Method for preparing fused ring KIF18a inhibitor

Abstract

Provided in the present invention is a method for preparing a fused ring KIF18A inhibitor compound. The method for preparing the fused ring KIF18A inhibitor compound is simple to operate, has relatively high yield, is suitable for mass production, and can meet the requirements of actual production.

Description

A preparation method of fused-ring KIF18A inhibitor

[0001] This application claims priority from the following prior application: Patent application number 202410265568.X, filed with the State Intellectual Property Office of China on March 7, 2024, entitled “A Method for Preparing a Condensed-Ring KIF18A Inhibitor.” The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a fused-ring KIF18A inhibitor. Background Art

[0003] PCT / CN2023 / 117322 (filing date September 6, 2023) discloses a compound shown in the following formula (I), the full name of which is 4-(2-hydroxyethanesulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide. Experiments have shown that the compound not only has good KIF18A inhibitory effect and OVCAR-3 in vitro cell activity, but also has significantly improved physicochemical properties (solubility, permeability), significantly improved OVCAR-3 in vivo efficacy, and good safety. However, the yield of the compound is low and cannot meet the needs of practical applications. Summary of the Invention

[0004] To improve the above technical problems, the present invention provides a method for preparing the compound represented by formula (I), comprising the following steps:

[0005] When R1 is selected from halogen, -OTf, -OTs and -OMs, R2 is The method comprises the following steps (1): reacting compound A with compound 4 to obtain a compound represented by formula (I);

[0006] When R1 is R2 is selected from OH, C 1-6 Alkoxy, -OC 6-14 Aryl, -O-(5-14 membered heteroaryl), halogen (preferably, R2 is selected from OH, C 1-6 alkoxy), comprising the following steps (2): reacting compound A with compound 2 to obtain a compound represented by formula (I);

[0007] According to an embodiment of the present invention, in step (1), the reaction is carried out in the presence of a catalyst, the catalyst comprising a main catalyst (such as at least one selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous cyanide, and cuprous thiophene-2-carboxylate) and a ligand (such as at least one selected from trans-N,N'-dimethyl-1,2-cyclohexanediamine, 1,2-dimethylethylenediamine, 1,1,2,2,-tetramethylethylenediamine, 8-hydroxyquinoline, 1,10-phenanthroline, 2,4-pentanedione, N,N'-dibenzyloxamide and the like); preferably, the molar ratio of the main catalyst to the ligand in the catalyst is 1:(0.5-5), for example, 1:(1-3), such as 1:2.

[0008] According to an embodiment of the present invention, in step (1), the reaction is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base, for example, at least one selected from potassium phosphate, potassium carbonate, sodium carbonate, sodium tert-butoxide, sodium tert-amyloxide, and sodium methoxide.

[0009] According to an embodiment of the present invention, in step (1), the molar ratio of compound A to base in the reaction is 1:(0.5-10), for example 1:(1-5), such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4.

[0010] According to an embodiment of the present invention, in step (1), the molar ratio of compound A to the main catalyst in the catalyst in the reaction is 1:(0.05-2), for example 1:(0.1-1), such as 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8.

[0011] According to an embodiment of the present invention, in step (1), the molar ratio of compound A to compound 4 in the reaction is 1:(0.2-5), for example 1:(0.5-3), such as 1:0.8, 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.8.

[0012] According to an embodiment of the present invention, in step (2), the reaction is carried out in the presence of a condensing agent, and the condensing agent is selected from at least one of HATU, HBTU, HOBT, TBTU, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-chloro-1-methylpyridinium iodide.

[0013] According to an embodiment of the present invention, in step (2), the molar ratio of compound A to compound 2 in the reaction is 1:(0.2-5), for example 1:(0.5-3), such as 1:0.8, 1:1, 1:1.2, 1:1.5.

[0014] According to an embodiment of the present invention, in step (2), when R2 is OH, the reaction is carried out in the presence of a base, and the base is selected from an organic base, for example, at least one selected from triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and N,N-dimethylaminopyridine.

[0015] According to an embodiment of the present invention, in step (2), when R2 is OH, the reaction temperature is 10-60°C, for example, 20-50°C, such as 25°C, 30°C, 35°C, 40°C, 45°C.

[0016] According to an embodiment of the present invention, in step (2), when R2 is OH, the reaction time is 0.5-24 h, for example, 1-18 h, such as 2-16 h.

[0017] According to an embodiment of the present invention, in step (2), when R2 is selected from C 1-6 When the alkyl group is present, compound A and compound 2 undergo amine ester exchange reaction to obtain the compound represented by formula (I).

[0018] According to an embodiment of the present invention, the amine transesterification reaction is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base, for example, at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amylate, and potassium tert-butoxide.

