperature of the hydrolysis reaction in the art, preferably a temperature at which the solvent boils.

[0095] In the method for preparing the compound as shown in Formula IV, the hydrolysis reaction further includes post-treatment, and the post-treatment can be conventional post-treatment of hydrolysis reactions in the art.

[0096] In the preparation method of the compound shown in formula I, the preparation method of the compound shown in formula IV also includes the preparation method of the compound shown in formula III, and the preparation method of the compound shown in formula III includes the following steps: in a solvent, in the presence of a base, the compound shown in formula II undergoes a substitution reaction with CH3I to obtain a compound shown in formula III;

[0097]

[0098] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0099] R 2 For H, L 2 For M', R 3 For H, L 3 for M';

[0100] or R 2 For M', L 2 For H, R 3 For M', L 3 is H;

[0101] L 2 , R 2 , L3 and R 3 In the example, M' is a protective group for a hydroxyl group, and M' is

[0102] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0103] In the method for preparing the compound represented by Formula III, the solvent may be a conventional solvent for substitution reactions in the art, preferably THF.

[0104] In the method for preparing the compound of formula III, the base can be a conventional base for substitution reactions in the art, preferably NaH.

[0105] In the method for preparing the compound of formula III, the molar ratio of the base to the compound of formula II can be the conventional amount used in substitution reactions in the art, preferably 1.2:1.

[0106] In the method for preparing the compound of formula III, the molar ratio of CH3I to the compound of formula II can be the conventional amount used in substitution reactions in the art, preferably 2.0:1.

[0107] In the method for preparing the compound of formula III, the reaction temperature of the substitution reaction can be a conventional reaction temperature of substitution reactions in the art, preferably 66°C.

[0108] In the method for preparing the compound as shown in Formula III, the substitution reaction further includes post-treatment, and the post-treatment can be a conventional post-treatment for substitution reactions in the art.

[0109] In the preparation method of the compound shown in formula I, the preparation method of the compound shown in formula III also includes the preparation method of the compound shown in formula II, and the preparation method of the compound shown in formula II includes the following steps: in a solvent, in the presence of TsOH, the compound shown in formula I' undergoes a substitution reaction with THP to obtain a compound shown in formula II;

[0110]

[0111] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0112] R 1 For H, L 1 For OH, R 2 For H, L 2 for M';

[0113] or R 1 OH, L 1For H, R 2 For M', L 2 is H;

[0114] L 2 and R 2 In the example, M' is a protective group for a hydroxyl group, and M' is

[0115] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0116] In the method for preparing the compound shown in Formula II, the solvent can be a conventional solvent for substitution reactions in the art, preferably acetonitrile.

[0117] In the method for preparing the compound of formula II, the molar ratio of THP to the compound of formula I' can be the conventional amount used in substitution reactions in the art, preferably 1.2:1.

[0118] In the method for preparing the compound of formula II, the molar ratio of TsOH to the compound of formula I' can be the conventional amount used in substitution reactions in the art, preferably 0.05:1.

[0119] In the method for preparing the compound of formula II, the reaction temperature of the substitution reaction can be a conventional reaction temperature of substitution reactions in the art, preferably 81.6°C.

[0120] In the method for preparing the compound as shown in Formula II, the substitution reaction further includes post-treatment, and the post-treatment can be a conventional post-treatment for substitution reactions in the art.

[0121] In the method for preparing the compound of formula I, the method for preparing the compound of formula II also includes a method for preparing the compound of formula I', and the method for preparing the compound of formula I' comprises the following steps: in a solvent, in the presence of a condensation reagent, a catalyst and an organic base, a carboxylic acid compound of formula A and an amino alcohol compound of formula B undergo a condensation reaction to obtain a compound of formula I';

[0122]

[0123] Wherein, X, Y, and Z are each independently H, F, or CF3, and X, Y, and Z are not H at the same time;

[0124] The amino acid compound shown in formula B is R 1 For H, L 1 for OH;

[0125] Or the amino acid compound shown in formula B is R 1 OH, L 1 is H;

[0126] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0127] In the method for preparing the compound represented by Formula I', the solvent may be a conventional solvent for condensation reaction in the art, preferably acetonitrile.

[0128] In the method for preparing the compound represented by Formula I', the condensation reagent may be a conventional condensation reagent for condensation reaction in the art, preferably EDC.

[0129] In the method for preparing the compound represented by Formula I', the catalyst may be a conventional catalyst for condensation reaction in the art, preferably 1-hydroxybenzotriazole.

[0130] In the method for preparing the compound represented by Formula I', the organic base may be a conventional organic base for condensation reaction in the art, preferably triethylamine.

[0131] In the method for preparing the compound of formula I', the molar ratio of the amino alcohol compound of formula B to the carboxylic acid compound of formula A can be the conventional amount used in condensation reactions in the art, preferably 1.2:1.

[0132] In the method for preparing the compound of formula I', the molar ratio of the condensation reagent to the carboxylic acid compound of formula A can be the conventional amount used in condensation reactions in the art, preferably 1.2:1.

[0133] In the method for preparing the compound of formula I', the molar ratio of the catalyst to the carboxylic acid compound of formula A can be the conventional amount used in condensation reactions in the art, preferably 1.2:1.

[0134] In the method for preparing the compound of formula I', the molar ratio of the organic base to the carboxylic acid compound of formula A can be a conventional amount used in condensation reactions in the art, preferably 1.5:1.

[0135] In the method for preparing the compound represented by Formula I', the reaction temperature of the condensation reaction can be a conventional reaction temperature of condensation reaction in the art, preferably room temperature.

[0136] In the method for preparing the compound as shown in Formula I', the condensation reaction further includes post-treatment, and the post-treatment can be conventional post-treatment of condensation reactions in the art.

[0137] The present invention also provides a method for preparing a compound as shown in Formula VI, which comprises the following steps: in a solvent, the compound as shown in Formula V and an alkali metal salt of fluorine undergo a substitution reaction to obtain a compound as shown in Formula VI;

[0138]

[0139] wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time;

[0140] R 5 For H, L 5 M, R 6 For H, L 6 is F;

[0141] or R 5 For M, L 5 H; R 6 For F, L 6 is H;

[0142] L 5 and R 5 In the formula, M is a leaving group and M is

[0143] It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

[0144] In the method for preparing the compound represented by Formula VI, the solvent may be a conventional solvent for substitution reactions in the art, preferably DMF.

[0145] In the method for preparing the compound of Formula VI, the alkali metal salt of fluorine can be a conventional base metal salt of fluorine for substitution reaction in the art, preferably CsF.

[0146] In the method for preparing the compound of Formula VI, the molar ratio of the alkali metal salt of fluorine to the compound of Formula V can be the conventional amount used in substitution reactions in the art, preferably 1.5:1.

[0147] In the method for preparing the compound of Formula VI, the temperature of the substitution reaction can be a conventional reaction temperature for substitution reactions in the art, preferably 100°C.

[0148] 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.

[0149] The atoms in the compounds of the invention and their structures may be naturally abundant or isotopically enriched (e.g. 11 C or 18F) and, unless otherwise indicated, are in their natural abundance.

[0150] In the present invention, "boiling point" refers to the temperature at which a pure substance boils under 1 standard atmosphere pressure.

[0151] The reagents and raw materials used in the present invention are commercially available.

[0152] The positive and progressive effects of the present invention are that the derivative has a high yield, a long half-life, simple labeling conditions, and is convenient for long-distance transportation. As an imaging agent, it can be used for the diagnosis, prevention and / or treatment of diseases related to TSPO changes. BRIEF DESCRIPTION OF THE DRAWINGS

[0153] Figure 1 This is a Micro PET image of the brain of a rat before surgery.

[0154] Figure 2 This is a scan of the rat's brain after surgery - Micro PET imaging. DETAILED DESCRIPTION

[0155] 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.

