Preparation methods, intermediates, and applications of nitrogen-containing polycyclic fused-ring compounds

Abstract

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

Description

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

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

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

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

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

[0006] To address the aforementioned problems, the present invention provides a method M1A for preparing a compound of formula I, wherein the preparation method includes a compound of formula XX and R. k The -C(O)-H reaction yields compound I:

[0007]

[0008] in:

[0009] X 1 X 2 X 3 X 4 Same or different, selected independently from CR 1 Or N;

[0010] Each R 1 They may be identical or different, independently selected from H, halogens, CN, OH, unsubstituted or optionally substituted by one, two or more R atoms. a The following groups are substituted: C 1-40 Alkyl, C 3-40 cycloalkyl, C 1-40 Alkyloxy, C 3-40 Cycloalkyloxy, NR 2 R 3 -C(O)R 4 -OCR 5 -S(O)2R 6 OS(O)2R 7 ;

[0011] D and E may be the same or different, and are independently selected from H, halogens, CN, OH, and -OR. 21 The following groups, either unsubstituted or optionally substituted by one, two or more Rc groups: C 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NR 2 R 3 The condition is that at least one of D and E is selected from -OR 21 ;

[0012] R 21 Selected from unsubstituted or arbitrarily assigned to one, two or more R d The following groups are substituted: C 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0013] G is selected from unsubstituted or optionally by one, two or more Rs. e The following groups are substituted: C 3-40 cycloalkyl, C 3-40 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 3-40 Cycloalkyloxy, C 3-40Cycloalkenyloxy, C 6-20 Aryloxy group, 5-20 membered heteroaryloxy group or 3-20 membered heterocyclic oxy group;

[0014] R k Selected from unsubstituted or arbitrarily assigned to one, two or more R g The following groups are substituted: C 1-40 Alkyl, C 3-40 cycloalkyl, C 3-40 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0015] Each R 2 Whether the two are the same or different, they are selected independently from H and C. 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, -C(O)R 4 -S(O)2R 6 ;

[0016] Each R 3 Whether the two are the same or different, they are selected independently from H and C. 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, -C(O)R 4 -S(O)2R 6 ;

[0017] Or, R 2 and R 3 Together with the attached N atom, it forms a 5-20 membered heteroaryl group or a 3-20 membered heterocyclic group;

[0018] Each R 4 Whether the two are the same or different, they are selected independently from H and C. 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-40 Alkyloxy, C 3-40 Cycloalkyloxy, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 ;

[0019] Each R5 may be the same or different, and is independently selected from H and C. 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C1-40 alkyl carbonyl, C 3-40 cycloalkyl carbonyl, C 6-20 aryl carbonyl, 5-20 membered heteroaryl carbonyl, 3-20 membered heterocyclic carbonyl;

[0020] Each R 6 They are either the same or different, and are independently selected from H and C. 1-40 Alkyl, C 2-40 alkenyl, C 2-40 alkynyl group, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-40 Alkyloxy, C 3-40 Cycloalkyloxy, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, NR 2 R 3 ;

[0021] Each R 7 They are either the same or different, and are independently selected from H and C. 1-40 Alkyl, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0022] Each R a R c R d R e They may be identical or different, and are independently selected from halogens, CN, OH, SH, oxo (=O), NO2, without substitution or optionally by one, two or more Rs. g The following groups are substituted: C 1-40 Alkyl, C 2-40 alkenyl, C 2-40 alkynyl group, C 3-40 cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-40 Alkyloxy, C 3-40 Cycloalkyloxy, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group;

[0023] Each R g The following groups, selected independently of each other and identical or different from halogens, CN, OH, SH, oxo (=O), NO2, are unsubstituted or optionally substituted by one, two or more Rh groups: C 1-40 Alkyl, C 2-40 alkenyl, C 2-40 alkynyl group, C 3-40 cycloalkyl, C3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-40 Alkyloxy, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group;

[0024] Each R h They may be the same or different, and are independently selected from halogens, CN, OH, SH, oxo (=O), NO2, unsubstituted, or optionally substituted by one, two, or more Rs. g The following groups are substituted: C 1-40 Alkyl, C 2-40 alkenyl, C 2-40 alkynyl group, C 3-40 cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-40 Alkyloxy, C 2-40 alkenyloxy group, C 2-40 alkynyloxy group, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group;

[0025] Or, when the above C 3-40 cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 When a cycloalkynyl group or a 3-20 membered heterocyclic group is replaced at different positions by two or more substituents, any two of the substituents may also form a bridged ring together with the atoms they are attached to, wherein the bridge atoms in the bridged ring, excluding the bridgehead atom, may contain 1, 2, 3, 4 or 5 divalent groups selected from CH2, O, NH.

[0026] Alternatively, when an atom (such as a carbon atom) is replaced by two or more substituents, two of the substituents may also form a cyclic group with the atom they are connected to, such as C. 3-40 cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl or 3-20 membered heterocyclic groups, etc.

[0027] According to an embodiment of the present invention, X 1 X 2 X 3 X 4 Same or different, selected independently from CR 1 Or N; for example, X 1 X 2 X 3 X 4 At least one of them is N, for example, X 1 X 2 X 3 X 4 One, two, or three of them are N;

[0028] According to an embodiment of the present invention, each R 1 They may be identical or different, independently selected from H, halogens, CN, OH, unsubstituted or optionally substituted by one, two or more Rs. a The following groups are substituted: C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkyloxy, C 3-10 Cycloalkyloxy groups, for example, selected from unsubstituted or optionally surrounded by one, two, or three R groups. a The following groups are substituted: C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyloxy;

[0029] According to embodiments of the present invention, D and E may be the same or different, and are independently selected from H, halogens, CN, NH2, and C. 1-6 Alkyl or -OR 21 The condition is that at least one of D and E is selected from -OR 21 ;

[0030] According to an embodiment of the present invention, at least one of D and E is selected from the following groups:

[0031] According to an embodiment of the present invention, R 2 Selected from unsubstituted or arbitrarily substituted by one, two or more R d Replacement C 1-6 alkyl;

[0032] According to an embodiment of the present invention, each R a R c R d They may be identical or different, independently selected from halogens, CN, OH, unsubstituted or optionally substituted by one, two or more R atoms.g The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkyloxy, C 3-10 cycloalkyl, C 3-10 Cycloalkyloxy;

[0033] According to an embodiment of the present invention, each R g They may be the same or different, and are independently selected from halogens or C. 3-10 cycloalkyl;

[0034] According to an embodiment of the present invention, G is selected from C. 3-10 cycloalkyl, C 6-1 4-aryl, 5-14-membered heteroaryl, 3-10-membered heterocyclic groups, such as 6-7-membered heterocyclic groups with monocyclic, bicyclic, or bridged ring structures, which may contain 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0035] According to an embodiment of the present invention, R k Selected from unsubstituted or arbitrarily assigned to one, two or more R g The following groups are substituted: C 3-10 cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclic group; wherein the heteroaryl group can be pyridyl, for example selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl; the aryl group can be phenyl.

[0036] According to an exemplary embodiment of the present invention, X 1 X 2 X 3 X 4 Same or different, selected independently from CH or N; for example, X 1 X 2 X 3 X 4 At least one of them is N, for example, X 1 X 2 X 3 X 4 One, two, or three of them are N;

[0037] According to an exemplary embodiment of the present invention, R 1 For H;

[0038] According to an exemplary embodiment of the present invention, E is H;

[0039] According to an exemplary embodiment of the present invention, D is selected from the following groups: halogen, BnO-, H, -CN, -NH2, -OCH3, and the following groups:

[0040]

[0041]

[0042] According to an exemplary embodiment of the present invention, G is selected from...

[0043] According to an exemplary embodiment of the present invention, R k Selected from unsubstituted or arbitrarily assigned to one, two or more R g Substituted pyridyl or phenyl, wherein one, two or more R are present. g When replaced, the R g Substitution can be performed at the 1, 2, 3, 4, 5, or 6 positions of pyridine or phenyl, as long as it does not affect R. k This can be achieved by connecting a methylene group to a group G.

[0044] As an example, R in compound I k It can form groups selected from the following groups with methylene:

[0045] Or, R in compound I k It can be selected from 1, 2, 3 or 4 selected from C 1-6 Alkyl and C 1-6 Alkyloxy group substituted group

[0046] According to an exemplary embodiment of the present invention, the compound of formula I may be selected from the following compounds:

[0047]

[0048]

[0049]

[0050] As an example, the compound of formula I is selected from the following compounds:

[0051]

[0052]

[0053] According to an embodiment of the present invention, compound XX and R k The -C(O)-H reaction can be carried out in the presence of borane, pyridineborane, 2-methylpyridineborane (Pic-BH3), sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride, preferably in the presence of 2-methylpyridineborane.

[0054] According to an embodiment of the present invention, compound XX and R k The -C(O)-H reaction can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is preferably n-methylpyrrolidone (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine); nitrile solvents (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is n-propanol.

[0055] According to an embodiment of the present invention, in the method for preparing compound I, compound XX and R... k The molar ratio of -C(O)-H can be from 1:1 to 1:5, preferably from 1:1.1 to 1:1.3.

[0056] According to an embodiment of the present invention, in the method for preparing compound I, the molar ratio of compound XX to borane or 2-methylpyridineborane can be 1:1 to 1:5, preferably 1:1.1 to 1:1.3.

[0057] According to an embodiment of the present invention, in the preparation method of compound I, the molar ratio of compound XX to base can be 1:1 to 1:5, preferably 1:1.5 to 1:3.5, such as 1:1.8 to 1:2.2.

[0058] According to an embodiment of the present invention, the reaction temperature of the preparation method of compound I can be 15-50°C, for example 20-30°C, such as room temperature.

[0059] According to embodiments of the present invention, the compound of formula XX can also be reacted using its salt form (e.g., an acid addition salt) as a starting material. Preferably, when the salt form of the compound of formula XX is used for the reaction, a base can be used to release it into the compound of formula XX. This release can be carried out alone or in conjunction with the reaction in the preparation method M1A described above via a one-pot process.

[0060] According to an embodiment of the present invention, the alkali can be an organic alkali or an inorganic alkali, for example:

[0061] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium tert-butoxide, potassium tert-butoxide; or

[0062] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0063] According to an exemplary embodiment of the present invention, the preparation method M1A includes preparing compound 1 by reacting compound 20 as follows:

[0064]

[0065] The present invention also provides compounds of the above formula XX, such as compound 20.