[0019] According to an embodiment of the present invention, in step (2), when R2 is selected from C 1-6 When the alkoxy group is present, compound A is first subjected to a hydrolysis reaction to obtain a compound wherein R2 is OH in formula A, and then the compound wherein R2 is OH in formula A is reacted with compound 2 to obtain a compound represented by formula (I). Preferably, the hydrolysis reaction is carried out under alkaline conditions.

[0020] According to an embodiment of the present invention, the compound A (R2 is The preparation method further comprises the following steps (1'): converting compound A-2 into compound A;

[0021] R4 is selected from leaving groups other than halogen, -OTf, -OTs and -OMs.

[0022] According to an embodiment of the present invention, in step (1'), the group R1 can be introduced into the compound by conventional methods in the art, for example, compound A can be prepared by nucleophilic substitution reaction or elimination reaction.

[0023] According to an embodiment of the present invention, the method for preparing compound A in step (1) comprises the following steps (1a): compound B reacts with compound 2 to obtain compound A;

[0024] Among them, R 21 Selected from OH or C 1-6 Alkoxy, R1 is selected from halogen, -OTf, -OTs and -OMs, R2 is

[0025] According to an embodiment of the present invention, in step (1a), the reaction is carried out in the presence of a base, and the base is selected from an organic base, for example, at least one selected from triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and N,N-dimethylaminopyridine.

[0026] According to an embodiment of the present invention, in step (1a), the reaction is carried out in the presence of a condensing agent, and the condensing agent is selected from at least one of HATU, HBTU, HOBT, TBTU, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-chloro-1-methylpyridinium iodide.

[0027] According to an embodiment of the present invention, in step (1a), the molar ratio of compound B to compound 2 in the reaction is 1:(0.2-5), for example 1:(0.5-3), such as 1:0.8, 1:1, 1:1.2, 1:1.5.

[0028] According to an embodiment of the present invention, in step (1a), when R 21 C 1-6 In the case of alkoxy, R 21 Compound B containing OH further reacts with compound 2 to obtain compound A; or compound B directly undergoes an amine ester exchange reaction with compound 2 to obtain compound A.

[0029] According to an embodiment of the present invention, in step (1a), the reaction temperature is 10-60°C, for example, 20-50°C, such as 25°C, 30°C, 35°C, 40°C, 45°C.

[0030] According to an embodiment of the present invention, in step (1a), the reaction time is 0.5-24 h, such as 1-18 h, for example 2-12 h.

[0031] According to an embodiment of the present invention, in step (2), when R2 is OH, the preparation method of compound A comprises the following steps:

[0032] (2a) Compound D reacts with compound 4 to obtain compound C;

[0033] (2b) Compound C undergoes hydrolysis to obtain Compound A;

[0034] Among them, R 12 is selected from halogen (eg, chlorine, bromine, iodine), -OTf, -OTs, or -OMs; R 22 Selected from C 1-6 Alkoxy, R1 is R2 is OH.

[0035] According to an embodiment of the present invention, in step (2a), the reaction is carried out in the presence of a catalyst, and the catalyst includes a main catalyst (such as at least one selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous cyanide, and cuprous thiophene-2-carboxylate) and a ligand (such as at least one selected from trans-N,N'-dimethyl-1,2-cyclohexanediamine, 1,1,2,2,-tetramethylethylenediamine, 8-hydroxyquinoline, 1,10-phenanthroline, 2,4-pentanedione, N,N'-dibenzyloxamide and the like); preferably, the molar ratio of the main catalyst to the ligand in the catalyst is 1:(0.5-5), for example, 1:(1-3), such as 1:1.

[0036] According to an embodiment of the present invention, in step (2a), the reaction is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base, for example, at least one selected from potassium phosphate, potassium carbonate, sodium carbonate, sodium tert-butoxide, sodium tert-amyloxide, and sodium methoxide.

[0037] According to an embodiment of the present invention, in step (2a), the molar ratio of compound D to base in the reaction is 1:(0.5-10), for example 1:(1-5), such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4.

[0038] According to an embodiment of the present invention, in step (2a), the molar ratio of compound D in the reaction to the main catalyst in the catalyst is 1:(0.05-2), for example 1:(0.1-1), such as 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8.

[0039] According to an embodiment of the present invention, in step (2a), the molar ratio of compound D to compound 4 in the reaction is 1:(0.2-5), for example 1:(0.5-3), such as 1:0.8, 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.8.

[0040] According to an embodiment of the present invention, in step (2b), the reaction is carried out in the presence of a base, and the base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, and potassium carbonate.

[0041] According to an embodiment of the present invention, compound C can be directly subjected to an amine transesterification reaction with compound 2 to obtain a compound represented by formula (I).