[0156] Example 1 Preparation of Compound O1

[0157]

[0158] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide), 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0159] Compound O1, yield 59%, 1 H NMR(400MHz; CDCl3), δ8.32(brs,1H,NH),8.14(d, 3 J HH =8.6Hz,1H,Ar-H),7.71-7.84(m,4H,Ar-H),7.49-7.58(m,2H,Ar-H),7.27(t, 3 J HH=8.6Hz,1H),4.38(brs,1H,OH),4.13(pent, 3 J HH =6.0Hz,1H),3.80(t, 3 J HH =6.0Hz,2H),1.68(m,2H),1.26(d, 3 J HH =6.0Hz,3H).

[0160] Example 2 Preparation of Compound O2

[0161]

[0162] General synthesis steps: 1.0 mmol 1.2 equivalents of THP (tetrahydropyran), 0.05 equivalents of TsOH (p-toluenesulfonic acid), acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0163] Compound O2, yield 86%, 1 H NMR(400MHz; CDCl3), δ8.30(brs,1H,NH),8.10(d, 3 J HH =8.6Hz,1H,Ar-H),7.70-7.8(m,4H,Ar-H),7.47-7.56(m,2H,Ar-H),7.25(t, 3 J HH =8.6Hz,1H),4.56(t, 3 J HH =6.0Hz,1H),4.11(pent, 3 J HH =6.0Hz,1H),3.61-3.71(m,2H),3.34(t, 3 J HH =6.0Hz,2H),1.50-1.72(m,8H),1.23(d, 3 J HH =6.0Hz,3H).

[0164] Example 3 Preparation of Compound O3

[0165]

[0166] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF (tetrahydrofuran) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0167] Compound O3, yield 86%, 1 H NMR (400MHz; CDCl3), δ8.08(d, 3 J HH =8.6Hz,1H,Ar-H),7.68-7.75(m,4H,Ar-H),7.45-7.58(m,2H,Ar-H),7.21(t, 3 J HH =8.6Hz,1H),4.51(t, 3 J HH =6.0Hz,1H),4.11(pent, 3 J HH =6.0Hz,1H),3.65-3.75(m,3H),3.30(t, 3 J HH =6.0Hz,2H),3.25(s,3H),1.45-1.76(m,8H),1.20(d, 3 J HH =6.0Hz,3H).

[0168] Example 4 Preparation of Compound O4

[0169]

[0170] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0171] Compound O4, yield 86%, 1 H NMR (400MHz; CDCl3), δ8.18(d, 3 J HH =8.6Hz,1H,Ar-H),7.60-7.75(m,4H,Ar-H),7.45-7.50(m,2H,Ar-H),7.20(t, 3 J HH =8.6Hz,1H),4.50(t, 3 J HH=6.0Hz,1H),4.08(pent, 3 J HH =6.0Hz,1H),3.55-3.75(m,2H),3.30(t, 3 J HH =6.0Hz,2H),3.20(s,3H),1.53-1.76(m,8H),1.20(d, 3 J HH =6.0Hz,3H).

[0172] Example 5 Preparation of Compound O5

[0173]

[0174] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl (methylsulfonyl chloride), 3.0 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0175] Compound O5, yield 86%, 1 H NMR (400MHz; CDCl3), δ8.15(d, 3 J HH =8.6Hz,1H,Ar-H),7.66-7.85(m,4H,Ar-H),7.50-7.58(m,2H,Ar-H),7.15(t, 3 J HH =8.6Hz,1H),4.44(t, 3 J HH =6.0Hz,1H),4.18(pent, 3 J HH =6.0Hz,1H),3.75-3.85(m,2H),3.25(t, 3 J HH =6.0Hz,2H),3.15(s,3H),1.51-1.79(m,8H),1.32(d, 3 J HH =6.0Hz,3H).

[0176] Example 6 Preparation of Compound O6

[0177]

[0178] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF (N,N-dimethylformamide) as solvent, the reaction mixture was stirred at 100°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.

[0179] Compound O6, yield 86%, 1 H NMR (400MHz; CDCl3), δ8.12(d, 3 J HH =8.6Hz,1H,Ar-H),7.61-7.81(m,4H,Ar-H),7.59-7.68(m,2H,Ar-H),7.19(t, 3 J HH =8.6Hz,1H),4.24(pent, 3 J HH =6.0Hz,1H),4.06(dt, 2 J HF =46Hz, 3 J HH =6.0Hz,1H),3.79-3.94(m,2H),3.20(t, 3 J HH =6.0Hz,2H),3.11(s,3H),1.56-1.71(m,8H),1.12(d, 3 J HH =6.0Hz,3H).

[0180] Example 7 Preparation of Compound M1

[0181]

[0182] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0183] Compound M1, yield 59%, 1 H NMR(400MHz; CDCl3), δ8.30(brs,1H,NH),8.09(d, 3 J HH =8.6Hz,1H,Ar-H),7.82-7.84(m,2H,Ar-H),7.52-7.62(m,4H,Ar-H),7.20(t,3 J HH =8.6Hz,1H),4.34(brs,1H,OH),4.17(pent, 3 J HH =6.0Hz,1H),3.76(t, 3 J HH =6.0Hz,2H),1.64(m,2H),1.20(d, 3 J HH =6.0Hz,3H).

[0184] Example 8 Preparation of Compound M2

[0185]

[0186] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0187] Compound M2, yield 86%, 1 H NMR(400MHz; CDCl3), δ8.25(brs,1H,NH),8.06(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.84(m,2H,Ar-H),7.52-7.64(m,4H,Ar-H),7.20(t, 3 J HH =8.6Hz,1H),4.52(t, 3 J HH =6.0Hz,1H),4.10(pent, 3 J HH =6.0Hz,1H),3.65-3.75(m,2H),3.31(t, 3 J HH =6.0Hz,2H),1.50-1.70(m,8H),1.18(d, 3 J HH =6.0Hz,3H).

[0188] Example 9 Preparation of Compound M3

[0189]

[0190] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0191] Compound M3, yield 42%, 1 H NMR (400MHz; CDCl3), δ8.15(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.84(m,2H,Ar-H),7.52-7.64(m,4H,Ar-H),7.19(t, 3 J HH =8.6Hz,1H),4.53(t, 3 J HH =6.0Hz,1H),4.11(pent, 3 J HH =6.0Hz,1H),3.60-3.70(m,3H),3.32(t, 3 J HH =6.0Hz,2H),3.21(s,3H),1.52-1.79(m,8H),1.24(d, 3 J HH =6.0Hz,3H).

[0192] Example 10 Preparation of Compound M4

[0193]

[0194] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0195] Compound M4, yield 58%, 1 H NMR (400MHz; CDCl3), δ8.09(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.54-7.64(m,4H,Ar-H),7.18(t, 3 J HH =8.6Hz,1H),4.40(s,1H),3.81(t, 3 JHH =6.0Hz,1H),3.56(pent, 3 J HH =6.0Hz,1H),3.23(s,3H),1.67(m,2H),1.21(d, 3 J HH =6.0Hz,3H).

[0196] Example 11 Preparation of Compound M5

[0197]

[0198] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0199] Compound M5, yield 49%, 1 H NMR (400MHz; CDCl3), δ8.07(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.50-7.65(m,4H,Ar-H),7.17(t, 3 J HH =8.6Hz,1H),3.60(pent, 3 J HH =6.0Hz,1H),3.49(t, 3 J HH =6.0Hz,1H),3.25(t, 3 J HH =6.0Hz,2H),3.14(s,3H),1.66(m,2H),1.22(d, 3 J HH =6.0Hz,3H).

