Preparation method of nitrogen-containing polycyclic fused-ring compounds, intermediates and use thereof

Abstract

This invention relates to a method for preparing nitrogen-containing polycyclic fused-ring compounds and their intermediates. The method of this invention enables the high-yield, low-cost, and environmentally friendly synthesis of Formula I compounds and their intermediates, allowing for industrial-scale production of Formula I compounds. This method eliminates column chromatography separation and purification steps and avoids the use of hydrogen as a hydrogenation or reduction reagent, thus improving production efficiency and safety. The method of this invention achieves efficient utilization of positional isomers IIIA and IIIB, avoiding the adverse effects of discarding IIIA on the yield of the target product. The overall yield using the IIIA method can reach 9.4%, significantly higher than the less than 4% yield using IIIB. Furthermore, when both positional isomers are used simultaneously in the preparation of compound I, the yield is more than three times higher than when IIIB is used alone.

Description

Technical Field

[0001] This invention claims priority to an earlier application filed on July 9, 2021, with the China National Intellectual Property Administration, patent application number 202110780873.9, entitled "Preparation method of nitrogen-containing polycyclic fused ring compounds, intermediates thereto and uses". The entire contents of the earlier application are incorporated herein by reference.

[0002] This invention relates to the field of pharmaceutical compound preparation methods, specifically to methods for preparing nitrogen-containing polycyclic fused-ring compounds, their intermediates, and uses. Prior Technology

[0003] The RET (Rearranged During Transfection) proto-oncogene was first identified in 1985 through transfection of NIH3T3 (mouse embryonic fibroblast cell line) cells with human lymphoma DNA (Cell, 1985, 42(2): 581-588). The RET proto-oncogene is located on chromosome 10q11.2, with a full-length DNA of 60 kb containing 21 exons, encoding a RET protein composed of 1100 amino acids. This RET protein is a tyrosine kinase receptor containing an extracellular region composed of cysteine, a transmembrane region, and an intracellular region that catalyzes tyrosine kinase activity (Mol Cell Endocrinol, 2010, 322(1-2): 2-7). RET is involved in cell proliferation, nerve conduction, cell migration and cell differentiation. Through the signaling of the ligand / complex receptor / RET multiprotein complex, it initiates various downstream pathways, such as the RAS / RAF / MEK / ERK, PI3K / AKT and STAT pathways, to induce cell proliferation (J Clin Oncol, 2012, 30(2): 200-202).

[0004] RET kinase signaling plays a crucial role in various human cancers, including thyroid cancer. The RET 804V mutation, a gatekeeper residue of RET, is a significant cause of tumor resistance to currently approved non-selective RET inhibitors such as cabozantinib and vandetanib. One important mutation in the extracellular or intracellular domains of RET in dissociated familial medullary thyroid carcinoma is the V804M mutation, a gatekeeper residue at the ATP-binding site of the kinase, which leads to a decreased affinity of existing drugs for the ATP-binding site. Literature reports (RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies, Journal of Thoracic Oncology, 2020, Vol.15, No.4, 541-549) that although the selective RET inhibitor LOXO-292 (Selpercatinib) can avoid the aforementioned RET 804V mutation, other mutations can still occur after using this selective RET inhibitor, leading to drug resistance. For example, in non-small cell lung cancer, it can cause G810 mutations at the solvent front residue of the kinase ATP binding site, such as G810R, G810S, and G801C mutations, which lead to a decrease in the ATP binding site of LOXO-292, resulting in drug resistance and cancer progression.

[0005] Patent document WO2021023209A1 discloses compounds with excellent activity or selectivity as RET inhibitors. These compounds exhibit strong inhibitory effects against the RET gatekeeper residue mutant RET V804M, the RET solvent-front residue mutant G810R, other clinically relevant RET mutants, and wt-RET. These compounds also significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba / F3 cells transformed from various RET mutants, with good inhibitory effects. Furthermore, these compounds largely block RET autophosphorylation and its downstream pathways, significantly induce TT cell death, and possess excellent pharmacokinetic properties. Therefore, it is necessary to develop more efficient, more suitable for large-scale production, and / or more cost-effective preparation methods for these compounds, as well as intermediate compounds and their preparation methods to achieve the aforementioned objectives. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a method M1A for preparing compound I, wherein the method comprises reacting compound XX with R kC(O)-H to obtain compound I: in: X1, X2, X3, and X4 may be the same or different, and are independently selected from CR1 or N; Each R1 may be the same or different, independently selected from H, halogen, CN, OH, and unsubstituted or optionally substituted by one, two or more Ra groups: C1-40 alkyl, C3-40 cycloalkyl, C1-40 alkyloxy, C3-40 cycloalkyloxy, NR 2R 3, -C(O)R 4, -OCR 5, -S(O) 2R 6, OS(O) 2R 7; D and E may be the same or different, and are independently selected from H, halogen, CN, OH, -OR 21, without substitution or optionally substituted by one, two or more R c of the following groups: C 1-40 alkyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, NR 2R 3, provided that at least one of D and E is selected from -OR 21; R 21 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more R d: C 1-40 alkyl, C 3-40 cycloalkyl, C 6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic; G is selected from the following groups that are unsubstituted or optionally substituted with one, two or more Re groups: C3-40 cycloalkyl, C3-40 cycloalkenyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C3-40 cycloalkyloxy, C3-40 cycloalkenyloxy, C6-20 aryloxy, 5-20 heteroaryloxy or 3-20 heterocyclicoxy; Rk is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rg: C1-40 alkyl, C3-40 cycloalkyl, C3-40 cycloalkenyl, C6-20 aryl, 5-20 heteroaryl, and 3-20 heterocyclic. Each R2 may be the same or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, -C(O)R4, -S(O)2R6; Each R3 may be the same or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, -C(O)R4, -S(O)2R6; Alternatively, R2 and R3 together with the attached N atom form a 5-20 member heteroaryl or a 3-20 member heterocyclic group; Each R4 may be the same or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C1-40 alkyloxy, C3-40 cycloalkyloxy, C6-20 aryloxy, 5-20 heteroaryloxy, 3-20 heterocyclicoxy, NR2R3; Each R5 may be the same or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C1-40 alkylcarbonyl, C3-40 cycloalkylcarbonyl, C6-20 arylcarbonyl, 5-20 heteroarylcarbonyl, and 3-20 heterocyclic carbonyl. Each R 6 may be the same or different, and is independently selected from H, C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C1-40 alkyloxy, C3-40 cycloalkyloxy, C6-20 aryloxy, 5-20 heteroaryloxy, 3-20 heterocyclic oxy, NR 2R 3; Each R7 may be the same or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, and 3-20 heterocyclic groups; Each Ra, Rc, Rd, and Re may be the same or different, and is independently selected from halogens, CN, OH, SH, oxo (=O), NO2, and may be unsubstituted or optionally substituted by one, two, or more Rg groups of the following groups: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C1-40 alkyloxy, C3-40 cycloalkyloxy, C6-20 aryloxy, 5-20 heteroaryloxy, 3-20 heterocyclicoxy; Each Rg may be the same or different, and is independently selected from halogens, CN, OH, SH, oxo (=O), NO 2, and is unsubstituted or optionally substituted by one, two or more Rh groups of the following groups: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloalkynyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C1-40 alkyloxy, C2-40 alkenyloxy, C2-40 alkynyloxy, C3-40 cycloalkyloxy, C3-40 cycloalkenyloxy, C3-40 cycloalkynyloxy, C6-20 aryloxy, 5-20 heteroaryloxy, 3-20 heterocyclic alkyloxy; Each Rh may be the same or different, and is independently selected from halogens, CN, OH, SH, oxo (=O), NO2, unsubstituted or optionally substituted by one, two or more Rg groups of the following groups: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloalkynyl, C6-20 aryl, 5-20 heteroaryl, 3-20 heterocyclic, C1-40 alkyloxy, C2-40 alkenyloxy, C2-40 alkynyloxy, C3-40 cycloalkyloxy, C3-40 cycloalkenyloxy, C3-40 cycloalkynyloxy, C6-20 aryloxy, 5-20 heteroaryloxy, 3-20 heterocyclic alkyloxy; Alternatively, when different positions of the aforementioned C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloynyl, or 3-20 member heterocyclic groups are replaced by two or more substituents, any two of the substituents may also form a bridged ring together with the atoms they are attached to, wherein the bridge atoms in the bridged ring, excluding the bridgehead atom, may contain 1, 2, 3, 4, or 5 divalent groups selected from CH2, O, and NH; Alternatively, when an atom (such as a carbon atom) is replaced by two or more substituents, two of the substituents may also form cyclic groups such as C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloynyl, or 3-20 member heterocyclic groups with the atoms they are connected to.

[0007] According to embodiments of the present invention, X1, X2, X3, and X4 may be the same or different, and are independently selected from CR1 or N; for example, at least one of X1, X2, X3, and X4 is N, such as 1, 2, or 3 of X1, X2, X3, and X4 being N;

[0008] According to embodiments of the invention, each R1 may be the same or different, and is independently selected from H, halogen, CN, OH, and is unsubstituted or optionally substituted by one, two or more Ra groups, including: C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkyloxy, C3-10 cycloalkyloxy, for example selected from the following groups unsubstituted or optionally substituted by one, two or three Ra groups: C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy or C3-6 cycloalkyloxy;

[0009] According to embodiments of the present invention, D and E may be the same or different, and are independently selected from H, halogen, CN, NH₂, C₁-6 alkyl or -OR₂, provided that at least one of D and E is selected from -OR₂.

[0010] According to an embodiment of the present invention, at least one of D and E is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0011] According to embodiments of the present invention, R2 is selected from unsubstituted or optionally substituted with one, two or more C1-6 alkyl groups by Rd;

[0012] According to embodiments of the present invention, each Ra, Rc, Rd may be the same or different, and is independently selected from halogens, CN, OH, and is unsubstituted or optionally substituted by one, two or more Rg groups of the following: C1-6 alkyl, C1-6 alkyloxy, C3-10 cycloalkyl, C3-10 cycloalkyloxy;

[0013] According to embodiments of the present invention, each Rg may be the same or different, and is independently selected from halogens or C3-10 cycloalkyl groups;

[0014] According to embodiments of the present invention, G is selected from C3-10 cycloalkyl, C6-14 aryl, 5-14 heteroaryl, 3-10 heterocyclic, for example, 6-7 heterocyclic with monocyclic, bicyclic, or bridged ring structures, which may contain 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0015] According to embodiments of the present invention, Rk is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rg: C3-10 cycloalkyl, C6-14 aryl, 5-14 heteroaryl, 3-10 heterocyclic; wherein the heteroaryl can be pyridyl, for example selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl; and the aryl can be phenyl.