[0066] The present invention also provides the use of the above-described compound of formula XX (e.g., compound 20) in the preparation of compound of formula I (e.g., compound 1).

[0067] This invention also provides compounds of formula XIX:

[0068]

[0069] in:

[0070] G is selected from unsubstituted or optionally by one, two or more Rs. e The following groups are substituted: 5-20-membered heteroaryl, 3-20-membered heterocyclic, 5-20-membered heteroaryloxy, or 3-20-membered heterocyclicoxy, wherein G has at least one N atom and the N atom is related to PG. 19 connect;

[0071] X 1 X 2 X 3 X 4 D, E, R e Independently possessing the definition described above;

[0072] PG 19 It is an amino protecting group.

[0073] According to an embodiment of the present invention, PG 19 The amino protecting group can be selected from those known to those skilled in the art, such as tert-butoxycarbonyl (Boc), cyclobutoxycarbonyl, benzyloxycarbonyl (CBz), p-methoxybenzylcarbonyl (Moz), 2-biphenyl-2-propoxycarbonyl (BPoc), 2,2,2-trichloroethoxycarbonyl (Troc), phthalimide, p-toluenesulfonyl, trifluoroacetyl, (9H-fluorene-9-ylmethoxy)carbonyl (Fmoc), benzyl, 4-methoxybenzyl, diphenylmethyl, 2-(trimethylsilyl)ethoxycarbonyl (Teoc), adamantyloxycarbonyl (Adoc), formyl, acetyl, etc.

[0074] The present invention also provides a method M20 for preparing a compound of formula XX, comprising removing PG from a compound of formula XIX. 19 The reaction under the specified conditions yielded compound XX.

[0075] PG of the de-XIX compound 19 The conditions for removing the amino protecting group are known to those skilled in the art. For example, the PG of compound XIX can be removed in the presence of an acid. 19The acid can be selected from one, two or more inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, formic acid, and acetic acid.

[0076] According to an embodiment of the present invention, in the preparation method of compound XX, the molar ratio of compound XIX to acid can be 1:1 to 1:5, such as 1:3 to 1:4.

[0077] According to an embodiment of the present invention, the compound of formula XIX is de-PG 19 The reaction can be carried out in the presence of an organic solvent. The organic solvent has the definition described above, such as an alcohol solvent, selected from one, two, or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol.

[0078] According to an embodiment of the present invention, the reaction temperature of the method for preparing compound I can be 40–70°C, for example 50–60°C.

[0079] According to an embodiment of the present invention, the preparation method M20 includes preparing compound 20 by reacting compound 19 as follows:

[0080]

[0081] Therefore, the present invention also provides compound 19.

[0082] The present invention also provides the use of the above-described compound XIX (e.g., compound 19) in the preparation of compound XX (e.g., compound 20).

[0083] This invention also provides compounds of formula XI:

[0084]

[0085] in:

[0086] D and E independently possess the definitions described above;

[0087] L 11 Selected from leaving groups, such as the following groups that are unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 halogens: C 1-6 alkylsulfonyloxy, C 1-6 Alkylbenzenesulfonyloxy, such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyloxy (TfO-), p-toluenesulfonyloxy (TsO-), halogens (such as F, Cl, Br or I).

[0088] This invention also provides compounds of formula XVIII:

[0089]

[0090] Among them, X 1 X 2 X 3 X 4 G, PG 19 It independently possesses the definition described above.

[0091] This invention also provides a method M19A for preparing a compound of formula XIX, comprising reacting a compound of formula XI with a compound of formula XVIII to obtain a compound of formula XIX:

[0092]

[0093] Among them, X 1 X 2 X 3 X 4 D, E, G, L 11 PG 19 It independently possesses the definition described above.

[0094] According to an embodiment of the present invention, in the method for preparing the above-described compound of formula XIX, the reaction can be carried out in the presence of a base.

[0095] The base can be an organic base or an inorganic base, for example:

[0096] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium tert-butoxide, potassium tert-butoxide; or

[0097] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0098] According to embodiments of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of an organic solvent or a mixture of an organic solvent and water. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is preferably dioxane. The solvent may contain: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0099] According to embodiments of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of a catalyst, which can be a palladium catalyst, such as Pd(dba)2, PdCl2, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(t-Bu)3, PdCl2(PPh3)2·CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHOS)2, P dCl2(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.

[0100] According to an embodiment of the present invention, the reaction temperature of the method for preparing the above-described compound of formula XIX can be above 50°C, for example above 80°C, such as 85°C.

[0101] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound XIX, the molar ratio of compound XI to compound XVIII can be 1:1 to 1:2, for example 1:1.1 to 1:1.3, such as 1:1.2 to 1:1.3.

[0102] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XI to base can be 1:1 to 1:5, for example 1:1.5 to 1:3.5, such as 1:1.8 to 1:2.2.

[0103] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XI to catalyst can be from 1:0.001 to 1:0.05, such as from 1:0.02 to 1:0.03.

[0104] According to an embodiment of the present invention, the preparation method M19A includes preparing compound 19 by reacting compound 11 and compound 18 as follows:

[0105]

[0106] Therefore, the present invention also provides the above-described compound 11 or compound 18.

[0107] The present invention also provides the use of the above-described compounds of formula XI (e.g., compound 11) and / or compounds of formula XVIII (e.g., compound 18) in the preparation of compounds of formula XIX (e.g., compound 19).

[0108] The present invention also provides a method M11 for preparing a compound of formula XI, comprising reacting a compound of formula X with hydrazine (such as hydrazine hydrate) to obtain a compound of formula XI:

[0109]

[0110] in:

[0111] D, E, L 11 Independently possessing the definition described above;

[0112] L 10 Selected from leaving groups, such as halogens, such as F, Cl, Br or I.

[0113] According to embodiments of the present invention, the preparation method of the compound of formula XI can be carried out in the presence of an organic solvent or a mixture of an organic solvent and water. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is preferably dimethyl pyrrolidone (DML), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dimethyl sulfoxide.

[0114] According to an embodiment of the present invention, in the preparation method of compound XI, the reaction temperature can be above 100°C, such as 110-115°C.

[0115] According to an embodiment of the present invention, in the preparation method of compound X1, the molar ratio of compound X to hydrazine can be 1:1 to 1:15, for example 1:2 to 1:10, such as 1:6 to 1:8.

[0116] According to an embodiment of the present invention, the preparation method M11 includes preparing compound 11 by reacting compound 10 as follows:

[0117]

[0118] The present invention also provides compounds of formula X, such as compound 10.

[0119] The present invention also provides the use of the above-described compound X (e.g., compound 10) in the preparation of compound XI (e.g., compound 11).

[0120] The present invention also provides a method M10A for preparing a compound of formula X, comprising reacting a compound of formula XIII with compound R. 21 -L 13 The reaction yields compound X:

[0121]

[0122] in:

[0123] D, L 10 L 11 R 21 Independently possessing the definition described above;

[0124] E is selected from -OR 21 ;

[0125] L 13 Selected from leaving groups, such as halogens, such as the following groups that are unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 halogens: C 1-6 alkylsulfonyloxy, C 1-6 Alkylbenzenesulfonyloxy, such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyloxy (TfO-), p-toluenesulfonyloxy (TsO-), F, Cl, Br or I.

[0126] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of a base.

[0127] According to an embodiment of the present invention, the alkali can be an organic alkali or an inorganic alkali, for example:

[0128] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium tert-butoxide, potassium tert-butoxide; or

[0129] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0130] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is selected from dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile solvents (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethylformamide.

[0131] According to an embodiment of the present invention, in the method for preparing compound X, compound XIII and compound R... 21 -L 13 The molar ratio can be 1:1 to 1:2, for example 1:1 to 1:1.2, such as 1:1 to 1:1.1.

[0132] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound XIII to base can be 1:1 to 1:2, for example 1:1.1 to 1:1.3, such as 1:1.1 to 1:1.2.

[0133] According to an embodiment of the present invention, the reaction temperature in the preparation method of compound X can be above 50°C, for example 60-70°C, such as 65°C.

[0134] According to an embodiment of the present invention, the preparation method M10A includes preparing compound 10 by reacting compound 13 as follows:

[0135]

[0136] The present invention also provides compounds of the above formula XIII, such as compound 13.

[0137] The present invention also provides the use of the above-described compound XIII (e.g., compound 13) in the preparation of compound X (e.g., compound 10).

[0138] The present invention also provides a method M13 for preparing compound XIII, comprising reacting compound IIIB in the presence of phosphorus oxychloride (POCl3), wherein compound IIIB has the following structure:

[0139]

[0140] in:

[0141] L 10 L 11 Independently possessing the definition described above;

[0142] PG 3 Selected from hydroxyl protecting groups.

[0143] According to an embodiment of the present invention, PG 3 The protecting group may be selected from those known to those skilled in the art, such as unsubstituted or optionally protected by 1, 2, 3, 4 or 5 groups selected from C. 1-6 Alkyl, C 1-6 Alkyloxy groups and halogen substituents can replace the following groups: benzyl, C 1-6 Alkyl, tri(C) 1-6 Alkyl)silyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, triphenylmethyl, C 1-6 Alkyloxymethyl, benzyloxymethyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 Alkyl carbonyl, benzoyl, examples of which may be selected from benzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl or 2,3,4-trimethoxybenzyl.

[0144] According to an embodiment of the present invention, the preparation method M13 includes reacting compound 3b in the presence of phosphorus oxychloride (POCl3), wherein compound 3b has the following structure:

[0145]

[0146] According to an embodiment of the present invention, in the preparation method of compound XIII, compound IIIB (e.g., compound 3b) can first react with phosphorus oxychloride to obtain compound XII, and then compound XII further reacts to obtain compound XIII, wherein compound XII has the following structure:

[0147]

[0148] Among them, L 10 L 11 PG 3 It independently possesses the definition described above.

[0149] According to an embodiment of the present invention, in the method for preparing compound XIII, the molar ratio of compound IIIB to phosphorus oxychloride can be 1:2 to 1:4. For example, 1:2 to 1:3, such as 1:2.4 to 1:2.5.

[0150] According to an embodiment of the present invention, the preparation method of compound XIII can be carried out in a one-pot process.

[0151] According to an embodiment of the present invention, the reaction solvent for reacting compound IIIB with phosphorus oxychloride to obtain compound XII can be the above-mentioned organic solvent, such as N,N-dimethylformamide.

[0152] According to an embodiment of the present invention, the reaction temperature for reacting compound IIIB with phosphorus oxychloride to obtain compound XII can be from -5°C to 80°C, for example from 0°C to 70°C.