[0200] Example 12 Preparation of Compound M6

[0201]

[0202] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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 M6, yield 57%, 1 H NMR (400MHz; CDCl3), δ8.07(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,4H,Ar-H),7.54-7.67(m,2H,Ar-H),7.16(t, 3 J HH =8.6Hz,1H),4.01(dt, 2 J HF =46Hz, 3 J HH =6.0Hz,1H),3.58(pent, 3 J HH =6.0Hz,1H),3.22(t, 3 J HH =6.0Hz,2H),1.67(m,2H),1.23(d, 3 J HH =6.0Hz,3H).

[0204] Example 13 Preparation of Compound P1

[0205]

[0206] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0207] Compound P1, yield 71%, 1 H NMR(400MHz; CDCl3), δ8.28(brs,1H,NH),8.11(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.91(m,4H,Ar-H),7.56(t, 3 J HH =8.6Hz,1H),7.29(t, 3 J HH =8.6Hz,1H),4.30(brs,1H,OH),4.10(pent, 3 J HH =6.0Hz,1H),3.73(t,3 J HH =6.0Hz,2H),1.62(m,2H),1.31(d, 3 J HH =6.0Hz,3H).

[0208] Example 14 Preparation of Compound P2

[0209]

[0210] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0211] Compound P2, yield 86%, 1 H NMR(400MHz; CDCl3), δ8.29(brs,1H,NH),8.08(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.89(m,4H,Ar-H),7.53(t, 3 J HH =8.6Hz,1H),7.29(t, 3 J HH =8.6Hz,2H),4.54(t, 3 J HH =6.0Hz,1H),4.09(pent, 3 J HH =6.0Hz,1H),3.65-3.75(m,2H),3.30(t, 3 J HH =6.0Hz,2H),1.50-1.70(m,8H),1.25(d, 3 J HH =6.0Hz,3H).

[0212] Example 15 Preparation of Compound P3

[0213]

[0214] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0215] Compound P3, yield 42%, 1 H NMR (400MHz; CDCl3), δ8.18(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.89(m,4H,Ar-H),7.59(t, 3 J HH =8.6Hz,1H),7.29(t, 3 J HH =8.6Hz,2H),4.51(t, 3 J HH =6.0Hz,1H),3.60-3.75(m,3H),3.31(t, 3 J HH =6.0Hz,2H),3.20(s,3H),1.55-1.79(m,8H),1.22(d, 3 J HH =6.0Hz,3H).

[0216] Example 16 Preparation of Compound P4

[0217]

[0218] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0219] Compound P4, yield 73%, 1 H NMR (400MHz; CDCl3), δ8.07(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.89(m,4H,Ar-H),7.58(t, 3 J HH =8.6Hz,1H),7.29(t, 3 J HH =8.6Hz,1H),4.35(s,1H),3.75(t, 3 JHH =6.0Hz,1H),3.52(pent, 3 J HH =6.0Hz,1H),3.20(s,3H),1.65(m,2H),1.24(d, 3 J HH =6.0Hz,3H).

[0220] Example 17 Preparation of Compound P5

[0221]

[0222] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0223] Compound P5, yield 49%, 1 H NMR (400MHz; CDCl3), δ8.09(d, 3 J HH =8.6Hz,1H,Ar-H),7.81-7.88(m,4H,Ar-H),7.57(t, 3 J HH =8.6Hz,1H),7.27(t, 3 J HH =8.6Hz,1H),3.54(pent, 3 J HH =6.0Hz,1H),3.46(t, 3 J HH =6.0Hz,1H),3.25(t, 3 J HH =6.0Hz,2H),3.12(s,3H),1.61(m,2H),1.27(d, 3 J HH =6.0Hz,3H).

[0224] Example 18 Preparation of Compound P6

[0225]

[0226] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0227] Compound M6, yield 43%, 1 H NMR (400MHz; CDCl3), δ8.03(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.89(m,4H,Ar-H),7.52(t, 3 J HH =8.6Hz,1H),7.21(t, 3 J HH =8.6Hz,2H),4.11(dt, 2 J HF =46Hz, 3 J HH =6.0Hz,1H),3.51(pent, 3 J HH =6.0Hz,1H),3.21(t, 3 J HH =6.0Hz,2H),1.61(m,2H),1.20(d, 3 J HH =6.0Hz,3H).

[0228] Example 19 Preparation of Compound TO1

[0229]

[0230] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0231] Compound TO1, yield 69%, 1 H NMR(400MHz; CDCl3), δ8.22(brs,1H,NH),8.02(d, 3 J HH=8.6Hz,1H,Ar-H),7.81-7.85(m,2H,Ar-H),7.55-7.70(m,3H,Ar-H),7.30-7.40(m,2H,Ar-H),4.28(brs,1H,OH),4.07(pent, 3 J HH =6.0Hz,1H),3.71(t, 3 J HH =6.0Hz,2H),1.62(m,2H),1.21(d, 3 J HH =6.0Hz,3H).

[0232] Example 20 Preparation of Compound TO2

[0233]

[0234] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0235] Compound TO2, yield 66%, 1 H NMR(400MHz; CDCl3), δ8.38(brs,1H,NH),8.12(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.55-7.67(m,3H,Ar-H),7.31-7.38(m,2H,Ar-H),4.61(t, 3 J HH =6.0Hz,1H),4.17(pent, 3 J HH =6.0Hz,1H),3.65-3.75(m,2H),3.38(t, 3 J HH =6.0Hz,2H),1.55-1.67(m,8H),1.26(d, 3 J HH =6.0Hz,3H).

[0236] Example 21 Preparation of Compound TO3

[0237]

[0238] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0239] Compound TO3, yield 57%, 1 H NMR (400MHz; CDCl3), δ8.16(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.55-7.66(m,3H,Ar-H),7.33-7.38(m,2H,Ar-H),4.58(t, 3 J HH =6.0Hz,1H),3.62-3.78(m,3H),3.38(t, 3 J HH =6.0Hz,2H),3.25(s,3H),1.55-1.80(m,8H),1.27(d, 3 J HH =6.0Hz,3H).

[0240] Example 22 Preparation of Compound TO4

[0241]

[0242] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0243] Compound TO4, yield 73%, 1 H NMR (400MHz; CDCl3), δ8.07(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.55-7.67(m,3H,Ar-H),7.30-7.41(m,2H,Ar-H),4.20(brs,1H,OH),3.71(t, 3 J HH =6.0Hz,1H),3.56(pent, 3 J HH=6.0Hz,1H),3.20(s,3H),1.66(m,2H),1.22(d, 3 J HH =6.0Hz,3H).

[0244] Example 23 Preparation of Compound TO5

[0245]

[0246] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0247] Compound TO5, yield 79%, 1 H NMR (400MHz; CDCl3), δ8.05(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.55-7.67(m,3H,Ar-H),7.31-7.38 (m,2H,Ar-H),3.50-3.61(m,3H),3.25(s,2H),3.14(s,3H),1.67(m,2H),1.30(d, 3 J HH =6.0Hz,3H).

[0248] Example 24 Preparation of Compound TO6

[0249]

[0250] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0251] Compound TO6, yield 58%, 1 H NMR (400MHz; CDCl3), δ8.04(d, 3 J HH =8.6Hz,1H,Ar-H),7.81-7.85(m,2H,Ar-H),7.57-7.69(m,3H,Ar-H),7.33-7.39(m,2H,Ar-H),4.01(dt,2 J HF =46Hz, 3 J HH =6.0Hz,1H),3.51(pent, 3 J HH =6.0Hz,1H),3.21(s,3H),1.71(m,2H),1.22(d, 3 J HH =6.0Hz,3H).