[0042] The present invention also provides the intermediate compound shown below:

[0043] wherein R3 is selected from a leaving group, such as OH, halogen (such as chlorine, bromine, iodine), -OTf, -OTs or -OMs.

[0044] The present invention also provides a method for preparing compound 2, comprising the following steps:

[0045] (a) mixing compound 2b, phosphorus oxychloride and compound 2-1 to react to obtain compound 2-2;

[0046] (b) Compound 2-2 reacts in the presence of a catalyst and a base to obtain compound 2-3;

[0047] (c) Compound 2-3 reacts with an ammonia solution in the presence of a catalyst and a base to obtain compound 2;

[0048] wherein X1 and X2 are the same or different and are independently selected from halogen, such as chlorine, bromine or iodine.

[0049] According to an embodiment of the present invention, in step (a), the molar ratio of compound 2b to compound 2-1 is 1:(0.1-5), for example 1:(0.2-3), such as 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.3, 1:1.5.

[0050] According to an embodiment of the present invention, in step (a), the molar ratio of compound 2b to phosphorus oxychloride is 1:(0.1-5), for example 1:(0.2-3), such as 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.3, 1:1.5.

[0051] According to an embodiment of the present invention, phosphorus oxychloride is first added to a solution of compound 2b and then compound 2-1 is added to react to obtain compound 2-2.

[0052] According to an embodiment of the present invention, in step (b), the catalyst is selected from a monovalent copper catalyst, such as cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide.

[0053] According to an embodiment of the present invention, in step (b), the base is selected from an inorganic base, such as at least one of potassium carbonate, sodium carbonate, and cesium carbonate.

[0054] According to an embodiment of the present invention, in step (c), the amine solution is an organic solution of ammonia, for example, an alcohol solution of ammonia, such as ammonia / methanol, ammonia / ethanol, or ammonia / isopropanol.

[0055] According to an embodiment of the present invention, in step (c), the catalyst is selected from metal oxide catalysts, such as copper oxide, zinc oxide, cuprous oxide, nickel oxide, and cobalt oxide.

[0056] According to an embodiment of the present invention, in step (c), the base is selected from an inorganic base, for example, at least one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, and potassium carbonate.

[0057] According to an embodiment of the present invention, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropyl alcohol, and n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; Amides, such as dimethylformamide, dimethylacetamide, etc.; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, xylene, dimethyl sulfoxide; and aliphatic, cycloaliphatic or aromatic hydrocarbons optionally substituted by halogen atoms, such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene, bromobenzene or dichlorobenzene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate, dibutyl carbonate or ethylene carbonate. Beneficial effects

[0058] The present invention provides a method for preparing a compound represented by formula (I). The method for preparing the compound is simple to operate, has a high yield, is suitable for mass production, and can meet the needs of actual production. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 shows the structure of compound 2c 1 H NMR spectrum.

[0060] Figure 2 is the MS spectrum of compound 2c.

[0061] Figure 3 is the MS spectrum of compound 2d.

[0062] Figure 4 shows the 1 H NMR spectrum.

[0063] Figure 5 is the MS spectrum of compound 2.

[0064] Figure 6 shows compound 3a 1 H NMR spectrum.

[0065] Figure 7 is the MS spectrum of compound 3a.

[0066] Figure 8 shows the compound of formula (I) 1 H NMR spectrum.

[0067] FIG9 is the MS spectrum of the compound of formula (I).

[0068] Figure 10 is the MS spectrum of compound 6a.

[0069] Figure 11 is the MS spectrum of compound 7.

[0070] Definitions and Explanations of Terms

[0071] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0072] The term "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0073] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or polyaromatic rings fused together, preferably "C 6-10 Aryl". The term "C 6-14"Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6- 20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0074] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzofused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-oxo-1-carbazolyl, -phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzoisoquinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3

[0015] In some embodiments, the present invention further comprises carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5- to 14-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0075] The term "halogen" denotes fluorine, chlorine, bromine or iodine.

[0076] The term "amine transesterification" refers to "-C(O)OC 1-6 The reaction of an "alkyl" group with a "primary amine" group to form a "-C(O)NH-" group.

[0077] The term "OTf" refers to a trifluoromethanesulfonate group.

[0078] The term "OTs" refers to p-toluenesulfonate.

[0079] The term "OMs" refers to a mesylate group. DETAILED DESCRIPTION

[0080] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0081] The analytical instrument information and analysis method are as follows:

[0082] Liquid chromatography-mass spectrometry (LC-MS)

[0083] Agilent 1290 InfinityII with mass spectrometer detector (G6125C)

[0084] The HPLC-MS / MS was performed on an Agilent 1290 InfinityII mass spectrometer (G6125C). The test conditions are shown in Table 1.

