Method for producing nitrogen-containing polycyclic fused ring compounds, intermediates therefor, and use thereof

Abstract

The present invention provides a method for preparing a nitrogen-containing polycyclic fused ring compound and its intermediates. The method can synthesize the compound of formula I and its intermediates in a high yield, low cost and environmentally friendly manner, thereby producing the compound of formula I on an industrial scale. The method does not require separation and purification steps by column chromatography such as silica gel column chromatography, and does not require hydrogen gas as a hydrogenation or reduction reagent, significantly improving production efficiency and safety. The method also realizes efficient utilization of positional isomers IIIA and IIIB, and avoids the negative impact of disposal of positional isomer IIIA on the yield of the target product. When using the method of positional isomer IIIA, the total yield can reach 9.4%, which is significantly higher than the yield of less than 4% when positional isomer IIIB is used, and when the two positional isomers are simultaneously applied to the preparation of compound I, the yield is improved by more than 3 times compared to the case of using positional isomer IIIB alone.

Description

Detailed Description of the Invention

[0001] This application claims priority from a prior patent application bearing patent application number 202110780873.9 and entitled "Method for producing nitrogen-containing polycyclic fused ring compounds, intermediates thereof, and uses thereof," filed with the State Intellectual Property Administration of China on July 9, 2021, the entire text of which is incorporated herein by reference.

[0002] [Technical field] The present invention relates to the field of pharmaceutical compound manufacturing processes, particularly to a method for manufacturing nitrogen-containing polycyclic fused ring compounds and their intermediates and uses.

[0003] [Background technology] The RET (Rearranged During Transfection) proto-oncogene was first identified in 1985 by 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, spans 60 kb of DNA, contains 21 exons, and encodes the RET protein, which consists of 1,100 amino acids. The RET protein is a tyrosine kinase receptor and contains an extracellular domain consisting of cysteines, a transmembrane domain, and an intracellular domain that functions as a tyrosine kinase catalyst (Mol-Cell-Endocrinol, 2010, 322(1-2): 2-7). RET is involved in cell proliferation, neurotransmission, cell migration, and cell differentiation, and through the signaling of the ligand / receptor complex / RET multiprotein complex, it activates various downstream signaling pathways, such as RAS / RAF / MEK / ERK, PI3K / AKT, and STAT, thereby inducing cell proliferation (J-Clin-Oncol, 2012, 30(2): 200-202).

[0004] RET kinase signaling plays an important role in various human cancers, including thyroid cancer. Among these, the RET gatekeeper residue RET 804V mutation is a factor that causes tumor resistance to currently approved nonselective RET inhibitors (e.g., cabozantinib and vandetanib). One of the key mutations in the RET extracellular or intracellular domains of isolated familial medullary thyroid cancer, namely the gatekeeper residue V804M mutation in the kinase ATP-binding site, reduces the affinity of conventional drugs for the ATP-binding site. Although the selective RET inhibitor LOXO-292 (selpercatinib) can avoid the RET 804V mutation described above, other mutations can occur and lead to drug resistance even after use of the selective RET inhibitor. For example, in non-small cell lung cancer, it has been reported that the solvent-front residue G810 in the kinase ATP binding site, such as G810R, G810S, and G801C mutations, causes a decrease in the ATP binding site of LOXO-292, resulting in drug resistance and cancer progression (RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies, Journal of Thoracic Oncology, 2020, Vol. 15, No. 4, pp. 541-549).

[0005] Patent document WO2021023209A1 discloses compounds with excellent activity or selectivity as RET inhibitors, exhibiting potent inhibitory effects against the RET gatekeeper residue mutant RET V804M, the RET solvent-edge residue mutant G810R, other clinically relevant RET mutants, and wild-type RET. Compounds of this type significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba / F3 cells transformed with various RET mutants, and exhibit good inhibitory effects. Furthermore, compounds of this type significantly block cellular RET autophosphorylation and its downstream pathways, significantly induce TT cell death, and have excellent pharmacokinetic properties. Therefore, there is a need to develop compounds of this type, more efficient methods suitable for scalable production, and / or more cost-effective methods for producing them, as well as intermediate compounds and methods for producing the same that achieve the above objectives.

[0006] [Summary of the Invention] In order to improve the above problem, the present invention provides a compound of formula XX, k and -C(O)-H to obtain a compound of formula I,

[0007] [ka]

[0008] Among them, X 1 , X 2 , X 3 , X 4 are homologous or different and independently 1 or N, Each R 1 are identical or different and independently represent H, halogen, CN, OH, unsubstituted or optionally one, two or more R a C replaced with 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 1-40 Alkyloxy group, C 3-40 Cycloalkyloxy group, NR 2R 3 , -C(O)R 4 , -OCR 5 , -S(O)2R 6 , OS(O)2R 7 Selected from D and E are the same or different and independently represent H, halogen, CN, OH, -OR 21 , unsubstituted or optionally one, two or more R c C replaced with 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, NR 2 R 3 and at least one of D and E is -OR 21 Selected from R 21 is unsubstituted or optionally substituted with one, two or more R d C replaced with 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group; G is unsubstituted or optionally contains one, two or more R e C replaced with 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 6-20 an aryloxy group, a 5- to 20-membered heteroaryloxy group, or a 3- to 20-membered heterocyclyloxy group; R k is unsubstituted or optionally substituted with one, two or more R g C replaced with 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 6-20selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group; Each R 2 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, -C(O)R 4 , -S(O)2R 6 Selected from Each R 3 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, -C(O)R 4 , -S(O)2R 6 Selected from Or, R 2 and R 3 form a 5- to 20-membered heteroaryl group or a 3- to 20-membered heterocyclyl group together with the N atom to which they are linked, Each R 4 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 3-40 Cycloalkyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NR 2 R 3 Selected from Each R 5 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkylcarbonyl group, C 3-40 Cycloalkylcarbonyl group, C 6-20an arylcarbonyl group, a 5- to 20-membered heteroarylcarbonyl group, or a 3- to 20-membered heterocyclylcarbonyl group; Each R 6 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 3-40 Cycloalkyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NR 2 R 3 Selected from Each R 7 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 6-20 selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group; Each R a , R c , R d , R e are the same or different and independently represent halogen, CN, OH, SH, oxo (=O), NO, unsubstituted or optionally one, two or more R g C replaced with 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 3-40 Cycloalkyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, and a 3- to 20-membered heterocyclyloxy group; Each R gare the same or different and independently represent halogen, CN, OH, SH, oxo (=O), NO, unsubstituted or optionally one, two or more R h C replaced with 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, and a 3- to 20-membered heterocyclyloxy group; Each R h are the same or different and independently represent halogen, CN, OH, SH, oxo (=O), NO, unsubstituted or optionally one, two or more R g C replaced with 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, and a 3- to 20-membered heterocyclyloxy group; Or, C above 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 When different positions of a cycloalkynyl group or a 3- to 20-membered heterocyclyl group are substituted with two or more substituents, any two of the substituents may form a bridged ring together with the atom connecting thereto, and among them, the bridge atoms other than the bridgehead atoms in the bridged ring may contain 1, 2, 3, 4 or 5 divalent groups selected from CH, O and NH; Alternatively, when an atom (e.g., a carbon atom) is substituted with two or more substituents, two of the substituents, together with the atom commonly connected thereto, form a C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 It is also possible to form a cyclic group such as a cycloalkynyl group or a 3- to 20-membered heterocyclyl group.

[0009] According to an embodiment of the present invention, X 1 , X 2 , X 3 , X 4 are homologous or different and independently 1 or N, for example, X 1 , X 2 , X 3 , X 4 At least one of them is N, e.g., X 1 , X 2 , X 3 , X 4 one, two or three of which are N; According to an embodiment of the present invention, each R 1 are identical or different and independently represent H, halogen, CN, OH, unsubstituted or optionally one, two or more R a C replaced with 1-6 Alkyl group, C 3-10 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-10 cycloalkyloxy groups, e.g., unsubstituted or optionally containing one, two or three R a C replaced with 1-6 Alkyl group, C3-6 Cycloalkyl groups, C 1-6 Alkoxy group or C 3-6 cycloalkyloxy groups, According to an embodiment of the present invention, D and E are the same or different and independently represent H, halogen, CN, NH, C 1-6 Alkyl group or -OR 21 and at least one of D and E is -OR 21 Selected from According to an embodiment of the present invention, at least one of D and E is

[0010] [ka]

[0011] It is selected from the group:

[0012] According to an embodiment of the present invention, R 2 is unsubstituted or optionally substituted with one, two or more R d C replaced with 1-6 selected from alkyl groups, According to an embodiment of the present invention, each R a , R c , R d are the same or different and independently represent halogen, CN, OH, unsubstituted or optionally one, two or more R g C replaced with 1-6 Alkyl group, C 1-6 Alkyloxy group, C 3-10 Cycloalkyl groups, C 3-10 cycloalkyloxy groups, According to an embodiment of the present invention, each R g are the same or different and independently represent halogen or C 3-10 cycloalkyl groups, According to an embodiment of the present invention, G is C 3-10 Cycloalkyl groups, C 6-14selected from aryl groups, 5- to 14-membered heteroaryl groups, and 3- to 10-membered heterocyclyl groups, for example, 6- to 7-membered heterocyclyl groups having a monocyclic, bicyclic, or bridged ring structure, which may contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; According to an embodiment of the present invention, R k is unsubstituted or optionally substituted with one, two or more R g C replaced with 3-10 Cycloalkyl groups, C 6-14 It is selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 10-membered heterocyclyl group, wherein the heteroaryl group may be a pyridinyl group, for example, selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, and pyridin-6-yl, and the aryl group may be a phenyl group.

[0013] According to an exemplary embodiment of the present invention, 1 , X 2 , X 3 , X 4 are identical or different and are independently selected from CH or N, for example, X 1 , X 2 , X 3 , X 4 At least one of them is N, e.g., X 1 , X 2 , X 3 , X 4 one, two or three of which are N; According to an exemplary embodiment of the present invention, R 1 is H, According to an exemplary embodiment of the present invention, E is H; According to an exemplary embodiment of the present invention, D is selected from the group consisting of halogen, BnO—, H, —CN, —NH 2 , —OCH 3 , and

[0014] [ka]

[0015] Selected from According to an exemplary embodiment of the present invention, G is

[0016] [ka]

[0017] Selected from According to an exemplary embodiment of the present invention, R k is unsubstituted or optionally substituted with one, two or more R g pyridinyl or phenyl groups substituted with g If substitution is present, R k The above R g may be substituted at the 1, 2, 3, 4, 5, or 6 position of the pyridinyl or phenyl group.

[0018] For example, R in compounds of formula I k together with the methylene group,

[0019] [ka]

[0020] may form a group selected from:

[0021] Alternatively, R in the compound of formula I k is C 1-6 Alkyl groups and C 1-6 A group substituted with 1, 2, 3 or 4 groups selected from alkyloxy groups

[0022] [ka]

[0023] may be selected from

[0024] According to an exemplary embodiment of the present invention, the compound of formula I may be selected from the following compounds:

[0025] [ka] JPEG0007798397000008.jpg234169JPEG0007798397000009.jpg97169

[0026] By way of example, the compound of formula I is selected from the following compounds:

[0027] [ka] JPEG0007798397000011.jpg1169JPEG0007798397000012.jpg97169

[0028] According to an embodiment of the present invention, a compound of formula XX and R k The reaction with -C(O)-H may be carried out in the presence of borane, pyridine borane, 2-methylpyridine borane (Pic-BH), sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, preferably in the presence of 2-methylpyridine borane.