[0252] Example 25 Preparation of Compound TM1

[0253]

[0254] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0255] Compound TM1, yield 67%, 1 H NMR (400MHz; CDCl3), δ8.26(brs,1H,NH),8.07-8.11(m,2H,Ar-H),7.80-7.84(m,3H,Ar-H),7.65(d, 3 J HH =8.6Hz,1H),7.55(t, 3 J HH =8.6Hz,1H),7.45(t, 3 J HH =8.6Hz,1H),4.30(brs,1H,OH),4.07(pent, 3 J HH =6.0Hz,1H),3.74(t, 3 J HH =6.0Hz,2H),1.62(m,2H),1.27(d, 3 J HH =6.0Hz,3H).

[0256] Example 26 Preparation of Compound TM2

[0257]

[0258] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0259] Compound TM2, yield 75%, 1 H NMR (400MHz; CDCl3), δ8.28(brs,1H,NH),8.05-8.12(m,2H,Ar-H),7.80-7.85(m,3H,Ar-H),7.65(d, 3 J HH =8.6Hz,1H),7.56(t, 3 J HH =8.6Hz,1H),7.45(t, 3 J HH =8.6Hz,1H),4.50(t, 3 J HH =6.0Hz,1H),4.07(pent, 3 J HH =6.0Hz,1H),3.65-3.79(m,2H),3.38(t, 3 J HH =6.0Hz,2H),1.55-1.80(m,8H),1.28(d, 3 J HH =6.0Hz,3H).

[0260] Example 27 Preparation of Compound TM3

[0261]

[0262] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0263] Compound TM3, yield 82%, 1 H NMR (400MHz; CDCl3), δ8.05-8.13(m,2H,Ar-H),7.81-7.86(m,3H,Ar-H),7.60(d, 3 J HH =8.6Hz,1H),7.55(t, 3 J HH=8.6Hz,1H),7.45(t, 3 J HH =8.6Hz,1H),4.50(t, 3 J HH =6.0Hz,1H),3.60-3.75(m,3H),3.26(t, 3 J HH =6.0Hz,2H),3.22(s,3H),1.50-1.78(m,8H),1.30(d, 3 J HH =6.0Hz,3H).

[0264] Example 28 Preparation of Compound TM4

[0265]

[0266] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0267] Compound TM4, yield 58%, 1 H NMR (400MHz; CDCl3), δ8.05-8.13(m,2H,Ar-H),7.80-7.85(m,3H,Ar-H),7.61(d, 3 J HH =8.6Hz,1H),7.55(t, 3 J HH =8.6Hz,1H),7.41(t, 3 J HH =8.6Hz,1H),4.20(s,1H,OH),3.71(t, 3 J HH =6.0Hz,2H),3.51(pent, 3 J HH =6.0Hz,1H),3.21(s,3H),1.61(m,2H),1.24(d, 3 J HH =6.0Hz,3H).

[0268] Example 29 Preparation of Compound TM5

[0269]

[0270] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0271] Compound TM5, yield 79%, 1 H NMR (400MHz; CDCl3), δ8.05-8.14(m,2H,Ar-H),7.80-7.86(m,3H,Ar-H),7.61(d, 3 J HH =8.6Hz,1H),7.51(t, 3 J HH =8.6Hz,1H),7.39(t, 3 J HH =8.6Hz,1H),3.50-3.56(m,2H),3.25(s,3H),3.14(s,3H),1.61(m,2H),1.28(d, 3 J HH =6.0Hz,3H).

[0272] Example 30 Preparation of Compound TM6

[0273]

[0274] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0275] Compound TM6, yield 77%, 1 H NMR (400MHz; CDCl3), δ8.05-8.09(m,2H,Ar-H),7.80-7.87(m,3H,Ar-H),7.62(d, 3 J HH =8.6Hz,1H),7.50(t, 3 J HH =8.6Hz,1H),7.38(t, 3 J HH =8.6Hz,1H),4.03(dt, 2 J HF =46Hz, 3 J HH=6.0Hz,1H),3.55(pent, 3 J HH =6.0Hz,1H),3.22(s,3H),1.61(m,2H),1.21(d, 3 J HH =6.0Hz,3H).

[0276] Example 31 Preparation of Compound TP1

[0277]

[0278] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0279] Compound TP1, yield 63%, 1 H NMR(400MHz; CDCl3), δ8.24(brs,1H,NH),8.08(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.86(m,2H,Ar-H),7.56-7.68(m,5H,Ar-H),4.24(brs,1H,OH),4.09(pent, 3 J HH =6.0Hz,1H),3.71(t, 3 J HH =6.0Hz,2H),1.66(m,2H),1.28(d, 3 J HH =6.0Hz,3H).

[0280] Example 32 Preparation of Compound TP2

[0281]

[0282] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0283] Compound TP2, yield 54%, 1H NMR(400MHz; CDCl3), δ8.24(brs,1H,NH),8.06(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.91(m,2H,Ar-H),7.58-7.63(m,5H,Ar-H),4.50(t, 3 J HH =6.0Hz,1H),4.04(pent, 3 J HH =6.0Hz,1H),3.61-3.71(m,2H),3.28(t, 3 J HH =6.0Hz,2H),1.48-1.74(m,8H),1.23(d, 3 J HH =6.0Hz,3H).

[0284] Example 33 Preparation of Compound TP3

[0285]

[0286] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0287] Compound TP3, yield 72%, 1 H NMR (400MHz; CDCl3), δ8.03(d, 3 J HH =8.6Hz,1H,Ar-H),7.82-7.93(m,2H,Ar-H),7.51-7.67(m,5H,Ar-H),4.55(t, 3 J HH =6.0Hz,1H),3.60-3.79(m,3H),3.39(t, 3 J HH =6.0Hz,2H),3.26(s,3H),1.50-1.65(m,8H),1.27(d, 3 J HH =6.0Hz,3H).

[0288] Example 34 Preparation of Compound TP4

[0289]

[0290] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0291] Compound TP4, yield 53%, 1 H NMR (400MHz; CDCl3), δ8.09(d, 3 J HH =8.6Hz,1H,Ar-H),7.82-7.93(m,2H,Ar-H),7.55-7.65(m,5H,Ar-H),4.24(s,1H,OH),3.71(t, 3 J HH =6.0Hz,2H),3.50(pent, 3 J HH =6.0Hz,1H),3.23(s,3H),1.63(m,2H),1.26(d, 3 J HH =6.0Hz,3H).

[0292] Example 35 Preparation of Compound TP5

[0293]

[0294] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0295] Compound TP5, yield 69%, 1 H NMR (400MHz; CDCl3), δ8.05(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.86(m,2H,Ar-H),7.60-7.70(m,5H,Ar-H),3.51-3.62(m,3H),3.25(s,3H),3.10(s,3H),1.62(m,2H),1.31(d, 3 J HH =6.0Hz,3H).

[0296] Example 36 Preparation of Compound TP6

[0297]

[0298] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0299] Compound TM6, yield 83%, 1 H NMR (400MHz; CDCl3), δ8.16(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.88(m,2H,Ar-H),7.55-7.68(m,5H,Ar-H),4.14(dt, 2 J HF =46Hz, 3 J HH =6.0Hz,1H),3.63(pent, 3 J HH =6.0Hz,1H),3.24(s,3H),1.71(m,2H),1.29(d, 3 J HH =6.0Hz,3H).

[0300] Example 37 Preparation of Compound LO1

[0301]

[0302] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0303] Compound LO1, yield 76%, 1 H NMR(400MHz; CDCl3), δ8.27(brs,1H,NH),8.10(d, 3 J HH =8.6Hz,1H,Ar-H),7.71-7.86(m,4H,Ar-H),7.57(t, 3 J HH=8.6Hz,1H),7.45(t, 3 J HH =8.6Hz,1H),7.24(t, 3 J HH =8.6Hz,1H),4.30(brs,1H,OH),3.78(pent, 3 J HH =6.0Hz,1H),3.50(m,1H),3.23(m,1H),1.40(m,2H),0.91(t, 3 J HH =6.0Hz,3H).