[0153] 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 can be a mixture of the above-mentioned organic solvent and water, such as a mixture of N,N-dimethylformamide and water.

[0154] According to an embodiment of the present invention, the reaction temperature for further reacting the compound of formula XII to obtain the compound of formula XIII can be 15 to 40°C, for example 20 to 35°C, such as 25 to 30°C.

[0155] According to an embodiment of the present invention, the preparation method M13 includes preparing compound 12 from compound 3b by the following reaction, and preparing compound 13 from compound 12:

[0156]

[0157] The present invention also provides compounds of the above formula IIIB, such as compound 3b.

[0158] The present invention also provides compounds of the above formula XII, such as compound 12.

[0159] The present invention also provides the use of the above-described compounds of formula IIIB (e.g., compound 3b) and / or compounds of formula XII (e.g., compound 12) in the preparation of compounds of formula XIII (e.g., compound 13).

[0160] The present invention also provides the use of the above-described compound IIIB (e.g., compound 3b) in the preparation of compound XII (e.g., compound 12).

[0161] The present invention also provides a method M10B for preparing compound X, comprising reacting compound XVII with phosphorus oxychloride to obtain compound X:

[0162]

[0163] Among them, D, E, L 10 L 11 It independently possesses the definition described above.

[0164] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is selected from dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile solvents (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethylformamide.

[0165] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound XVII to phosphorus oxychloride can be 1:2 to 1:8. For example, 1:3 to 1:6, such as 1:4 to 1:5:2 to 1:4, such as 1:2 to 1:3, such as 1:2.4 to 1:2.5.

[0166] According to an embodiment of the present invention, the preparation method M10B includes preparing compound 10 by reacting compound 17 as follows:

[0167]

[0168] The present invention also provides compounds of formula XVII, such as compound 17.

[0169] The present invention also provides the use of compounds of formula XVII (e.g., compound 17) in the preparation of compounds of formula X (e.g., compound 10).

[0170] The present invention also provides a method M17 for preparing compounds of formula XVII, comprising reacting a compound of formula XVI with an alkali metal halide or an organohalide to obtain a compound of formula XVII:

[0171]

[0172] Among them, D, E, L 10 Independently possessing the definition described above;

[0173] L 16 The following groups are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens: C 1-6 alkylsulfonyl, C 1-6 Alkylbenzenesulfonyl groups, such as methanesulfonyl (Ms-), trifluoromethanesulfonyl (Tf-), and p-toluenesulfonyl (Ts-).

[0174] According to an embodiment of the present invention, in the method for preparing compound XVII, the alkali metal halide or organic halide can be selected from at least one of LiBr, NaBr, KBr, CsBr, and Bu4NBr.

[0175] According to embodiments of the present invention, the preparation method of compound XVII can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and ethylene oxide and... / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... Caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is n-propanol.

[0176] According to an embodiment of the present invention, in the method for preparing compound XVII, the molar ratio of compound XVI to alkali metal halide or organohalide can be 1:1 to 1:5, for example 1:1 to 1:2, such as 1:1.5.

[0177] According to embodiments of the present invention, the preparation method of compound XVII can be carried out in the presence of a catalyst. The catalyst may be, for example, pentamethylcyclopentadiene ditriphenylphosphine ruthenium(II) chloride, tri(acetonitrile)pentamethylcyclopentadiene trifluoromethanesulfonate ruthenium(II) acid, pentamethylcyclopentadienyl tri(acetonitrile)hexafluorophosphate ruthenium(II) chloride (dimer), pentamethylcyclopentadienyl ruthenium(I) chloride (tetramer), tri(acetonitrile)tetramethylcyclopentadiene trifluoromethanesulfonate ruthenium(II) acid, or cyclooctadiene diruthenium(II) chloride.

[0178] According to an embodiment of the present invention, in the method for preparing compound XVII, the molar ratio of compound XVI to catalyst can be from 1:0.01 to 1:0.1, such as 1:0.05.

[0179] According to embodiments of the present invention, the reaction temperature of the method for preparing compound XVII can be above 50°C, for example above 80°C, such as 90 to 100°C.

[0180] According to an embodiment of the present invention, the preparation method M17 includes preparing compound 17 by reacting compound 16 as follows:

[0181]

[0182] The present invention also provides compounds of the above formula XVI, such as compound 16.

[0183] The present invention also provides the use of compounds of formula XVI (e.g., compound 16) in the preparation of compounds of formula XVII (e.g., compound 17).

[0184] The present invention also provides a method M16 for preparing a compound of formula XVI, comprising reacting a compound of formula XV with a sulfonating agent to obtain a compound of formula XVI:

[0185]

[0186] Among them, D, E, L 10 It independently possesses the definition described above.

[0187] According to embodiments of the present invention, the preparation method of compound XVI can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is selected from dichloromethane. It can be substituted with 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile solvents (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzylnitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); or ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dichloromethane.

[0188] According to an embodiment of the present invention, in the method for preparing the compound of formula XVI, the sulfonating agent may be selected from unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens. 1-6 Alkyl sulfonyl chloride, unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens. 1-6 Alkyl sulfonic anhydride, unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens. 1-6 Alkylbenzene sulfonyl chloride, such as methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (PhN(Tf)2).

[0189] 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 agent can be 1:1 to 1:5, for example 1:1 to 1:1.2, such as 1:1.1 to 1:1.15.

[0190] According to an embodiment of the present invention, the preparation method M16 includes preparing compound 16 by reacting compound 15 as follows:

[0191]

[0192] The present invention also provides compounds of the above formula XV, such as compound 15.

[0193] The present invention also provides the use of the above-described XV compounds (e.g., compound 15) in the preparation of XVI compounds (e.g., compound 16).

[0194] The present invention also 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:

[0195]

[0196] Among them, D, E, L 10 PG 3 It independently possesses the definition described above.

[0197] According to an embodiment of the present invention, in the method for preparing compound XV, the acid may be selected from organic or inorganic acids, such as at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, trifluoroacetic acid, phosphorus oxychloride, succinic acid, and ascorbic acid.

[0198] According to embodiments of the present invention, the preparation method of compound XV can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is selected from dichloromethane. It can be substituted with 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzylnitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); or ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dichloromethane.

[0199] According to an embodiment of the present invention, in the method for preparing compound XV, the molar ratio of compound XIV to trifluoroacetic acid can be 1:1 to 1:10, for example 1:4 to 1:6, such as 1:5 to 1:5.5.

[0200] According to an embodiment of the present invention, in the preparation method of compound XV, trifluoroacetic acid can participate in the reaction by dropwise addition.

[0201] According to an embodiment of the present invention, the preparation method M15 includes preparing compound 15 by reacting compound 14 as follows:

[0202]

[0203] The present invention also provides compounds of the above formula XIV, such as compound 14.

[0204] The present invention also provides the use of the above-described XIV compounds (e.g., compound 14) in the preparation of XV compounds (e.g., compound 15).

[0205] This invention also provides a method M14 for preparing compound XIV, comprising reacting compound IIIA with ethanol to obtain compound XIV:

[0206]

[0207] Among them, D and L 10 PG 3 Independently possessing the definition described above;

[0208] L 3a Selected from leaving groups, such as halogens, like chlorine, bromine, or iodine.

[0209] According to an embodiment of the present invention, the preparation method of compound XIV can be carried out in the presence of a copper catalyst and a ligand.

[0210] According to an embodiment of the present invention, the copper catalyst may be selected from at least one of cuprous iodide (CuI), cuprous bromide (CuBr), and copper acetylacetonate (Cu(acac)2).

[0211] According to an embodiment of the present invention, the ligand may be selected from at least one of N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, 8-hydroxyquinoline, N,N′-bis(2,4,6-trimethoxyphenyl)oxalamide, N-benzyl-N-(2-methylnaphthyl-1-yl)glyoxalamide, and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide.

[0212] According to embodiments of the present invention, the preparation method of compound XIV can be further carried out in the presence of a base. The base can be an organic base or an inorganic base, for example:

[0213] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, Quinoline, Methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, Diazabicyclooctane (DABCO), Diazabicyclononane (DBN), Diazabicycloundecane (DBU), Butylimidazole, Methylimidazole, Sodium tert-butoxide, Potassium tert-butoxide; or

[0214] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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.

[0215] According to an embodiment of the present invention, in the preparation method of compound XIV, the molar volume ratio of compound IIIA to ethanol can be 1 mol: (2-5) L, such as 1 mol: (3-4) L.

[0216] According to an embodiment of the present invention, in the method for preparing compound XIV, the molar ratio of compound IIIA to cuprous catalyst can be from 1:0.01 to 1:0.2, such as 1:0.02.

[0217] According to an embodiment of the present invention, in the preparation method of compound XIV, the molar ratio of compound IIIA to base can be 1:1 to 1:10, such as 1:2 to 1:4, such as 1:3.

[0218] According to an embodiment of the present invention, in the preparation method of the compound of formula XIV, the molar ratio of the compound of formula IIIA to the ligand can be from 1:0.01 to 1:0.2, such as 1:0.02.

[0219] According to an embodiment of the present invention, in the preparation method of compound XIV, the reaction temperature can be above 50°C, for example above 70°C, such as 80 to 100°C.

[0220] According to an embodiment of the present invention, the preparation method M14 includes preparing compound 14 by reacting compound 3a as follows:

[0221]

[0222] The present invention also provides compounds of the above formula IIIA, such as compound 3a.

[0223] The present invention also provides the use of the above-described compound IIIA (e.g., compound 3a) in the preparation of compound XIV (e.g., compound 14).

[0224] This invention also provides a method M10C for preparing compound X, comprising reacting compound IX with an alkali metal halide or an organohalide to obtain compound X:

[0225]

[0226] Among them, D, E, L 10 L 16 It independently possesses the definition described above.

[0227] According to an embodiment of the present invention, in the preparation method of compound X, the alkali metal halide or organic halide can be selected from at least one of LiBr, NaBr, KBr, CsBr, and Bu4NBr.

[0228] According to an embodiment of the present invention, the preparation method of compound X can be carried out in the presence of a base. The base can be an organic base or an inorganic base, for example:

[0229] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium tert-butoxide, potassium tert-butoxide; or

[0230] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0231] According to an embodiment of the present invention, in the preparation method of compound X, the molar ratio of compound IX to alkali metal halide or organohalide can be 1:1 to 1:5, for example 1:1 to 1:2, such as 1:1.5.