[0016] According to an exemplary embodiment of the present invention, X1, X2, X3, and X4 may be the same or different, and are independently selected from CH or N; for example, at least one of X1, X2, X3, and X4 is N, such as 1, 2, or 3 of X1, X2, X3, and X4 being N;

[0017] According to an exemplary embodiment of the present invention, R1 is H;

[0018] According to an exemplary embodiment of the present invention, E is H;

[0019] According to an exemplary embodiment of the present invention, D is selected from the following groups: halogen, BnO-, H, -CN, -NH2, -OCH3, and the following groups: , ; According to an exemplary embodiment of the present invention, G is selected from... , , , , , , or ;

[0020] According to an exemplary embodiment of the present invention, Rk is selected from pyridyl or phenyl groups that are unsubstituted or optionally substituted with one, two or more Rg groups, wherein when one, two or more Rg groups are substituted, the Rg groups may be substituted at the 1, 2, 3, 4, 5, or 6 positions of the pyridyl or phenyl group, as long as it does not affect the connection of Rk to the group G via the methylene group.

[0021] As an example, Rk in compound I can form a group selected from the following groups with the methylene group: , , , , , , , , , , , , , or . Alternatively, Rk in Formula I may be selected from groups substituted with 1, 2, 3, or 4 groups selected from C1-6 alkyl and C1-6 alkyloxy groups. . According to an exemplary embodiment of the present invention, the compound of formula I may be selected from the following compounds: . . As an example, the compounds of formula I are selected from the following compounds: .

[0022] According to embodiments of the present invention, the reaction of compound XX with R kC(O)-H can be carried out in the presence of borane, pyridineborane, 2-methylpyridineborane (Pic-BH 3), sodium borohydride, sodium triethoxyborohydride, or sodium cyanoborohydride, preferably in the presence of 2-methylpyridineborane.

[0023] According to an embodiment of the present invention, the reaction of compound XX with R kC(O)-H can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent may be 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyrrolidine; nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is n-propanol.

[0024] According to an embodiment of the present invention, in the method for preparing compound I, the molar ratio of compound XX to R kC(O)-H can be 1:1 to 1:5, preferably 1:1.1 to 1:1.3.

[0025] According to an embodiment of the present invention, in the method for preparing compound I, the molar ratio of compound XX to borane or 2-methylpyridineborane can be 1:1 to 1:5, preferably 1:1.1 to 1:1.3.

[0026] According to an embodiment of the present invention, in the method for preparing compound I, the molar ratio of compound XX to base can be 1:1 to 1:5, preferably 1:1.5 to 1:3.5, such as 1:1.8 to 1:2.2.

[0027] According to an embodiment of the present invention, the reaction temperature of the preparation method of compound I can be 15~50 °C, for example 20~30 °C, such as room temperature.

[0028] According to embodiments of the present invention, the compound of formula XX can also be reacted using its salt form (e.g., an acid addition salt) as a starting material. Preferably, when the salt form of the compound of formula XX is used for the reaction, a base can be used to release it into the compound of formula XX. This release can be carried out alone or in conjunction with the reaction in the preparation method M1A described above via a one-pot process.

[0029] According to an embodiment of the present invention, the alkali can be an organic alkali or an inorganic alkali, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases are selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0030] According to an exemplary embodiment of the present invention, the preparation method M1A includes preparing compound 1 by reacting compound 20 as follows: .

[0031] The present invention also provides compounds of the above formula XX, such as compound 20.

[0032] The present invention also provides the use of the above-described compound of formula XX (e.g., compound 20) in the preparation of compound of formula I (e.g., compound 1).

[0033] This invention also provides compounds of formula XIX: in: G is selected from the following groups, either unsubstituted or optionally substituted with one, two or more Re groups: 5-20-membered heteroaryl, 3-20-membered heterocyclic, 5-20-membered heteroaryloxy or 3-20-membered heterocyclicoxy, wherein G has at least one N atom and the N atom is attached to PG 19; X1, X2, X3, X4, D, E, and Re independently possess the definitions described above; PG 19 is an amine protecting group.

[0034] According to embodiments of the present invention, PG 19 may be selected from amine protecting groups known to those skilled in the art, such as tert-butoxycarbonyl (Boc), cyclobutoxycarbonyl, benzyloxycarbonyl (CBz), p-methoxybenzylcarbonyl (Moz), 2-biphenyl-2-propoxycarbonyl (BPoc), 2,2,2-trichloroethoxycarbonyl (Troc), phthalimide, p-toluenesulfonyl, trifluoroacetyl, (9H-fluorene-9-ylmethoxy)carbonyl (Fmoc), benzyl, 4-methoxybenzyl, diphenylmethyl, 2-(trimethylsilyl)ethoxycarbonyl (Teoc), adamantyloxycarbonyl (Adoc), methyl, acetyl, etc.

[0035] The present invention also provides a method M20 for preparing compound of formula XX, comprising reacting compound of formula XIX under conditions of removing PG 19 to obtain compound of formula XX.

[0036] The conditions for removing PG 19 from compound XIX are those known to those skilled in the art for the removal of an amino protecting group. For example, the PG 19 group of compound XIX can be removed in the presence of an acid, which may be selected from one, two or more inorganic or organic acids such as hydrochloric acid, sulfuric acid, formic acid, and acetic acid.

[0037] According to an embodiment of the present invention, in the preparation method of compound XX, the molar ratio of compound XIX to acid can be 1:1 to 1:5, such as 1:3 to 1:4.

[0038] According to an embodiment of the present invention, the reaction of compound XIX removing PG 19 can be carried out in the presence of an organic solvent. The organic solvent has the definition described above, such as an alcohol solvent, like one, two, or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol.

[0039] According to an embodiment of the present invention, the reaction temperature of the preparation method of compound I can be 40~70 °C, for example 50~60 °C.

[0040] According to an embodiment of the present invention, the preparation method M20 includes preparing compound 20 by reacting compound 19 as follows: Therefore, the present invention also provides compound 19.

[0041] The present invention also provides the use of the above-described compound XIX (e.g., compound 19) in the preparation of compound XX (e.g., compound 20).

[0042] This invention also provides compounds of formula XI: in: D and E independently possess the definitions described above; L 11 is selected from leaving groups, such as unsubstituted or substituted groups with 1, 2, 3, 4, 5 or 6 halogens: C1-6 alkylsulfonyloxy, C1-6 alkylbenzenesulfonyloxy, such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyloxy (TfO-), p-toluenesulfonyloxy (TsO-), halogens (such as F, Cl, Br or I).

[0043] This invention also provides compounds of formula XVIII: Among them, X1, X2, X3, X4, G, and PG19 independently have the definitions described above.

[0044] This invention also provides a method M19A for preparing a compound of formula XIX, comprising reacting a compound of formula XI with a compound of formula XVIII to obtain a compound of formula XIX: Among them, X1, X2, X3, X4, D, E, G, L11, and PG19 independently have the definitions described above.

[0045] According to an embodiment of the present invention, in the method for preparing the above-described compound of formula XIX, the reaction can be carried out in the presence of a base. The base can be an organic base or an inorganic base, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases are selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0046] According to an embodiment of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of an organic solvent or a mixture of an organic solvent and water. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is preferably dioxane. The solvent may contain: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethoxypyridine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0047] According to embodiments of the present invention, the preparation method of the above-mentioned compound XIX can be carried out in the presence of a catalyst, which can be a palladium catalyst, such as Pd(dba)₂, PdCl₂, Pd(OAc)₂, Pd(dppf)Cl₂, Pd₂(dba)₃, PdCl₂(CH₃CN)₂, Pd(PPh₃)₄, PdCl₂(PPh₃)₂, Pd(t-Bu)₃, PdCl₂(PPh₃)₂·CH₂Cl₂, Pd(OAc) / PPh₃, PdCl₂[(Pet₃)]₂, Pd(DIPHOS)₂, PdCl₂(Bipy), [PdCl(Ph₂PCH₂PPh₂)]₂, PdCl₂[P(o-Tol)₃]₂, Pd₂(dba)₂ 3 / P(o-Tol) 3. Pd 2(dba) / P(furyl) 3. PdCl 2[P(furyl) 3] 2. PdCl 2(PMePh 2) 2. PdCl 2[P(4-F-Ph) 3] 2. PdCl 2[P(C 6F 6) 3] 2. PdCl 2[P(2-COOH-Ph)(Ph) 2] 2. PdCl 2[P(4-COOH-Ph)(Ph) 2] 2.

[0048] According to an embodiment of the present invention, the reaction temperature of the method for preparing the above-described compound of formula XIX can be above 50 °C, for example above 80 °C, such as 85 °C.

[0049] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound XIX, the molar ratio of compound XI to compound XVIII can be 1:1 to 1:2, for example 1:1.1 to 1:1.3, such as 1:1.2 to 1:1.3.

[0050] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XI to base can be 1:1 to 1:5, for example 1:1.5 to 1:3.5, such as 1:1.8 to 1:2.2.

[0051] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XI to catalyst can be from 1:0.001 to 1:0.05, such as from 1:0.02 to 1:0.03.

[0052] According to an embodiment of the present invention, the preparation method M19A includes preparing compound 19 by reacting compound 11 and compound 18 as follows: Therefore, the present invention also provides the above-described compound 11 or compound 18.

[0053] The present invention also provides the use of the above-described compounds of formula XI (e.g., compound 11) and / or compounds of formula XVIII (e.g., compound 18) in the preparation of compounds of formula XIX (e.g., compound 19).

[0054] This invention also provides a method M11 for preparing a compound of formula XI, comprising reacting a compound of formula X with hydrazine (such as hydrazine hydrate) to obtain a compound of formula XI: in: D, E, and L11 independently possess the definitions described above; L10 is selected from leaving groups, such as halogens, such as F, Cl, Br or I.

[0055] According to embodiments of the present invention, the preparation method of the compound of formula XI can be carried out in the presence of an organic solvent or a mixture of an organic solvent and water. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is preferably dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyrrolidone; nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dimethyl sulfoxide.

[0056] According to an embodiment of the present invention, in the preparation method of compound XI, the reaction temperature can be above 100 °C, such as 110~115 °C.

[0057] According to an embodiment of the present invention, in the method for preparing compound X1, the molar ratio of compound X to hydrazine can be 1:1 to 1:15, for example 1:2 to 1:10, such as 1:6 to 1:8.

[0058] According to an embodiment of the present invention, the preparation method M11 includes preparing compound 11 by reacting compound 10 as follows: .

[0059] The present invention also provides compounds of the above formula X, such as compound 10.

[0060] The present invention also provides the use of the above-described compound X (e.g., compound 10) in the preparation of compound XI (e.g., compound 11).

[0061] The present invention also provides a method M10A for preparing compound X, comprising reacting compound XIII with compound R 21-L 13 to obtain compound X: in: D, L10, L11, and R21 each independently possess the definitions described above; E is selected from -OR 21; L 13 is selected from leaving groups, such as halogens, such as unsubstituted or substituted groups with 1, 2, 3, 4, 5 or 6 halogens: C1-6 alkylsulfonyloxy, C1-6 alkylbenzenesulfonyloxy, such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyloxy (TfO-), p-toluenesulfonyloxy (TsO-), F, Cl, Br or I.

[0062] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of a base.

[0063] According to an embodiment of the present invention, the alkali can be an organic alkali or an inorganic alkali, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases are selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0064] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is selected from dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyridine; nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethyl pyrrolidone.