[0085] Table 1 LC-MS test conditions

[0086] NMR analysis ( 1 H NMR)

[0087] Several milligrams of solid sample were dissolved in deuterated dimethyl sulfoxide, deuterated methanol or deuterated chloroform solvent and subjected to nuclear magnetic resonance analysis on a Varian 400-MR.

[0088] High-performance liquid chromatography (HPLC)

[0089] The model of the HPLC reverse phase test was Agilent 1260 HPLC Infinity II, and the model of the HPLC normal phase test was Agilent 1260 HPLC Infinity II. The test conditions are shown in Tables 2 and 3.

[0090] Table 2 HPLC reverse phase test conditions

[0091] Table 3 HPLC normal phase test conditions

[0092] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0093] Example 1 Synthesis of (1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-amine (Compound 2)

[0094] Step 1 Synthesis of (1S,4R)-N-(2,6-dibromophenyl)-2-azabicyclo[2.2.1]heptane-3-imine (Compound 2c)

[0095] Under nitrogen atmosphere, (1S, 4R) -2-azabicyclo [2.2.1] heptane -3- one (compound 2b) (2.76g, 25mmol, 1.0eq.) was dissolved in 60mL acetonitrile, the reaction temperature was lowered to 0°C, POCl3 (3.73g, 25mmol, 1.0eq.) was added dropwise, the reaction was maintained at 0°C for 2h, 2,6-dibromoaniline (compound 2a) (6.20g, 25mmol, 1.0eq.) was added and the reaction was continued for 2h. TLC detection showed that the reaction was complete, 20mL saturated NaHCO3 was added to quench the reaction solution, 2×20mL ethyl acetate was added for extraction, the liquids were separated, the organic layers were combined, and the organic phases were washed with 2×20mL brine. The organic phase was spin-dried and slurried with a mixed solution of ethyl acetate / petroleum ether = 1 / 1 to obtain a crude product of compound 2c (5.60g), which was used directly in the next reaction without purification. Compound 2c 1 The H NMR is shown in Figure 1 , and the MS is shown in Figure 2 .

[0096] 1 H NMR (400MHz, CDCl3) δ7.52-7.49 (m, 2H), 6.5 (t, J = 8.0, 1H), 3.85 (d, 1H), 3.20 (s, 1H) ,1.98-1.95(m,2H),1.85(t,1H),1.48(d,1H),1.46-1.44(m,1H),1.37-1.36(m,2H).

[0097] MS:(ESI,m / z):345.1[M+H] + .

[0098] Step 2 Synthesis of (1S,4R)-6-bromo-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridine (Compound 2d)

[0099] The crude product of compound 2c (1.50 g, 4.4 mmol, 1.0 eq.) was weighed and dissolved in 30 mL of DMSO. Potassium carbonate (1.21 g, 8.8 mmol, 2 eq.) and cuprous iodide (0.08 g, 0.44 mmol, 0.1 eq.) were added. The mixture was heated to 80°C for 2 h. The reaction was completed after HPLC detection. The mixture was cooled to room temperature, and 600 mL of water was added. The mixture was extracted with 2 × 30 mL of ethyl acetate. The organic layers were combined and concentrated to dryness to obtain a crude product of compound 2d (0.48 g).

[0100] MS:(ESI,m / z):262.8[M+H] + (Figure 3).

[0101] Step 3 Synthesis of Compound 2

[0102] Compound 2d (0.50 g, 1.9 mmol, 1.0 eq.), cuprous oxide (100 mg, 0.07 mmol, 0.35 eq.), potassium hydroxide (0.12 g, 1.9 mmol, 1.0 eq.) and 10 mL of ammonia-ethanol solution (20% ammonia / ethanol solution) were stirred at 80°C for 12 hours. The reaction was completed by HPLC. After filtration, the filtrate was concentrated under reduced pressure and dried. 20 mL of water was added and the mixture was extracted with dichloromethane (2×10 mL). The organic phase was concentrated and dried. Ethyl acetate / n-heptane = 1 / 3 was added for crystallization to obtain compound 2 (250 mg, yield 66%). 1 The H NMR is shown in Figure 4 , and the MS is shown in Figure 5 .

[0103] 1 H NMR(400MHz, CDCl3)δ7.18(t,1H),6.83(dd,1H),6.54(dd,1H),4.95(qd,1H),4. 31(s,2H),3.62(d,1H),2.22-2.16(m,1H),2.10-2.07(m,3H),1.37-1.36(m,2H).

[0104] MS:(ESI,m / z):199.9[M+H] + .