[0232] According to embodiments of the present invention, the preparation method of compound X can be carried out in the presence of a catalyst. The catalyst may be, for example, pentamethylcyclopentadiene ditriphenylphosphine ruthenium(II) chloride, tri(acetonitrile)pentamethylcyclopentadiene trifluoromethanesulfonate ruthenium(II) acid, pentamethylcyclopentadienyl tri(acetonitrile)hexafluorophosphate ruthenium(II) chloride (dimer), pentamethylcyclopentadienyl ruthenium(I) chloride (tetramer), tri(acetonitrile)tetramethylcyclopentadiene trifluoromethanesulfonate ruthenium(II) acid, or cyclooctadiene diruthenium(II) chloride.

[0233] According to an embodiment of the present invention, in the method for preparing compound X, the molar ratio of compound IX to catalyst can be from 1:0.01 to 1:0.1, such as 0.05.

[0234] According to an embodiment of the present invention, the reaction temperature of the method for preparing compound X can be above 50°C, for example above 80°C, such as 90 to 100°C.

[0235] According to the preparation method of the present invention, the preparation method M10C includes preparing compound 10 by reacting compound 9 as follows:

[0236]

[0237] The present invention also provides compounds of formula IX, such as compound 9.

[0238] The present invention also provides the use of the above-described compound IX (e.g., compound 9) in the preparation of compound X (e.g., compound 10).

[0239] According to embodiments of the present invention, compound IX can also be prepared from compound IIIA as a starting material. For example, compound IIIA can be reacted with phosphorus oxychloride to obtain compound IV as follows:

[0240]

[0241] Among them, D and L 10 PG 3 L 3a It independently possesses the definition described above.

[0242] According to embodiments of the present invention, the reaction of compound IIIA with phosphorus oxychloride can be carried out in the presence of an organic solvent. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is selected from dimethyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolidone, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile solvents (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); and ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is selected from dimethyl sulfoxide or N,N-dimethylformamide.

[0243] According to an embodiment of the present invention, in the above preparation method, the molar ratio of compound IIIA to phosphorus oxychloride can be 1:2 to 1:8. For example, 1:3 to 1:6, such as 1:4 to 1:5.

[0244] According to an embodiment of the present invention, the group L3a of the compound of formula IV can be derived into the group E as defined above according to a known organic synthesis method. For example, L3a can be first converted into a hydroxyl-derived intermediate and then derived into group E.

[0245] Alternatively, referring to the preparation method M14 described above, the L group of compound IV can be... 3a It is derived into the group E.

[0246] Alternatively, according to an embodiment of the present invention, the compound of formula IV or the above derivative may be reacted with trifluoroacetic acid in preparation method M15 to make the group PG 3 The derivative is derived to a hydroxyl group; and / or, referring to preparation method M16 above, the derivative is reacted with the sulfonating agent described above to obtain a C-hydroxyl group in which the hydrogen atom is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 halogens. 1-6 Alkyl sulfonyl groups, such as methanesulfonyl (Ms) or trifluoromethanesulfonyl-substituted derivatives.

[0247] As an example, the reaction of compound IV with trifluoroacetic acid yields compound XXIII as follows:

[0248]

[0249] Among them, D and L 10 L 3a It independently possesses the definition described above.

[0250] According to an embodiment of the present invention, the compound of formula XXIII can be reacted with hydrazine (such as hydrazine hydrate) in accordance with the preparation method M11 described above to obtain the compound of formula XXXI as follows:

[0251]

[0252] Among them, D and L 3a It independently possesses the definition described above.

[0253] According to embodiments of the present invention, the L group of the compound of formula XXXI can be synthesized using known organic synthesis methods. 3a It can be derived into the group E defined above, for example, L can be first... 3a The intermediate is converted to a hydroxyl-derived compound, which is then further derivatized into group E to obtain compound of formula XXIX:

[0254]

[0255] Alternatively, referring to the preparation method M14 above, the group L3a of compound XXXI can be derived into group E to obtain compound XXIX.

[0256] According to an embodiment of the present invention, the above-described preparation method M16 can also be used to react the above-described compound of formula XXIX with the above-described sulfonating reagent to obtain the following groups in which the hydrogen atom on the hydroxyl group is unsubstituted or substituted by 1, 2, 3, 4, 5 or 6 halogens: C 1-6 alkylsulfonyl, C 1-6 Compounds of formula XXX substituted with alkylbenzenesulfonyl groups, such as methanesulfonyl (Ms-), trifluoromethanesulfonyl (Tf-), or p-toluenesulfonyl (Ts-):

[0257]

[0258] Among them, D and E independently have the definitions described above;

[0259] L 30 The following groups are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens: C 1-6 alkylsulfonyl, C 1-6 Alkylbenzenesulfonyl groups, such as methanesulfonyl (Ms-), trifluoromethanesulfonyl (Tf-), and p-toluenesulfonyl (Ts-).

[0260] According to embodiments of the present invention, compound 3a can be used to prepare compounds 4, 5, 6, 7, 8, and / or 9 via the following reactions:

[0261]

[0262] According to embodiments of the present invention, compound 3a can also be used to prepare compounds 4, 23, 31, 29 and / or 30 via the following reactions:

[0263]

[0264] According to embodiments of the present invention, compound 4 can also be used to prepare compounds 23, 31, 25, 26, 27, 28, 29 and / or 30 via the following reactions:

[0265]

[0266] The present invention also provides compounds of formula IV (e.g., compound 4), formula XXIII (e.g., compound 23), formula XXXI (e.g., compound 31), formula XXIX (e.g., compound 29), and formula XXX (e.g., compound 30), and the use of any of the above compounds in the preparation of compounds of formula I.

[0267] According to an embodiment of the present invention, a method M19B for preparing a compound of formula XIX is also provided, comprising reacting a compound of formula XXX with a compound of formula XVIII to obtain a compound of formula XIX, wherein the compound of formula XVIII and the compound of formula XIX have the definitions described above.

[0268] According to an embodiment of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of a base.

[0269] The base can be an organic base or an inorganic base, for example:

[0270] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium tert-butoxide, potassium tert-butoxide; or

[0271] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0272] According to embodiments of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of an organic solvent or a mixture of an organic solvent and water. The organic solvent may be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene); halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is preferably dioxane. It can be 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); or ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0273] According to embodiments of the present invention, the preparation method of the above-described compound of formula XIX can be carried out in the presence of a catalyst, which can be a palladium catalyst, such as Pd(dba)2, PdCl2, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(t-Bu)3, PdCl2(PPh3)2·CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHOS)2, P dCl2(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.

[0274] According to an embodiment of the present invention, the reaction temperature of the method for preparing the above-described compound of formula XIX can be above 80°C, for example above 100°C, such as 120°C.

[0275] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound XIX, the molar ratio of compound XXX to compound XVIII can be 1:1 to 1:5, for example 1:2 to 1:4, such as 1:3.

[0276] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound of formula XIX, the molar ratio of compound of formula XXX to base can be 1:1 to 1:10, for example 1:4 to 1:8, such as 1:5 to 1:6.

[0277] According to an embodiment of the present invention, in the preparation method of the above-mentioned compound XIX, the molar ratio of compound XXX to catalyst can be from 1:0.01 to 1:0.2, such as from 1:0.05 to 1:0.1.

[0278] This invention also provides a method M1B for preparing a compound of formula I, wherein the method comprises reacting a compound of formula XXX with a compound of formula XXXX to obtain a compound of formula I:

[0279]

[0280] Among them, D, E, L 30 X 1 X 2 X 3X 4 G, R k They each possess the definitions described above independently.

[0281] According to an embodiment of the present invention, the reaction of the above-described preparation method M1B can be carried out in the presence of a catalyst, which can be a palladium catalyst, such as Pd(dba)2, PdCl2, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(t-Bu)3, PdCl2(PPh3)2·CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHOS)2, Pd Cl2(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.

[0282] According to an embodiment of the present invention, the reaction of M1B in the above preparation method can be carried out in the presence of a base.

[0283] The base can be an organic base or an inorganic base, for example:

[0284] Selected from the following organic bases: tertiary amines, substituted or unsubstituted pyridines, and substituted or unsubstituted triethylamine, trimethylamine, N,N-diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2,3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethyl... 2,4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, methylquinoline, N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium tert-butoxide, potassium tert-butoxide; or

[0285] The inorganic bases are selected from the following: hydrides, hydroxides, ammonides, alkoxides, acetates, fluorides, phosphates, carbonates, and bicarbonates of alkali metals or alkaline earth metals, 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, potassium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate.

[0286] According to an embodiment of the present invention, the reaction of the above-described preparation method M1B can be carried out in the presence of an organic solvent. The organic solvent can be selected from one or a mixture of two or more of the following: ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and epoxy...). Ethane and / or propylene oxide polyethers); sulfoxides (e.g., tetrahydrodioxothiophene and dimethyl sulfoxide, tetramethyl sulfoxide, dipropylene sulfoxide, benzylmethyl 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, cyclopentane, etc.). Hexane, methylcyclohexane, petroleum ether, crude gasoline, octane, benzene, toluene, or xylene; halogenated alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methyl... The organic solvent is preferably dioxane. The solvent may contain: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine, or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzyl nitrile); alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol); ketones (e.g., acetone, N-methylpyrrolidone). Preferably, the organic solvent is dioxane.

[0287] According to an embodiment of the present invention, the reaction of the preparation method M1B can be carried out at 100°C to 150°C, for example, 115°C to 125°C.

[0288] According to an embodiment of the present invention, the preparation method M1B includes preparing compound 1 by reacting compound 30 and compound 40 as follows:

[0289]

[0290] The present invention also provides the use of the above-described XXX compound in the preparation of the XIX compound.

[0291] The present invention also provides a method for preparing a compound of formula I, a pharmaceutically acceptable salt thereof, or an intermediate thereof, comprising the preparation method of the above-described compound of formula IIIA and / or compound of formula IIIB as a starting material or the reaction thereof.

[0292] The present invention also provides the use of the compound of formula IIIA in the preparation of the compound of formula I, its pharmaceutically acceptable salt, or the intermediates described above.

[0293] According to a preferred embodiment of the present invention, any of the preparation methods or uses described above can be carried out under an inert atmosphere (such as a nitrogen atmosphere).

[0294] According to a preferred embodiment of the present invention, in any of the preparation methods or uses described above, the compound used as a raw material may be provided and participate in the reaction in the form of its acid addition salt, as needed.