[0065] According to an embodiment of the present invention, in the preparation method of compound X, the molar ratio of compound XIII to compound R 21-L 13 can be 1:1 to 1:2, for example 1:1 to 1:1.2, such as 1:1 to 1:1.1.

[0066] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound XIII to base can be 1:1 to 1:2, for example 1:1.1 to 1:1.3, such as 1:1.1 to 1:1.2.

[0067] According to an embodiment of the present invention, the reaction temperature in the preparation method of compound X can be above 50 °C, for example 60~70 °C, such as 65 °C.

[0068] According to an embodiment of the present invention, the preparation method M10A includes preparing compound 10 by reacting compound 13 as follows: .

[0069] The present invention also provides compounds of the above formula XIII, such as compound 13.

[0070] The present invention also provides the use of the above-described compound XIII (e.g., compound 13) in the preparation of compound X (e.g., compound 10).

[0071] The present invention also provides a method M13 for preparing compound XIII, comprising reacting compound IIIB in the presence of phosphorus oxychloride (POCl3), wherein compound IIIB has the following structure: in: L10 and L11 independently possess the definitions described above; PG 3 is selected from hydroxyl protecting groups.

[0072] According to embodiments of the present invention, PG 3 may be selected from hydroxyl protecting groups known to those skilled in the art, such as unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents selected from C1-6 alkyl, C1-6 alkyloxy, and halogen: benzyl, C1-6 alkyl, tris(C1-6 alkyl)silyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, triphenylmethyl, C1-6 alkyloxymethyl, benzyloxymethyl, C1-6 alkylcarbonyl, halogenated C1-6 alkylcarbonyl, benzoyl, examples of which may be selected from benzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl or 2,3,4-trimethoxybenzyl.

[0073] According to an embodiment of the present invention, the preparation method M13 includes reacting compound 3b in the presence of phosphorus oxychloride (POCl3), wherein compound 3b has the following structure: .

[0074] According to an embodiment of the present invention, in the preparation method of compound XIII, compound IIIB (e.g., compound 3b) can first react with phosphorus oxychloride to obtain compound XII, and then compound XII further reacts to obtain compound XIII, wherein compound XII has the following structure: Among them, L10, L11, and PG3 independently have the definitions described above.

[0075] According to an embodiment of the present invention, in the method for preparing compound XIII, the molar ratio of compound IIIB to phosphorus oxychloride can be 1:2 to 1:4. For example, 1:2 to 1:3, such as 1:2.4 to 1:2.5.

[0076] According to an embodiment of the present invention, the preparation method of compound XIII can be carried out in a one-pot process.

[0077] According to an embodiment of the present invention, the reaction solvent for reacting compound IIIB with phosphorus oxychloride to obtain compound XII can be the above-mentioned organic solvent, such as N,N-dimethylformamide.

[0078] According to an embodiment of the present invention, the reaction temperature for reacting compound IIIB with phosphorus oxychloride to obtain compound XII can be from -5 °C to 80 °C, for example from 0 °C to 70 °C.

[0079] According to an embodiment of the present invention, the reaction solvent for further reacting compound XII to obtain compound XIII can be a mixture of the above-mentioned organic solvent and water, such as a mixture of N,N-dimethylformamide and water.

[0080] According to an embodiment of the present invention, the reaction temperature for further reacting the compound of formula XII to obtain the compound of formula XIII can be 15 to 40 °C, for example 20 to 35 °C, such as 25 to 30 °C.

[0081] According to an embodiment of the present invention, the preparation method M13 includes preparing compound 12 from compound 3b by the following reaction, and preparing compound 13 from compound 12: .

[0082] The present invention also provides compounds of the above formula IIIB, such as compound 3b.

[0083] The present invention also provides compounds of the above formula XII, such as compound 12.

[0084] The present invention also provides the use of the above-described compounds of formula IIIB (e.g., compound 3b) and / or compounds of formula XII (e.g., compound 12) in the preparation of compounds of formula XIII (e.g., compound 13).

[0085] The present invention also provides the use of the above-described compound IIIB (e.g., compound 3b) in the preparation of compound XII (e.g., compound 12).

[0086] This invention also provides a method M10B for preparing compound X, comprising reacting compound XVII with phosphorus oxychloride to obtain compound X: Among them, D, E, L10, and L11 independently have the definitions described above.

[0087] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is selected from dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyridine; nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethyl pyrrolidone.

[0088] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound XVII to phosphorus oxychloride can be 1:2 to 1:8. For example, 1:3 to 1:6, such as 1:4 to 1:5:2 to 1:4, such as 1:2 to 1:3, such as 1:2.4 to 1:2.5.

[0089] According to an embodiment of the present invention, the preparation method M10B includes preparing compound 10 by reacting compound 17 as follows: .

[0090] The present invention also provides compounds of the above formula XVII, such as compound 17.

[0091] The present invention also provides the use of compounds of formula XVII (e.g., compound 17) in the preparation of compounds of formula X (e.g., compound 10).

[0092] This invention also provides a method M17 for preparing compounds of formula XVII, comprising reacting a compound of formula XVI with an alkali metal halide or an organohalide to obtain a compound of formula XVII: Among them, D, E, and L 10 independently have the definitions described above; L 16 is any of the following groups that are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens: C1-6 alkylsulfonyl, C1-6 alkylbenzenesulfonyl, such as methanesulfonyl (Ms-), trifluoromethanesulfonyl (Tf-), p-toluenesulfonyl (Ts-).

[0093] According to an embodiment of the present invention, in the preparation method of compound XVII, the alkali metal halide or organic halide can be selected from at least one of LiBr, NaBr, KBr, CsBr, and Bu 4NBr.

[0094] According to an embodiment of the present invention, the preparation method of compound XVII can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and ethylene oxide and... / or propylene oxide polyethers); cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene and cyclopentadiene); aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane... Alkanes, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methyl... The organic solvent is preferably caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyridine; nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is n-propanol.

[0095] According to an embodiment of the present invention, in the method for preparing compound XVII, the molar ratio of compound XVI to alkali metal halide or organohalide can be 1:1 to 1:5, for example 1:1 to 1:2, such as 1:1.5.

[0096] According to embodiments of the present invention, the preparation method of compound XVII can be carried out in the presence of a catalyst. The catalyst may be, for example, ruthenium(II) chloride pentamethylcyclopentadiene ditriphenylphosphine, ruthenium(II) tri(acetonitrile)pentamethylcyclopentadiene trifluoromethanesulfonate, ruthenium(II) pentamethylcyclopentadiene tri(acetonitrile)hexafluorophosphate, ruthenium(II) chloride (dimer), ruthenium(I) chloride (tetramer), ruthenium(II) tri(acetonitrile)tetramethylcyclopentadiene trifluoromethanesulfonate, or ruthenium(II) dichlorocyclooctadiene.

[0097] According to an embodiment of the present invention, in the method for preparing compound XVII, the molar ratio of compound XVI to catalyst can be from 1:0.01 to 1:0.1, such as 1:0.05.

[0098] According to an embodiment of the present invention, the reaction temperature of the method for preparing compound XVII can be above 50 °C, for example above 80 °C, such as 90 to 100 °C.

[0099] According to an embodiment of the present invention, the preparation method M17 includes preparing compound 17 by reacting compound 16 as follows: .

[0100] The present invention also provides compounds of the above formula XVI, such as compound 16.

[0101] The present invention also provides the use of compounds of formula XVI (e.g., compound 16) in the preparation of compounds of formula XVII (e.g., compound 17).

[0102] This invention also provides a method M16 for preparing compound XVI, comprising reacting compound XV with a sulfonating agent to obtain compound XVI: Among them, D, E, and L 10 independently have the definitions described above.

[0103] According to an embodiment of the present invention, the preparation method of compound XVI can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is selected from dichloromethane. The solvents include: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyrrolidine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dichloromethane.

[0104] According to an embodiment of the present invention, in the method for preparing compound XVI, the sulfonating agent may be selected from C1-6 alkylsulfonyl chlorides that are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens, C1-6 alkylsulfonic anhydrides that are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens, C1-6 alkylbenzenesulfonyl chlorides that are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens, such as methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (PhN(Tf)2).

[0105] According to an embodiment of the present invention, in the method for preparing compound XVI, the molar ratio of compound XV to sulfonating agent can be 1:1 to 1:5, for example 1:1 to 1:1.2, such as 1:1.1 to 1:1.15.

[0106] According to an embodiment of the present invention, the preparation method M16 includes preparing compound 16 by reacting compound 15 as follows: .

[0107] The present invention also provides compounds of the above formula XV, such as compound 15.

[0108] The present invention also provides the use of the above-described XV compounds (e.g., compound 15) in the preparation of XVI compounds (e.g., compound 16).

[0109] This invention also provides a method M15 for preparing compound XV, comprising reacting compound XIV with an acid to obtain compound XV: Among them, D, E, L10, and PG3 independently have the definitions described above.

[0110] According to an embodiment of the present invention, in the method for preparing compound XV, the acid may be selected from organic or inorganic acids, such as at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, trifluoroacetic acid, phosphorus oxychloride, succinic acid, and ascorbic acid.

[0111] According to an embodiment of the present invention, the preparation method of compound XV can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is selected from dichloromethane. The solvents include: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyrrolidine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dichloromethane.

[0112] According to an embodiment of the present invention, in the method for preparing compound XV, the molar ratio of compound XIV to trifluoroacetic acid can be 1:1 to 1:10, for example 1:4 to 1:6, such as 1:5 to 1:5.5.

[0113] According to an embodiment of the present invention, in the preparation method of compound XV, trifluoroacetic acid can participate in the reaction by dropwise addition.

[0114] According to an embodiment of the present invention, the preparation method M15 includes preparing compound 15 by reacting compound 14 as follows: .

[0115] The present invention also provides compounds of the above formula XIV, such as compound 14.

[0116] The present invention also provides the use of the above-described XIV compounds (e.g., compound 14) in the preparation of XV compounds (e.g., compound 15).

[0117] This invention also provides a method M14 for preparing compound XIV, comprising reacting compound IIIA with ethanol to obtain compound XIV: Among them, D, L10, and PG3 independently have the definitions described above; L3a is selected from leaving groups, such as halogens, such as chlorine, bromine or iodine.

[0118] According to an embodiment of the present invention, the preparation method of compound XIV can be carried out in the presence of a copper catalyst and a ligand.

[0119] According to an embodiment of the present invention, the copper catalyst may be selected from at least one of cuprous iodide (CuI), cuprous bromide (CuBr), and copper acetone (Cu(acac)2).

[0120] According to an embodiment of the present invention, the ligand may be selected from at least one of N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)glyoxalamide, 8-hydroxyquinoline, N,N'-bis(2,4,6-trimethoxyphenyl)glyoxalamide, N-benzyl-N-(2-methylnaphthyl-1-yl)ethylenediamine, and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)glyoxalamide.

[0121] According to an embodiment of the present invention, the preparation method of compound XIV can be further carried out in the presence of a base. The base can be an organic base or an inorganic base, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0122] According to an embodiment of the present invention, in the preparation method of compound XIV, the molar volume ratio of compound IIIA to ethanol can be 1 mol : (2~5) L, such as 1 mol : (3~4) L.