[0029] According to an embodiment of the present invention, a compound of formula XX and R kThe reaction with -C(O)-H may be carried out in the presence of an organic solvent. The organic solvent may be an ether (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), a sulfoxide (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide), a sulfone (e.g., dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, octane, benzene, toluene or xylene), halogenated alkanes (e.g. dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane), halogenated aromatic compounds (e.g. chloro benzene or dichlorobenzene), amides (e.g. hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine or N,N'-1,The organic solvent may be one, two or more selected from the group consisting of 4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile), 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 n-propanol.

[0030] According to an embodiment of the present invention, a method for preparing a compound of formula I comprises reacting a compound of formula XX with R k The molar ratio to —C(O)—H may be 1:1 to 1:5, and is preferably 1:1.1 to 1:1.3.

[0031] According to an embodiment of the present invention, in the method for preparing the compound of formula I, the molar ratio of the compound of formula XX to borane or 2-methylpyridine borane may be 1:1 to 1:5, preferably 1:1.1 to 1:1.3.

[0032] According to an embodiment of the present invention, in the method for preparing the compound of formula I, the molar ratio of the compound of formula XX to the base may be 1:1 to 1:5, preferably 1:1.5 to 1:3.5, for example 1:1.8 to 1:2.2.

[0033] According to an embodiment of the present invention, the reaction temperature of the process for preparing the compound of formula I may be 15-50°C, for example 20-30°C, for example room temperature.

[0034] According to an embodiment of the present invention, the compound of formula XX may be reacted starting from a salt form (e.g., an acid addition salt). Preferably, when the compound of formula XX is reacted in a salt form, it can be liberated to the compound of formula XX by the addition of a base. The liberation may be carried out alone or in a "one-pot synthesis" together with the reaction in the above-mentioned Preparation Method M1A.

[0035] According to an embodiment of the present invention, the base may be an organic base or an inorganic base, for example: 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-dimethylpyridine, an organic base selected from 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0036] According to an exemplary embodiment of the present invention, the above-mentioned preparation method M1A comprises reacting compound 20 to prepare compound 1 as follows:

[0037] [ka]

[0038] The present invention further provides compounds of formula XX above, such as compound 20.

[0039] The present invention further provides the use of a compound of formula XX above (eg, compound 20) in the preparation of a compound of formula I (eg, compound 1).

[0040] The present invention further provides a compound of formula XIX:

[0041] [ka]

[0042] Among them, G is unsubstituted or optionally contains one, two or more R e wherein G has at least one N atom, and the N atom is selected from a 5- to 20-membered heteroaryl group, a 3- to 20-membered heterocyclyl group, a 5- to 20-membered heteroaryloxy group, and a 3- to 20-membered heterocyclyloxy group substituted with 19 Connected to X 1 , X 2 , X 3 , X 4 , D, E, R e are independently as defined above; PG 19 is an amino protecting group.

[0043] According to an embodiment of the present invention, a PG 19may be one selected from amino-protecting groups known to those skilled in the art, such as a tert-butoxycarbonyl group (Boc), a cyclobutoxycarbonyl group, a benzyloxycarbonyl group (CBz), a p-methoxybenzylcarbonyl group (Moz), a 2-biphenyl-2-propoxycarbonyl group (BPoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), a phthalimide group, a p-toluenesulfonyl group, a trifluoroacetyl group, a (9H-fluoren-9-ylmethoxy)carbonyl group (Fmoc), a benzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc), an adamantyloxycarbonyl group (Adoc), a formyl group, and an acetyl group.

[0044] The present invention relates to a compound of formula XIX, 19 Further provided is a method M20 for preparing a compound of formula XX, comprising reacting under conditions in which is removed to obtain a compound of formula XX.

[0045] PG of the compound of formula XIX 19 The conditions for removing an amino protecting group are known to those skilled in the art. For example, the PG of the compound of formula XIX can be removed by the presence of an acid. 19 The acid may be one, two or more selected from inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, etc.

[0046] According to an embodiment of the present invention, in the method for preparing the compound of formula XX, the molar ratio of the compound of formula XIX to the acid may be 1:1 to 1:5, for example, 1:3 to 1:4.

[0047] According to an embodiment of the present invention, a compound of formula XIX is prepared from PG 19 The reaction for removing may be carried out in the presence of an organic solvent, which is as defined above and is, for example, an alcohol solvent, such as one, two or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and tert-butanol.

[0048] According to an embodiment of the present invention, the reaction temperature in the process for preparing the compound of formula I may be 40-70°C, for example, 50-60°C.

[0049] According to an embodiment of the present invention, the above-mentioned preparation method M20 comprises reacting compound 19 as follows to prepare compound 20.

[0050] [ka]

[0051] Accordingly, the present invention further provides compound 19.

[0052] The present invention further provides the use of a compound of formula XIX above (eg, compound 19) in the preparation of a compound of formula XX (eg, compound 20).

[0053] The present invention further provides a compound of formula XI:

[0054] [ka]

[0055] Among them, D, E are independently as defined above; L 11 is selected from leaving groups, e.g., unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens, C 1-6 Alkylsulfonyloxy group, C 1-6 Alkylbenzenesulfonyloxy groups, for example, methanesulfonyloxy groups (MsO-), trifluoromethanesulfonyloxy groups (TfO-), p-toluenesulfonyloxy groups (TsO-), halogens (for example, F, Cl, Br or I).

[0056] The present invention further provides a compound of formula XVIII:

[0057] [ka]

[0058] Among them, X 1 , X 2 , X 3 , X 4 , G, P.G. 19 are independently as defined above.

[0059] The present invention further 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,

[0060] [ka]

[0061] Among them, X 1 , X 2 , X 3 , X 4 , D, E, G, L 11 , P.G. 19 are independently as defined above.

[0062] According to an embodiment of the present invention, in the method for preparing the compound of formula XIX, the reaction may be carried out in the presence of a base.

[0063] The base may be an organic or inorganic base, for example: 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-dimethylpyridine, an organic base selected from 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0064] According to an embodiment of the present invention, the method for preparing the compound of formula XIX may 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 the group consisting of ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, and diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone), and the like. , dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,The organic solvent may be one or a mixture of two or more selected from the group consisting of 3-dimethyl-2-imidazolinedione, N-formylpiperidine, and N,N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, and benzonitrile), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol), and ketones (e.g., acetone and N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0065] According to an embodiment of the present invention, the method for preparing the compound of formula XIX may be carried out in the presence of a catalyst, and the catalyst may 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)2CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHO) S)2, PdCl2(Bipy), [PdCl(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(PMePh2)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.

[0066] According to an embodiment of the present invention, the reaction temperature of the above process for preparing the compound of formula XIX may be 50°C or higher, such as 80°C or higher, for example 85°C.

[0067] According to an embodiment of the present invention, in the above method for preparing the compound of formula XIX, the molar ratio of the compound of formula XI to the compound of formula XVIII may be 1:1 to 1:2, for example, 1:1.1 to 1:1.3, for example, 1:1.2 to 1:1.3.

[0068] According to an embodiment of the present invention, in the above method for preparing the compound of formula XIX, the molar ratio of the compound of formula XI to the base may be 1:1 to 1:5, for example, 1:1.5 to 1:3.5, for example, 1:1.8 to 1:2.2.

[0069] According to an embodiment of the present invention, in the above method for preparing the compound of formula XIX, the molar ratio of the compound of formula XI to the catalyst may be 1:0.001 to 1:0.05, for example, 1:0.02 to 1:0.03.

[0070] According to an embodiment of the present invention, the above-mentioned preparation method M19A comprises reacting compound 11 with compound 18 to prepare compound 19 as follows:

[0071] [ka]

[0072] Therefore, the present invention further provides compound 11 or compound 18 above.

[0073] The present invention further provides the use of a compound of formula XI (eg, compound 11) and / or a compound of formula XVIII (eg, compound 18) above in the preparation of a compound of formula XIX (eg, compound 19).

[0074] The present invention further provides a method M11 for preparing a compound of formula XI, comprising reacting a compound of formula X with hydrazine (e.g., hydrazine hydrate) to obtain a compound of formula XI;

[0075] [ka]

[0076] Among them, D, E, L 11 are independently as defined above; L 10 is selected from leaving groups, for example halogens such as F, Cl, Br or I.

[0077] According to an embodiment of the present invention, the method for preparing the compound of formula XI may 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 the group consisting of ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, and diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone), and the like. , dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,The organic solvent may be one or a mixture of two or more selected from the group consisting of 3-dimethyl-2-imidazolinedione, N-formylpiperidine, and N,N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, and benzonitrile), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol), and ketones (e.g., acetone and N-methylpyrrolidone). Preferably, the organic solvent is dimethyl sulfoxide.

[0078] According to an embodiment of the present invention, in the method for preparing the compound of formula XI, the reaction temperature may be 100°C or higher, for example, 110-115°C.

[0079] According to an embodiment of the present invention, in the method for preparing the compound of formula XI, the molar ratio of the compound of formula X to hydrazine may be 1:1 to 1:15, such as 1:2 to 1:10, for example, 1:6 to 1:8.

[0080] According to an embodiment of the present invention, the above-mentioned preparation method M11 includes reacting compound 10 as follows to prepare compound 11.

[0081] [ka]

[0082] The present invention further provides compounds of formula X above, such as compound 10.

[0083] The present invention further provides the use of a compound of formula X above (eg, compound 10) in the preparation of a compound of formula XI (eg, compound 11).

[0084] The present invention relates to a compound of formula XIII and a compound R 21 -L 13 and (b) reacting the compound of formula X with the compound of formula X to form a compound of formula X;

[0085] [ka]

[0086] Among them, D, L 10 , L 11 , R 21 are independently as defined above; E is -OR 21 Selected from L 13 is selected from leaving groups, such as halogen, e.g., C which is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens 1-6 Alkylsulfonyloxy group, C 1-6 Alkylbenzenesulfonyloxy groups, for example, methanesulfonyloxy groups (MsO-), trifluoromethanesulfonyloxy groups (TfO-), p-toluenesulfonyloxy groups (TsO-), F, Cl, Br, or I.

[0087] According to an embodiment of the present invention, the process for preparing the compound of formula X may be carried out in the presence of a base.

[0088] According to an embodiment of the present invention, the base may be an organic base or an inorganic base, for example: 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-dimethylpyridine, an organic base selected from 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0089] According to an embodiment of the present invention, the method for preparing a compound of formula X may be carried out in the presence of an organic solvent. The organic solvent may be selected from the group consisting of ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, and diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, and the like), and the like. hexane, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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. hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine or N,The organic solvent may be one or a mixture of two or more selected from the group consisting of N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile), 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-dimethylformamide.

[0090] According to an embodiment of the present invention, a method for preparing a compound of formula X comprises reacting a compound of formula XIII with a compound R 21 -L 13 The molar ratio may be 1:1 to 1:2, for example, 1:1 to 1:1.2, for example, 1:1 to 1:1.1.

[0091] According to an embodiment of the present invention, in the method for preparing the compound of formula X, the molar ratio of the compound of formula XIII to the base may be 1:1 to 1:2, for example, 1:1.1 to 1:1.3, for example, 1:1.1 to 1:1.2.

[0092] According to an embodiment of the present invention, the reaction temperature in the process for preparing the compound of formula X may be 50°C or higher, for example 60-70°C, for example 65°C.

[0093] According to an embodiment of the present invention, the above-mentioned preparation method M10A includes reacting compound 13 to prepare compound 10 as follows:

[0094] [ka]

[0095] The present invention further provides compounds of formula XIII above, such as compound 13.

[0096] The present invention further provides the use of a compound of formula XIII above (eg, compound 13) in the preparation of a compound of formula X (eg, compound 10).