[0295] According to a preferred embodiment of the present invention, in any of the preparation methods or uses described above, when the compound used as a raw material is provided in the form of an acid addition salt and participates in the reaction, if necessary, the acid addition salt can be freed by a base (organic base or inorganic base) as defined above before participating in the reaction, or the freeing step and subsequent reaction can be carried out in situ by a "one-pot" method.

[0296] The present invention also provides a preparation method, comprising combining one, two, three or more of the above-described preparation methods sequentially to prepare the target compound. Those skilled in the art should understand that when combining one, two, three or more of the above-described preparation methods sequentially, it is preferable to use the product obtained from one preparation method as a raw material for the next preparation method.

[0297] The present invention also provides a preparation method M-IIIB-I, comprising the above-described preparation methods M13, M10A, M11, M19A, M20, and M1A, or a combination of two, three, or more of the above-described preparation methods. Preferably, the preparation methods in the combination are performed sequentially, with the product obtained from the first preparation method used as the reaction substrate for the subsequent preparation method.

[0298] The present invention also provides a preparation method M-IIIA-X1, comprising the above-described preparation methods M14, M15, M16, M17, and M10B, or a combination of two, three, or more of the above-described preparation methods. Preferably, the preparation methods in the combination are performed sequentially, with the product obtained from the first preparation method used as the reaction substrate for the subsequent preparation method.

[0299] The present invention also provides a preparation method M-IIIA-X2, comprising preparing compounds of formula IV, V, VI, VII, VIII, and IX by the above preparation method, and preparing compound X by the preparation method M10C.

[0300] The present invention also provides a preparation method M-IIIA-XXX, comprising preparing compound XXIII, compound XXXI, compound XXIX and compound XXX by the above method.

[0301] According to embodiments of the present invention, it should be understood that one of the different preparation methods for preparing the same intermediate can be combined with a preparation method for further preparing other compounds using the intermediate as a reaction substrate. Such a combination should also be understood as described in this specification, and should not be limited to a specific combination of preparation methods described above. For example, in the above description, the preparation methods for compound X include M10A, M10B, and M10C, any of which can be combined with preparation method M19A, or further combined with M20 and / or M1. Similarly, the different preparation methods for compound XXX described above can all be combined with preparation method M1B to prepare compound I.

[0302] According to embodiments of the present invention, in any of the preparation methods or uses described above, it is preferable not to use chromatographic methods such as column chromatography to separate or purify the raw materials, reaction products or intermediates.

[0303] According to embodiments of the present invention, in any of the preparation methods or uses described above, it is preferable not to use hydrogen as a hydrogenation or reduction agent, and not to use hydrogen for the reaction by means of catalytic hydrogenation.

[0304] According to embodiments of the present invention, in any of the preparation methods or uses described above, when an organic solvent or a mixture of an organic solvent and water is used, it is inert to the reaction substrate and reagents.

[0305] Terminology Definitions and Explanations

[0306] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0307] Unless otherwise stated, the numerical ranges described in this specification and claims correspond to at least each specific integer value described herein. For example, the numerical range "1-40" corresponds to each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40. It should be understood that when describing substituents herein, "more than" in the context of one, two, or more means an integer ≥3, such as 3, 4, 5, 6, 7, 8, 9, or 10.

[0308] The term "halogen" refers to a substituent group selected from fluorine, chlorine, bromine, or iodine.

[0309] Term "C" 1-40 "alkyl" should be understood to preferably represent a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0310] Term "C" 2-40 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 40 carbon atoms, preferably "C". 2-6 "Alkenyl". "C" 2-6 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C"). 2-3The term "alkenyl" should be understood to refer to a group containing more than one double bond, where the double bonds can be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl. -alkenyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2 -Methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl 1,1-dimethylprop-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0311] Term "C" 2-40"Alynyl" should be understood to refer to a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, preferably "C2-C6-alkynyl". The term "C2-C6-alkynyl" should be understood to preferably refer to a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl"). The C2-C6-alkynyl is, for example, ethynyl, propynyl-1-alkynyl, propynyl-2-alkynyl, butynyl-1-alkynyl, butynyl-2-alkynyl, butynyl-3-alkynyl, pentynyl-1-alkynyl, pentynyl-2-alkynyl, pentynyl-3-alkynyl, pentynyl-4-alkynyl, hexynyl-1-alkynyl, hexynyl-2-alkynyl, hexynyl-3-alkynyl, hexynyl-4-alkynyl, hexynyl-5-alkynyl, 1-methylpropynyl-2-alkynyl, 2-methylbutynyl-3 ...2-methylpropynyl-2-alkynyl, 2-methylpropynyl-2-alkynyl, 2-methylpropynyl-2-alkynyl, 2-methylpropynyl-2-alkynyl, 2-methylpropynyl-2-alkynyl, 3-methylbut-2-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpentan-4-ynyl, 2-methylpentan-4-ynyl, 1-methylpentan-4-ynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl 2-Ethylbut-3-ynyl, 1-Ethylbut-3-ynyl, 1-Ethylbut-2-ynyl, 1-Prop-2-ynyl, 1-Isopropylp-2-ynyl, 2,2-Dimethylbut-3-ynyl, 1,1-Dimethylbut-3-ynyl, 1,1-Dimethylbut-2-ynyl, or 3,3-Dimethylbut-1-ynyl. In particular, the ynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl.

[0312] Term "C" 3-40 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic, or bridged cycloalkanes having 3 to 40 carbon atoms, preferably "C". 3-10 cycloalkyl. The term "C" 3-10 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic, or bridged cycloalkanes having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring.

[0313] The term "3-20 membered heterocyclic group" refers to a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane comprising 1-5 heteroatoms independently selected from N, O, and S, forming a non-aromatic cyclic group with a total ring atomic number of 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably a "3-10 membered heterocyclic group". The term "3-10 membered heterocyclic group" also refers to a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane comprising 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic. When the 3-20 membered heterocyclic group is linked to other groups to form the compounds of the invention, the carbon atom on the 3-20 membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring can be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be linked to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and its para-carbon atom can be linked to other groups.

[0314] Term "C" 6-20 "Aryl" should be understood to preferably represent a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms and possessing monovalent aromaticity or partial aromaticity, preferably "C". 6-14 Aryl. The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0315] The term "5-20-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purinyl, and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylonitrileyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenotoxazinyl, etc. When the 5-20 membered heteroaryl group is linked with other groups to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be linked with other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be linked with other groups. When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom linked to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen atom linked to the heteroatom on the heteroaryl ring may be substituted.

[0316] Unless otherwise stated, heterocyclic, heteroaryl, or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, forms may include those in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene groups include thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0317] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0318] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, such as C. 1-6 The definition of alkyl also applies to C 1-6 Alkyloxy group, -N(C) 1-6 Alkyl)2、-NHC 1-6 Alkyl or -S(O)2-C 1-6 Alkyl groups, etc.

[0319] Those skilled in the art will understand that the compounds shown in Formula I can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0320] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0321] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention or their intermediates can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, 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 advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate, or other carbohydrate derivatives or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0322] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0323] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0324] Beneficial effects

[0325] The preparation method of the present invention does not use the separation and purification steps of column chromatography such as silica gel column chromatography, nor does it use hydrogen as a hydrogenation or reduction reagent, which significantly improves production efficiency and safety.

[0326] Furthermore, the preparation method of this invention achieves efficient utilization of positional isomers IIIA and IIIB, avoiding the adverse effects of discarding positional isomer IIIA on the yield of the target product. Even more surprisingly, the overall yield using positional isomer IIIA is as high as 9.4%, significantly higher than the less than 4% yield using positional isomer IIIB. When both positional isomers are used simultaneously in the preparation of compound I, the yield is more than three times higher than when using positional isomer IIIB alone.

[0327] Therefore, the preparation method of the present invention can synthesize compounds of formula I and their intermediates in high yield, low cost and environmentally friendly manner, thereby enabling compounds of formula I to be produced on an industrial scale. Detailed Implementation

[0328] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0329] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0330] Example 1: Preparation of compounds 3a and 3b

[0331] (1) 2,4,6-Trimethylbenzenesulfonic acid 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridine-1-onium (Compound 1)

[0332]

[0333] In a reaction vessel, trifluoroacetic acid (340 kg) was added, purged three times with nitrogen, and cooled to 0-10 °C. Under nitrogen protection, N-Boc-O-2,4,6-trimethylbenzenesulfonylhydroxylamine (90 kg, 285 mol) was added in batches, releasing a large amount of gas after each addition. After reacting for 2 hours, the reaction was quenched with water, precipitating a solid. The solid was dissolved in dichloromethane and washed with NaHCO3 aqueous solution until the pH of the organic phase was approximately 7. The liquid was then separated. The organic phase was again cooled to 0-10 °C under nitrogen protection and held at 0-10 °C. 3-Bromo-5-(4-methoxybenzyloxy)pyridine (64 kg, 217 mol) was added in batches, reacting for 1-2 hours. After filtration, 89 kg of the product was obtained. 1H-NMR (400MHz, 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] + .

[0334] (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).

[0335]

[0336] 188 kg of tetrahydrofuran was added to the reactor, followed by 91 kg (179 mol) of 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridine-1-onium and 51 kg (218 mol) of 2,4,6-trimethylbenzenesulfonic acid 1-amino-3-bromo-5-(4-methoxybenzyloxy)pyridine-1-onium and 109 kg (717 mol) of 1,8-diazacyclo[5,4,0]undecene-7. After the addition was complete, the reaction was carried out at room temperature for 1 h. Then, 560 kg of dichloromethane and 240 kg of saturated ammonium chloride solution were added. The organic phase was washed with 210 kg of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from acetonitrile to obtain 35 kg of 6-bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine. 1 H-NMR (400MHz, DMSO-d6): δ8.59 (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] + 8.2 kg of 4-bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine 1 H-NMR (400MHz, DMSO-d6): 68.50-8.51 (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] + .

[0337] Example 2: Preparation of Compound 11

[0338] (1) 4-Bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 12)

[0339]

[0340] Add 7.4 kg (21 mol) of 4-bromo-2-fluoro-6-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine and 21 kg of DMF to the reaction vessel in sequence, purge with nitrogen three times, control the temperature at 0-10 °C, add phosphorus oxychloride (8.0 kg, 52 mol) dropwise, heat to 20-30 °C, and react for 17 h. The resulting product solution can be directly used for the next reaction. 1 H-NMR (400MHz, DMSO-d6): δ10.50 (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] + .