[0123] According to an embodiment of the present invention, in the method for preparing compound XIV, the molar ratio of compound IIIA to cuprous catalyst can be from 1:0.01 to 1:0.2, such as 1:0.02.

[0124] According to an embodiment of the present invention, in the preparation method of compound XIV, the molar ratio of compound IIIA to base can be 1:1 to 1:10, such as 1:2 to 1:4, such as 1:3.

[0125] According to an embodiment of the present invention, in the preparation method of the compound of formula XIV, the molar ratio of the compound of formula IIIA to the ligand can be from 1:0.01 to 1:0.2, such as 1:0.02.

[0126] According to an embodiment of the present invention, in the preparation method of compound XIV, the reaction temperature can be above 50 °C, for example above 70 °C, such as 80 to 100 °C.

[0127] According to an embodiment of the present invention, the preparation method M14 includes preparing compound 14 by reacting compound 3a as follows: .

[0128] The present invention also provides compounds of the above formula IIIA, such as compound 3a.

[0129] The present invention also provides the use of the above-described compound IIIA (e.g., compound 3a) in the preparation of compound XIV (e.g., compound 14).

[0130] This invention also provides a method M10C for preparing compound X, comprising reacting compound IX with an alkali metal halide or an organohalide to obtain compound X: Among them, D, E, L10, and L16 independently have the definitions described above.

[0131] According to an embodiment of the present invention, in the preparation method of compound X, the alkali metal halide or organic halide can be selected from at least one of LiBr, NaBr, KBr, CsBr, and Bu 4NBr.

[0132] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of a base. The base can be an organic base or an inorganic base, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases are selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0133] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound IX to alkali metal halide or organic halide can be 1:1 to 1:5, for example 1:1 to 1:2, such as 1:1.5.

[0134] According to embodiments of the present invention, the preparation method of compound X can be carried out in the presence of a catalyst. The catalyst may be, for example, ruthenium(II) chloride pentamethylcyclopentadiene ditriphenylphosphine, ruthenium(II) tri(acetonitrile)pentamethylcyclopentadiene trifluoromethanesulfonate, ruthenium(II) pentamethylcyclopentadiene tri(acetonitrile)hexafluorophosphate, ruthenium(II) chloride (dimer), ruthenium(I) chloride (tetramer), ruthenium(II) tri(acetonitrile)tetramethylcyclopentadiene trifluoromethanesulfonate, or ruthenium(II) dichlorocyclooctadiene.

[0135] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound IX to catalyst can be from 1:0.01 to 1:0.1, such as 0.05.

[0136] According to an embodiment of the present invention, the reaction temperature of the method for preparing compound X can be above 50 °C, for example above 80 °C, such as 90 to 100 °C.

[0137] According to the preparation method of the present invention, the preparation method M10C includes preparing compound 10 by reacting compound 9 as follows: .

[0138] The present invention also provides compounds of formula IX, such as compound 9.

[0139] The present invention also provides the use of the above-described compound IX (e.g., compound 9) in the preparation of compound X (e.g., compound 10).

[0140] According to embodiments of the present invention, compound IX can also be prepared from compound IIIA as a starting material. For example, compound IIIA can be reacted with phosphorus oxychloride to obtain compound IV as follows: Among them, D, L10, PG3, and L3a independently have the definitions described above.

[0141] According to an embodiment of the present invention, the reaction of compound IIIA with phosphorus oxychloride can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is selected from dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethylpyridine; nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethyl pyrrolidone.

[0142] According to an embodiment of the present invention, in the above preparation method, the molar ratio of the compound of formula IIIA to phosphorus oxychloride can be 1:2 to 1:8. For example, 1:3 to 1:6, such as 1:4 to 1:5.

[0143] According to embodiments of the present invention, the group L3a of the compound of formula IV can be derived into the group E as defined above according to known organic synthesis methods. For example, L3a can be first converted into a hydroxyl-derived intermediate and then derived into group E. Alternatively, referring to the preparation method M14 described above, the group L3a of compound IV can be derived into the group E. Alternatively, according to an embodiment of the present invention, the compound of formula IV or the above derivative may be reacted with trifluoroacetic acid with reference to the preparation method M15 above to derive the group PG 3 into a hydroxyl group; and / or the above derivative may be reacted with the above sulfonating agent with reference to the preparation method M16 above to obtain a C 1-6 alkyl sulfonyl group, such as methanesulfonyl (Ms) or trifluoromethanesulfonyl, in which the hydrogen atom on the hydroxyl group is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens.

[0144] As an example, the reaction of compound IV with trifluoroacetic acid yields compound XXIII as follows: Among them, D, L10, and L3a independently have the definitions described above.

[0145] According to an embodiment of the present invention, the compound of formula XXIII can be reacted with hydrazine (such as hydrazine hydrate) in accordance with the preparation method M11 described above to obtain the compound of formula XXXI as follows: Among them, D and L3a independently have the definitions described above.

[0146] According to an embodiment of the present invention, the group L3a of the compound of formula XXXI can be derived into the group E as defined above using a known organic synthesis method. For example, L3a can be first converted into a hydroxyl-derived intermediate, and then derived into group E to obtain the compound of formula XXIX. Alternatively, referring to the preparation method M14 above, the group L 3a of compound XXXI can be derived into group E to obtain compound XXIX.

[0147] According to an embodiment of the present invention, the above-described preparation method M16 can also be used to react the above-described compound of formula XXIX with the above-described sulfonating reagent to obtain the following groups in which the hydrogen atom on the hydroxyl group is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens: C1-6 alkylsulfonyl, C1-6 alkylbenzenesulfonyl, such as methanesulfonyl (Ms-), trifluoromethanesulfonyl (Tf-), p-toluenesulfonyl (Ts-) substituted compounds of formula XXX: Among them, D and E independently possess the definitions described above; L 30 is an unsubstituted or substituted group with 1, 2, 3, 4, 5 or 6 halogens of the following groups: C1-6 alkylsulfonyl, C1-6 alkylbenzenesulfonyl, such as methanesulfonyl (Ms-), trifluoromethanesulfonyl (Tf-), p-toluenesulfonyl (Ts-).

[0148] According to embodiments of the present invention, compound 3a can be used to prepare compounds 4, 5, 6, 7, 8, and / or 9 via the following reactions: .

[0149] According to embodiments of the present invention, compound 3a can also be used to prepare compounds 4, 23, 31, 29 and / or 30 via the following reactions: .

[0150] According to embodiments of the present invention, compound 4 can also be used to prepare compounds 23, 31, 25, 26, 27, 28, 29 and / or 30 via the following reactions: .

[0151] The present invention also provides compounds of formula IV (e.g., compound 4), formula XXIII (e.g., compound 23), formula XXXI (e.g., compound 31), formula XXIX (e.g., compound 29), and formula XXX (e.g., compound 30), and the use of any of the above compounds in the preparation of compounds of formula I.

[0152] According to an embodiment of the present invention, a method M19B for preparing a compound of formula XIX is also provided, comprising reacting a compound of formula XXX with a compound of formula XVIII to obtain a compound of formula XIX, wherein the compound of formula XVIII and the compound of formula XIX have the definitions described above.

[0153] According to an embodiment of the present invention, the preparation method of the above-described compound XIX can be carried out in the presence of a base.

[0154] The base can be an organic base or an inorganic base, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases are selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0155] According to an embodiment of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of an organic solvent or a mixture of an organic solvent and water. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is preferably dioxane. The solvent may contain: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethoxypyridine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0156] According to embodiments of the present invention, the preparation method of the above-mentioned compound XIX can be carried out in the presence of a catalyst, which can be a palladium catalyst, such as Pd(dba)₂, PdCl₂, Pd(OAc)₂, Pd(dppf)Cl₂, Pd₂(dba)₃, PdCl₂(CH₃CN)₂, Pd(PPh₃)₄, PdCl₂(PPh₃)₂, Pd(t-Bu)₃, PdCl₂(PPh₃)₂·CH₂Cl₂, Pd(OAc) / PPh₃, PdCl₂[(Pet₃)]₂, Pd(DIPHOS)₂, PdCl₂(Bipy), [PdCl(Ph₂PCH₂PPh₂)]₂, PdCl₂[P(o-Tol)₃]₂, Pd₂(dba)₂ 3 / P(o-Tol) 3. Pd 2(dba) / P(furyl) 3. PdCl 2[P(furyl) 3] 2. PdCl 2(PMePh 2) 2. PdCl 2[P(4-F-Ph) 3] 2. PdCl 2[P(C 6F 6) 3] 2. PdCl 2[P(2-COOH-Ph)(Ph) 2] 2. PdCl 2[P(4-COOH-Ph)(Ph) 2] 2.

[0157] According to an embodiment of the present invention, the reaction temperature of the method for preparing the above-described compound of formula XIX can be above 80 °C, for example above 100 °C, such as 120 °C.

[0158] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound XIX, the molar ratio of compound XXX to compound XVIII can be 1:1 to 1:5, for example 1:2 to 1:4, such as 1:3.

[0159] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XXX to base can be 1:1 to 1:10, for example 1:4 to 1:8, such as 1:5 to 1:6.

[0160] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XXX to catalyst can be from 1:0.01 to 1:0.2, such as from 1:0.05 to 1:0.1.

[0161] This invention also provides a method M1B for preparing a compound of formula I, wherein the method comprises reacting a compound of formula XXX with a compound of formula XXXX to obtain a compound of formula I: Among them, D, E, L30, X1, X2, X3, X4, G, and Rk each have the definitions described above independently.

[0162] According to an embodiment of the present invention, the reaction of the above-mentioned preparation method M1B can be carried out in the presence of a catalyst, which can be a palladium catalyst, such as Pd(dba)2, PdCl2, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(t-Bu)3, PdCl2(PPh3)2·CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHOS)2, PdCl2(Bipy), [PdCl(Ph2PCH2PPh2)]2, PdCl2[P(o-Tol)3]2, Pd2(dba)3 / P(o-Tol) 3. Pd 2(dba) / P(furyl) 3. PdCl 2[P(furyl) 3] 2. PdCl 2(PMePh 2) 2. PdCl 2[P(4-F-Ph) 3] 2. PdCl 2[P(C 6F 6) 3] 2. PdCl 2[P(2-COOH-Ph)(Ph) 2] 2. PdCl 2[P(4-COOH-Ph)(Ph) 2] 2.