[0097] The present invention further provides a method M13 for preparing a compound of formula XIII, comprising reacting a compound of formula IIIB having the following structure in the presence of phosphorus oxychloride (POCl3):

[0098] [ka]

[0099] Among them, L 10 , L 11 are independently as defined above; PG 3 is selected from hydroxy protecting groups.

[0100] According to an embodiment of the present invention, a PG 3 may be selected from hydroxy protecting groups known to those skilled in the art, such as unsubstituted or optionally C 1-6 Alkyl group, C 1-6 a benzyl group substituted with 1, 2, 3, 4 or 5 substituents selected from an alkyloxy group and a halogen; 1-6 Alkyl group, tris(C 1-6 alkyl)silyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, allyl group, triphenylmethyl group, C 1-6 Alkyloxymethyl group, benzyloxymethyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 alkylcarbonyl group, and benzoyl group, examples of which may be selected from benzyl group, 4-methoxybenzyl group, 4-methylbenzyl group, 4-chlorobenzyl group, 4-bromobenzyl group, and 2,3,4-trimethoxybenzyl group.

[0101] According to an embodiment of the present invention, the above process M13 comprises reacting compound 3b having the following structure in the presence of phosphorus oxychloride (POCl 3 ).

[0102] [ka]

[0103] According to an embodiment of the present invention, in a method for preparing a compound of formula XIII, a compound of formula IIIB (e.g., compound 3b) may first be reacted with phosphorus oxychloride to obtain a compound of formula XII having the following structure, and then the compound of formula XII may be further reacted to obtain a compound of formula XIII:

[0104] [ka]

[0105] Among them, L 10 , L 11 , P.G. 3 are independently as defined above.

[0106] According to an embodiment of the present invention, in the method for preparing the compound of formula XIII, the molar ratio of the compound of formula IIIB to phosphorus oxychloride may be 1:2 to 1:4, for example, 1:2 to 1:3, such as 1:2.4 to 1:2.5.

[0107] According to an embodiment of the present invention, the process for preparing the compound of formula XIII may be carried out in a one-pot synthesis.

[0108] According to an embodiment of the present invention, the reaction solvent for reacting the compound of formula IIIB with phosphorus oxychloride to obtain the compound of formula XII may be the above organic solvents such as N,N-dimethylformamide.

[0109] According to an embodiment of the present invention, the reaction temperature for reacting the compound of formula IIIB with phosphorus oxychloride to obtain the compound of formula XII may be -5°C to 80°C, for example, 0 to 70°C.

[0110] According to an embodiment of the present invention, the reaction solvent for further reacting the compound of formula XII to obtain the compound of formula XIII may be a mixed solvent of the above organic solvent and water, for example, a mixed solvent of N,N-dimethylformamide and water.

[0111] 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 may be 15-40°C, for example, 20-35°C, for example, 25-30°C.

[0112] According to an embodiment of the present invention, the above-mentioned preparation method M13 comprises the following reactions of preparing compound 12 from compound 3b, and further preparing compound 13 from compound 12.

[0113] [ka]

[0114] The present invention further provides compounds of formula IIIB above, such as compound 3b.

[0115] The present invention further provides compounds of formula XII above, such as compound 12.

[0116] The present invention further provides the use of a compound of formula IIIB (eg, compound 3b) and / or a compound of formula XII (eg, compound 12) above in the preparation of a compound of formula XIII (eg, compound 13).

[0117] The present invention further provides the use of a compound of formula IIIB above (eg, compound 3b) in the preparation of a compound of formula XII (eg, compound 12).

[0118] The present invention further provides a method M10B for preparing a compound of formula X, comprising reacting a compound of formula XVII with phosphorus oxychloride to obtain a compound of formula X:

[0119] [ka]

[0120] Among them, D, E, L 10 , L 11 are independently as defined above.

[0121] According to an embodiment of the present invention, the method for preparing a compound of formula X may be carried out in the presence of an organic solvent. The organic solvent may be selected from the group consisting of ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, and diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, and the like), and the like. hexane, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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. hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine or N,The organic solvent may be one or a mixture of two or more selected from the group consisting of N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile), 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-dimethylformamide.

[0122] According to an embodiment of the present invention, in the method for preparing a compound of formula X, the molar ratio of the compound of formula XVII to phosphorus oxychloride may be 1:2 to 1:8, for example, 1:3 to 1:6, for example, 1:4 to 1:5:2 to 1:4, for example, 1:2 to 1:3, for example, 1:2.4 to 1:2.5.

[0123] According to an embodiment of the present invention, the above-mentioned preparation method M10B comprises reacting compound 17 to prepare compound 10 as follows:

[0124] [ka]

[0125] The present invention further provides compounds of formula XVII above, such as compound 17.

[0126] The present invention further provides the use of a compound of formula XVII above (eg, compound 17) in the preparation of a compound of formula X (eg, compound 10).

[0127] The present invention further provides a method M17 for preparing a compound of formula XVII, comprising reacting a compound of formula XVI with an alkali metal halide or organic halide salt to obtain a compound of formula XVII,

[0128] [ka]

[0129] Among them, D, E, L 10 are independently as defined above; L 16 is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens 1-6 Alkylsulfonyl group, C 1-6 Alkylbenzenesulfonyl groups include, for example, methanesulfonyl groups (Ms-), trifluoromethanesulfonyl groups (Tf-), and p-toluenesulfonyl groups (Ts-).

[0130] According to an embodiment of the present invention, in the method for preparing the compound of formula XVII, the alkali metal halide or organic halide salt may be at least one selected from LiBr, NaBr, KBr, CsBr, and Bu4NBr.

[0131] According to an embodiment of the present invention, the method for preparing a compound of Formula XVII may be carried out in the presence of an organic solvent, such as ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone), , diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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. hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine or N,The organic solvent may be one or a mixture of two or more selected from the group consisting of N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile), 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 n-propanol.

[0132] According to an embodiment of the present invention, in the method for preparing the compound of formula XVII, the molar ratio of the compound of formula XVI to the alkali metal halide or organic halide salt may be 1:1 to 1:5, for example, 1:1 to 1:2, for example, 1:1.5.

[0133] According to an embodiment of the present invention, the method for producing the compound of formula XVII may be carried out in the presence of a catalyst, such as pentamethylcyclopentadienyltriphenylphosphineruthenium chloride(II), tris(acetonitrile)pentamethylcyclopentadieneruthenium trifluoromethanesulfonate(II), pentamethylcyclopentadienyltris(acetonitrile)ruthenium hexafluorophosphate(II), (pentamethylcyclopentadienyl)ruthenium chloride(II) (dimer), (pentamethylcyclopentadienyl)ruthenium chloride(I) (tetramer), tris(acetonitrile)tetramethylcyclopentadieneruthenium trifluoromethanesulfonate(II), or cyclooctadieneruthenium dichloride(II).

[0134] According to an embodiment of the present invention, in the method for preparing the compound of formula XVII, the molar ratio of the compound of formula XVI to the catalyst may be 1:0.01 to 1:0.1, for example, 1:0.05.

[0135] According to an embodiment of the present invention, the reaction temperature in the process for preparing the compound of formula XVII may be 50°C or higher, for example 80°C or higher, for example 90-100°C.

[0136] According to an embodiment of the present invention, the above-mentioned preparation method M17 comprises reacting compound 16 as follows to prepare compound 17:

[0137] [ka]

[0138] The present invention further provides compounds of formula XVI above, such as compound 16.

[0139] The present invention further provides the use of a compound of formula XVI above (eg, compound 16) in the preparation of a compound of formula XVII (eg, compound 17).

[0140] The present invention further provides a method M16 for preparing a compound of formula XVI, comprising reacting a compound of formula XV with a sulfonating reagent to obtain a compound of formula XVI,

[0141] [ka]

[0142] Among them, D, E, L 10 are independently as defined above.

[0143] According to an embodiment of the present invention, the method for preparing the compound of formula XVI may be carried out in the presence of an organic solvent, such as ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone), , dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,The organic solvent may be one or a mixture of two or more selected from the group consisting of 3-dimethyl-2-imidazolinedione, N-formylpiperidine, and N,N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, and benzonitrile), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol), and ketones (e.g., acetone and N-methylpyrrolidone). Preferably, the organic solvent is selected from dichloromethane.

[0144] According to an embodiment of the present invention, in the process for preparing a compound of formula XVI, the sulfonating reagent is a C 1-6 Alkyl sulfonyl chlorides, unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens, C 1-6 Alkyl sulfonic anhydrides, unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens C 1-6 The alkylbenzenesulfonyl chloride may be one selected from 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).

[0145] According to an embodiment of the present invention, in the method for preparing the compound of formula XVI, the molar ratio of the compound of formula XV to the sulfonating reagent may be 1:1 to 1:5, for example, 1:1 to 1:1.2, for example, 1:1.1 to 1:1.15.

[0146] According to an embodiment of the present invention, the above-mentioned preparation method M16 comprises reacting compound 15 as follows to prepare compound 16.

[0147] [ka]

[0148] The present invention further provides compounds of formula XV above, such as compound 15.

[0149] The present invention further provides the use of a compound of formula XV above (eg, compound 15) in the preparation of a compound of formula XVI (eg, compound 16).

[0150] The present invention further provides a method M15 for preparing a compound of formula XV, comprising reacting a compound of formula XIV with an acid to obtain a compound of formula XV,

[0151] [ka]

[0152] Among them, D, E, L 10 , P.G. 3 are independently as defined above.

[0153] According to an embodiment of the present invention, in the method for preparing the compound of formula XV, the acid may be at least one selected from organic acids or inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylsilyl triflate, trifluoroacetic acid, phosphorus oxychloride, succinic acid, and ascorbic acid.

[0154] According to an embodiment of the present invention, the method for preparing a compound of formula XV may be carried out in the presence of an organic solvent, such as ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, hexane, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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. hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine or N,The organic solvent may be one or a mixture of two or more selected from the group consisting of N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile), 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.

[0155] According to an embodiment of the present invention, in the method for preparing the compound of formula XV, the molar ratio of the compound of formula XIV to trifluoroacetic acid may be 1:1 to 1:10, for example, 1:4 to 1:6, for example, 1:5 to 1:5.5.

[0156] According to an embodiment of the present invention, in the method for preparing the compound of formula XV, trifluoroacetic acid may be added dropwise to participate in the reaction.

[0157] According to an embodiment of the present invention, the above-mentioned preparation method M15 comprises reacting compound 14 as follows to prepare compound 15.

[0158] [ka]

[0159] The present invention further provides compounds of formula XIV above, such as compound 14.

[0160] The present invention further provides the use of a compound of formula XIV above (eg, compound 14) in the preparation of a compound of formula XV (eg, compound 15).

[0161] The present invention further provides a method M14 for preparing a compound of formula XIV, comprising reacting a compound of formula IIIA with ethanol to obtain a compound of formula XIV;

[0162] [ka]

[0163] Among them, D and L 10 , P.G. 3 are independently as defined above; L 3a is selected from leaving groups, for example halogens such as chlorine, bromine or iodine.

[0164] According to an embodiment of the present invention, the process for preparing the compound of formula XIV may be carried out in the presence of a copper catalyst and a ligand.

[0165] According to an embodiment of the present invention, the copper catalyst may be at least one selected from cuprous iodide (CuI), cuprous bromide (CuBr), and copper acetylacetonate (Cu(acac)2).

[0166] According to an embodiment of the present invention, the ligand may be at least one selected from N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, 8-hydroxyquinoline, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N-benzyl-N-(2-methylnaphthalen-1-yl)ethanediamide, and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide.