[0341] (2) 4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 13)

[0342]

[0343] The reaction solution in the reactor from the previous step was heated to 70°C, and HPLC sampling was used to monitor the reaction until the raw materials were completely reacted. The reaction solution was then cooled to 25°C and added to 66 kg of water. The mixture was stirred at 30°C for 2 hours, filtered, and the filter cake was slurried with 17 kg of dichloromethane for 1 hour. After filtering again, the filter cake was obtained and vacuum dried to yield 4.7 kg of the product. 1 H-NMR (400MHz, DMSO-d6): δ10.62 (brs, 1H), 10.46 (d, 1H), 8.32 (t, 1H), 7.80 (s, 1H).m / z=259[M+1] + .

[0344] (3) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 10)

[0345]

[0346] 4-Bromo-2-fluoro-6-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (4.7 kg, 18 mol), dimethyl sulfoxide (15.5 kg), potassium carbonate (2.8 kg, 20 mol), and iodoethane (3.0 kg, 19 mol) were added sequentially to a reaction vessel. Nitrogen gas was purged three times, and the reaction was heated to 65°C. HPLC sampling was used to monitor the reaction until the reactants were completely reacted. The temperature was then lowered to 25°C, and 47 kg of water was added to the reaction vessel. The mixture was stirred at 25–30°C for 1 hour and then vacuum-filtered to dryness. Acetonitrile (9.0 kg) was added to the reaction vessel, and the filter cake was added to the reaction vessel. The mixture was stirred at 25–30°C for 1–2 hours, vacuum-filtered to dryness, and then vacuum-dried to obtain 4.6 kg of the product. 1 H-NMR (400MHz, DMSO-d6): δ10.49 (s, 1H), 8.69 (d, 1H), 8.00 (d, 1H), 4.16 (q, 2H), 1.37 (t, 3H).m / z=287[M+1] + .

[0347] (4) Synthesis of 4-bromo-6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (Compound 11)

[0348]

[0349] 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (4.6 kg, 16 mol), dimethyl sulfoxide (46 L), and 85% hydrazine hydrate (4.7 kg) were added to a reaction vessel. The mixture was heated to 110–115 °C and the reaction was monitored by HPLC until complete. The mixture was then cooled to 30–40 °C, and water (138 L) was added. The mixture was stirred and kept at this temperature for 1–2 hours. After filtration, the filter cake was vacuum dried to obtain 4.0 kg of the product. 1 H-NMR (400MHz, DMSO-d6): δ12.81 (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]+.

[0350] Example 3: Preparation of Compound I

[0351] (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)

[0352]

[0353] Add 30 g (0.11 mol) of 4-bromo-6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine, 57 g (0.14 mol) of 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxapentylborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.3]heptane-6-carbonate tert-butyl ester, 1.5 g (2.2 mmol) of bis(triphenylphosphine)palladium dichloride, 16 g (0.22 mol) of lithium carbonate, 300 mL of dioxane, and 150 mL of water to the reaction flask in sequence. Replace the nitrogen gas three times, heat to 85 °C and react for 20 hours. Filter with diatomaceous earth, pour the filtrate into 3 L of water, and filter to obtain a solid. The solid was dissolved in 1.2 L of tetrahydrofuran, and 60 g of silica gel was added. The mixture was heated to 60 °C and stirred for 12 hours. After cooling to room temperature, the silica gel was removed by filtration with diatomaceous earth. The filtrate was concentrated under reduced pressure to about 100 mL. 300 mL of methyl tert-butyl ether was added, and the mixture was concentrated again under reduced pressure to about 100 mL. This step was repeated at least twice. The mixture was stirred at room temperature overnight, filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The solid was dried under vacuum to obtain 42.3 g of product with an HPLC purity of 98.8%. 1 H-NMR (400MHz, DMSO-d6): δ12.64 (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] + .

[0354] (2) 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (compound 20)

[0355]

[0356] 3-(5-(6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptane-6-carbonate tert-butyl ester (30 g, 0.063 mol), methanol (500 mL), and concentrated sulfuric acid (25 g, 0.25 mol) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 12 h. The methanol was removed by concentration under reduced pressure. 500 mL of methyl tert-butyl ether was added and the mixture was stirred. The product was filtered to obtain 43 g of product with an HPLC purity of 99.5%, which was directly used in the next reaction step. 1H NMR (400MHz, DMSO-d6): δ12.67 (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, 1m / z=376[M+1] + .

[0357] (3) 6-ethoxy-4-(6-(6-((6-methoxypyridin-3-yl)methylene)-3,6-diazabicyclo[3.3.1]heptane-3-yl)pyridin-3-yl)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (compound I)

[0358]

[0359] Add the product from step (2) (30g), 6-methoxy-3-pyridinecarboxaldehyde (20g, 0.14mol), 2-methylpyridine-N-methylborane (16g, 0.15mol), triethylamine (34mL, 0.24mol), and 650mL n-propanol to the reaction flask in sequence. React at room temperature for 18 hours. Add 300mL dichloromethane, wash once with saturated ammonium chloride solution, wash twice with water, concentrate under reduced pressure, add 300mL methanol, heat to reflux, and reduce the pressure. The mixture was heated to 40-45℃, and 160 mL of methyl tert-butyl ether was slowly added. The mixture was then cooled to 25℃ and stirred for 12 hours. Another 160 mL of methyl tert-butyl ether was added and stirred for 1 hour. The mixture was concentrated under reduced pressure to about 160 mL. Then, 300 mL of methyl tert-butyl ether was added, and the mixture was concentrated under reduced pressure to about 160 mL again. This step was repeated at least twice. The mixture was stirred at room temperature overnight. The mixture was filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. The solid was dried under vacuum to obtain 19 g of product with an HPLC purity of 98.9%. 1H-NMR (400MHz, DMSO-d6): δ12.64 (brs, 1H), 8.64 (s, 1H), 8.51 (s, 1H), 8.08-8.1 1(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), 3.5 3-3.59(m, 4H), 2.53-2.56(m, 1H), 1.56-1.58(m, 1H), 1.40(t, 3H).m / z=497[M+1] + .

[0360] Example 4: Preparation of Compound 11

[0361] (1) 6-ethoxy-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine (compound 14)

[0362]

[0363] 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 sequentially to the reaction flask. The reaction solution was heated to 80 °C for 16 hours under nitrogen protection. After cooling, water (150 mL) was added to the reaction solution with stirring for 30 minutes. The solid was obtained by filtration and dried under vacuum to obtain 37 g of product. 1 H-NMR (400MHz, DMSO-d6): δ7.91 (s, 1H), 7.41 (d, J = 11.2Hz, 2H), 6.97 (d, J = 11.2Hz, 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] + .

[0364] (2) 6-ethoxy-2-fluopyrazole[1,5-a]pyridine-4-ol (compound 15)

[0365]

[0366] Dichloromethane (450 mL) and 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine (37 g, 117.0 mmol) were added sequentially to a reaction flask. Trifluoroacetic acid (45 mL) was added dropwise, and the reaction was allowed to proceed for 3 hours. The reaction solution was washed with water (300 mL), then washed with saturated brine (150 mL), and concentrated to obtain a crude product solution (approximately 60 mL). Heptane (250 mL) was added to the crude product solution, and the mixture was stirred for 1 hour. The mixture was then filtered and dried under vacuum to obtain 16.5 g of the product. 1 H-NMR (400MHz, DMSO-d6): δ10.78 (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] + .

[0367] (3) 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-yltrifluoromethane sulfonate (compound 16)

[0368]

[0369] Dichloromethane (200 mL) and a solution of 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-ol (14.8 g, 75.5 mmol), triethylamine (11.5 g, 113.3 mmol), and trifluoromethanesulfonic anhydride (23.4 g, 83.1 mmol) in dichloromethane (50 mL) were added sequentially to a reaction flask, and the reaction was carried out at room temperature for 16 hours. The reaction solution was washed with water (200 mL), washed with saturated brine (100 mL), and then concentrated to obtain a crude product. The crude product was dissolved in DMF (150 mL), and water (1000 mL) was slowly poured in with stirring. After stirring for 30 minutes, the mixture was filtered, washed with water, and dried in a forced-air environment at 60 °C for 16 hours to obtain 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-yltrifluoromethanesulfonate (23.4 g, yield 95%), which was a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): 68.56 (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] + .

[0370] (4) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine (compound 17)

[0371]

[0372] NMP (60 mL), 6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (6.6 g, 20.0 mmol), pentamethylcyclopentadiene ditriphenylphosphine ruthenium(II) chloride (800 mg, 1.0 mmol), and LiBr (2.6 g, 30.0 mmol) were added sequentially to the reaction flask. Nitrogen gas was purged three times, and the reaction mixture was heated to 90 °C for 16 hours. The reaction solution was slowly poured into water (800 mL) and stirred for 1 hour. The mixture was then filtered, washed with water, and dried under vacuum to obtain 3.9 g of the product. 1 H-NMR (400MHz, DMSO-d6): δ8.40 (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] + .

[0373] (5) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 10)

[0374]

[0375] DMF (60 mL), 4-bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine (3.5 g, 13.5 mmol), and POCl3 (8.3 g, 54 mmol) were added sequentially to the reaction flask, and the mixture was reacted at room temperature for 48 hours. The reaction solution was then slowly poured into water (600 mL) and stirred for 1 hour. The mixture was filtered, washed with water, and the solid was dried under vacuum to obtain 4.2 g of the product. 1 H-NMR (400MHz, DMSO-d6): δ10.49 (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] + .

[0376] (6) 4-Bromo-6-ethoxy-1H-pyrazole [3′,4′:3,4]pyrazole [1,5-a]pyridine (compound 11)

[0377]

[0378] The operation is the same as step (4) in Example 2.

[0379] Example 5: Preparation of Compound 30

[0380] (1) 6-Bromo-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-ol (compound 31)

[0381]

[0382] DMSO (200 mL), acetylhydrazine (8.6 g, 115.8 mmol), and 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (20.0 g, 77.2 mmol), and 80% hydrazine hydrate aqueous solution (24.1 g, 386 mmol) were added sequentially to a reaction flask. The mixture was heated to 140 °C and reacted for 6 hours. After cooling, the reaction solution was slowly poured into water (2000 mL), extracted twice with ethyl acetate (1000 mL), washed with water (400 mL), washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give 10.5 g of product. 1 H-NMR (400MHz, DMSO-d6): δ12.68 (brs, 1H), 11.35 (s, 1H), 8.67 (s, 1H), 7.61 (s, 1H), 6.84 (s, 1H). m / z=253 / 255[M+1] + .