[0163] According to an embodiment of the present invention, the reaction of M1B in the above preparation method can be carried out in the presence of a base. The base can be an organic base or an inorganic base, for example: Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or The inorganic bases are selected from the following: hydrides, hydroxides, amines, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates of alkali metals or alkaline earth metals, such as sodium amino, sodium hydride, diisopropylaminolithium, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0164] According to an embodiment of the present invention, the reaction of the above-described preparation method M1B can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers; cyclopentadienes (e.g., tetrahydrodioxothiophene and dimethyl cyclopentadiene, tetramethyl cyclopentadiene, dipropylene cyclopentadiene, benzylmethyl cyclopentadiene, diisobutyl cyclopentadiene, dibutyl cyclopentadiene, or diisopentyl cyclopentadiene); cyclopentadienes (e.g., dimethyl cyclopentadiene, diethyl cyclopentadiene, dipropyl cyclopentadiene, dibutyl cyclopentadiene, diphenyl cyclopentadiene, dihexyl cyclopentadiene, methyl ethyl cyclopentadiene, ethylpropyl cyclopentadiene, ethyl isobutyl cyclopentadiene, and cyclopentyl cyclopentadiene); aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, ... Cyclohexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethylmethamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidine, N-methylmethamide ... The organic solvent is preferably dioxane. The solvent may contain: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypyridine, or N,N'-1,4-dimethoxypyridine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0165] According to an embodiment of the present invention, the reaction of the preparation method M1B can be carried out at 100 °C to 150 °C, for example, 115 °C to 125 °C.

[0166] According to an embodiment of the present invention, the preparation method M1B includes preparing compound 1 by reacting compound 30 and compound 40 as follows: .

[0167] The present invention also provides the use of the above-described XXX compound in the preparation of the XIX compound.

[0168] The present invention also provides a method for preparing a compound of formula I, a pharmaceutically acceptable salt thereof, or an intermediate thereof, comprising the preparation method using a compound of formula IIIA and / or a compound of formula IIIB as a starting material or the reaction thereof.

[0169] The present invention also provides the use of the compound of formula IIIA in the preparation of the compound of formula I, its pharmaceutically acceptable salt, or the intermediates described above.

[0170] According to a preferred embodiment of the present invention, any of the preparation methods or uses described above can be carried out under an inert atmosphere (such as a nitrogen atmosphere).

[0171] According to a preferred embodiment of the present invention, in any of the preparation methods or uses described above, the compound used as a raw material may be provided and participate in the reaction in the form of its acid addition salt, as needed.

[0172] According to a preferred embodiment of the present invention, in any of the preparation methods or uses described above, when the compound used as a raw material is provided in the form of an acid addition salt and participates in the reaction, if necessary, the acid addition salt can be freed by a base (organic base or inorganic base) as defined above before participating in the reaction, or the freeing step and subsequent reaction can be carried out in situ by a "one-pot" method.

[0173] This invention also provides a preparation method, comprising combining one, two, three, or more of the above-described preparation methods sequentially to prepare the target compound. Those skilled in the art will understand that when combining one, two, three, or more of the above-described preparation methods sequentially, it is preferable to use the product obtained from one preparation method as a raw material for the next preparation method.

[0174] The present invention also provides a preparation method M-IIIB-I, comprising the above-mentioned preparation methods M13, M10A, M11, M19A, M20, and M1A, or a combination of two, three, or more of the above-mentioned preparation methods. Preferably, the preparation methods in the combination are performed sequentially, with the product obtained from the first preparation method used as the reaction substrate for the subsequent preparation method.

[0175] The present invention also provides a preparation method M-IIIA-X1, comprising the above-mentioned preparation methods M14, M15, M16, M17 and M10B, or a combination of two, three or more of the above-mentioned preparation methods. Preferably, the preparation methods in the combination are performed sequentially, with the product obtained by the first preparation method used as the reaction substrate for the subsequent preparation method.

[0176] The present invention also provides a preparation method M-IIIA-X2, which includes preparing compounds of formula IV, V, VI, VII, VIII, and IX by the above preparation method, and preparing compound X by the preparation method M10C.

[0177] The present invention also provides a preparation method M-IIIA-XXX, comprising preparing compound XXIII, compound XXXI, compound XXIX and compound XXX by the above method.

[0178] According to embodiments of the present invention, it should be understood that one of the different preparation methods for preparing the same intermediate can be combined with a preparation method for further preparing other compounds using the intermediate as a reaction substrate. Such a combination should also be understood as described in this specification, and should not be limited to a reaction route composed of a specific combination of preparation methods described above. For example, in the above description, the preparation methods for compound X include M10A, M10B, and M10C, any of which can be combined with preparation method M19A, or further combined with M20 and / or M1. Similarly, the different preparation methods for compound XXX described above can all be combined with preparation method M1B to prepare compound I.

[0179] According to embodiments of the present invention, in any of the preparation methods or uses described above, it is preferable not to use chromatographic methods such as column chromatography to separate or purify the raw materials, reaction products or intermediates.

[0180] According to embodiments of the present invention, in any of the preparation methods or uses described above, it is preferable not to use hydrogen as a hydrogenation or reduction agent, and not to use hydrogen for the reaction by means of catalytic hydrogenation.

[0181] According to embodiments of the present invention, in any of the preparation methods or uses described above, when an organic solvent or a mixture of an organic solvent and water is used, it is inert to the reaction substrate and reagents.

[0182] Terminology Definitions and Explanations Unless otherwise stated, the definitions of functional groups and terms described in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of functional group definitions and compound structures should fall within the scope of this application specification. Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1 to 40" is equivalent to describing each integer value in the numerical range "1 to 10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11 to 40", namely 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40. It should be understood that when describing substituents, "one, two, or more" as used herein, "more" should refer to integers ≥3, such as 3, 4, 5, 6, 7, 8, 9, or 10. The term "halogen" refers to a substituent group selected from fluorine, chlorine, bromine, or iodine. The term "C1-40 alkyl" should be understood to preferably refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C1-6 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, etc., or isomers thereof. The term "C 2-40 alkenyl" should be understood to preferably refer to a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 40 carbon atoms, preferably "C 2-6 alkenyl". "C 2-6 alkenyl" should be understood to preferably refer to a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2-3 alkenyl"). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The term "C2-40 ynyl" should be understood to refer to a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, preferably "C2-C6-ynyl". The term "C2-C6-ynyl" should also be understood to refer to a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-ynyl"). The C2-C... 6-Alynyl groups include, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, and 2-methylpent-4-ynyl. -Alynyl, 1-methylpentan-4-ynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl. The term "C 3-40 cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic, or bridged cycloalkanes having 3 to 40 carbon atoms, preferably "C 3-10 cycloalkyl". The term "C 3-10 cycloalkyl" should also be understood to refer to a saturated monovalent monocyclic, bicyclic, or bridged cycloalkanes having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C 3-10 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon group, such as decahydronaphthalene. The term "3-20-membered heterocyclic group" refers to a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane comprising 1-5 heteroatoms independently selected from N, O, and S, forming a non-aromatic cyclic group with a total ring atomic number of 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably "3-10-membered heterocyclic group". The term "3-10-membered heterocyclic group" also refers to a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane comprising 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclic group can be attached to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirmonobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piriminyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piriminyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic. When the 3-20 member heterocyclic group is linked to other groups to form the compounds of the invention, the carbon atom on the 3-20 member heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-20 member heterocyclic ring can be linked to other groups. For example, when the 3-20 member heterocyclic group is selected from pirazine, the nitrogen atom on the pirazine group can be linked to other groups. Or when the 3-20 member heterocyclic group is selected from pirazine, the nitrogen atom on the pirazine ring and its para-carbon atom can be linked to other groups. The term "C 6-20 aryl" should be understood to preferably refer to a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms with monovalent aromaticity or partial aromaticity, preferably "C 6-14 aryl". The term "C 6-14 aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, particularly a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), such as indenyl or indene, 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 anthracene. When the C 6-20 aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be an adjacent, para, or meta substitution. The term "5-20 member heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as "5-14 member heteroaryl". The term "5-14 member heteroaryl" should also be 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, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O, and S, and in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[a] derivatives, such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, and iso[a] Indolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrile, indazinyl, purine, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthidyl, pteridinyl, zozolyl, acrylonitrile, phenazinyl, phenothiazinyl, phenotoxazinyl, etc. When the 5-20 member heteroaryl group is connected to other groups to form the compound of the present invention, the carbon atom on the 5-20 member heteroaryl ring can be connected to other groups, or the heteroatom on the 5-20 member heteroaryl ring can be connected to other groups. When the 5-20 member heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site; for example, the hydrogen atom connected to the carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom connected to the heteroatom on the heteroaryl ring can be substituted. Unless otherwise stated, heterocyclic, heteroaryl, or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, forms may be included in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene groups include thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl. The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation. Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, for example, the definition of C1-6 alkyl also applies to C1-6 alkyloxy, -N(C1-6 alkyl)2, -NHC1-6 alkyl or -S(O)2-C1-6 alkyl, etc.

[0183] As will be understood by those skilled in the art, the compounds represented by Formula I can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0184] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0185] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various optical isomer forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be isolated as optically isomer compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in this form. In the case of racemic amines, non-optical isomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylurea proline), or various optically active camphorsulfonic acids. Column chromatography optical isomer resolution can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or palmiticly derivatized isobutylene ester polymers immobilized on silicone). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0186] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0187] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0188] Beneficial effects The preparation method of the present invention does not use the separation and purification steps of column chromatography methods such as silicone column chromatography, nor does it use hydrogen as a hydrogenation or reduction reagent, which significantly improves production efficiency and safety. Furthermore, the preparation method of this invention achieves efficient utilization of positional isomers IIIA and IIIB, avoiding the adverse effects of discarding positional isomer IIIA on the yield of the target product. Even more surprisingly, the overall yield using positional isomer IIIA is as high as 9.4%, significantly higher than the less than 4% yield using positional isomer IIIB. When both positional isomers are used simultaneously in the preparation of compound I, the yield is more than three times higher than when positional isomer IIIB is used alone. Therefore, the preparation method of the present invention can synthesize compounds of formula I and their intermediates in high yield, low cost and in an environmentally friendly manner, thereby enabling compounds of formula I to be produced on an industrial scale. Implementation

[0189] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0190] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0191] Example 1: Preparation of compounds 3a and 3b

[0192] (1) 2,4,6-Trimethylbenzenesulfonic acid 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridine-1-onium (Compound 1) In a reaction vessel, trifluoroacetic acid (340 kg) was added, purged with nitrogen three times, and the temperature was lowered to 0-10 °C. Under nitrogen protection, N-Boc-O-2,4,6-trimethylbenzenesulfonylhydroxylamine (90 kg, 285 mol) was added in batches. A large amount of gas was released after each batch was added. After reacting for 2 h, the reaction was quenched with water, and a solid was precipitated. The solid was dissolved in dichloromethane and washed with NaHCO3 aqueous solution until the pH of the organic phase was about 7. The mixture was then separated. The organic phase was then cooled to 0–10 °C under nitrogen protection. 3-Bromo-5-(4-methoxybenzyloxy)pyridine (64 kg, 217 mol) was added in batches while maintaining the temperature at 0–10 °C. After reacting for 1–2 h, the mixture was filtered to obtain 89 kg of the product. ¹H-NMR (400 MHz, DMSO-d₆): δ. 8.67–8.72 (m, 2H), 8.58 (brs, 2H), 8.34 (d, 1H), 7.43 (d, 2H), 7.00 (d, 2H), 6.75 (s, 2H), 5.23 (s, 2H), 3.78 (s, 3H), 2.51 (s, 6H), 2.17 (s, 3H), m / z = 311 [M+1]⁺.