[0105] Example 2 Synthesis of Compound of Formula (I)

[0106] Step 1 Synthesis of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-((1S,4R)-1,2,3,4-tetrahydro-1,4-methylenebenzo[4,5]imidazo[1,2-a]pyridin-6-yl)benzamide (Compound 3a)

[0107] Under nitrogen protection, 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid (compound 1a) (6.70 g, 21.6 mmol, 1.0 eq.), compound 2 (4.38 g, 22 mmol, 1.02 eq.) and DMF (33.5 mL) were added to the reactor, the temperature was controlled at 25±5°C, DIEA (5.42 g, 47 mmol, 2.2 eq.) was added dropwise to the system. After the addition was complete, HATU (10.36 g, 27 mmol, 1.3 eq.) and EDCI (5.22 g, 27 mmol, 1.3 eq.) were added to the system, the temperature was controlled at 25±5°C, and the mixture was stirred for at least 10 hours. After the reaction was completed by HPLC detection, the temperature in the autoclave was controlled at 25±5°C, H2O (40.2mL) was added dropwise to the system, stirred for at least 1 hour, centrifuged, the filter cake was rinsed with H2O (13.4mL), and the filter cake was collected. The above wet filter cake and H2O (33.5mL) were added to the reactor, the temperature in the autoclave was controlled at 25±5°C, stirred for at least 1 hour, centrifuged, the filter cake was rinsed with H2O (13.4mL), and the filter cake was collected. The filter cake was vacuum dried at 45±5oC to obtain compound 3a as a brown solid (9.88g, yield 93%). Compound 3a 1 The H NMR is shown in Figure 6 , and the MS is shown in Figure 7 .

[0108] Characterization of compound 3a:

[0109] 1 H NMR (400MHz, CDCl3) δ12.28(s,1H),8.46(d,1H),8.10(d,1H),7.44-7.39(m,1H),7.36-7. 30(m,1H),7.24(dd,1H),7.14-7.12(m,1H),4.97(s,1H),3.79(t,1H),3.67(s,1H),3.13- 3.11(m,4H),2.40(d,1H),2.38-2.37(m,1H),2.36-2.35(m,2H),2.16-2.13(m,2H),2.02- 1.96(m,3H),1.94-1.58(m,4H),1.22-1.14(m,4H),0.31(s,4H).MS(EI,m / z):492.5[M+H] +

[0110] Step 2: Synthesis of the compound of formula (I)

[0111] Under nitrogen protection, compound 3a (9.30 g, 19 mmol, 1.0 eq.), 2-hydroxyethane-1-sulfonamide (compound 4) (3.14 g, 25 mmol, 1.3 eq.), K3PO4 (10.26 g, 48 mmol, 2.5 eq.), DMF (38 mL), trans-NN-dimethyl-1,2-cyclohexanediamine (2.75 g, 19 mmol, 1.0 eq.) were added to the reactor, and the nitrogen atmosphere was replaced three times. CuI (1.84 g, 9.5 mmol, 0.5 eq.) was added to the system, and the reactor was rinsed with DMF (9.5 mL). The nitrogen atmosphere was replaced three times, the temperature was raised to 85 ° C, and the reaction was stirred for at least 2 hours. After the reaction was completed under HPLC monitoring, the temperature was lowered to 25° C. The reaction solution was treated and purified by column chromatography to obtain the compound of formula (I) (white solid, 7.55 g, purity 99.0%, ee value 99.5%, yield 73%).

[0112] HPLC: Chiralpak IC column, 254 nm, 35° C., 0.1% diethylamine (n-hexane:ethanol:dichloromethane=75:15:10) / ethanol=70 / 30, flow rate=1.0 mL / min, retention time 9.4 min and 12.0 min (main peak).

[0113] Compounds of formula (I) 1 The H NMR is shown in Figure 8 , and the MS is shown in Figure 9 .

[0114] 1 H NMR (400MHz, methanol-d4) δ12.28(s,1H),10.16(s,1H),8.20(d,1H),8.00(d,1H),7.30 -7.25(m,2H),7.19-7.15(m,1H),7.08(dd,1H),5.18(s,1H),3.77(t,2H),3.63(d,1H),3.36(t,2H),2.98(q,4H),2.5 1-2.49(m,1H),2.25(d,1H),2.16-2.13(m,1H),2.02-1.96(m,2H),1.94-1.58(m,3H),1.22-1.14(m,2H),0.28(s,4H).

[0115] MS (EI, m / z): 536.6 [M+H] + .