[0304] Example 38 Preparation of Compound LO2

[0305]

[0306] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0307] Compound LO2, yield 66%, 1 H NMR(400MHz; CDCl3), δ8.27(brs,1H,NH),8.08(d, 3 J HH =8.6Hz,1H,Ar-H),7.70-7.86(m,4H,Ar-H),7.60(t, 3 J HH =8.6Hz,1H),7.50(t, 3 J HH =8.6Hz,1H),7.31(t, 3 J HH =8.6Hz,1H),4.51(t, 3 J HH =6.0Hz,1H),3.98(m,1H),3.40-3.75(m,4H),1.50-1.78(m,8H),0.84(t, 3 J HH =6.0Hz,3H).

[0308] Example 39 Preparation of Compound LO3

[0309]

[0310] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0311] Compound LO3, yield 77%, 1 H NMR (400MHz; CDCl3), δ8.14(d, 3 J HH =8.6Hz,1H,Ar-H),7.71-7.85(m,4H,Ar-H),7.56(t, 3 J HH =8.6Hz,1H),7.44(t, 3 J HH =8.6Hz,1H),7.25(t, 3 J HH =8.6Hz,1H),4.41(t, 3 J HH =6.0Hz,1H),3.44-3.75(m,5H),3.25(s,3H),1.55-1.75(m,8H),0.85(t, 3 J HH =6.0Hz,3H).

[0312] Example 40 Preparation of Compound LO4

[0313]

[0314] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0315] Compound LO4, yield 96%, 1 H NMR (400MHz; CDCl3), δ8.10(d, 3 J HH =8.6Hz,1H,Ar-H),7.71-7.87(m,4H,Ar-H),7.55(t, 3 J HH =8.6Hz,1H),7.42(t, 3 J HH =8.6Hz,1H),7.17(t,3 J HH =8.6Hz,1H),4.30(brs,1H,OH),3.25-3.51(m,6H),1.57(m,2H),0.84(t, 3 J HH =6.0Hz,3H).

[0316] Example 41 Preparation of Compound LO5

[0317]

[0318] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0319] Compound LO5, yield 89%, 1 H NMR (400MHz; CDCl3), δ8.17(d, 3 J HH =8.6Hz,1H,Ar-H),7.71-7.84(m,4H,Ar-H),7.61(t, 3 J HH =8.6Hz,1H),7.52(t, 3 J HH =8.6Hz,1H),7.34(t, 3 J HH =8.6Hz,1H),3.60-3.85(m,3H),3.24(s,3H),3.15(s,3H),1.64(m,2H),0.82(t, 3 J HH =6.0Hz,3H).

[0320] Example 42 Preparation of Compound LO6

[0321]

[0322] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0323] Compound LO6, yield 66%, 1H NMR (400MHz; CDCl3), δ8.01(d, 3 J HH =8.6Hz,1H,Ar-H),7.71-7.81(m,4H,Ar-H),7.56(t, 3 J HH =8.6Hz,1H),7.44(t, 3 J HH =8.6Hz,1H),7.21(t, 3 J HH =8.6Hz,1H),4.15-4.45(m,3H),3.21(s,3H),1.62(m,2H),0.80(t, 3 J HH =6.0Hz,3H).

[0324] Example 43 Preparation of Compound LM1

[0325]

[0326] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0327] Compound LM1, yield 69%, 1 H NMR(400MHz; CDCl3), δ8.23(brs,1H,NH),8.13(d, 3 J HH =8.6Hz,1H,Ar-H),7.81-7.83(m,2H,Ar-H),7.50-7.59(m,4H,Ar-H),7.13(t, 3 J HH =8.6Hz,1H),4.37(brs,1H,OH),3.80(pent, 3 J HH =6.0Hz,1H),3.25-3.50(m,2H),1.49(m,2H),0.81(t, 3 J HH =6.0Hz,3H).

[0328] Example 44 Preparation of Compound LM2

[0329]

[0330] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0331] Compound LM2, yield 76%, 1 H NMR(400MHz; CDCl3), δ8.21(brs,1H,NH),8.08(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.82(m,2H,Ar-H),7.50-7.57(m,4H,Ar-H),7.17(t, 3 J HH =8.6Hz,1H),4.54(t, 3 J HH =6.0Hz,1H),3.99(m,1H),3.40-3.70(m,4H),1.50-1.78(m,8H),0.81(t, 3 J HH =6.0Hz,3H).

[0332] Example 45 Preparation of Compound LM3

[0333]

[0334] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0335] Compound LM3, yield 37%, 1 H NMR (400MHz; CDCl3), δ8.11(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.82(m,2H,Ar-H),7.50-7.57(m,4H,Ar-H),7.17(t, 3 J HH =8.6Hz,1H),4.54(t, 3 J HH=6.0Hz,1H),3.44-3.74(m,5H),3.25(s,3H),1.53-1.75(m,8H),0.82(t, 3 J HH =6.0Hz,3H).

[0336] Example 46 Preparation of Compound LM4

[0337]

[0338] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0339] Compound LM4, yield 90%, 1 H NMR (400MHz; CDCl3), δ8.05(d, 3 J HH =8.6Hz,1H,Ar-H),7.81-7.84(m,2H,Ar-H),7.50-7.59(m,4H,Ar-H),7.16(t, 3 J HH =8.6Hz,1H),4.34(s,1H),3.25-3.50(m,6H),1.60(m,2H),0.84(t, 3 J HH =6.0Hz,3H).

[0340] Example 47 Preparation of Compound LM5

[0341]

[0342] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0343] Compound LM5, yield 88%, 1 H NMR (400MHz; CDCl3), δ8.12(d, 3 J HH=8.6Hz,1H,Ar-H),7.83-7.85(m,2H,Ar-H),7.53-7.85(m,4H,Ar-H),7.21(t, 3 J HH =8.6Hz,1H),3.60-3.85(m,3H),3.25(s,3H),3.14(s,3H),1.60(m,2H),0.81(t, 3 J HH =6.0Hz,3H).

[0344] Example 48 Preparation of Compound LM6

[0345]

[0346] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0347] Compound LM6, yield 58%, 1 H NMR (400MHz; CDCl3), δ8.14(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.85(m,2H,Ar-H),7.51-7.64(m,4H,Ar-H),7.14(t, 3 J HH =8.6Hz,1H),4.15-4.43(m,3H),3.25(s,3H),1.64(m,2H),0.83(t, 3 J HH =6.0Hz,3H).

[0348] Example 49 Preparation of Compound LP1

[0349]

[0350] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0351] Compound LP1, yield 61%,1 H NMR(400MHz; CDCl3), δ8.20(brs,1H,NH),8.01(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.91(m,4H,Ar-H),7.55(t, 3 J HH =8.6Hz,1H),7.27(t, 3 J HH =8.6Hz,2H),4.20(brs,1H,OH),3.79(pent, 3 J HH =6.0Hz,2H),3.25-3.48(m,2H),1.37(m,2H),0.84(t, 3 J HH =6.0Hz,3H).

[0352] Example 50 Preparation of Compound LP2

[0353]

[0354] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0355] Compound LP2, yield 81%, 1 H NMR(400MHz; CDCl3), δ8.23(brs,1H,NH),8.14(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.88(m,4H,Ar-H),7.56(t, 3 J HH =8.6Hz,1H),7.27(t, 3 J HH =8.6Hz,2H),4.20(brs,1H,OH),3.80(pent, 3 J HH =6.0Hz,1H),3.24-3.48(m,2H),1.47(m,2H),0.81(t, 3 J HH =6.0Hz,3H).