[0193] (2) 6-bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (compound 3a) and 4-bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (compound 3b). 188 kg of tetrahydrofuran was added to the reactor, followed by 91 kg (179 mol) of 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridine-1-onium (2,4,6-trimethylbenzenesulfonic acid) and 51 kg (218 mol) of 2,4,6-trimethylbenzenesulfonic acid. 109 kg (717 mol) of 1,8-diazacyclo[5,4,0]undecene-7 was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 1 h. 560 kg of dichloromethane was added, followed by 240 kg of saturated ammonium chloride solution. The organic phase was washed with water (210 kg), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from acetonitrile to obtain 35 kg of 6-bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.59 (s, 1H), 7.43–7.46 (m, 2H), 7.07 (s, 1H), 6.97–7.00 (m, 2H), 6.39 (d, 1H), 5.22 (s, 2H), 3.78 (s, 3H), m / z = 351 [M+1] +; 4-bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine 8.2 kg, 1H-NMR (400 MHz, DMSO-d 6): δ 8.50–8.51 (m, 1H), 7.64 (d, 1H), 7.39–7.45 (m, 2H), 6.95–6.99 (m, 2H), 6.33–6.34 (m, 1H), 5.05 (s, 3 ... 2H), 3.77 (d, 3H), m / z = 351 [M+1] +.

[0194] Example 2: Preparation of Compound 11

[0195] (1) 4-Bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 12) Add 7.4 kg, 21 mol of 4-bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine and 21 kg of DMF to the reaction vessel in sequence, purge with nitrogen three times, control the temperature at 0-10 °C, add 8.0 kg, 52 mol of phosphorus oxychloride dropwise, heat to 20-30 °C, and react for 17 h. The resulting product solution can be directly used for the next reaction. 1H-NMR (400 MHz, DMSO-d 6): δ 10.50 (s, 1H), 8.80 (d, 1H), 8.08 (d, 1H), 7.39-7.43 (m, 2H), 6.95-6.99 (m, 2H), 5.12 (s, 2H), 3.77 (s, 3H). m / z = 379 [M+1] +.

[0196] (2) 4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 13) The reaction solution in the reactor from the previous step was heated to 70 °C. HPLC sampling was used to monitor the reaction until the raw materials were completely reacted. The reaction solution was then cooled to 25 °C and added to 66 kg of water. The mixture was stirred at 30 °C for 2 h, filtered, and the filter cake was slurried with 17 kg of dichloromethane for 1 h. After filtration again, the filter cake was obtained and dried under vacuum to obtain 4.7 kg of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.62 (brs, 1H), 10.46 (d, 1H), 8.32 (t, 1H), 7.80 (s, 1H). m / z = 259 [M+1]+.

[0197] (3) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 10) 4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (4.7 kg, 18 mol), dimethyl sulfoxide (15.5 kg), potassium carbonate (2.8 kg, 20 mol), and iodoethane (3.0 kg, 19 mol) were added sequentially to a reaction vessel. Nitrogen gas was purged three times, and the reaction was heated to 65 °C. HPLC sampling was used to monitor the reaction until the reactants were completely reacted. The temperature was then lowered to 25 °C, and 47 kg of water was added to the reaction vessel. The mixture was stirred at 25–30 °C for 1 h and then vacuum-filtered to dryness. Acetonitrile (9.0 kg) was added to the reaction vessel, and the filter cake was added to the reaction vessel. The mixture was stirred at 25–30 °C for 1–2 h, vacuum-filtered to dryness, and then vacuum-dried to obtain 4.6 kg of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.49 (s, 1H), 8.69 (d, 1H), 8.00 (d, 1H), 4.16 (q, 2H), 1.37 (t, 3H). m / z = 287 [M+1] +.

[0198] (4) Synthesis of 4-bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 11) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (4.6 kg, 16 mol), dimethyl sulfoxide (46 L), and 85% hydrazine hydrate (4.7 kg) were added to a reaction vessel. The mixture was heated to 110–115 °C and the reaction was monitored by HPLC until complete. The mixture was then cooled to 30–40 °C, and water (138 L) was added. The mixture was stirred at this temperature for 1–2 h and then filtered. The filter cake was dried under vacuum to obtain 4.0 kg of the product. ¹H-NMR (400 MHz, DMSO-d6): δ 12.81 (brs, 1H), 8.64 (s, 1H), 7.92 (s, 1H), 7.58 (s, 1H), 4.11–4.17 (m, 2H), 1.35–1.38 (t, 3H). m / z = 281 [M+1]+.

[0199] Example 3: Preparation of Compound I

[0200] (1) 3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-tert-butyl carbonate (compound 19) Add 30 g (0.11 mol) of 4-bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine, 57 g (0.14 mol) of 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.3]heptane-6-tert-butyl carbonate, 1.5 g (2.2 mmol) of bis(triphenylphosphine)palladium dichloride, 16 g (0.22 mol) of lithium carbonate, 300 mL of dioxane, and 150 mL of water to the reaction flask in sequence. Replace the nitrogen gas three times, heat to 85 °C and react for 20 hours. Filter with diatomaceous earth, pour the filtrate into 3 L of water, and filter to obtain a solid. The solid was dissolved in 1.2 L of tetrahydrofuran, and 60 g of SILICYCLE silicone was added. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the silicone was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to about 100 mL, and 300 mL of methyl tert-butyl ether was added. The mixture was then concentrated again under reduced pressure to about 100 mL. This step was repeated at least twice. The mixture was stirred at room temperature overnight, filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The solid was dried under vacuum to obtain 42.3 g of product with an HPLC purity of 98.8%. 1H-NMR (400 MHz, DMSO-d 6): δ 12.64 (s, 1H), 8.62 (d, 2H), 8.51 (d, 2H), 8.08 (q, 1H), 7.55 (s, 1H), 7.26 (d, 1H), 6.90 (d, 1H), m / z = 476[M+1]+.

[0201] (2) 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 20) 3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-carbonate tert-butyl ester (30 g, 0.063 mol), methanol 500 mL, and concentrated sulfuric acid (25 g, 0.25 mol) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 12 h. The methanol was removed by concentration under reduced pressure. 500 mL of methyl tert-butyl ether was added and the mixture was stirred. The product was filtered to obtain 43 g of product with an HPLC purity of 99.5%, which was directly used in the next reaction. 1H NMR (400 MHz, DMSO-d 6): δ 12.67 (s, 1H), 8.62 (d, 1H), 8.50 (d, 1H), 8.07 (q, 1H), 7.59 (s, 1H), 7.23 (d, 1H), 6.84 (d, 1H), 4.15-4.20 (m, 2H), 3.66-3.73 (m, 6H), 3.18 (s, 1H), 2.56-2.57 (m, 1H), 1.49 (d, 1H), 1.35-1.45 (m, 3H). m / z = 376 [M+1] +.

[0202] (3) 6-ethoxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound I) Add the product from step (2) (30 g), 6-methoxy-3-pyridinecarboxaldehyde (20 g, 0.14 mol), 2-methylpyridine-N-methylborane (16 g, 0.15 mol), triethylamine (34 mL, 0.24 mol), and 650 mL of n-propanol to the reaction flask in sequence. React at room temperature for 18 hours. Add 300 mL of dichloromethane, wash once with saturated ammonium chloride solution, wash twice with water, concentrate under reduced pressure, add 300 mL of methanol, heat to reflux, cool to 40-45 °C, slowly add 160 mL of methyl tert-butyl ether, cool to 25 °C and stir for 12 hours, add another 160 mL of methyl tert-butyl ether and stir for 1 hour, concentrate under reduced pressure to about 160 mL, add 300 mL of methyl tert-butyl ether, concentrate again under reduced pressure to about 160 mL, repeat this step more than twice, stir the mixture at room temperature overnight, filter the mixture, wash the filter cake with a small amount of methyl tert-butyl ether, and dry the solid under vacuum to obtain product 19. g, HPLC purity 98.9%. 1H-NMR (400 MHz, DMSO-d 6): δ 12.64 (brs, 1H), 8.64 (s,1H), 8.51 (s,1H), 8.08-8.11 (m, 2H), 7.69 (d, 1H), 7.63 (s, 1H), 7.26 (s, 1H), 6.90 (d, J = 8.8Hz, 1H), 6.77 (d, J = 8.8Hz, 1H), 4.16-4.21 (m, 2H), 3.83 (s, 3H), 3.76-3.79 (m, 2H), 3.68 (s, 2H), 3.53-3.59 (m, 4H), 2.53-2.56 (m, 1H), 1.56-1.58 (m, 1H), 1.40 (t, 3H). m / z = 497 [M+1] +.

[0203] Example 4: Preparation of Compound 11

[0204] (1) 6-ethoxy-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (compound 14) Ethanol (500 mL), 6-bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (52.5 g, 150.0 mmol), cuprous iodide (570 mg, 3.0 mmol), sodium tert-butoxide (43.2 g, 450 mmol), and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxadiazine (1.0 g, 3.0 mmol) were added sequentially to the reaction flask. The reaction solution was heated to 80 °C for 16 hours under nitrogen protection. After cooling, water (150 mL) was added to the reaction solution with stirring for 30 minutes. The solid was obtained by filtration and dried under vacuum to obtain 37 g of product. 1H-NMR (400 MHz, DMSO-d 6): δ 7.91 (s, 1H), 7.41 (d, J = 11.2 Hz, 2H), 6.97 (d, J = 11.2 Hz, 2H), 6.69 (s, 1H), 6.19 (s, 1H), 5.18 (s, 2H), 3.98-4.03 (m, 2H), 3.76 (s, 3H), 1.32-1.36 (t, 3H). m / z = 317 [M+1] +.

[0205] (2) 6-ethoxy-2-fluopyrazole[1,5-a]pyridine-4-ol (compound 15) Dichloromethane (450 mL) and 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine (37 g, 117.0 mmol) were added sequentially to a reaction flask. Trifluoroacetic acid (45 mL) was added dropwise, and the reaction was allowed to proceed for 3 hours. The reaction solution was washed with water (300 mL), then washed with saturated brine (150 mL), and concentrated to obtain a crude product solution (approximately 60 mL). Heptane (250 mL) was added to the crude product solution, and the mixture was stirred for 1 hour. The mixture was then filtered and dried under vacuum to obtain 16.5 g of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.78 (s, 1H), 7.81 (s, 1H), 6.33 (s, 1H), 6.16 (s, 1H), 3.94-4.00 (m, 2H), 1.35-1.39 (t, 3H). m / z = 197[M+1]+.

[0206] (3) 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-yltrifluoromethane sulfonate (compound 16) Dichloromethane (200 mL) and a solution of 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-ol (14.8 g, 75.5 mmol), triethylamine (11.5 g, 113.3 mmol), and trifluoromethanesulfonic anhydride (23.4 g, 83.1 mmol) in dichloromethane (50 mL) were added sequentially to a reaction flask, and the reaction was carried out at room temperature for 16 hours. The reaction solution was washed with water (200 mL), washed with saturated brine (100 mL), and then concentrated to obtain a crude product. The crude product was dissolved in DMF (150 mL), and water (1000 mL) was slowly poured in with stirring. After stirring for 30 minutes, the mixture was filtered, washed with water, and dried in a forced-air environment at 60 °C for 16 hours to obtain 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-yltrifluoromethanesulfonate (23.4 g, yield 95%), which was a pale yellow solid. 1H-NMR (400 MHz, DMSO-d 6): δ 8.56 (s, 1H), 7.60 (s, 1H), 6.48 (s, 1H), 4.08-4.13 (m, 2H), 1.34-1.38 (t, 3H). m / z = 329 [M+1] +.