[0167] According to an embodiment of the present invention, the process for preparing the compound of formula XIV may further be carried out in the presence of a base, which may be an organic or inorganic base, for example: 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, 2,3,4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 2,3,4 ... an organic base selected from the group consisting of 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, 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.

[0168] According to an embodiment of the present invention, in the method for preparing the compound of formula XIV, the molar volume ratio of the compound of formula IIIA to ethanol may be 1 mol:(2-5) L, for example, 1 mol:(3-4) L.

[0169] According to an embodiment of the present invention, in the method for preparing the compound of formula XIV, the molar ratio of the compound of formula IIIA to the cuprous catalyst may be 1:0.01 to 1:0.2, for example, 1:0.02.

[0170] According to an embodiment of the present invention, in the method for preparing the compound of formula XIV, the molar ratio of the compound of formula IIIA to the base may be 1:1 to 1:10, such as 1:2 to 1:4, for example 1:3.

[0171] According to an embodiment of the present invention, in the method for preparing the compound of formula XIV, the molar ratio of the compound of formula IIIA to the ligand may be 1:0.01 to 1:0.2, for example, 1:0.02.

[0172] According to an embodiment of the present invention, in the method for preparing the compound of formula XIV, the reaction temperature may be 50°C or higher, for example 70°C or higher, for example 80-100°C.

[0173] According to an embodiment of the present invention, the above-mentioned preparation method M14 comprises reacting compound 3a as follows to prepare compound 14:

[0174] [ka]

[0175] The present invention further provides compounds of formula IIIA above, such as compound 3a.

[0176] The present invention further provides the use of a compound of formula IIIA above (eg, compound 3a) in the preparation of a compound of formula XIV (eg, compound 14).

[0177] The present invention further provides a method M10C for preparing a compound of formula X, comprising reacting a compound of formula IX with an alkali metal halide or organic halide salt to obtain a compound of formula X,

[0178] [ka]

[0179] Among them, D, E, L 10 , L 16 are independently as defined above.

[0180] According to an embodiment of the present invention, in the method for preparing the compound of formula X, the alkali metal halide or organic halide salt may be at least one selected from LiBr, NaBr, KBr, CsBr, Bu4NBr, etc.

[0181] According to an embodiment of the present invention, the process for preparing a compound of formula X may be carried out in the presence of a base. The base may be an organic or inorganic base, for example: 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-dimethylpyridine, an organic base selected from 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0182] According to an embodiment of the present invention, in the method for preparing the compound of formula X, the molar ratio of the compound of formula IX to the alkali metal halide or organic halide salt may be 1:1 to 1:5, for example, 1:1 to 1:2, for example, 1:1.5.

[0183] According to an embodiment of the present invention, the method for producing the compound of formula X may be carried out in the presence of a catalyst, such as pentamethylcyclopentadienyltriphenylphosphineruthenium chloride(II), tris(acetonitrile)pentamethylcyclopentadieneruthenium trifluoromethanesulfonate(II), pentamethylcyclopentadienyltris(acetonitrile)ruthenium hexafluorophosphate(II), (pentamethylcyclopentadienyl)ruthenium chloride(II) (dimer), (pentamethylcyclopentadienyl)ruthenium chloride(I) (tetramer), tris(acetonitrile)tetramethylcyclopentadieneruthenium trifluoromethanesulfonate(II), or cyclooctadieneruthenium dichloride(II).

[0184] According to an embodiment of the present invention, in the method for preparing the compound of formula X, the molar ratio of the compound of formula IX to the catalyst may be 1:0.01 to 1:0.1, for example, 0.05.

[0185] According to an embodiment of the present invention, the reaction temperature in the process for preparing the compound of formula X may be 50°C or higher, for example 80°C or higher, for example 90-100°C.

[0186] According to the production method of the present invention, the above production method M10C comprises reacting compound 9 as follows to produce compound 10.

[0187] [ka]

[0188] The present invention further provides compounds of formula IX above, such as compound 9.

[0189] The present invention further provides the use of a compound of formula IX above (eg, compound 9) in the preparation of a compound of formula X (eg, compound 10).

[0190] According to an embodiment of the present invention, the compound of formula IX may be prepared from the compound of formula IIIA. For example, the compound of formula IIIA may be reacted with phosphorus oxychloride to obtain the compound of formula IV:

[0191] [ka]

[0192] Among them, D and L 10 , P.G. 3 , L 3a are independently as defined above.

[0193] According to an embodiment of the present invention, the reaction of the compound of formula IIIA with phosphorus oxychloride may be carried out in the presence of an organic solvent, such as ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone), , dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,The organic solvent may be one or a mixture of two or more selected from the group consisting of 3-dimethyl-2-imidazolinedione, N-formylpiperidine, and N,N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, and benzonitrile), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol), and ketones (e.g., acetone and N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethylformamide.

[0194] 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 may be 1:2 to 1:8, such as 1:3 to 1:6, for example, 1:4 to 1:5.

[0195] According to an embodiment of the present invention, the group L of the compound of formula IV is reacted with a hydroxyl group according to known organic synthesis methods. 3a may be derivatized to the group E as defined above, for example by first 3a may be converted to an intermediate derivatized with a hydroxy group and further derivatized to group E.

[0196] Alternatively, see Preparation M14 above, and the group L of the compound of formula IV may be 3a may be derivatized to the group E.

[0197] Alternatively, according to an embodiment of the present invention, referring to the above Preparation Method M15, the compound of formula IV or the above derivative is reacted with trifluoroacetic acid to form a group PG 3 to a hydroxy group, and / or, referring to the above-mentioned Production Method M16, by reacting the above-mentioned derivative with the above-mentioned sulfonation reagent to obtain C in which the hydrogen atoms in the hydroxy group are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens. 1-6 Alkylsulfonyl groups may also be obtained, such as methanesulfonyl (Ms) or trifluoromethanesulfonyl substituted derivatives.

[0198] For example, a compound of formula IV may be reacted with trifluoroacetic acid to give a compound of formula XXIII:

[0199] [ka]

[0200] Among them, D and L 10 , L 3a are independently as defined above.

[0201] According to an embodiment of the present invention, referring to Preparation M11 described above, a compound of formula XXIII may be reacted with hydrazine (e.g., hydrazine hydrate) to obtain a compound of formula XXXI:

[0202] [ka]

[0203] Among them, D and L 3a are independently as defined above.

[0204] According to an embodiment of the present invention, the group L of the compound of formula XXXI is reacted with a compound of formula XXXI according to known organic synthesis methods. 3a may be derivatized to the group E as defined above, for example by first 3a may be converted to an intermediate derivatized with a hydroxy group and further derivatized to group E to give a compound of formula XXIX,

[0205] [ka]

[0206] Alternatively, see Preparation M14 above, and the group L of the compound of formula XXXI may be 3a may be derivatized to group E to give compounds of formula XXIX.

[0207] According to an embodiment of the present invention, referring to the above Preparation Method M16, the compound of the above Formula XXIX is reacted with the above sulfonating reagent to obtain a C 1 , in which the hydrogen atoms in the hydroxy groups are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens. 1-6 Alkylsulfonyl group, C 1-6 Alkylbenzenesulfonyl groups may be obtained, for example compounds of formula XXX substituted with methanesulfonyl groups (Ms-), trifluoromethanesulfonyl groups (Tf-), p-toluenesulfonyl groups (Ts-),

[0208] [ka]

[0209] wherein D and E are independently as defined above; L 30 is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens 1-6 Alkylsulfonyl group, C 1-6 Alkylbenzenesulfonyl groups include, for example, methanesulfonyl groups (Ms-), trifluoromethanesulfonyl groups (Tf-), and p-toluenesulfonyl groups (Ts-).

[0210] According to embodiments of the present invention, compound 3a may be reacted as follows to produce compound 4, compound 5, compound 6, compound 7, compound 8 and / or compound 9.

[0211] [ka]

[0212] According to embodiments of the present invention, compound 3a may also be reacted as follows to produce compound 4, compound 23, compound 31, compound 29, and / or compound 30.

[0213] [ka]

[0214] According to embodiments of the present invention, compound 4 may also be reacted as follows to produce compound 23, compound 31, compound 25, compound 26, compound 27, compound 28, compound 29, and / or compound 30.

[0215] [ka]

[0216] The present invention further provides the use of any one of the compounds of formula IV (e.g., compound 4), compounds of formula XXIII (e.g., compound 23), compounds of formula XXXI (e.g., compound 31), compounds of formula XXIX (e.g., compound 29) and compounds of formula XXX (e.g., compound 30), and the above compounds, in the preparation of compounds of formula I.

[0217] According to an embodiment of the present invention, there is further provided a method M19B for preparing a compound of formula XIX, 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 are as defined above.

[0218] According to an embodiment of the present invention, the above process for preparing the compound of formula XIX may be carried out in the presence of a base.

[0219] The base may be an organic or inorganic base, for example: 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-dimethylpyridine, an organic base selected from 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0220] According to an embodiment of the present invention, the method for preparing the compound of formula XIX may 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 the group consisting of ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), sulfoxides (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, and diisopentyl sulfoxide), sulfones (e.g., dimethyl sulfone, diethyl sulfone), and the like. , dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,The organic solvent may be one or a mixture of two or more selected from the group consisting of 3-dimethyl-2-imidazolinedione, N-formylpiperidine, and N,N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, and benzonitrile), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol), and ketones (e.g., acetone and N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0221] According to an embodiment of the present invention, the method for preparing the compound of formula XIX may be carried out in the presence of a catalyst, and the catalyst may 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)2CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHO) S)2, PdCl2(Bipy), [PdCl(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(PMePh2)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.

[0222] According to an embodiment of the present invention, the reaction temperature of the above method for preparing the compound of formula XIX may be 80°C or higher, such as 100°C or higher, for example 120°C.

[0223] According to an embodiment of the present invention, in the above method for preparing the compound of formula XIX, the molar ratio of the compound of formula XXX to the compound of formula XVIII may be 1:1 to 1:5, for example, 1:2 to 1:4, for example, 1:3.

[0224] According to an embodiment of the present invention, in the above method for preparing the compound of formula XIX, the molar ratio of the compound of formula XXX to the base may be 1:1 to 1:10, for example, 1:4 to 1:8, for example, 1:5 to 1:6.

[0225] According to an embodiment of the present invention, in the above method for preparing the compound of formula XIX, the molar ratio of the compound of formula XXX to the catalyst may be 1:0.01 to 1:0.2, for example, 1:0.05 to 1:0.1.

[0226] The present invention further provides a method M1B for preparing a compound of formula I, comprising reacting a compound of formula XXX with a compound of formula XXXX to obtain a compound of formula I,

[0227] [ka]

[0228] Among them, D, E, L 30 , X 1 , X 2 , X 3 , X 4 , G, R k are each independently as defined above.

[0229] According to an embodiment of the present invention, the reaction of Preparation Method M1B may be carried out in the presence of a catalyst, and the catalyst may 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)2CH2Cl2, 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, Pd2(dba) / P(Furyl)3, PdCl2[P(Furyl)3]2, PdCl2(PMePh2)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.

[0230] According to an embodiment of the present invention, the reaction in the above production method M1B may be carried out in the presence of a base.

[0231] The base may be an organic or inorganic base, for example: 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-dimethylpyridine, an organic base selected from 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, and potassium tert-butoxide; and inorganic bases selected from alkali metal or alkaline earth metal hydrides, hydroxides, ammoniates, alkoxides, acetates, fluorides, phosphates, carbonates and bicarbonates, such as sodium amide, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, sodium phosphate, potassium phosphate, potassium fluoride, cesium fluoride, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate.