[0356] Example 51 Preparation of Compound LP3

[0357]

[0358] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0359] Compound LP3, yield 62%, 1 H NMR (400MHz; CDCl3), δ8.14(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.87(m,4H,Ar-H),7.55(t, 3 J HH =8.6Hz,1H),7.26(t, 3 J HH = 3 J HF =8.6Hz,2H),4.53(t, 3 J HH =6.0Hz,1H),3.45-3.76(m,5H),3.20(s,3H),1.53-1.74(m,8H),0.87(t, 3 J HH =6.0Hz,3H).

[0360] Example 52 Preparation of Compound LP4

[0361]

[0362] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0363] Compound LP4, yield 93%, 1 H NMR (400MHz; CDCl3), δ8.17(d, 3 J HH =8.6Hz,1H,Ar-H),7.85-7.93(m,4H,Ar-H),7.60(t, 3 J HH =8.6Hz,1H),7.33(t,3 J HH =8.6Hz,1H),4.30(s,1H,OH),3.24-3.52(m,6H),1.65(m,2H),0.94(t, 3 J HH =6.0Hz,3H).

[0364] Example 53 Preparation of Compound LP5

[0365]

[0366] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0367] Compound LP5, yield 89%, 1 H NMR (400MHz; CDCl3), δ8.02(d, 3 J HH =8.6Hz,1H,Ar-H),7.82-7.87(m,4H,Ar-H),7.54(t, 3 J HH =8.6Hz,1H),7.24(t, 3 J HH =8.6Hz,1H),3.60-3.87(m,3H),3.25(s,3H),3.12(s,3H),1.57(m,2H),0.89(t, 3 J HH =6.0Hz,3H).

[0368] Example 54 Preparation of Compound LP6

[0369]

[0370] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0371] Compound LM6, yield 83%, 1 H NMR (400MHz; CDCl3), δ8.13(d, 3 J HH=8.6Hz,1H,Ar-H),7.82-7.88(m,4H,Ar-H),7.54(t, 3 J HH =8.6Hz,1H),7.32(t, 3 J HH = 3 J HF =8.6Hz,2H),4.14-4.45(m,3H),3.22(s,3H),1.58(m,2H),0.91(t, 3 J HH =6.0Hz,3H).

[0372] Example 55 Preparation of Compound ZO1

[0373]

[0374] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0375] Compound ZO1, yield 77%, 1 H NMR(400MHz; CDCl3), δ8.35(brs,1H,NH),8.11(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.85(m,2H,Ar-H),7.68(d, 3 J HH =8.6Hz,1H,Ar-H),7.54-7.60(m,2H,Ar-H),7.32-7.40(m,2H,Ar-H),4.32(brs,1H,OH),3.79(pent, 3 J HH =6.0Hz,1H),3.25-3.51(m,2H),1.47(m,2H),0.85(t, 3 J HH =6.0Hz,3H).

[0376] Example 56 Preparation of Compound ZO2

[0377]

[0378] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0379] Compound ZO2, yield 78%, 1 H NMR(400MHz; CDCl3), δ8.22(brs,1H,NH),8.06(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.87(m,2H,Ar-H),7.54-7.68(m,3H,Ar-H),7.32-7.39(m,2H,Ar-H),4.51(t, 3 J HH =6.0Hz,1H),3.99(m,1H),3.44-3.74(m,4H),1.50-1.77(m,8H),0.87(t, 3 J HH =6.0Hz,3H).

[0380] Example 57 Preparation of Compound ZO3

[0381]

[0382] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0383] Compound ZO3, yield 47%, 1 H NMR (400MHz; CDCl3), δ8.13(d, 3 J HH =8.6Hz,1H,Ar-H),7.83-7.87(m,2H,Ar-H),7.53-7.68(m,3H,Ar-H),7.33-7.39(m,2H,Ar-H),4.48(t, 3 J HH =6.0Hz,1H),3.44-3.70(m,5H),3.25(s,3H),1.54-1.75(m,8H),0.88(t, 3 J HH =6.0Hz,3H).

[0384] Example 58 Preparation of Compound ZO4

[0385]

[0386] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0387] Compound ZO4, yield 94%, 1 H NMR (400MHz; CDCl3), δ8.10(d, 3 J HH =8.6Hz,1H,Ar-H),7.85-7.88(m,2H,Ar-H),7.55-7.69(m,3H,Ar-H),7.33-7 .40(m,2H,Ar-H),4.31(brs,1H,OH),3.26-3.52(m,6H),1.62(m,2H),0.83(t, 3 J HH =6.0Hz,3H).

[0388] Example 59 Preparation of Compound ZO5

[0389]

[0390] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0391] Compound ZO5, yield 82%, 1 H NMR (400MHz; CDCl3), δ8.02(d, 3 J HH =8.6Hz,1H,Ar-H),7.80-7.83(m,2H,Ar-H),7.53-7.63(m,3H,Ar-H),7.33-7.37 (m,2H,Ar-H),3.60-3.86(m,3H),3.25(s,2H),3.12(s,3H),1.60(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0392] Example 60 Preparation of Compound ZO6

[0393]

[0394] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0395] Compound ZO6, yield 78%, 1 H NMR (400MHz; CDCl3), δ8.15(d, 3 J HH =8.6Hz,1H,Ar-H),7.79-7.83(m,2H,Ar-H),7.53-7.67(m,3H,Ar-H),7.30 -7.37(m,2H,Ar-H),4.15-4.45(m,3H),3.24(s,3H),1.57(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0396] Example 61 Preparation of Compound ZM1

[0397]

[0398] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0399] Compound ZM1, yield 47%, 1 H NMR (400MHz; CDCl3), δ8.23(brs,1H,NH),8.05-8.09(m,2H,Ar-H),7.79-7.82(m,3H,Ar-H),7.65(d, 3 J HH =8.6Hz,1H),7.54(t, 3 J HH =8.6Hz,1H),7.44(t, 3 J HH=8.6Hz,1H),4.25(brs,1H,OH),3.79(pent, 3 J HH =6.0Hz,1H),3.25-3.50(m,2H),1.45(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0400] Example 62 Preparation of Compound ZM2

[0401]

[0402] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0403] Compound ZM2, yield 75%, 1 H NMR (400MHz; CDCl3), δ8.21(brs,1H,NH),8.08-8.10(m,2H,Ar-H),7.81-7.83(m,3H,Ar-H),7.63(d, 3 J HH =8.6Hz,1H),7.54(t, 3 J HH =8.6Hz,1H),7.41(t, 3 J HH =8.6Hz,1H),4.46(t, 3 J HH =6.0Hz,1H),3.97(m,1H),3.44-3.72(m,4H),1.50-1.80(m,8H),0.76(t, 3 J HH =6.0Hz,3H).

[0404] Example 63 Preparation of Compound ZM3

[0405]

[0406] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0407] Compound ZM3, yield 42%, 1 H NMR (400MHz; CDCl3), δ8.05-8.11(m,2H,Ar-H),7.79-7.81(m,3H,Ar-H),7.67(d, 3 J HH =8.6Hz,1H),7.52(t, 3 J HH =8.6Hz,1H),7.43(t, 3 J HH =8.6Hz,1H),4.47(t, 3 J HH =6.0Hz,1H),3.44-3.73(m,5H),3.25(s,3H),1.53-1.77(m,8H),0.77(t, 3 J HH =6.0Hz,3H).