[0207] (4) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine (compound 17) NMP (60 mL), 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (6.6 g, 20.0 mmol), pentamethylcyclopentadiene ditriphenylphosphine ruthenium(II) chloride (800 mg, 1.0 mmol), and LiBr (2.6 g, 30.0 mmol) were added sequentially to the reaction flask. Nitrogen gas was purged three times, and the reaction mixture was heated to 90 °C for 16 hours. The reaction solution was slowly poured into water (800 mL) and stirred for 1 hour. The mixture was then filtered, washed with water, and dried under vacuum to obtain 3.9 g of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 8.40 (s, 1H), 7.56 (s, 1H), 6.32 (s, 1H), 4.03-4.08 (m, 2H), 1.32-1.35 (t, 3H). m / z = 259 [M+1] +.

[0208] (5) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (Compound 10) DMF (60 mL), 4-bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine (3.5 g, 13.5 mmol), and POCl3 (8.3 g, 54 mmol) were added sequentially to the reaction flask, and the reaction was carried out at room temperature for 48 hours. The reaction solution was slowly poured into water (600 mL) and stirred for 1 hour. The mixture was filtered, washed with water, and the solid was dried under vacuum to obtain 4.2 g of product. ¹H-NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 4.10–4.16 (m, 2H), 1.30–1.34 (t, 3H). m / z = 287 [M+1]+.

[0209] (6) 4-Bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 11) The operation is the same as step (4) in Example 2.

[0210] Example 5: Preparation of Compound 30

[0211] (1) 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (compound 31) DMSO (200 mL), acetylhydrazine (8.6 g, 115.8 mmol), and 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (20.0 g, 77.2 mmol), and 80% hydrazine hydrate aqueous solution (24.1 g, 386 mmol) were added sequentially to the reaction flask. The mixture was heated to 140 °C and reacted for 6 hours. After cooling, the reaction solution was slowly poured into water (2000 mL), extracted twice with ethyl acetate (1000 mL), washed with water (400 mL), washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give 10.5 g of product. 1H-NMR (400MHz, DMSO-d 6): δ 12.68 (brs, 1H), 11.35 (s, 1H), 8.67 (s, 1H), 7.61 (s, 1H), 6.84 (s, 1H).m / z = 253 / 255 [M+1] +.

[0212] (2) 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (compound 29) Ethanol (50 mL), 6-bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (2 g, 8 mmol), cuprous iodide (160 mg, 8 mmol), cesium carbonate (8 g, 24 mmol), and 8-hydroxyquinoline (240 mg, 1.6 mmol) were added sequentially to a sealed reaction flask. The reaction was heated to 100 °C for 4 days. After stopping the reaction, 200 mL of dioxane was added, and the mixture was heated to reflux. The mixture was filtered through diatomaceous earth while hot, and the filtrate was concentrated under reduced pressure to approximately 50 mL. This filtrate was then poured into 500 mL of water, filtered to obtain a solid, and dried under vacuum to obtain 1.5 g of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 12.51 (brs, 1H), 11.02 (brs, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 6.48 (s, 1H), 4.02-4.08 (m, 2H), 1.35 (t, 3H).m / z = 219[M+1] +.

[0213] (3) 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (compound 30) 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (250 mg, 0.68 mmol), diisopropylethylamine (264 mg, 2.0 mmol), and DMF (5 mL) were added to a reaction flask. After cooling to 5 °C, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (183 mg, 0.51 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was then poured into 200 mL of water, filtered to obtain a solid, and dried to obtain 200 mg of the product with an HPLC purity of 97.5%. 1H-NMR (400 MHz, DMSO-d 6): δ 12.98 (brs, 1H), 8.77 (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 4.15-4.21 (m, 2H), 1.38 (t, 3H).m / z = 351 [M+1] +.

[0214] Example 6: Preparation of Compound 30

[0215] (1) 6-Bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 23) Dichloromethane (15 mL) and 6-bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (1.1 g, 3.0 mmol) were added sequentially to the reaction flask. Trifluoroacetic acid (3 mL) was added dropwise, and the reaction was stirred at room temperature for 3 hours. The product was concentrated under reduced pressure to obtain 0.6 g. ¹H-NMR (400 MHz, DMSO-d 6): δ 11.97 (s, 1H), 10.03 (s, 1H), 8.76 (s, 1H), 7.14 (s, 1H). m / z = 259 [M+1]+.

[0216] (2) 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (compound 31) DMSO (200 mL), acetylhydrazine (8.6 g, 115.8 mmol), 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (20.0 g, 77.2 mmol), and 80% hydrazine hydrate (24.1 g, 386 mmol) were added sequentially to the reaction flask. The mixture was heated to 110 °C and reacted for 12 hours. After cooling, the reaction solution was slowly poured into water (2000 mL), filtered, and the solid was dried under vacuum to obtain 10.5 g of product. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.68 (brs, ¹H), 11.35 (s, ¹H), 8.67 (s, ¹H), 7.61 (s, ¹H), 6.84 (s, ¹H). m / z = 253 [M+1]⁺.

[0217] (3) 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 25) 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (5.0 g, 20.0 mmol), 1-(chloromethyl)-4-methoxybenzene (3.4 g, 22.0 mmol), potassium carbonate (8.3 g, 60.0 mmol), and DMF (50 mL) were added sequentially to the reaction flask. The reaction solution was heated to 40 °C and reacted for 16 hours. After cooling, the reaction solution was slowly poured into water (500 mL) with stirring. After stirring for 1 hour, the mixture was filtered, washed with water, and dried to obtain 3.7 g of product. 1H-NMR (400 MHz, DMSO-d 6): δ 12.78 (brs, 1H), 8.81 (s, 1H), 7.83 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.33 (s, 2H), 3.77 (s, 3H). m / z = 373 / 375 [M+1] +.

[0218] (4) 4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-ol (compound 27) 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (3.7 g, 10.0 mmol), bis(naphthyl)boronic acid ester (3.8 g, 15.0 mmol), potassium acetate (2.9 g, 30.0 mmol), PdCl₂(dppf) (731 mg, 1.0 mmol), and 1,4-dioxane (70 mL) were added sequentially to the reaction flask. The reaction solution was heated to 90 °C for 16 hours under nitrogen protection. The solution was filtered through diatomaceous earth while hot, and the filtrate was concentrated under reduced pressure to obtain crude 4-(4-methoxybenzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine. Add 70 mL of THF to the crude product, cool in an ice bath to 5 °C, and add 6.5 mL of 30% H₂O₂ dropwise. React at room temperature for 1.5 hours. Add 150 mL of ethyl acetate to the reaction mixture, filter, wash the filtrate with 50 mL of 0.1 N hydrochloric acid aqueous solution, wash twice with 40 mL of water, wash with 40 mL of saturated brine, dry to anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain 900 mg of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 12.50 (brs, 1H), 9.83 (s, 1H), 7.88 (s, 1H), 7.69(s, 1H), 7.48(d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 5.28 (s, 2H), 3.79 (s, 3H). m / z = 311 [M+1] +.

[0219] (5) 6-ethoxy-1-ethyl-4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 28) 4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-6-ol (680 mg, 2.2 mmol), K₂CO₃ (911 mg, 6.6 mmol), iodoethane (378 mg, 2.4 mmol), and DMF (15 mL) were added sequentially to a reaction flask. The reaction solution was heated to 30 °C and reacted for 16 hours. The reaction solution was slowly poured into water (150 mL), stirred for 0.5 hours, filtered, washed with water, and dried to obtain a crude product. The crude product was dissolved in 10 mL of 1,4-dioxane by heating, and 10 mL of methyl tert-butyl ether was slowly added. The mixture was cooled to room temperature, concentrated to 5 mL, and then 20 mL of methyl tert-butyl ether was added. The mixture was stirred for 12 hours, filtered, and dried to obtain 227 mg of the product, a yellow solid. H 1-NMR (400 MHz, DMSO-d 6): δ 12.53 (brs, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.82 (s, 1H), 5.31 (s, 2H), 4.06-4.12 (m, 2H), 3.77 (s, 3H), 1.37 (t, 3H). m / z = 339 [M+1] +.

[0220] (6) 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-ol (compound 29) 6-ethoxy-1-ethyl-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (230 mg, 0.68 mmol) and dichloromethane (15 mL) were added sequentially to the reaction flask. Trifluoroacetic acid (0.5 mL) was then added, and the reaction mixture was heated to room temperature and stirred for 16 hours. The product was concentrated to obtain 250 mg, which was used directly in the next reaction step. 1H-NMR (400 MHz, DMSO-d 6): δ 12.51 (brs, 1H), 11.02 (brs, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 6.48 (s, 1H), 4.02-4.08 (m, 2H), 1.35 (t, 3H).m / z = 219 [M+1] +.

[0221] (7) 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (compound 30) Compound 30 was prepared by referring to step (3) of Example 5.

[0222] Example 7: Preparation of Compound 19 3-(5-(6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-tert-butyl carbonate (compound 19) 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonate tert-butyl ester (60 mg, 0.15 mmol), 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (35 mg, 0.05 mmol), PdCl₂(dppf) (4 mg, 0.005 mmol), potassium fluoride (18 mg, 0.3 mmol), and 1,4-dioxane (0.5 mL) were added sequentially to the reaction flask. The reaction was carried out at 120 °C for 16 hours under nitrogen protection. After concentrating the organic phase, 50 mL of methyl tert-butyl ether was added and the mixture was stirred. The mixture was then filtered to obtain 12 mg of the product. m / z = 476[M+1] +.

[0223] Example 8: Preparation of Compound 10 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 10).

[0224] (1) 6-Bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 4) DMF (35 mL) and 6-bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine (3.5 g, 10.0 mmol) were added sequentially to the reaction flask. The mixture was cooled to 5 °C, and POCl3 (6.1 g, 40.0 mmol) was added dropwise. The mixture was then stirred at room temperature for 48 hours. The reaction solution was slowly poured into water (350 mL) and stirred for 1 hour. The mixture was filtered, and the solid was dried under vacuum to obtain 3.6 g of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.01 (s, 1H), 8.88 (s, 1H), 7.59 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.34 (s, 2H), 3.78 (s, 3H). m / z = 379 [M+1] +.

[0225] (2) 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde (compound 5) 6-Bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (7.6 g, 20.0 mmol), bis(4-methyl)-pyrrolidone ester (5.6 g, 22.0 mmol), potassium acetate (5.9 g, 60.0 mmol), PdCl₂(dppf) (1.5 g, 2.0 mmol), and 1,4-dioxane (100 mL) were added sequentially to the reaction flask. Nitrogen gas was purged three times, and the reaction mixture was heated to 85 °C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 8.6 g of product, which was directly used in the next reaction step. m / z = 465 [M+1]⁺.