[0116] Example 3 Synthesis of Compound of Formula (I)

[0117] Step 1: Synthesis of methyl 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (Compound 6a)

[0118] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid methyl ester (Compound 5a) (19.8 g, 61.05 mmol, 1.0 eq), Compound 4 (15.3 g, 122.1 mmol, 2.0 eq), CuI (11.6 g, 61.05 mmol, 1.0 eq), trans-N,N'-dimethyl-1,2-cyclohexanediamine (8.7 g, 61.05 mmol, 1.0 eq) were added. 0eq), K3PO4 (64.8g, 305.2g, 5.0eq) and DMF (300mL) were added sequentially into a 1000mL three-necked flask, replaced with nitrogen, and then heated to 110±5°C, reacted for 16 hours, cooled to room temperature, diluted with ethyl acetate, and then filtered through a pad of celite. The filtrate was concentrated, mixed with 200-300 mesh silica gel, and purified by chromatography column to obtain compound 6a (light yellow solid, 20.2g, yield 90%).

[0119] MS (ESI, m / z): 369.3 [M+H] + (Figure 10)

[0120] Step 2 Synthesis of 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (Compound 7)

[0121] In a 250 mL reaction flask, compound 6a (20.0 g, 54.28 mmol, 1.0 eq) and NaOH (6.51 g, 162.85 mmol, 3.0 eq) were weighed and dissolved in a mixed solution of H2O (80 mL) and THF (100 mL). The mixture was then heated to 70°C and reacted for 19 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The filtrate was concentrated and mixed with 200-300 mesh silica gel. The mixture was purified by chromatography to obtain compound 7 (light white solid, 18.3 g, yield 95%).

[0122] MS (ESI, m / z): 355.3 [M+H] + (Figure 11)

[0123] Step 3: Synthesis of the compound of formula (I)

[0124] Compound 7 (33.38 g, 94.2 mmol, 1.0 eq) and HATU (42.96 g, 98.9 mmol, 1.05 eq) were suspended in DMF (167 mL); DIEA (41.72 g, 282.6 mmol, 3.0 eq) was then added dropwise, and the temperature was controlled at 30±5°C; after the addition was complete, the reaction was incubated at 30±5°C for 1 h; Compound 2 (19.7 g, 98.9 mmol, 1.05 eq) was added in batches, and the temperature was controlled at 30±5°C. The mixture was heated to 30±5°C and reacted at this temperature for 16 hours; water (334 mL) was added dropwise during the reaction, the temperature was controlled at 30±5°C, and the mixture was stirred for 0.5 h after the addition was completed, and then filtered. The filter cake was evaporated dry with an oil pump to obtain a brown solid; the mixture was then dissolved in THF (250 mL), 30 grams of activated carbon (30 g) was added, and the mixture was stirred at 55-60°C for 0.5 h for decolorization; the mixture was cooled to 35°C and filtered, and the filtrate was concentrated to obtain the compound of formula (I) (off-white solid, 37.41 g, yield: 75%).

[0125] Biological evaluation

[0126] Test Example 1

[0127] Test Name: Imaging-based Nuclear Count Analysis (NCA) in OVCAR-3 cells

[0128] Day 0 Compound Dilution and Treatment

[0129] a) Final tested concentrations of AM-5308 were: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, and 0.5 nM.

[0130] b) Test compounds, final test concentrations: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM.

[0131] c) The cells were cultured in a 37°C, 5% CO2 incubator for 4 days.

[0132] d) The DMSO concentration was 0.1%.

[0133] On day 1, cells were seeded into 384-well cell culture plates.

[0134] a) When the cell confluence reaches 80%-90%, treat the cells.

[0135] b) Resuspend the cells in culture medium, then count and dilute the cells to the desired density.

[0136] c) Add 30 μL / well of the cell suspension containing appropriate cells to a 384-well plate: 600 cells / well.

[0137] Day 4 testing

[0138] a) Add 30 μL of 8% fixative (final concentration 4%) and incubate the plate at room temperature for 30 minutes.

[0139] b) Centrifuge the plate at 1000 RPM for 30 seconds.

[0140] c) Wash twice with 60 μl / well PBS.

[0141] d) After fixation, cells were permeabilized and stained in 60 μL of wash buffer (1% BSA, 0.2% Triton X-100, 1× PBS) containing 2 μg / mL Hoechst 33342 DNA dye.

[0142] e) Seal the plate and incubate at room temperature in the dark for 1 hour.

[0143] f) Wash three times with PBS.

[0144] g) Add 50 μL PBS / well and scan the plate using HCS.

[0145] h) Data collection and detection

[0146] Data Analysis

[0147] Inhibition rate (%) = 100-(compound well reading value-low reading control well reading value) / (high reading control well reading value-low reading control well reading value)*100

[0148] High-reading control wells: cells were added with 30 nL DMSO; low-reading control wells: 10 μM AM-5308 wells.

[0149] IC was calculated using GraphPad Prism 8 software. 50 (nM) and draw the effect-dose curve of the compound.