[0232] According to an embodiment of the present invention, the reaction in Preparation Method M1B may be carried out in the presence of an organic solvent. The organic solvent may be an ether (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, phenyl methyl ether, phenyl ethyl 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 ethylene oxide and / or propylene oxide polyethers), a sulfoxide (e.g., tetrahydrodioxythiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide), a sulfone (e.g., dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, or diisopentyl sulfoxide), or a methyl ether (e.g., methyl ether, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, or diisopentyl sulfoxide). hexane, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone and cyclopentyl sulfone), aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, naphtha, 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. hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidine, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine or N,The organic solvent may be one or a mixture of two or more selected from the group consisting of N'-1,4-diformylpiperazine, nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile), 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 dioxane.

[0233] According to an embodiment of the present invention, the reaction in the above production method M1B may be carried out at 100°C to 150°C, for example, 115°C to 125°C.

[0234] According to an embodiment of the present invention, the above-mentioned preparation method M1B comprises reacting compound 30 with compound 40 to prepare compound 1 as follows:

[0235] [ka]

[0236] The present invention further provides the use of a compound of formula XXX above in the preparation of a compound of formula XIX.

[0237] The present invention further provides a method for producing a compound of formula I, a pharmaceutically acceptable salt thereof, or the above intermediate, which includes a reaction carried out during or in a production process using the compound of formula IIIA and / or the compound of formula IIIB as a starting material.

[0238] The present invention further provides the use of a compound of formula IIIA in the preparation of a compound of formula I, a pharmaceutically acceptable salt thereof, or the above intermediate.

[0239] According to a preferred embodiment of the present invention, any of the above-described manufacturing methods or uses may be carried out in an inert gas atmosphere (for example, a nitrogen atmosphere).

[0240] According to a preferred embodiment of the present invention, in any of the above-described production methods or uses, the starting compound may be provided in the form of an acid addition salt thereof, if necessary, and may participate in the reaction.

[0241] According to a preferred embodiment of the present invention, in any of the above-described production methods or uses, when a starting compound is provided in the form of an acid addition salt and participates in the reaction, the acid addition salt may be liberated with a base (organic base or inorganic base) as defined above, if necessary, and then participates in the reaction, or the liberation step may be carried out together with a subsequent reaction by a "one-pot synthesis method".

[0242] The present invention further provides a method for producing a target compound, which comprises combining one, two, three or more of the above-mentioned methods in sequence. Those skilled in the art should understand that when combining one, two, three or more of the above-mentioned methods in sequence, the product obtained in one method is preferably reacted as a raw material in the next method.

[0243] The present invention further provides Production Method M-IIIB-I, which includes the above Production Methods M13, M10A, M11, M19A, M20, and M1A, or a combination of two, three, or more selected from the above Production Methods. Preferably, the production methods in the combination are carried out sequentially so that the product obtained in the first production method can be used as a reaction substrate in the second production method.

[0244] The present invention further provides Production Methods M-IIIA-X1, which include the above Production Methods M14, M15, M16, M17, and M10B, or a combination of two, three, or more selected from the above Production Methods. Preferably, the production methods in the combination are carried out sequentially so that the product obtained from the first production method can be used as a reaction substrate for the second production method.

[0245] The present invention further provides Processes M-IIIA-X2, which include the preparation of compounds of formula IV, V, VI, VII, VIII, and IX by the above-described processes, and the preparation of compounds of formula X by the above-described Process M10C.

[0246] The present invention further provides methods of preparation M-IIIA-XXX, which include preparing compounds of formula XXIII, compounds of formula XXXI, compounds of formula XXIX, and compounds of formula XXX by the above methods.

[0247] According to an embodiment of the present invention, one of different preparation methods for preparing the same intermediate can be combined with a preparation method for further preparing another compound using the intermediate as a reaction substrate. Such combinations should be understood in the same manner as described herein, and should not be limited to a reaction route consisting of a combination of the specific preparation methods described above. For example, in the above description, the preparation methods for the compound of formula X include M10A, M10B, and M10C, any one of which can be combined with preparation method M19A, or with M20 and / or M1. Similarly, any of the different preparation methods for the compound of formula XXX described above can be combined with preparation method M1B to prepare a compound of formula I.

[0248] According to embodiments of the present invention, in any of the above-mentioned production methods or uses, preferably no separation or purification of raw materials, reaction products or intermediates by chromatography, such as column chromatography, is carried out.

[0249] According to an embodiment of the present invention, in any of the above-mentioned methods of preparation or uses, the reaction is preferably carried out with hydrogen gas without using hydrogen gas as a hydrogenation or reduction reagent and without using catalytic hydrogenation methods.

[0250] According to an embodiment of the present invention, in any of the above-mentioned production methods or uses, when an organic solvent or a mixed solvent of an organic solvent and water is used, it is inert to the reaction substrates and reagents.

[0251] [Term definitions and explanations] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application, including their illustrative definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined or combined with each other. The group definitions and compound structures after such combination and combination should fall within the scope described in the specification of this application.

[0252] Unless otherwise specified, the numerical ranges described in the present 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 the integer values ​​1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 in the numerical range "1 to 10," and the integer values ​​11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, and 40 in the numerical range "11 to 40." In this application, when describing a substituent, "one, two, or more" should be understood to refer to an integer of 3 or more, such as 3, 4, 5, 6, 7, 8, 9, or 10.

[0253] The term "halogen" refers to a substituent selected from fluorine, chlorine, bromine or iodine.

[0254] "C 1-40 The term "alkyl group" should be understood to denote a linear or branched saturated monovalent hydrocarbon group, preferably having from 1 to 40 carbon atoms. For example, "C 1-6The term "alkyl group" refers to straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include 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, and 1,2-dimethylbutyl groups, and isomers thereof.

[0255] "C 2-40 The term "alkenyl group" denotes a linear or branched monovalent hydrocarbon group, preferably containing one or more double bonds and having 2 to 40 carbon atoms, and preferably "C 2-6 It should be understood that "C" refers to an alkenyl group. 2-6 An "alkenyl group" preferably contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("C 2-3It should be understood that the term "alkenyl group" refers to a straight or branched chain monovalent hydrocarbon group having two or more double bonds, and that when the alkenyl group contains two or more double bonds, the double bonds may be separated or conjugated with each other. Examples of the alkenyl group include 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)-pent- 1-enyl group, (Z)-pent-1-enyl group, hex-5-enyl group, (E)-hex-4-enyl group, (Z)-hex-4-enyl group, (E)-hex-3-enyl group, (Z)-hex-3-enyl group, (E)-hex-2-enyl group, (Z)-hex-2-enyl group, (E)-hex-1-enyl group, (Z)-hex-1-enyl group, isopropenyl group, 2-methylprop-2-enyl group, 1-methylprop- 2-enyl group, 2-methylprop-1-enyl group, (E)-1-methylprop-1-enyl group, (Z)-1-methylprop-1-enyl group, 3-methylbut-3-enyl group, 2-methylbut-3-enyl group, 1-methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group 1-ethylbut-2-enyl group, (E)-3-methylbut-1-enyl group, (Z)-3-methylbut-1-enyl group, (E)-2-methylbut-1-enyl group, (Z)-2-methylbut-1-enyl group, (E)-1-methylbut-1-enyl group, (Z)-1-methylbut-1-enyl group, 1,1-dimethylprop-2-enyl group, 1-ethylprop-1-enyl group, 1-propylvinyl group, and 1-isopropylvinyl group.

[0256] "C2- 40The term "alkynyl group" should be understood to denote a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, preferably a "C2-C6-alkynyl group". The term "C2-C6-alkynyl group" should be understood to denote a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C2-C3-alkynyl group"). Examples of the C2-C6-alkynyl group include an ethynyl group, a prop-1-ynyl group, a prop-2-ynyl group, a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, a pent-1-ynyl group, a pent-2-ynyl group, a pent-3-ynyl group, a pent-4-ynyl group, a hex-1-ynyl group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-ynyl group, a 1-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, 2-methylpent-4-ynyl group, 1-methylpent-4-ynyl group, 2-methylpent-3-ynyl group, 1-methylpent-3-ynyl group, 4-methylpent-2-ynyl group, 1-methylpent-2-ynyl group, 4-methylpent-1-ynyl group, 3-methylpent-1-ynyl group, 2-ethylbut-3-ynyl group, 1-ethylbut-3-ynyl group, 1-ethylbut-2-ynyl group, 1-propylprop-2-ynyl group, 1-isopropylprop-2-ynyl group, 2,2-dimethylbut-3-ynyl group, 1,1-dimethylbut-3-ynyl group, 1,1-dimethylbut-2-ynyl group, or 3,3-dimethylbut-1-ynyl group. In particular, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0257] "C 3-40 The term "cycloalkyl group" refers to a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 40 carbon atoms, preferably "C 3-10 It should be understood that "C" is a cycloalkyl group. 3-10The term "cycloalkyl group" should be understood to denote a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be, for example, a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, or a cyclodecyl group, or may be a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0258] The term "3- to 20-membered heterocyclyl group" refers to a saturated monocyclic or bicyclic hydrocarbon ring or bridged cycloalkane containing a non-aromatic cyclic group having a total of 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.) and 1 to 5 heteroatoms independently selected from N, O, and S, preferably a "3- to 10-membered heterocyclyl group." The term "3- to 10-membered heterocyclyl group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring or bridged cycloalkane containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclyl group can be linked to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl group may include, but is not limited to, a 4-membered ring such as azetidinyl or oxetanyl, a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or pyrrolinyl, a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl, or a 5,6-membered bicyclic ring such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl. The nitrogen-containing ring may be partially unsaturated, i.e., contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or may be benzo-fused, such as, but not limited to, a dihydroisoquinolinyl group. According to the present invention, the heterocyclyl group is non-aromatic.When the 3- to 20-membered heterocyclyl group is linked to another group to form a compound of the present invention, a carbon atom in the 3- to 20-membered heterocyclyl group may be linked to another group, or a heterocyclic atom in the 3- to 20-membered heterocyclyl ring may be linked to another group. For example, when the 3- to 20-membered heterocyclyl group is selected from a piperazinyl group, a nitrogen atom in the piperazinyl group may be linked to another group. Alternatively, when the 3- to 20-membered heterocyclyl group is selected from a piperidinyl group, a nitrogen atom in the piperidinyl ring and a carbon atom at the para-position thereto may be linked to another group.

[0259] "C 6-20 The term "aryl group" preferably denotes a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having from 6 to 20 carbon atoms, preferably "C 6-14 It should be understood that "C" is an aryl group. 6-14 The term "aryl group" preferably refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14 or a ring having six carbon atoms ("C aryl group"), such as a phenyl group; or a biphenyl group, or a ring having nine carbon atoms ("C aryl group"), such as an indanyl or indenyl group, or a ring having ten carbon atoms ("C aryl group"), such as a tetrahydronaphthyl, dihydronaphthyl or naphthyl group. 10 aryl group), or a ring with 13 carbon atoms, such as a fluorenyl group ("C 13 aryl group), or a ring with 14 carbon atoms, such as an anthryl group ("C 14 It should be understood that the above C refers to an aryl group. 6-20 When the aryl group is substituted, it may be mono- or polysubstituted. The substitution site is not limited, and it may be substituted, for example, at the ortho, para, or meta position.