[0226] (3) 2-Fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 6) 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde (4.3 g, 10.1 mmol) and 1,4-dioxane (110 mL) were added sequentially to a reaction flask. The mixture was cooled to 5 °C in an ice bath, and 30% H₂O₂ (4 mL) was added dropwise. The reaction mixture was then allowed to react at room temperature for 2 hours. 200 mL of dichloromethane was added, and the mixture was washed sequentially with 50 mL of water, 50 mL of NaHSO₃ solution, and 50 mL of saturated brine. The solution was dried over anhydrous sodium sulfate. The organic phase was concentrated to 10 mL, and 100 mL of methyl tert-butyl ether was added. The mixture was filtered to obtain 2.1 g of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.27 (s, 1H), 9.97 (s, 1H), 7.84 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 5.28 (s, 2H), 3.78 (s, 3H). m / z = 317 [M+1] +.

[0227] (4) 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 7) 2-Fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (2.0 g, 6.3 mmol), K₂CO₃ (1.8 g, 12.6 mmol), iodoethane (1.2 g, 7.6 mmol), and DMF (19 mL) were added sequentially to the reaction flask. The reaction solution was heated to 40°C and reacted for 3 hours. The reaction solution was poured into 400 mL of water and extracted with 100 mL × 3 dichloromethane. The filtrate was concentrated to 10 mL, 100 mL of methyl tert-butyl ether was added, and the solution was concentrated under reduced pressure to approximately 10 mL. Another 100 mL of methyl tert-butyl ether was added, and the solution was concentrated again under reduced pressure to approximately 10 mL. This step was repeated twice to obtain 1.25 g of product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.07 (s, 1H), 8.20 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 5.32 (s, 2H), 4.07-4.12 (m, 2H), 3.78 (s, 3H), 1.32-1.39 (t, 3H). m / z = 345 [M+1] +.

[0228] (5) 6-ethoxy-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 8) Add 450 mg of 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde and 30 mL of dichloromethane to a reaction flask. Add 2 mL of trifluoroacetic acid dropwise and react at room temperature for 2 hours. Concentrate under reduced pressure to 10 mL, add 100 mL of methyl tert-butyl ether, concentrate under reduced pressure to about 10 mL, add another 100 mL of methyl tert-butyl ether, concentrate under reduced pressure to about 10 mL again, and repeat this step twice to obtain 305 mg of product. 1H-NMR (400 MHz, DMSO-d 6): δ 11.59 (s, 1H), 9.85 (s, 1H), 8.15 (s, 1H), 6.83 (s, 1H), 4.04-4.09 (m, 2H), 1.30-1.36 (t, 3H). m / z = 225[M+1]+.

[0229] (6) 6-Ethoxy-2-fluoro-3-methylpyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (compound 9) Add 6-ethoxy-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (315 mg, 1.4 mmol), diisopropylethylamine (362 mg, 2.8 mmol), and DMF (5 mL) to the reaction flask. Cool to 5 °C and add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (660 mg, 1.7 mmol). Incubate the reaction mixture at room temperature for 2 hours. Pour the reaction mixture into 200 mL of water, extract with 100 mL × 3 dichloromethane, dry to anhydrous sodium sulfate, concentrate the organic phase to obtain 430 mg of product, which can be used directly in the next reaction step. 1H-NMR (400 MHz, DMSO-d 6): δ 9.89 (s, 1H), 8.85 (s, 1H), 7.89 (s, 1H), 4.17-4.22 (m, 2H), 1.32-1.38 (t, 3H). m / z = 357 [M+1] +.

[0230] (7) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (Compound 10) NMP (0.5 mL), 6-ethoxy-2-fluoro-3-methylpyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (5 mg, 0.015 mmol), ruthenium(II) tris(acetonitrile)pentamethylcyclopentadiene trifluoromethanesulfonate (1.0 mg, 0.002 mmol), and LiBr (4 mg, 0.045 mmol) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 2 hours. The reaction solution was poured into 100 mL of water, extracted with 100 mL × 3 dichloromethane solutions, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 2 mg of the product. 1H-NMR (400 MHz, DMSO-d 6): δ 10.49 (s, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 4.10-4.16 (m, 2H), 1.30-1.34 (t, 3H). m / z = 287 [M+1] +.

[0231] The foregoing has described exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, variations, etc., made by those skilled in the art within the spirit and principles of the present invention should be covered within the scope of protection of the claims of this application.

Claims

1. A method for preparing a compound of formula I, the method comprising steps M1A, M19A, M20, M11, M10A, and M13, wherein step M1A comprises reacting a compound of formula XX with Rk-C(O)-H to obtain a compound of formula I: Wherein: X1 and X3 may be the same or different, and are independently selected from CR1; X2 is N; X4 is selected from CR1 or N; each R1 may be the same or different, and are independently selected from H, halogen, CN, C1-6 alkyl, C1-6 alkyloxy; D is selected from H, halogen, CN, C1-6 alkyl, C1-6 alkyloxy; E is selected from C1-6 alkyloxy, halo-C1-6 alkyloxy; G is selected from the following groups that are unsubstituted or optionally substituted with one, two or more Re: 5-9 member heterocyclic groups comprising 1, 2 or 3 N atoms; Rk is selected from the following groups that are unsubstituted or optionally substituted with one, two or more Rg: C6-10 aryl, 5-10 member heteroaryl; each Re may be the same or different, and are independently selected from C1-6 alkyl, C1-6 alkyloxy; each Rg may be the same or different, and are independently selected from CN, C1-6 alkyl, C1-6 alkyloxy; Step M20 The compound of formula XIX is reacted under conditions of PG19 removal to obtain the compound of formula XX: PG19 is selected from one of tert-butoxycarbonyl, cyclobutoxycarbonyl, benzyloxycarbonyl, p-methoxybenzylcarbonyl, 2-biphenyl-2-propoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phthalimino, p-toluenesulfonyl, trifluoroacetyl, (9H-fluorene-9-ylmethoxy)carbonyl, benzyl, 4-methoxybenzyl, diphenylmethyl, 2-(trimethylsilyl)ethoxycarbonyl, adamantyloxycarbonyl, methyl, and acetyl; In step M20, the PG19 removal condition is the removal of the PG19 group in the presence of an acid, wherein the acid is selected from one, two, or more of hydrochloric acid, sulfuric acid, formic acid, and acetic acid; The molar ratio of the compound of formula XIX to the acid is 1:1 to 1:5; Step M19A Reaction of compound XI with compound XVIII yields compound XIX: L11 is selected from halogens;Step M19A is carried out in the presence of a catalyst selected from Pd(dba)2, PdCl2, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(t-Bu)3, PdCl2(PPh3)2•CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHOS)2, PdCl2(Bipy), [Pd Cl(Ph2PCH2PPh2)]2, PdCl2[P(o-Tol)3]2, Pd2(dba)3 / P(o-Tol)3, Pd2(dba) / P(furyl)3, PdCl2[P(furyl)3]2, PdCl2(P MePh2)2, PdCl2[P(4-F-Ph)3]2, PdCl2[P(C6F6)3]2, PdCl2[P(2-COOH-Ph)(Ph)2]2, PdCl2[P(4-COOH-Ph)(Ph)2]2; The molar ratio of compound XI to catalyst is 1:0.001 to 1:0.05; Step M19A is carried out in the presence of a base, with the molar ratio of compound XI to base being 1:1 to 1:5, and the molar ratio of compound XI to compound XVIII being 1:1 to 1:2; Step M11 reacts compound X with hydrazine hydrate to give compound XI: L10 is selected from F, Cl, Br, or I; In step M11, the molar ratio of compound X to hydrazine hydrate is 1:1 to 1:15; Step M10A reacts compound XIII with compounds R21-L13 to give compound X: L13 is selected from the following groups that are unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 halogens: C1-6 alkylsulfonyloxy, C1-6 alkylbenzenesulfonyloxy, or F, Cl, Br, or I; R21 is selected from C1-6 alkyl; In step M10A, the molar ratio of compound XIII to compound R21-L13 is 1:1 to 1:2; In step M13, compound IIIB reacts first with phosphorus oxychloride to obtain compound XII, and then compound XII further reacts to obtain compound XIII, wherein compounds IIIB and XII have the following structures: PG3 is selected from unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents selected from C1-6 alkyl, C1-6 alkyloxy, and halogen groups: benzyl, C1-6 alkyl, tris(C1-6 alkyl)silyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, triphenylmethyl, C1-6 alkyloxymethyl, benzyloxymethyl, C1-6 alkylcarbonyl, halo-C1-6 alkylcarbonyl, benzoyl.

2. The preparation method as described in claim 1, wherein: L13 is selected from methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, F, Cl, Br or I; PG3 is selected from benzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl or 2,3,4-trimethoxybenzyl.

3. The preparation method as described in claim 1 or 2, wherein, D is selected from the following groups: H, halogen, -CN, etc.; E is selected from the following groups: etc.

4. The preparation method as described in claim 1, wherein, Rk is selected from pyridyl or phenyl groups that are unsubstituted or optionally substituted with one, two or more Rg groups.

5. The preparation method as described in claim 1, wherein, G is selected from 5-membered heterocyclic groups with monocyclic or bridged ring structures, 6-7-membered heterocyclic groups with monocyclic, bicyclic, or bridged ring structures, and 8-9-membered heterocyclic groups with monocyclic, bicyclic, or bridged ring structures, wherein the heterocyclic group contains 1, 2, or 3 N atoms.

6. The preparation method as described in claim 1, wherein, G is selected from , , , , , or.

7. The preparation method as described in claim 1, wherein, Rk is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, or phenyl, either unsubstituted or optionally substituted with one, two, or more Rg.

8. The preparation method as claimed in claim 1, characterized in that Rk in the compound of formula I forms a group selected from the following groups with the methylene group: , , , , , , , , , or.

9. The preparation method as claimed in claim 1, characterized in that Rk in the compound of formula I is selected from groups substituted by 1, 2, 3 or 4 groups selected from C1-6 alkyl and C1-6 alkyloxy groups.

10. The preparation method M1A as described in claim 1, wherein the compound of formula I is selected from the following compounds: .

11. The preparation method as described in claim 1, wherein: The reaction of compound XX with Rk-C(O)-H can be carried out in the presence of 2-methylpyridineborane and a base; the molar ratio of compound XX to Rk-C(O)-H is 1:1.1 to 1:1.3; the molar ratio of compound XX to borane or 2-methylpyridineborane is 1:1.1 to 1:1.3; the molar ratio of compound XX to a base is 1:1.8 to 1:2.2; the reaction temperature for the preparation of compound I is 20~30 °C.

12. A method for preparing compound I, wherein, The preparation method includes the following reaction steps: .

13. The preparation method as described in claim 1, wherein, The molar ratio of compound IIIB to phosphorus oxychloride is 1:2 to 1:

4.

14. The preparation method as described in claim 13, wherein, The molar ratio of compound IIIB to phosphorus oxychloride is 1:2.4 to 1:2.5.