[0383] (2) 6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-ol (compound 29)

[0384]

[0385] Ethanol (50 mL), 6-bromo-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-ol (2 g, 8 mmol), cuprous iodide (160 mg, 8 mmol), cesium carbonate (8 g, 24 mmol), and 8-hydroxyquinoline (240 mg, 1.6 mmol) were added sequentially to a sealed reaction flask. The reaction was heated to 100 °C and reacted for 4 days. After stopping the reaction, 200 mL of dioxane was added, and the mixture was heated to reflux. The mixture was filtered through diatomaceous earth while hot, and the filtrate was concentrated under reduced pressure to approximately 50 mL. This filtrate was then poured into 500 mL of water, filtered to obtain a solid, and dried under vacuum to obtain 1.5 g of the product. 1 H-NMR (400MHz, DMSO-d6): δ12.51 (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] + .

[0386] (3) 6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (compound 30)

[0387]

[0388] 6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-ol (250 mg, 0.68 mmol), diisopropylethylamine (264 mg, 2.0 mmol), and DMF (5 mL) were added to a reaction flask. After cooling to 5 °C, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (183 mg, 0.51 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was then poured into 200 mL of N water, filtered to obtain a solid, and dried to obtain 200 mg of the product with an HPLC purity of 97.5%. 1 H-NMR (400MHz, DMSO-d6): δ12.98 (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] + .

[0389] Example 6: Preparation of Compound 30

[0390] (1) 6-Bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 23)

[0391]

[0392] Dichloromethane (15 mL) and 6-bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (1.1 g, 3.0 mmol) were added sequentially to the reaction flask. Trifluoroacetic acid (3 mL) was added dropwise, and the reaction was stirred at room temperature for 3 hours. The product was concentrated under reduced pressure to obtain 0.6 g of product. 1 H-NMR (400MHz, DMSO-d6): δ11.97 (s, 1H), 10.03 (s, 1H), 8.76 (s, 1H), 7.14 (s, 1H). m / z=259[M+1] + .

[0393] (2) 6-Bromo-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-ol (compound 31)

[0394]

[0395] DMSO (200 mL), acetylhydrazine (8.6 g, 115.8 mmol), 6-bromo-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (20.0 g, 77.2 mmol), and 80% hydrazine hydrate (24.1 g, 386 mmol) were added sequentially to the reaction flask, and the mixture was heated to 110 °C and reacted for 12 hours. After cooling, the reaction solution was slowly poured into water (2000 mL), filtered, and the solid was dried under vacuum to obtain 10.5 g of product. 1 H-NMR (400MHz, DMSO-d6): δ12.68(brs, 1H), 11.35(s, 1H), 8.67(s, 1H), 7.61(s, 1H), 6.84(s, 1H).m / z=253[M+1] + .

[0396] (3) 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (compound 25)

[0397]

[0398] 6-Bromo-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-ol (5.0 g, 20.0 mmol), 1-(chloromethyl)-4-methoxybenzene (3.4 g, 22.0 mmol), potassium carbonate (8.3 g, 60.0 mmol), and DMF (50 mL) were added sequentially to the reaction flask. The reaction solution was heated to 40 °C and reacted for 16 hours. After cooling, the reaction solution was slowly poured into water (500 mL) with stirring. After stirring for 1 hour, the mixture was filtered, washed with water, and dried to obtain 3.7 g of the product. 1 H-NMR (400MHz, DMSO-d6): δ12.78 (brs, 1H), 8.81 (s, 1H), 7.83 (s, 1H), 7.48 (d, J=8.4Hz , 2H), 7.24 (s, 1H), 6.94 (d, J=8.4Hz, 2H), 5.33 (s, 2H), 3.77 (s, 3H).m / z=373 / 375[M+1] + .

[0399] (4) 4-(4-methoxybenzyloxy)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-6-ol (compound 27)

[0400]

[0401] 6-Bromo-4-(4-methoxybenzyloxy)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (3.7 g, 10.0 mmol), bis(naphthyl)boronic acid ester (3.8 g, 15.0 mmol), potassium acetate (2.9 g, 30.0 mmol), PdCl2(dppf) (731 mg, 1.0 mmol), and 1,4-dioxane (70 mL) were added sequentially to the reaction flask. The reaction solution was heated to 90 °C for 16 hours under nitrogen protection. The solution was filtered through diatomaceous earth while hot, and the filtrate was concentrated under reduced pressure to obtain crude 4-(4-methoxybenzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine. Add 70 mL of THF to the crude product, cool in an ice bath to 5 °C, and add 6.5 mL of 30% H2O2 dropwise. React at room temperature for 1.5 hours. Add 150 mL of ethyl acetate to the reaction mixture, filter, wash the filtrate with 50 mL of 0.1 N hydrochloric acid aqueous solution, wash twice with water (40 mL), wash with saturated brine (40 mL), dry to anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain 900 mg of the product. 1 H-NMR (400MHz, DMSO-d6): δ12.50(brs, 1H), 9.83(s, 1H), 7.88(s, 1H), 7.69(s, 1H), 7.48(d , J=8.4Hz, 2H), 6.99 (d, J=8.4Hz, 2H), 6.70 (s, 1H), 5.28 (s, 2H), 3.79 (s, 3H).m / z=311[M+1] + .

[0402] (5) 6-ethoxy-1-ethyl-4-(4-methoxybenzyloxy)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (compound 28)

[0403]

[0404] 4-(4-methoxybenzyloxy)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-6-ol (680 mg, 2.2 mmol), K₂CO₃ (911 mg, 6.6 mmol), iodoethane (378 mg, 2.4 mmol), and DMF (15 mL) were added sequentially to a reaction flask. The reaction solution was heated to 30 °C and reacted for 16 hours. The reaction solution was slowly poured into water (150 mL), stirred for 0.5 hours, filtered, washed with water, and dried to obtain a crude product. 10 mL of 1,4-dioxane was added to the crude product and heated to dissolve it. 10 mL of methyl tert-butyl ether was slowly added, the mixture was cooled to room temperature, concentrated to 5 mL, and then 20 mL of methyl tert-butyl ether was added. The mixture was stirred for 12 hours, filtered, and dried to obtain 227 mg of the product, a yellow solid. 1 -NMR (400MHz, DMSO-d6): δ12.53 (brs, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7.46 (d, J=8.4Hz, 2H), 6.99 (d, J=8.4Hz, 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] + .

[0405] (6) 6-ethoxy-1H-pyrazole [3′,4′:3,4]pyrazole [1,5-a]pyridine-4-ol (compound 29)

[0406]

[0407] 6-ethoxy-1-ethyl-4-((4-methoxybenzyl)oxy)-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine (230 mg, 0.68 mmol) and dichloromethane (15 mL) were added sequentially to the reaction flask. Trifluoroacetic acid (0.5 mL) was then added, and the reaction mixture was heated to room temperature and stirred for 16 hours. The product was concentrated to obtain 250 mg, which was used directly in the next reaction step. 1 H-NMR (400MHz, DMSO-d6): δ12.51 (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] + .

[0408] (7) 6-ethoxy-1H-pyrazole[3′,4′:3,4]pyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (compound 30)

[0409]

[0410] Compound 30 was prepared by referring to step (3) of Example 5.

[0411] Example 7: Preparation of Compound 19

[0412] 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)

[0413]

[0414] 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborborane-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), PdCl2(dppf) (4 mg, 0.005 mmol), potassium fluoride (18 mg, 0.3 mmol), and 1,4-dioxane (0.5 mL) were added sequentially to the reaction flask. The reaction was carried out at 120 °C for 16 hours under nitrogen protection. After concentrating the organic phase, 50 mL of methyl tert-butyl ether was added and the mixture was stirred. The mixture was then filtered to obtain 12 mg of the product. m / z = 476 [M+1] + .

[0415] Example 8: Preparation of Compound 10

[0416] 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (Compound 10)

[0417] (1) 6-Bromo-2-fluoro-4-(4-methoxybenzyloxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 4)

[0418]

[0419] DMF (35 mL) and 6-bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine (3.5 g, 10.0 mmol) were added sequentially to the reaction flask. The mixture was cooled to 5 °C, and POCl3 (6.1 g, 40.0 mmol) was added dropwise. The mixture was then stirred at room temperature for 48 hours. The reaction solution was slowly poured into water (350 mL) and stirred for 1 hour. The mixture was filtered, and the solid was dried under vacuum to obtain 3.6 g of the product. 1H-NMR (400MHz, DMSO-d6): δ10.01 (s, 1H), 8.88 (s, 1H), 7.59 (s, 1H), 7.47 (d, J=8.8Hz, 2H), 7.01(d, J=8.8Hz, 2H), 5.34(s, 2H), 3.78(s, 3H).m / z=379[M+1] + .

[0420] (2) 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde (compound 5)

[0421]

[0422] 6-Bromo-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (7.6 g, 20.0 mmol), bis(4-methoxybenzyl)oxypyrazole[1,5-a]pyridine-3-carboxaldehyde (5.6 g, 22.0 mmol), potassium acetate (5.9 g, 60.0 mmol), PdCl2(dppf) (1.5 g, 2.0 mmol), and 1,4-dioxane (100 mL) were added sequentially to the reaction flask. Nitrogen gas was purged three times, and the reaction mixture was heated to 85 °C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 8.6 g of product, which was directly used in the next reaction step. m / z = 465 [M+1] + .

[0423] (3) 2-Fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 6)

[0424]

[0425] 2-Fluoro-4-((4-methoxybenzyl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazol[1,5-a]pyridine-3-carboxaldehyde (4.3 g, 10.1 mmol) and 1,4-dioxane (110 mL) were added sequentially to a reaction flask. The mixture was cooled to 5°C in an ice bath, and 30% H₂O₂ (4 mL) was added dropwise. The reaction solution was allowed to react at room temperature for 2 hours. 200 mL of dichloromethane was added, and the mixture was washed sequentially with 50 mL of water, 50 mL of NaHSO₃ solution, and 50 mL of saturated brine. The solution was dried over anhydrous sodium sulfate. The organic phase was concentrated to 10 mL, and 100 mL of methyl tert-butyl ether was added. The mixture was filtered to obtain 2.1 g of the product. 1H-NMR (400MHz, DMSO-d6): δ10.27 (s, 1H), 9.97 (s, 1H), 7.84 (s, 1H), 7.47 (d, J=8.4H z, 2H), 7.06 (s, 1H), 7.00 (d, J=8.4Hz, 2H), 5.28 (s, 2H), 3.78 (s, 3H).m / z=317[M+1] + .