[0260] The term "5- to 20-membered heteroaryl group" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example a "5- to 14-membered heteroaryl group". The term "5- to 14-membered heteroaryl group" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. In particular, heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl groups and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, or Alternatively, the 5- to 20-membered heteroaryl group may be selected from a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, and the like, and their benzo derivatives such as a quinolyl group, a quinazolinyl group, and an isoquinolyl group; an azocinyl group, an indolizinyl group, a purinyl group, and the like, and their benzo derivatives; or a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a pteridinyl group, a carbazolyl group, an acridinyl group, a phenazinyl group, a phenothiazinyl group, a phenoxazinyl group, and the like. When the 5- to 20-membered heteroaryl group is linked to another group to form the compound of the present invention, a carbon atom in the 5- to 20-membered heteroaryl ring may be linked to the other group, or a heteroatom in the 5- to 20-membered heteroaryl ring may be linked to the other group. When the 5- to 20-membered heteroaryl group is substituted, it may be mono- or polysubstituted.The substitution site is not limited, and for example, a hydrogen atom bonded to a carbon atom in the heteroaryl ring may be substituted, or a hydrogen atom bonded to a heteroatom in the heteroaryl ring may be substituted.

[0261] Unless otherwise specified, a heterocyclyl group, heteroaryl group, or heteroarylene group includes all possible isomeric forms thereof, for example, positional isomers thereof. Thus, some illustrative, non-limiting examples include those substituted or bonded to other groups at one, two, or more positions, such as 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-positions (if present), and include pyridin-2-yl, pyridylidene-2-yl, pyridin-3-yl, pyridylidene-3-yl, pyridin-4-yl, and pyridylidene-4-yl; thienyl or thienylidenyl groups, including thien-2-yl, thien-3-yl, and thienylidene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0262] The term "oxo" refers to an oxy substituent (=O) formed by oxidation of a carbon, nitrogen, or sulfur atom in a substituent.

[0263] Unless otherwise stated, the definitions of terms herein apply equally to groups that contain the term, e.g., C 1-6 The definition of an alkyl group is C 1-6 Alkyloxy group, -N(C 1-6 alkyl)2, -NHC 1-6 Alkyl group or -S(O)2-C 1-6 This also applies to alkyl groups.

[0264] Those skilled in the art will recognize that the compounds of Formula I can exist in a variety of pharmaceutically acceptable salt forms: if they contain a basic center, they can form acid addition salts; if they contain an acidic center, they can form base addition salts; and if they contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0265] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), in which the compounds of the present invention contain polar solvents, in particular, for example, water, methanol, or ethanol, which are constituents of the crystalline lattice of the compounds. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0266] Due to their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds can exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be isolated into enantiomeric compounds or used in synthesis in this form by chemical or physical methods well known to those skilled in the art. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be achieved using optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are solvent mixtures containing water or alcohols, for example hexane / isopropanol / acetonitrile.

[0267] The term "tautomer" refers to a functional isomer resulting from the rapid shift of an atom between two positions within a molecule. The compounds of the present invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Proton-shift tautomers result from the shift of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and isolating a single tautomer usually produces a mixture whose physicochemical properties match those of the compound. The position of the equilibrium is determined by the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0268] The corresponding stable isomer can be isolated by known methods, such as, for example, extraction, filtration or column chromatography.

[0269] [Beneficial effects] The production method of the present invention significantly improves production efficiency and safety without using a separation and purification step by column chromatography such as silica gel column chromatography, and without using hydrogen gas as a hydrogenation or reduction reagent.

[0270] Furthermore, the preparation method of the present invention realizes efficient utilization of regioisomers IIIA and IIIB, and avoids the negative impact on the yield of the target product caused by the disposal of regioisomer IIIA. Even more surprisingly, when using the method of regioisomer IIIA, the total yield can reach 9.4%, which is significantly higher than the yield of less than 4% when regioisomer IIIB is used. When the two regioisomers are simultaneously applied to the preparation of compound I, the yield is improved by more than three times compared to when regioisomer IIIB is used alone.

[0271] Therefore, the production method of the present invention enables the compound of formula I and its intermediates to be synthesized in high yield, at low cost, and in an environmentally friendly manner, thereby enabling the compound of formula I to be produced on an industrial scale.

[0272] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0273] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0274] Example 1: Preparation of Compound 3a and Compound 3b (1) 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (Compound 1)

[0275] [ka]

[0276] Trifluoroacetic acid (340 kg) was added to the reactor, and the mixture was purged with nitrogen gas three times. The temperature was then lowered to 0-10°C. N-Boc-O-2,4,6-trimethylphenylsulfonylhydroxylamine (90 kg, 285 mol) was added in several portions while maintaining the temperature under nitrogen gas protection, releasing a large amount of gas with each addition. After 2 h of reaction, water was added to quench the reaction, and the solid precipitated. The solid was dissolved in dichloromethane and washed with aqueous NaHCO3 until the organic phase reached a pH of approximately 7, followed by separation. The organic phase was further lowered to 0-10°C under nitrogen gas protection, maintained at 0-10°C, and 3-bromo-5-(4-methoxybenzyloxy)pyridine (64 kg, 217 mol) was added in several portions. After 1-2 h of reaction, the mixture was filtered to obtain 89 kg of 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] + .

[0277] (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)

[0278] [ka]

[0279] 188 kg of tetrahydrofuran was added to the reaction vessel, followed by 2,4,6-trimethylbenzenesulfonic acid 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridin-1-ium (91 kg, 179 mol) and p-toluenesulfonic acid 2,2-difluorovinyl ester (51 kg, 218 mol). 1,8-diazacyclo[5,4,0]undecene-7 (109 kg, 717 mol) was slowly added dropwise. After the addition was completed, the mixture was reacted at room temperature for 1 hour. Dichloromethane (560 kg) was added, followed by saturated ammonium chloride solution (240 kg). The organic phase was washed with water (210 kg), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from acetonitrile to give 6-bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine 35. 8.2 kg of 4-bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine were obtained. 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] + . 1 H-NMR (400 MHz, DMSO-d6): 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, 2H), 3.77 (d, 3H), m / z = 351 [M+1] + .

[0280] Example 2: Preparation of Compound 11 (1) 4-Bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine-3-formaldehyde (Compound 12)

[0281] [ka]

[0282] 4-Bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (7.4 kg, 21 mol) and DMF (21 kg) were added to the reaction vessel in that order, and the mixture was purged with nitrogen gas three times. The temperature was controlled at 0-10°C, and phosphorus oxychloride (8.0 kg, 52 mol) was added dropwise. The mixture was heated to 20-30°C and reacted for 17 hours. The resulting product solution was used directly in the next reaction. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0283] (2) 4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (Compound 13)

[0284] [ka]

[0285] The reaction solution in the reactor from the previous step was heated to 70°C and monitored by HPLC until the raw materials were completely reacted. The reaction solution was then cooled to 25°C and added to 66 kg of water, kept at 30°C and stirred for 2 hours, filtered, and the filter cake was slurried in 17 kg of dichloromethane for 1 hour, and further filtered to obtain a filter cake. After vacuum drying, 4.7 kg of product was obtained. 1 H-NMR (400 MHz, DMSO-d6): δ 10.62 (brs, 1H), 10.46 (d, 1H), 8.32 (t, 1H), 7.80 (s, 1H). m / z = 259 [M+1] + .

[0286] (3) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-formaldehyde (Compound 10)

[0287] [ka]

[0288] 4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (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 to the reactor in that order, and the mixture was purged with nitrogen three times. The temperature was raised to 65°C and the reaction mixture was allowed to react. The reaction mixture was monitored by HPLC until the raw materials were completely reacted. The temperature was then lowered to 25°C, and 47 kg of water was added to the reactor. The mixture was stirred at 25-30°C for 1 h and then suction filtered to dryness. 47 kg of water was added to the reactor, and the mixture was stirred at 25-30°C for 1 h and then suction filtered to dryness. Acetonitrile (9.0 kg) was added to the reactor, and the filter cake was added to the reactor and stirred at 25-30°C for 1-2 h. The cake was then suction filtered to dryness. 4.6 kg of product was obtained after vacuum drying. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0289] (4) Synthesis of 4-bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 11)

[0290] [ka]

[0291] 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-formaldehyde (4.6 kg, 16 mol), dimethyl sulfoxide (46 L), and 85% hydrazine hydrate (4.7 kg) were added to a reaction vessel, and the temperature was raised to 110-115°C to react. The reaction was monitored by HPLC until the reaction was complete. The temperature was then lowered to 30-40°C, and water (138 L) was added. The mixture was kept warm and stirred for 1-2 hours, and then filtered. The filter cake was dried in vacuo to obtain 4.0 kg of 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]+.

[0292] Example 3: Preparation of Compound I (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)

[0293] [ka]

[0294] A reaction flask was charged with 4-bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (30 g, 0.11 mol), 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.3]heptane-6-tert-butyl carbonate (57 g, 0.14 mol), bistriphenylphosphinepalladium dichloride (1.5 g, 2.2 mmol), lithium carbonate (16 g, 0.22 mol), 300 mL of dioxane, and 150 mL of water, in that order. The atmosphere was purged with nitrogen gas three times, heated to 85°C, and reacted for 20 hours. The mixture was then filtered through diatomaceous earth, and the filtrate was poured into 3 L of water and filtered to obtain a solid. Alternatively, the solid was dissolved in 1.2 L of tetrahydrofuran, 60 g of SILICYCLE silica gel was added, and the mixture was heated to 60°C and stirred for 12 hours. The mixture was then cooled to room temperature, filtered through diatomaceous earth to remove the silica gel, and the filtrate was concentrated under reduced pressure to approximately 100 mL. 300 mL of methyl tert-butyl ether was added, and the mixture was further concentrated under reduced pressure to approximately 100 mL. This step was repeated twice more, and the mixture was stirred at room temperature overnight. The mixture was filtered, the filter cake was rinsed with a small amount of methyl tert-butyl ether, and the solid was dried under vacuum to obtain 42.3 g of product, with an HPLC purity of 98.8%. 1 H-NMR (400 MHz, DMSO-d6): 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), 4.20-4.26 (m, 2H), 4.15-4.19 (m, 2H), 4.03-4.09 (m, 2H), 2.60 (d, 1H), 1.53 (d, 1H), 1.38-1.42 (m, 3H), 1.30 (s, 9H). m / z = 476 [M+1] + .

[0295] (2) 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 20)

[0296] [ka]

[0297] 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 (30 g, 0.063 mol), 500 mL of methanol, and concentrated sulfuric acid (25 g, 0.25 mol) were added to a reaction flask in that order, heated to 60 °C, and reacted for 12 h. The mixture was then concentrated under reduced pressure to remove the methanol, and 500 mL of methyl tert-butyl ether was added to form a slurry. The mixture was then suction filtered to obtain 43 g of product, which had an HPLC purity of 99.5% and was used directly in the next reaction. 1 H NMR (400 MHz, DMSO-d6): 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] + .