[0408] Example 64 Preparation of Compound ZM4

[0409]

[0410] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0411] Compound ZM4, yield 98%, 1 H NMR (400MHz; CDCl3), δ8.06-8.08(m,2H,Ar-H),7.83-7.85(m,3H,Ar-H),7.63(d, 3 J HH =8.6Hz,1H),7.52(t, 3 J HH =8.6Hz,1H),7.37(t, 3 J HH =8.6Hz,1H),4.40(s,1H,OH),3.25-3.52(m,6H),1.57(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0412] Example 65 Preparation of Compound ZM5

[0413]

[0414] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0415] Compound ZM5, yield 89%, 1 H NMR (400MHz; CDCl3), δ8.09-8.15(m,2H,Ar-H),7.81-7.85(m,3H,Ar-H),7.56(d, 3 J HH =8.6Hz,1H),7.48(t, 3 J HH =8.6Hz,1H),7.34(t, 3 J HH =8.6Hz,1H),3.25-3.64(m,3H),3.25(s,3H),3.13(s,3H),1.56(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0416] Example 66 Preparation of Compound ZM6

[0417]

[0418] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0419] Compound ZM6, yield 79%, 1 H NMR (400MHz; CDCl3), δ8.07-8.11(m,2H,Ar-H),7.83-7.89(m,3H,Ar-H),7.64(d, 3 J HH =8.6Hz,1H),7.48(t, 3 J HH =8.6Hz,1H),7.35(t, 3 J HH=8.6Hz,1H),4.17-4.42(m,3H),3.25(s,3H),1.57(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0420] Example 67 Preparation of Compound ZP1

[0421]

[0422] General synthesis steps: 1.0 mmol 1.2 equivalents of amine, 1.2 equivalents of EDC, 1.2 equivalents of 1-hydroxybenzotriazole, 1.5 equivalents of Et3N, acetonitrile as solvent, the reaction mixture is carried out at room temperature and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0423] Compound ZP1, yield 39%, 1 H NMR(400MHz; CDCl3), δ8.34(brs,1H,NH),8.16(d, 3 J HH =8.6Hz,1H,Ar-H),7.82-7.87(m,2H,Ar-H),7.55-7.67(m,5H,Ar-H),4.60(brs,1H,OH),3.79(pent, 3 J HH =6.0Hz,1H),3.25-3.50(m,2H),1.46(m,2H),088(t, 3 J HH =6.0Hz,3H).

[0424] Example 68 Preparation of Compound ZP2

[0425]

[0426] General synthesis steps: 1.0 mmol 1.2 equivalents of THP, 0.05 equivalents of TsOH, acetonitrile as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0427] Compound ZP2, yield 74%, 1 H NMR(400MHz; CDCl3), δ8.37(brs,1H,NH),8.09(d, 3 JHH =8.6Hz,1H,Ar-H),7.84-7.90(m,2H,Ar-H),7.55-7.68(m,5H,Ar-H),4.49(t, 3 J HH =6.0Hz,1H),3.97(m,1H),3.44-3.74(m,4H),1.48-1.76(m,8H),0.81(t, 3 J HH =6.0Hz,3H).

[0428] Example 69 Preparation of Compound ZP3

[0429]

[0430] General synthesis steps: 1.0 mmol 1.2 equivalents of NaH, 2.0 equivalents of CH3I, THF as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0431] Compound ZP3, yield 43%, 1 H NMR (400MHz; CDCl3), δ8.04(d, 3 J HH =8.6Hz,1H,Ar-H),7.79-7.83(m,2H,Ar-H),7.53-7.63(m,5H,Ar-H),4.45(t, 3 J HH =6.0Hz,1H),3.45-3.76(m,3H),3.28(s,3H),1.56-1.78(m,8H),0.77(t, 3 J HH =6.0Hz,3H).

[0432] Example 70 Preparation of Compound ZP4

[0433]

[0434] General synthesis steps: 1.0 mmol 0.05 equivalent of TsOH, acetonitrile-water (1:1) as solvent, the reaction mixture is carried out under boiling and stirred until the reaction is completed. The reaction mixture is separated between ethyl acetate and saturated brine, and the organic solvent phase is dried over magnesium sulfate. The solvent is drained and the crude product is separated using a silica gel column.

[0435] Compound ZP4, yield 93%,1 H NMR (400MHz; CDCl3), δ8.10(d, 3 J HH =8.6Hz,1H,Ar-H),7.78-7.83(m,2H,Ar-H),7.56-7.67(m,5H,Ar-H),4.44(s,1H,OH),3.25-3.50(m,6H),1.54(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0436] Example 71 Preparation of Compound ZP5

[0437]

[0438] General synthesis steps: 1.0 mmol 1.5 equivalents of MsCl, 3.0 equivalents of Et3N, acetonitrile 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.

[0439] Compound ZP5, yield 79%, 1 H NMR (400MHz; CDCl3), δ8.09(d, 3 J HH =8.6Hz,1H,Ar-H),7.78-7.82(m,2H,Ar-H),7.50-7.60(m,5H,Ar-H),3.61-3.82(m,3H),3.24(s,3H),3.11(s,3H),1.60(m,2H),0.77(t, 3 J HH =6.0Hz,3H).

[0440] Example 72 Preparation of Compound ZP6

[0441]

[0442] General synthesis steps: 1.0 mmol 1.5 equivalents of CsF, DMF as solvent, the reaction mixture was stirred at 100°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.

[0443] Compound ZM6, yield 81%, 1 H NMR (400MHz; CDCl3), δ8.13(d,3 J HH =8.6Hz,1H,Ar-H),7.77-7.81(m,2H,Ar-H),7.50-7.58(m,5H,Ar-H),4.15-4.45(m,3H),3.21(s,3H),1.61(m,2H),0.89(t, 3 J HH =6.0Hz,3H).

[0444] Example 73 Radiochemical Reaction Example

[0445]

[0446] A labeling compound is obtained by fluorination using a labeling precursor compound containing an activating group.

[0447] Experimental steps: a) 18 F - 1 mL K 222 / K2CO3 solution (160mg K 222 in 18.6mL acetonitrile / 29mg K2CO3 in 3.4mL water) to elute into the reaction tube;

[0448] b) evaporate to dryness at 110°C under nitrogen flow; add 1 mL of anhydrous acetonitrile to the evaporation residue and evaporate to dryness again, repeat the above process three times to obtain dry 18 F - / K 222 / K2CO3;

[0449] c) cooling the reaction solution, and adding the dried 18 F - / K 222 1 mg of labeled precursor solution (dissolved in 1 mL of acetonitrile) was added to the / K2C03 complex and reacted at 100 °C for 10 min;

[0450] d) Add 8 mL of water to the reaction tube, and then pass the diluted reaction solution through an Oasis HLB solid phase extraction column;

[0451] e) Rinse the Oasis HLB solid phase extraction column with 10 mL of water;

[0452] f) The solid phase extraction column was eluted with 1 mL of methanol solution, and then purified by semi-preparative HPLC (Phenomenex Gemini NXC18 110A (250X 4.6mm X 5micron, acetonitrile / 0.1% formic acid water = 6 / 4), the peak time was 11.7min, and the purity was greater than 95%.18 The F labeling conditions are simpler than those of the aromatic-labeled precursor [11C]ER-176 reported in the literature, making it suitable for long-distance transportation and conducive to practical clinical applications.

[0453] Testing brain uptake and inhibition experiments

[0454] Five model mice were selected per group, and the labeled compound and [11C]ER176 (~100MBq / mL) diluted with 10% ethanol-normal saline were injected into the mice through the tail vein (0.1mL). The mice were killed at the above 10 minutes, and the organs were dissected, weighed, and the radioactivity counts of each tissue were measured to calculate the uptake values ​​of each organ. As can be seen from Table 1, the compound invented by this patent has a comparable brain uptake as [11C]ER-176. The labeled compound was placed in PBS and mouse serum, incubated at 37°C for 2 hours, taken out at 5min, 30min, 60min and 120min, and the radiochemical purity (RCP) was determined by Radio-HPLC. The results showed that the RCP of the compound within 2 hours was >95%, indicating that the compound had good stability. The competitive drug ER-176 (2mg / kg) was then used to pretreat the mice to investigate the targeting of the target compound to TSPO. As can be seen from Table 1, after the ER-176 inhibition experiment, it can be seen that the brain entry amount of the compound example is significantly reduced, indicating that the compound provided by this patent has a similar target as ER-176, further proving that this type of compound targets TSPO.