[0426] (4) 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 7)

[0427]

[0428] 2-Fluoro-6-hydroxy-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde (2.0 g, 6.3 mmol), K₂CO₃ (1.8 g, 12.6 mmol), iodoethane (1.2 g, 7.6 mmol), and DMF (19 mL) were added sequentially to the reaction flask. The reaction solution was heated to 40°C and reacted for 3 hours. The reaction solution was poured into 400 mL of water and extracted with 100 mL × 3 dichloromethane. The filtrate was concentrated to 10 mL, 100 mL of methyl tert-butyl ether was added, and the solution was concentrated under reduced pressure to approximately 10 mL. Another 100 mL of methyl tert-butyl ether was added, and the solution was concentrated again under reduced pressure to approximately 10 mL. This step was repeated twice to obtain 1.25 g of product. 1 H-NMR (400MHz, DMSO-d6): δ10.07 (s, 1H), 8.20 (s, 1H), 7.47 (d, J=8.4Hz, 2H), 7.18 (s, 1H), 7.00 (d, J=8.4Hz, 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] + .

[0429] (5) 6-ethoxy-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 8)

[0430]

[0431] Add 450 mg (1.3 mmol) of 6-ethoxy-2-fluoro-4-((4-methoxybenzyl)oxy)pyrazole[1,5-a]pyridine-3-carboxaldehyde and 30 mL of dichloromethane to a reaction flask. Add 2 mL of trifluoroacetic acid dropwise and react at room temperature for 2 hours. Concentrate under reduced pressure to 10 mL, add 100 mL of methyl tert-butyl ether, concentrate under reduced pressure to approximately 10 mL, add another 100 mL of methyl tert-butyl ether, and concentrate under reduced pressure to approximately 10 mL again. Repeat this step twice to obtain 305 mg of product. 1 H-NMR (400MHz, DMSO-d6): δ11.59 (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] + .

[0432] (6) 6-Ethoxy-2-fluoro-3-carboxypyrazole[1,5-a]pyridine-4-trifluoromethane sulfonate (compound 9)

[0433]

[0434] Add 6-ethoxy-2-fluoro-4-hydroxypyrazole[1,5-a]pyridine-3-carboxaldehyde (315 mg, 1.4 mmol), diisopropylethylamine (362 mg, 2.8 mmol), and DMF (5 mL) to the reaction flask. Cool to 5 °C and add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (660 mg, 1.7 mmol). Incubate the reaction mixture at room temperature for 2 hours. Pour the reaction mixture into 200 mL of water, extract with 100 mL × 3 dichloromethane solutions, dry to anhydrous sodium sulfate, concentrate the organic phase to obtain 430 mg of the product, which can be used directly in the next reaction step. 1 H-NMR (400MHz, DMSO-d6): δ9.89 (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] + .

[0435] (7) 4-Bromo-6-ethoxy-2-fluoropyrazole[1,5-a]pyridine-3-carboxaldehyde (compound 10)

[0436]

[0437] NMP (0.5 mL), 6-ethoxy-2-fluoro-3-carboxypyrazole[1,5-a]pyridine-4-trifluoromethanesulfonate (5 mg, 0.015 mmol), ruthenium(II) tris(acetonitrile)pentamethylcyclopentadiene trifluoromethanesulfonate (1.0 mg, 0.002 mmol), and LiBr (4 mg, 0.045 mmol) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 2 hours. The reaction solution was poured into 100 mL of water, extracted with 100 mL × 3 dichloromethane solutions, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 2 mg of the product. 1 H-NMR (400MHz, DMSO-d6): δ10.49 (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] + .

[0438] The foregoing has described exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, variations, etc., made by those skilled in the art within the spirit and principles of the present invention should be covered within the scope of protection of the claims of this application.

Claims

1. A method for preparing a compound of formula I, wherein the method comprises steps M1A, M20, M11, M10A, and M13, wherein: Step M1A Compound XX and R k The -C(O)-H reaction yields compound I: X 1 X 3 Same or different, selected independently from CR 1 ; X 2 Let N be the number of people in the group. X 4 Selected from CR 1 Or N; Each R 1 They may be the same or different, and are independently selected from H, halogens, CN, and C. 1-6 Alkyl, C 1-6 Alkyloxy; D is selected from H, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkyloxy; E is selected from C 1-6 Alkyloxy group, halogenated C 1-6 Alkyloxy; G is selected from unsubstituted or optionally by one, two or more Rs. e The following groups are substituted: 5-9 membered heterocyclic groups containing 1, 2 or 3 N atoms; R k Selected from unsubstituted or arbitrarily assigned to one, two or more R g The following groups are substituted: C 6-10 Aryl, 5-10 heteroaryl; Each R e Same or different, selected independently from C 1-6 Alkyl, C 1-6 Alkyloxy; Each R g Whether the two are the same or different, they are selected independently from CN and C. 1-6 Alkyl, C 1-6 Alkyloxy; Compound XX and R k The -C(O)-H reaction is carried out in the presence of borane and 2-methylpyridineborane; Compound XX and R k The molar ratio of -C(O)-H is 1:1 to 1:5; The molar ratio of compound XX to borane or 2-methylpyridineborane is 1:1 to 1:5; The reaction temperature for preparing compound I is 15–50 °C; Step M20 The compound of formula XIX is deprotonated. 19 The reaction under the specified conditions yields compound XX: PG 19 It is selected from one of tert-butoxycarbonyl, cyclobutoxycarbonyl, benzyloxycarbonyl, p-methoxybenzylcarbonyl, 2-biphenyl-2-propoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phthalimide, p-toluenesulfonyl, trifluoroacetyl, (9H-fluorene-9-ylmethoxy)carbonyl, benzyl, 4-methoxybenzyl, diphenylmethyl, 2-(trimethylsilyl)ethoxycarbonyl, adamantyloxycarbonyl, formyl, and acetyl. In step M20, the removal of PG 19 The condition is the removal of PG in the presence of acid. 19 The group, wherein the acid is selected from one, two or more of hydrochloric acid, sulfuric acid, formic acid, and acetic acid; The molar ratio of the compound of formula XIX to the acid is 1:1 to 1:5; Step M19A Reaction of compound XI with compound XVIII yields compound XIX: L 11 Selected from halogens; Step M19A is carried out in the presence of a catalyst selected from Pd(dba)2, PdCl2, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, PdCl2(CH3CN)2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(t-Bu)3, PdCl2(PPh3)2·CH2Cl2, Pd(OAc) / PPh3, PdCl2[(Pet3)]2, Pd(DIPHOS)2, PdCl2(Bipy), [Pd Cl(Ph2PCH2PPh2)]2, PdCl2[P(o-Tol)3]2, Pd2(dba)3 / P(o-Tol)3, Pd2(dba) / P(furyl)3, PdCl2[P(furyl)3]2, PdCl2(P MePh2)2, PdCl2[P(4-F-Ph)3]2, PdCl2[P(C6F6)3]2, PdCl2[P(2-COOH-Ph)(Ph)2]2, PdCl2[P(4-COOH-Ph)(Ph)2]2; The molar ratio of compound XI to catalyst is from 1:0.001 to 1:0.05; Step M19A is carried out in the presence of a base, wherein the molar ratio of compound XI to base is 1:1 to 1:5, and the molar ratio of compound XI to compound XVIII is 1:1 to 1:

2. Step M11 Reaction of compound X with hydrazine hydrate yields compound XI: L 10 Selected from F, Cl, Br or I; In step M11, the molar ratio of compound X to hydrazine hydrate is 1:1 to 1:

15. Step M10A Compound XIII and compound R 21 -L 13 The reaction yields compound X: L 13 Selected from the following groups that are unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halogens: C 1-6 alkylsulfonyloxy, C 1-6 Alkylbenzenesulfonyloxy, or F, Cl, Br or I; R 21 Selected from C 1-6 alkyl; In step M10A, compound XIII and compound R 21 -L 13 The molar ratio is 1:1 to 1:2; Step M13 Compound IIIB reacts with phosphorus oxychloride to give compound XII, and then compound XII reacts further to give compound XIII, wherein compounds IIIB and XII have the following structures: PG 3 Selected from no substitutes or optionally selected from 1, 2, 3, 4 or 5 of C 1-6 Alkyl, C 1-6 Alkyloxy groups and halogen substituents can replace the following groups: benzyl, C 1-6 Alkyl, tri(C) 1-6 Alkyl)silyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, triphenylmethyl, C 1-6 Alkyloxymethyl, benzyloxymethyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 Alkyl carbonyl, benzoyl.

2. The preparation method according to claim 1 is characterized in that, L 13 Selected from methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, F, Cl, Br or I; PG 3 It is selected from benzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl or 2,3,4-trimethoxybenzyl.

3. The preparation method according to claim 1 or 2, characterized in that, D is selected from the following groups: H, halogens, E is selected from the following groups:

4. The preparation method according to claim 3, characterized in that, R k Selected from unsubstituted or arbitrarily assigned to one, two or more R g Substituted pyridyl or phenyl.

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

6. The preparation method according to claim 1, characterized in that, G is selected from 7. The preparation method according to claim 1, characterized in that, R k Selected from unsubstituted or arbitrarily assigned to one, two or more R g Substituted pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, or phenyl.

8. The preparation method according to claim 1, characterized in that, R in compound I k It can form a group selected from the following categories with the methylene group:

9. The preparation method according to claim 1, characterized in that, R in compound I k Selected from 1, 2, 3 or 4 selected from C 1-6 Alkyl and C 1-6 Alkyloxy group substituted group 10. The preparation method according to claim 1, characterized in that, The compound of formula I is selected from the following compounds:

11. The preparation method according to claim 1, characterized in that, in: Compound XX and R k The -C(O)-H reaction is carried out in the presence of 2-methylpyridineborane and a base; Compound XX and R k The molar ratio of -C(O)-H is 1:1.1 to 1:1.3; The molar ratio of compound XX to borane or 2-methylpyridineborane is 1:1.1 to 1:1.3; The molar ratio of compound XX to base is 1:1.8 to 1:2.2; The reaction temperature for preparing compound I is 20–30 °C.

12. A method for preparing compound 1, characterized in that, The preparation method includes the following reaction steps:

13. The preparation method according to claim 1, characterized in that, The molar ratio of compound IIIB to phosphorus oxychloride is 1:2 to 1:

4.

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

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