[0298] (3) 6-ethoxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1]-heptan-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound I)

[0299] [ka]

[0300] The product of step (2) (30 g), 6-methoxy-3-pyridineformaldehyde (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 were added to a reaction flask in this order and reacted at room temperature for 18 hours. 300 mL of dichloromethane was added, the mixture was washed once with saturated ammonium chloride solution and twice with water, concentrated under reduced pressure, 300 mL of methanol was added, the mixture was heated to reflux, and the temperature was lowered to 40-45°C. 160 mL of methyl tert-butyl ether was slowly added, the mixture was cooled to 25°C and stirred for 12 hours. 160 mL of methyl tert-butyl ether was added and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure to approximately 160 mL. 300 mL of methyl tert-butyl ether was added, and the mixture was cooled to approximately 160°C. This step was repeated twice more, the mixture was stirred at room temperature overnight, the mixture was filtered, the filter cake was rinsed with a small amount of methyl tert-butyl ether, and the solid was dried under vacuum to give 19 g of product with an HPLC purity of 98.9%. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0301] Example 4: Preparation of Compound 11 (1) 6-ethoxy-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (Compound 14)

[0302] [ka]

[0303] 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)oxalamide (1.0 g, 3.0 mmol) were added to a reaction flask in this order. The reaction mixture was heated to 80 °C under nitrogen gas protection and reacted for 16 hours. After cooling, water (150 mL) was added to the reaction mixture with stirring and stirred for 30 minutes. The solid was collected by suction filtration and dried under vacuum to give 37 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0304] (2) 6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-4-ol (Compound 15)

[0305] [ka]

[0306] 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 mixture was allowed to react for 3 hours. The reaction mixture was washed with water (300 mL), then with saturated brine (150 mL), and then concentrated to give a crude product solution (approximately 60 mL). n-Heptane (250 mL) was added to the crude product solution, and the mixture was stirred for 1 hour, then suction filtered and vacuum dried to give 16.5 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0307] (3) 6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (Compound 16)

[0308] [ka]

[0309] Dichloromethane (200 mL) and 6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-4-ol (14.8 g, 75.5 mmol) were added sequentially to a reaction flask. A solution of triethylamine (11.5 g, 113.3 mmol) and trifluoromethanesulfonic anhydride (23.4 g, 83.1 mmol) in dichloromethane (50 mL) was then added, and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was washed with water (200 mL), then with saturated brine (100 mL), and then concentrated to obtain the crude product. DMF (150 mL) was added to the crude product until it became transparent, and then water (1000 mL) was slowly added while stirring. After stirring for 30 minutes, the mixture was filtered under suction, washed with water, and dried under air at 60°C for 16 hours to give 6-ethoxy-2-fluoropyrazole[1,5-a]pyridin-4-yl trifluoromethanesulfonate (23.4 g, 95% yield) as a pale yellow solid. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0310] (4) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine (Compound 17)

[0311] [ka]

[0312] NMP (60 mL), 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (6.6 g, 20.0 mmol), pentamethylcyclopentadienyltriphenylphosphine ruthenium chloride(II) (800 mg, 1.0 mmol), and LiBr (2.6 g, 30.0 mmol) were added to a reaction flask in this order. The atmosphere was purged with nitrogen gas three times, and the mixture was heated to 90°C and reacted for 16 hours. The reaction solution was slowly poured into water (800 mL), stirred for 1 hour, suction filtered, washed with water, and the solid was dried under vacuum to obtain 3.9 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0313] (5) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-formaldehyde (Compound 10)

[0314] [ka]

[0315] 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 to a reaction flask in this order and reacted at room temperature for 48 hours. The reaction mixture was slowly poured into water (600 mL), stirred for 1 hour, suction filtered, washed with water, and the solid was dried under vacuum to give 4.2 g of product. 1 H-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] + .

[0316] (6) 4-Bromo-6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 11)

[0317] [ka]

[0318] The procedure was the same as in step (4) of Example 2.

[0319] Example 5: Preparation of Compound 30 (1) 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-ol (Compound 31)

[0320] [ka]

[0321] DMSO (200 mL), acetylhydrazine (8.6 g, 115.8 mmol), 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (20.0 g, 77.2 mmol), and 80% aqueous hydrazine hydrate (24.1 g, 386 mmol) were added to a reaction flask in this order, and the mixture was heated to 140 °C and reacted for 6 hours. After cooling, the reaction mixture 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. 1 H-NMR (400MHz, 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 / 255 [M+1] + .

[0322] (2) 6-Ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-ol (Compound 29)

[0323] [ka]

[0324] A sealed reaction flask was charged with ethanol (50 mL), 6-bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-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), in that order. The mixture was heated to 100 °C and reacted for 4 days. The reaction was then stopped, 200 mL of dioxane was added, heated to reflux, and filtered through diatomaceous earth while still hot. The filtrate was concentrated under reduced pressure to approximately 50 mL, then poured into 500 mL of water, filtered, and dried in vacuo to give 1.5 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0325] (3) 6-Ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (Compound 30)

[0326] [ka]

[0327] A reaction flask was charged with 6-ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-ol (250 mg, 0.68 mmol), diisopropylethylamine (264 mg, 2.0 mmol), and DMF (5 mL). The mixture was cooled to 5°C, and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (183 mg, 0.51 mmol) was added. The reaction mixture was allowed to react at room temperature for 2 hours, and the reaction mixture was poured into 200 mL of water. The solid was filtered and dried to give 200 mg of product, with an HPLC purity of 97.5%. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0328] Example 6: Preparation of Compound 30 (1) 6-Bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (Compound 23)

[0329] [ka]

[0330] Dichloromethane (15 mL) and 6-bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-formaldehyde (1.1 g, 3.0 mmol) were added sequentially to a reaction flask. Trifluoroacetic acid (3 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give 0.6 g of the product. 1 H-NMR (400 MHz, DMSO-d6): δ 11.97 (s, 1H), 10.03 (s, 1H), 8.76 (s, 1H), 7.14 (s, 1H). m / z = 259 [M+1] + .

[0331] (2) 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-ol (Compound 31)

[0332] [ka]

[0333] DMSO (200 mL), acetylhydrazine (8.6 g, 115.8 mmol), 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (20.0 g, 77.2 mmol), and 80% hydrazine hydrate (24.1 g, 386 mmol) were added to a reaction flask in this order, and the mixture was heated to 110°C and reacted for 12 hours. After cooling, the reaction mixture was slowly poured into water (2000 mL), filtered, and the solid was dried in vacuo to give 10.5 g of product. 1 H-NMR (400MHz, 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] + .

[0334] (3) 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (Compound 25)

[0335] [ka]

[0336] 6-Bromo-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-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 to a reaction flask in this order. The reaction mixture was heated to 40°C and reacted for 16 hours. After cooling, water (500 mL) was slowly poured into the reaction mixture while stirring. After stirring for 1 hour, the mixture was suction filtered, washed with water, and dried to obtain 3.7 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0337] (4) 4-(4-Methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (Compound 27)

[0338] [ka]

[0339] A reaction flask was charged with 6-bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (3.7 g, 10.0 mmol), bis(N-alcohol) borate (3.8 g, 15.0 mmol), potassium acetate (2.9 g, 30.0 mmol), PdCl(dppf) (731 mg, 1.0 mmol), and 1,4-dioxane (70 mL), in that order. The reaction mixture was heated to 90 °C under nitrogen gas protection and reacted for 16 h. The mixture was filtered through diatomaceous earth while still hot, and the filtrate was concentrated under reduced pressure to give crude 4-(4-methoxybenzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazo[3',4':3,4-]pyrazo[1,5-a]pyridine. The crude product was added to THF (70 mL), cooled to 5°C in an ice bath, and 30% H2O2 (6.5 mL) was added dropwise. The mixture was warmed to room temperature and reacted for 1.5 hours. Ethyl acetate (150 mL) was added to the reaction mixture, which was then suction filtered. The filtrate was washed with 0.1 N aqueous hydrochloric acid (50 mL), washed twice with water (40 mL), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give 900 mg of the product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0340] (5) 6-ethoxy-1-ethyl-4-(4-methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine (compound 28)

[0341] [ka]

[0342] 4-(4-Methoxybenzyloxy)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-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 to a reaction flask in this order. The reaction mixture was heated to 30 °C and reacted for 16 hours. The reaction mixture was slowly poured into water (150 mL) and stirred for 0.5 hours. After that, the mixture was suction filtered, washed with water, and dried to obtain the crude product. 10 mL of 1,4-dioxane was added to the crude product, which was then dissolved by heating. 10 mL of methyl tert-butyl ether was slowly added, the mixture was cooled to room temperature, and the mixture was concentrated to 5 mL. 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 as a yellow solid. 1 -NMR (400 MHz, DMSO-d6): 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] + .

[0343] (6) 6-Ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-4-ol (Compound 29)

[0344] [ka]

[0345] To a reaction flask, 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, followed by trifluoroacetic acid (0.5 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. After concentration, 250 mg of product was obtained, which was used directly in the next reaction. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0346] (7) 6-Ethoxy-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (Compound 30)

[0347] [ka]

[0348] Compound 30 was prepared by following step (3) of Example 5.

[0349] 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)

[0350] [ka]

[0351] A reaction flask was charged with 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-tert-butyl carbonate (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), PdCl(dppf) (4 mg, 0.005 mmol), potassium fluoride (18 mg, 0.3 mmol), and 1,4-dioxane (0.5 mL), in that order. The mixture was heated to 120 °C under nitrogen gas protection and reacted for 16 h. The organic phase was concentrated and then slurried with 50 mL of methyl tert-butyl ether. The mixture was filtered to give 12 mg of product. m / z = 476[M+1] + .

[0352] Example 8: Preparation of Compound 10 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-formaldehyde (Compound 10) (1) 6-Bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine-3-formaldehyde (Compound 4)

[0353] [ka]

[0354] 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 to a reaction flask in this order, and the temperature was lowered to 5°C. POCl (6.1 g, 40.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was slowly poured into water (350 mL) and stirred for 1 hour. The mixture was then suction filtered, and the solid was dried in vacuo to give 3.6 g of product. 1H-NMR (400 MHz, DMSO-d6): 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] + .

[0355] (2) 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole[1,5-a]pyridine-3-formaldehyde (Compound 5)

[0356] [ka]

[0357] A reaction flask was charged with 6-bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-formaldehyde (7.6 g, 20.0 mmol), bis(N-alcohol) borate (5.6 g, 22.0 mmol), potassium acetate (5.9 g, 60.0 mmol), PdCl(dppf) (1.5 g, 2.0 mmol), and 1,4-dioxane (100 mL), in that order. The atmosphere was purged with nitrogen gas three times, and the mixture was heated to 85°C and reacted for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 8.6 g of product, which was used directly in the next reaction. m / z = 465 [M+1] + .

[0358] (3) 2-Fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-formaldehyde (Compound 6)

[0359] [ka]

[0360] 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole[1,5-a]pyridine-3-formaldehyde (4.3 g, 10.1 mmol) and 1,4-dioxane (110 mL) were added sequentially to a reaction flask, cooled to 5 °C in an ice bath, and 30% H2O2 (4 mL) was added dropwise. The reaction mixture was warmed to room temperature and reacted for 2 hours. 200 mL of dichloromethane was added, washed sequentially with 50 mL of water, NaHSO3 solution (50 mL), and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated to a volume of 10 mL, 100 mL of methyl tert-butyl ether was added, and the mixture was filtered to obtain 2.1 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0361] (4) 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-formaldehyde (Compound 7)

[0362] [ka]

[0363] 2-Fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-formaldehyde (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 to a reaction flask in this order. The reaction mixture was heated to 40 °C and reacted for 3 hours. The reaction mixture was poured into 400 mL of water and extracted with dichloromethane (100 mL x 3). The filtrate was concentrated to a volume of 10 mL, 100 mL of methyl tert-butyl ether was added, and the mixture was concentrated under reduced pressure to approximately 10 mL. 100 mL of methyl tert-butyl ether was added, and the mixture was further concentrated under reduced pressure to approximately 10 mL. This step was repeated twice to obtain 1.25 g of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0364] (5) 6-ethoxy-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (compound 8)

[0365] [ka]

[0366] 6-Ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-formaldehyde (450 mg, 1.3 mmol) and 30 mL of dichloromethane were added sequentially to a reaction flask. Trifluoroacetic acid (2 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The mixture was concentrated under reduced pressure to a volume of 10 mL, and 100 mL of methyl tert-butyl ether was added, followed by further concentration under reduced pressure to approximately 10 mL. This step was repeated twice to obtain 305 mg of product. 1 H-NMR (400 MHz, DMSO-d6): 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] + .