[0150] Table 1 Biological activity data of compounds of formula (I)

[0151] Test Example 2

[0152] Test name: KIF18A enzyme activity detection

[0153] Steps:

[0154] 1) Compound dilution and treatment: The final test concentrations of AM-5308 are: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM, and the final test concentrations of the test compounds are: 10000, 3333.3, 1111.1, 370.3, 123.4, 41.1, 13.7, 4.5, 1.5, 0.5 nM.

[0155] 2) Transfer 100 nL of the diluted compound stock solution to each well of the reaction plate using an Echo 655. The final DMSO concentration is 1%.

[0156] 3) Seal the reaction plate with sealing film and centrifuge at 1000g for 1 minute.

[0157] 4) Prepare 2× enzyme solution using 1× reaction buffer.

[0158] 5) Add 5 μL of 2× enzyme solution to each well of the reaction plate. Seal the plate with film and centrifuge at 1000 g for 1 minute. Incubate at room temperature for 15 minutes.

[0159] 6) Prepare 2× ATP solution using 1× reaction buffer.

[0160] 7) Add 5 μL of 2× ATP solution to the reaction plate and centrifuge at 1000 g for 1 minute to start the reaction.

[0161] 8) React at room temperature for 60 minutes.

[0162] 9) Add 10 μL of ADP Glo reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

[0163] 10) Add 20 μL of kinase assay reagent, centrifuge at 1000 g for 1 minute, and incubate at room temperature for 60 minutes.

[0164] 11) Centrifuge at 1000g for 1 minute.

[0165] 12) Read the luminescence signal on Envision 2104.

[0166] Data Analysis:

[0167] The percentage inhibition was calculated as follows:

[0168] %inhibition=100-(Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100

[0169] Signal cmpd: Average value of test compounds on the reaction plate.

[0170] Signal Ave_PC : Average value of positive control (AM-5308) on the reaction plate.

[0171] Signal Ave_VC : Average value of negative control (DMSO) on the reaction plate.

[0172] Computing IC 50 And fitting compound dose-effect curve:

[0173] GraphPad 8.0 was used to obtain the IC values ​​of the compounds using a nonlinear fitting formula. 50 .

[0174] 3) Quality control

[0175] Z factor>0.5;S / B>2.

[0176] Table 2 Enzyme activity data of compounds of formula (I)

[0177] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the claims of this application.

Claims

1. A method for preparing a compound represented by formula (I), comprising the following steps: When R1 is selected from halogen, -OTf, -OTs and -OMs, R2 is The method comprises the following steps (1): reacting compound A with compound 4 to obtain a compound represented by formula (I); Or, when R1 is R2 is selected from OH, C 1-6 Alkoxy, -OC 6-14 Aryl, -O-(5-14 membered heteroaryl), halogen (preferably, R2 is selected from OH, C 1-6 alkoxy), comprising the following steps (2): reacting compound A with compound 2 to obtain a compound represented by formula (I); 2. The preparation method according to claim 1, characterized in that In step (1), the reaction is carried out in the presence of a catalyst, the catalyst comprising a main catalyst (such as at least one selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous cyanide, and cuprous thiophene-2-carboxylate) and a ligand (such as at least one selected from trans-N,N'-dimethyl-1,2-cyclohexanediamine, 1,2-dimethylethylenediamine, 1,1,2,2,-tetramethylethylenediamine, 8-hydroxyquinoline, 1,10-phenanthroline, 2,4-pentanedione, N,N'-dibenzyloxamide, etc.); preferably, the molar ratio of the main catalyst to the ligand in the catalyst is 1:(0.5-5); Preferably, in step (1), the reaction is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base, for example, at least one selected from potassium phosphate, potassium carbonate, sodium carbonate, sodium tert-butoxide, sodium tert-amyloxide, and sodium methoxide; Preferably, in step (1), the molar ratio of compound A to base in the reaction is 1:(0.5-10); Preferably, in step (1), the molar ratio of compound A to the main catalyst in the catalyst in the reaction is 1:(0.05-2); Preferably, in step (1), the molar ratio of compound A to compound 4 in the reaction is 1:(0.2-5).

3. The preparation method according to claim 1 or 2, characterized in that In step (2), the reaction is carried out in the presence of a condensing agent, wherein the condensing agent is selected from at least one of HATU, HBTU, HOBT, TBTU, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-chloro-1-methylpyridinium iodide; Preferably, in step (2), the molar ratio of compound A to compound 2 in the reaction is 1:(0.2-5); Preferably, in step (2), when R2 is OH, the reaction is carried out in the presence of a base, and the base is selected from an organic base, for example, at least one selected from triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and N,N-dimethylaminopyridine; Preferably, in step (2), when R2 is selected from C 1-6 When the alkoxy group is present, compound A undergoes an amine ester exchange reaction with compound 2 to obtain a compound represented by formula (I); Preferably, the amine transesterification reaction is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base, for example, at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amylate, and potassium tert-butoxide.