[0455] Table 1. Brain uptake and inhibition experiments

[0456]

[0457]

[0458]

[0459] Rats with permanent middle cerebral artery occlusion (pMCAO) were anesthetized and fixed on a rat board. After anesthesia, Example 18F-O6 (~1.5mCi / 0.1mL) was injected through the tail vein. After administration, a micro PET / CT dynamic scan was performed for 2 hours. The collected and reconstructed PET / CT images were transmitted to the workstation for image fusion and display to determine the radioactive distribution of Example 18F-O6 and its binding with TSPO. Figure 1 and Figure 2 It can be seen that the imaging agent example 18F-06 of the present invention is consistent with the imaging site reported in the literature, indicating that the compound targets TSPO. Figure 1 and Figure 2 The imaging position is consistent, which also shows that the developer of the present application has good repeatability.

Claims

1. A compound as shown in formula I, in, X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R is H, L is 18 F; or R is 18 F, L is H; It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

2. The compound according to claim 1, characterized in that The compound shown in formula I is selected from any of the following compounds, 3. A compound as shown below, in, X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 6 For H, L 6 F; or R 6 For F, L 6 is H; R 5 For H, L 5 M; or R 5 For M, L 5 H; L 5 and R 5 In the formula, M is a leaving group and M is R 4 For H, L 4 OH; or R 4 OH, L 4 is H; R 3 For H, L 3 M'; or R 3 For M', L 3 H; L 3 and R 3 In the example, M' is a protective group for a hydroxyl group, and M' is R 2 For H, L 2 M'; or R 2 For M', L 2 H; L 2 and R 2 In the example, M' is a protective group for a hydroxyl group, and M' is R 1 For H, L 1 OH; or R 1 OH, L 1 is H; It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

4. The compound according to claim 3, characterized in that The compound shown in formula VI is selected from any of the following compounds, Or, the compound as shown in formula V is selected from any of the following compounds, Or, the compound as shown in formula IV is selected from any of the following compounds, Or, the compound shown in formula III is selected from any of the following compounds, Or, the compound as shown in formula II is selected from any of the following compounds, Or, the compound represented by formula I' is selected from any of the following compounds, 5. Use of the compound of formula I as claimed in claim 1 in the preparation of an imaging agent; Preferably, the imaging agent is a positron emission tomography imaging agent; and / or, the imaging agent targets the TSPO receptor; and / or, the radiochemical purity of the imaging agent is >99%.

6. Use of the compound of formula I as claimed in claim 1 in the preparation of medicines, characterized in that: The drug is a drug for diagnosing, preventing and / or treating diseases related to changes in TSPO translocation proteins; Preferably, the disease associated with the change in TSPO translocation protein is stroke, brain trauma, Alzheimer's disease, epilepsy, glioma, ulcer or HIV encephalitis.

7. Use of the compound of formula VI as claimed in claim 3 in determining the radioactivity specific activity of the compound of formula I.

8. A method for preparing the compound of formula I as claimed in claim 1, characterized in that: The method comprises the following steps: in a solvent, a compound as shown in formula V is subjected to 18 F - Fluorination to obtain a compound as shown in Formula I; wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 5 For H, L 5 is M, R is H, L is 18 F; Or, R 5 For M, L 5 is H, R is 18 F, L is H; L 5 and R 5 In the formula, M is a leaving group and M is It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

9. The method for preparing the compound of formula I as claimed in claim 8, characterized in that: The method for preparing the compound as shown in Formula I further comprises the following steps: (1) QMA column and K 222 / K2CO3 solution elution, evaporation to dryness, preparation 18 F - / K 222 / K2CO3 complex; (2) in a solvent, the compound represented by the formula V, the 18 F - / K 222 / K2CO3 complex undergoes substitution reaction to obtain a compound as shown in formula I; Preferably, the method for preparing the compound as shown in Formula I satisfies one or more of the following conditions: ① the K 222 / K2CO3 solution is composed of the K 222 , the K2CO3, the solvent and water; ②K 222 The mass of the K2CO3, the volume of the solvent and the volume of the water are in a ratio of 47:8.5:5.5:1; ③The solvent is acetonitrile; ④ The evaporation temperature is 100-120°C, for example 110°C; ⑤ The reaction temperature of the substitution reaction is 90-110°C, for example 100°C; And / or, the preparation method of the compound shown in formula I also includes the preparation method of the compound shown in formula V, and the preparation method of the compound shown in formula V includes the following steps: in a solvent, in the presence of an organic base, a compound shown in formula IV undergoes a substitution reaction with M-Cl or M-Br to obtain a compound shown in formula V; wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 4 For H, L 4 For OH, R 5 For H, L 5 is M; Or, R 4 OH, L 4 For H, R 5 For M, L 5 is H; In L' and R', M is a leaving group, M is It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof; Preferably, the method for preparing the compound of formula V also includes the method for preparing the compound of formula IV, and the method for preparing the compound of formula IV includes the following steps: in a solvent, in the presence of TsOH, the compound of formula III undergoes a hydrolysis reaction to obtain a compound of formula IV; wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 3 For H, L 3 For M', R 4 For H, L 4 for OH; Or, R 3 For M', L 3 For H, R 4 OH, L 4 is H; L 3 and R 3 In the example, M' is a protective group for a hydroxyl group, and M' is It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof; More preferably, the preparation method of the compound as shown in formula IV also includes the preparation method of the compound as shown in formula III, and the preparation method of the compound as shown in formula III includes the following steps: in a solvent, in the presence of a base, the compound as shown in formula II undergoes a substitution reaction with CH3I to obtain a compound as shown in formula III; wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 2 For H, L 2 For M', R 3 For H, L 3 for M'; or R 2 For M', L 2 For H, R 3 For M', L 3 is H; L 2 , R 2 , L 3 and R 3 In the example, M' is a protective group for a hydroxyl group, and M' is It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof; Furthermore, the preparation method of the compound shown in formula III also includes the preparation method of the compound shown in formula II, and the preparation method of the compound shown in formula II includes the following steps: in a solvent, in the presence of TsOH, the compound shown in formula I' undergoes a substitution reaction with THP to obtain a compound shown in formula II; wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 1 For H, L 1 For OH, R 2 For H, L 2 for M'; or R 1 OH, L 1 For H, R 2 For M', L 2 is H; L 2 and R 2 In the example, M' is a protective group for a hydroxyl group, and M' is It means that when the carbon to which it is connected is a chiral carbon, it is R configuration, S configuration or a mixture thereof; Furthermore, the preparation method of the compound shown in formula II also includes the preparation method of the compound shown in formula I', and the preparation method of the compound shown in formula II includes the following steps: in a solvent, in the presence of a condensation reagent, a catalyst and an organic base, a carboxylic acid compound shown in formula A and an amino alcohol compound shown in formula B undergo a condensation reaction to obtain a compound shown in formula I'; Wherein, X, Y, and Z are each independently H, F, or CF3, and X, Y, and Z are not H at the same time; The amino acid compound shown in formula B is R 1 For H, L 1 for OH; Or the amino acid compound shown in formula B is R 1 OH, L 1 is H; It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

10. A method for preparing the compound of formula VI as claimed in claim 3 or 4, characterized in that: The method comprises the following steps: in a solvent, the compound represented by formula V and an alkali metal salt of fluorine undergo a substitution reaction to obtain a compound represented by formula VI; wherein X, Y and Z are each independently H, F or CF3, and X, Y and Z are not H at the same time; R 5 For H, L 5 M, R 6 For H, L 6 is F; or R 5 For M, L 5 H; R 6 For F, L 6 is H; L 5 and R 5 In the formula, M is a leaving group and M is It means that when the carbon to which it is connected is a chiral carbon, it is in the R configuration, the S configuration or a mixture thereof.

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