[0367] (6) 6-Ethoxy-2-fluoro-3-formylpyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (Compound 9)

[0368] [ka]

[0369] A reaction flask was charged with 6-ethoxy-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-formaldehyde (315 mg, 1.4 mmol), diisopropylethylamine (362 mg, 2.8 mmol), and DMF (5 mL). The mixture was cooled to 5°C, and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (660 mg, 1.7 mmol) was added. The reaction mixture was warmed to room temperature and reacted for 2 hours. The reaction mixture was poured into 200 mL of water, extracted with dichloromethane (100 mL x 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 430 mg of the product, which was used directly in the next reaction. 1H-NMR (400 MHz, DMSO-d6): 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] + .

[0370] (7) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-formaldehyde (Compound 10)

[0371] [ka]

[0372] NMP (0.5 mL), 6-ethoxy-2-fluoro-3-formylpyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (5 mg, 0.015 mmol), tris(acetonitrile)pentamethylcyclopentadiene ruthenium trifluoromethanesulfonate(II) (1.0 mg, 0.002 mmol), and LiBr (4 mg, 0.045 mmol) were added to a reaction flask in this order. The atmosphere was purged with nitrogen gas three times, and the mixture was heated to 100 °C and reacted for 2 hours. The reaction solution was poured into 100 mL of water, extracted with dichloromethane (100 mL x 3), dried over anhydrous sodium sulfate, and the organic phase was concentrated and separated by column chromatography to obtain 2 mg of product. 1 H-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] + .

[0373] The exemplary embodiments of the present invention have been described above. It should be understood that the scope of the claims of the present application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, variations, etc. made within the spirit and principle of the present invention by those skilled in the art should be included in the scope claimed by the claims of the present application.

Claims

1. 1. A process for preparing a compound of formula I comprising the steps M1A, M20, M19A, M11, M10A and M13: Process M1A: The compound of formula XX is reacted with R k -C(O)-H to give compounds of formula I: 【Chemistry 1】 Among them, X 1 and X 3 are homologous or different and independently 1 Selected from X ２ is N, X ４ is CR 1 and N, Each R 1 are the same or different and independently represent H, halogen, CN, NH 2 , O.H., C. 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkyloxy group, and C 3-6 cycloalkyloxy groups; D is H, halogen, CN, NH 2 , O.H., C. 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkyloxy group, and C 3-6 cycloalkyloxy groups; E is unsubstituted or optionally contains one, two or more R c C replaced with 1-6 alkyloxy groups, and each R c are the same or different and independently represent halogen, CN, OH, oxo (=O), C 3-6 Cycloalkyl groups, C 6-10 Aryl groups, 5- to 7-membered heteroaryl groups, 3- to 10-membered heterocyclyl groups, C 1-6 Alkyloxy group, and C 3-6 Cycloalkyloxy group, C 6-10 selected from an aryloxy group, a 5- to 7-membered heteroaryloxy group, and a 3- to 10-membered heterocyclyloxy group; G is unsubstituted or optionally contains one, two or more R e replaced with 【Chemistry 2】 Each R e are homologous or different, and independently of each other, C 1-6 Alkyl groups and C 1-6 alkyloxy groups, R k is unsubstituted or optionally substituted with one, two or more R g C replaced with 6-10 selected from aryl groups and 5- to 10-membered heteroaryl groups; Each R g are the same or different and independently represent halogen, CN, OH, SH, oxo (=O), NO 2 , unsubstituted or optionally one, two or more R h C replaced with 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkyloxy group and C 3-6 cycloalkyloxy groups, Each R h are the same or different and are independently selected from halogen, CN and OH; Process M20: The compound of formula XIX is reacted with PG 19 is removed to obtain a compound of formula XX; 【Transformation 3】 PG 19 is selected from a tert-butoxycarbonyl group (Boc), a cyclobutoxycarbonyl group, a benzyloxycarbonyl group (CBz), a p-methoxybenzylcarbonyl group (Moz), a 2-biphenyl-2-propoxycarbonyl group (BPoc), a 2,2,2-trichloroethoxycarbonyl group (Troc), a phthalimide group, a p-toluenesulfonyl group, a trifluoroacetyl group, a (9H-fluoren-9-ylmethoxy)carbonyl group (Fmoc), a benzyl group, a 4-methoxybenzyl group, a diphenylmethyl group, a 2-(trimethylsilyl)ethoxycarbonyl group (Teoc), an adamantyloxycarbonyl group (Adoc), a formyl group, and an acetyl group; Process M19A: Reacting a compound of formula XI with a compound of formula XVIII gives a compound of formula XIX: 【Chemistry 4】 L 11 is halogen, unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens 1-6 Alkyl sulfonyloxy group and C 1-6 alkylbenzenesulfonyloxy groups, Process M11: Reacting a compound of formula X with hydrazine gives a compound of formula XI: 【Transformation 5】 L 10 is selected from F, Cl, Br and I; Process M10A: Compound of Formula XIII and Compound R 21 -L 13 to give a compound of formula X: 【Transformation 6】 L 13 is F, Cl, Br, I and unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens 1-6 Alkyl sulfonyloxy group and C 1-6 alkylbenzenesulfonyloxy groups; R 21 is unsubstituted or optionally substituted with one, two or more R d C replaced with 1-6 is an alkyl group, and Each R d are the same or different and independently represent halogen, CN, OH, oxo (=O), C 3-6 Cycloalkyl groups, C 6-10 Aryl groups, 5- to 7-membered heteroaryl groups, 3- to 10-membered heterocyclyl groups, C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 selected from an aryloxy group, a 5- to 7-membered heteroaryloxy group, and a 3- to 10-membered heterocyclyloxy group; Process M13: The compound of formula IIIB having the following structure was prepared by reacting phosphorus oxychloride (POCl 3 ) to give the compound of formula XIII: 【Transformation 7】 PG 3 is unsubstituted or optionally C 1-6 Alkyl group, C 1-6 a benzyl group substituted with 1, 2, 3, 4 or 5 substituents selected from an alkyloxy group and a halogen; 1-6 Alkyl group, tris (C 1-6 alkyl)silyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, allyl group, triphenylmethyl group, C 1-6 Alkyloxymethyl group, benzyloxymethyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 selected from an alkylcarbonyl group and a benzoyl group; Manufacturing method.

2. In step M20, PG of the compound of formula XIX is 19 is removed in the presence of an acid, the acid being selected from hydrochloric acid, sulfuric acid, formic acid and acetic acid; and the molar ratio of the compound of formula XIX to the acid is 1:1 to 1:5; The method of claim 1.

3. Step M19A is carried out in the presence of a catalyst, and the catalyst is a palladium catalyst, Pd(dba) 2 , PdCl 2 , Pd(OAc) 2 , Pd(dppf)Cl 2 , Pd 2 (dba) 3 , PdCl 2 (CH 3 CN) 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(t-Bu) 3 , PdCl 2 (PPh 3 ) 2 CH 2 Cl 2 , Pd(OAc) / PPh 3 , PdCl 2 [(Pet 3 )] 2 , Pd(DIPHOS) 2 , PdCl 2 (Bipy), [PdCl(Ph 2 PCH 2 PPh 2 )] 2 , PdCl 2 [P(o-Tol) 3 ] 2 , Pd 2 (dba) 3 / P (o-Tol) 3 , Pd 2 (dba) / P (frill) 3 , PdCl 2 [P (frill) 3 ] 2 , PdCl 2 (PMePh 2 ) 2 , PdCl 2 [P(4-F-Ph) 3 ] 2 , PdCl 2 [P(C 6 F 6 ) 3 ] 2 , PdCl 2 [P(2-COOH-Ph)(Ph) 2 ] 2 and PdCl 2 [P(4-COOH-Ph)(Ph) 2 ] 2 Selected from the molar ratio of the compound of formula XI to the catalyst is 1:0.001 to 1:0.05; Step M19A is carried out in the presence of a base, and the molar ratio of the compound of formula XI to the base is 1:1 to 1:5, and the molar ratio of the compound of formula XI to the compound of formula XVIII is 1:1 to 1:2; The method of claim 1.

4. In step M11, the molar ratio of the compound of formula X to hydrazine is 1:1 to 1:

15. The method of claim 1.

5. In step M10A, a compound of formula XIII and a compound R 21 -L 13 The molar ratio of The method of claim 1.

6. L 11 is selected from a methanesulfonyloxy group (MsO-), a trifluoromethanesulfonyloxy group (TfO-) and a p-toluenesulfonyloxy group (TsO-), L 13 is selected from a methanesulfonyloxy group (MsO-), a trifluoromethanesulfonyloxy group (TfO-) and a p-toluenesulfonyloxy group (TsO-), PG 3 is selected from a benzyl group, a 4-methoxybenzyl group, a 4-methylbenzyl group, a 4-chlorobenzyl group, a 4-bromobenzyl group, and a 2,3,4-trimethoxybenzyl group; The method of claim 1.

7. D is H, halogen, -CN, -NH 2 , -OCH 3 , 【Transformation 8】 Selected from; and E is 【Chemistry 9】 Selected from; R k is unsubstituted or optionally substituted with one, two or more R g pyridinyl or phenyl groups substituted with G is selected from 6- to 7-membered heterocyclyl groups having a monocyclic or bridged ring structure containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; The manufacturing method according to any one of claims 1 to 6.

8. R k is unsubstituted or optionally substituted with one, two or more R g pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl and phenyl groups substituted with The method of claim 7.

9. R k together with the methylene group, 【Chemistry 10】 or forming a group selected from R in compounds of formula I k is C 1-6 Alkyl groups and C 1-6 A group substituted with 1, 2, 3 or 4 groups selected from alkyloxy groups 【Chemistry 11】 Selected from The method of claim 8.

10. The process according to any one of claims 1 to 6, wherein the compound of formula I is selected from the following compounds: 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】

11. Compound of formula XX and R k The reaction with -C(O)-H gives borane, pyridine borane, and 2-methylpyridine borane (Pic-BH 3 ), in the presence of sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride; Compound of formula XX and R k -C(O)-H molar ratio is 1:1 to 1:5; and The reaction temperature of the method for preparing the compound of formula I is 15-50°C. The method of claim 1.

12. Compound of formula XX and R k The reaction with -C(O)-H is carried out in the presence of borane or 2-methylpyridine borane and a base; Compound of formula XX and R k the molar ratio of —C(O)—H is 1:1.1 to 1:1.3; the molar ratio of the compound of formula XX to borane or 2-methylpyridine borane is 1:1.1 to 1:1.3; the molar ratio of the compound of formula XX to the base is 1:1.8 to 1:2.2; and The reaction temperature of the method for preparing the compound of formula I is 20-30°C. The method of claim 1.

13. The method for producing Compound 1 comprises the following reactions: The method of claim 1. 【Chemistry 15】

14. 10. The process of claim 1, wherein a compound of formula IIIB is first reacted with phosphorus oxychloride to give a compound of formula XII having the following structure, and then the compound of formula XII is further reacted to give a compound of formula XIII: 【Chemistry 16】 Among them, D and L 10 , L 11 and P.G. 3 are independently as defined in claim 1.

15. the molar ratio of the compound of formula IIIB to phosphorus oxychloride is 1:2 to 1:4; The preparation of compounds of formula XIII is carried out in a one-pot synthesis. The method of claim 14.

16. the molar ratio of the compound of formula IIIB to phosphorus oxychloride is 1:2.4 to 1:2.5; The reaction solvent for reacting the compound of formula IIIB with phosphorus oxychloride to obtain the compound of formula XII is N,N-dimethylformamide; The reaction temperature for reacting the compound of formula IIIB with phosphorus oxychloride to obtain the compound of formula XII is -5°C to 80°C. The method of claim 15.

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