4. The preparation method according to any one of claims 1 to 3, characterized in that The method for preparing compound A in step (1) comprises the following steps (1a): compound B reacts with compound 2 to obtain compound A; Among them, R 21 Selected from OH or C 1-6 Alkoxy, R1 is selected from halogen, -OTf, -OTs and -OMs, R2 is 5. The preparation method according to any one of claims 1 to 4, characterized in that In step (1a), the reaction is carried out in the presence of a base, and the base is selected from an organic base, for example, at least one selected from triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and N,N-dimethylaminopyridine; Preferably, in step (1a), the reaction is carried out in the presence of a condensing agent, and the condensing agent is selected from at least one of HATU, HBTU, HOBT, TBTU, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-chloro-1-methylpyridinium iodide; Preferably, in step (1a), the molar ratio of compound B to compound 2 in the reaction is 1:(0.2-5); Preferably, in step (1a), when R 21 C 1-6 In the case of alkoxy, R 21 Compound B containing OH further reacts with compound 2 to obtain compound A; or compound B directly undergoes an amine ester exchange reaction with compound 2 to obtain compound A.

6. The preparation method according to any one of claims 1 to 5, characterized in that In step (2), when R2 is OH, the preparation method of compound A comprises the following steps: (2a) Compound D reacts with compound 4 to obtain compound C; (2b) Compound C undergoes hydrolysis to obtain Compound A; Among them, R 12 is selected from halogen (eg, chlorine, bromine, iodine), -OTf, -OTs, or -OMs; R 22 Selected from C 1-6 Alkoxy, R1 is R2 is OH.

7. The preparation method according to any one of claims 1 to 6, characterized in that In step (2a), the reaction is carried out in the presence of a catalyst, the catalyst comprising a main catalyst (such as at least one selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cuprous cyanide, and cuprous thiophene-2-carboxylate) and a ligand (such as at least one selected from trans-N,N'-dimethyl-1,2-cyclohexanediamine, 1,1,2,2,-tetramethylethylenediamine, 8-hydroxyquinoline, 1,10-phenanthroline, 2,4-pentanedione, N,N'-dibenzyloxamide, and the like); preferably, the molar ratio of the main catalyst to the ligand in the catalyst is 1:(0.5-5); Preferably, in step (2a), the reaction is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base, for example, at least one selected from potassium phosphate, potassium carbonate, sodium carbonate, sodium tert-butoxide, sodium tert-amyloxide, and sodium methoxide. Preferably, in step (2a), the molar ratio of compound D to base in the reaction is 1:(0.5-10); Preferably, in step (2a), the molar ratio of compound D to the main catalyst in the catalyst in the reaction is 1:(0.05-2); Preferably, in step (2a), the molar ratio of compound D to compound 4 in the reaction is 1:(0.2-5).

8. The preparation method according to any one of claims 1 to 7, characterized in that In step (2b), the reaction is carried out in the presence of a base, and the base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, and potassium carbonate; Preferably, compound C can be directly subjected to an amine transesterification reaction with compound 2 to obtain the compound represented by formula (I).

9. The intermediate compound shown below: in, R3 is selected from a leaving group, for example OH, halogen (eg, chlorine, bromine, iodine), -OTf, -OTs or -OMs.

10. The method for preparing compound 2 according to claim 9, characterized in that: The following steps are involved: (a) mixing compound 2b, phosphorus oxychloride and compound 2-1 to react to obtain compound 2-2; (b) Compound 2-2 reacts in the presence of a catalyst and a base to obtain compound 2-3; (c) Compound 2-3 reacts with an ammonia solution in the presence of a catalyst and a base to obtain compound 2; wherein X1 and X2 are the same or different and are independently selected from halogen, such as chlorine, bromine or iodine; Preferably, in step (a), the molar ratio of compound 2b to compound 2-1 is 1:(0.1-5); Preferably, in step (a), the molar ratio of compound 2b to phosphorus oxychloride is 1:(0.1-5); Preferably, in step (b), the catalyst is selected from a monovalent copper catalyst, such as cuprous iodide, cuprous bromide, cuprous chloride, and cuprous oxide; Preferably, in step (b), the base is selected from an inorganic base, such as at least one of potassium carbonate, sodium carbonate, and cesium carbonate; Preferably, in step (c), the amine solution is an organic solution of ammonia, for example, an alcoholic solution of ammonia, such as ammonia / methanol, ammonia / ethanol, or ammonia / isopropanol; Preferably, in step (c), the catalyst is selected from metal oxide catalysts, such as copper oxide, zinc oxide, cuprous oxide, nickel oxide, and cobalt oxide; Preferably, in step (c), the base is selected from an inorganic base, for example, at least one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, and potassium carbonate.

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