Synthetic method of fused ring diaza aromatic skeleton

Abstract

The invention relates to the technical field of organic chemistry and medicinal chemistry, in particular to a fused ring diaza aromatic skeleton as well as a synthesis method and application thereof. According to the specific technical scheme, N-amino salt of an electron-deficient aza-aromatic compound reacts with aldehyde or ketone containing active methylene at the temperature of-78 DEG C to 150 DEG C in the presence of alkali, an oxidizing agent and an organic solvent, and then the fused ring diaza-aromatic skeleton compound can be synthesized. The method has the advantages of few reaction steps, mild conditions, high yield, high regioselectivity, simplicity in operation and the like.

Description

Technical Field

[0001] This invention relates to the fields of organic chemistry and medicinal chemistry, specifically to a fused-ring diaza aromatic skeleton and its synthesis method and application. Background Technology

[0002] Fused-ring diaza-aromatic skeletons, such as pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a]quinoline, and pyrazolo[1,5-a]isoquinoline, are an important class of diaza-aromatic skeletons that play a crucial role in medicinal chemistry and lead compound optimization. These structures cleverly combine the electronic properties and hydrogen-bonding capabilities of pyrazole with pyridine, quinoline, and isoquinoline, enabling them to bind efficiently to a variety of biological targets, including kinases (such as p38 and RET), phosphodiesterases (PDEs), Yck2, and various G protein-coupled receptors (such as the EP1 receptor and the dopamine receptor family). With their tunable pharmacophore layout, suitable lipophilicity, and favorable drug-like properties, these skeletons have become advantageous structures for developing therapies for inflammation, pain, tumors, and central nervous system diseases. Several drugs based on this core structure have entered clinical application, such as the phosphodiesterase inhibitor isobufotazone for the treatment of bronchial asthma, and the highly selective RET inhibitor serpatinib (LOXO-292), which has become a cornerstone drug for the treatment of RET fusion-positive thyroid cancer and non-small cell lung cancer. These success stories fully demonstrate the enormous value and broad prospects of this framework in the field of innovative drug development.

[0003] However, the further development of fused-ring diaza aromatic skeletons such as pyrazolo[1,5-a]pyridine derivatives faces multiple challenges. In synthetic chemistry, traditional methods heavily rely on the [3+2] cycloaddition reaction between aminopyridines and unsaturated alkynes or their synthetic equivalents (such as unsaturated alkenes with leaving groups). These methods often suffer from lengthy synthetic steps, moderate yields, and difficulties in controlling regioselectivity, which hinders large-scale synthesis and rapid exploration of structural diversity. Furthermore, the desired unsaturated alkene must be prepared from the corresponding aldehyde or ketone, further complicating the synthetic routes.

[0004] Therefore, developing greener and more efficient synthetic strategies, such as using simple starting materials like aldehydes and ketones to selectively construct these compounds through highly efficient, atom-economical catalytic processes, is crucial for enhancing their application in lead compound optimization and pharmacokinetic improvement. However, this remains a significant challenge, particularly in the regioselective synthesis of 4- / 6-substituted or 4,6-disubstituted pyrazolo[1,5-a]pyridines. This persistent regioselectivity problem stands in stark contrast to the widespread use of these compounds in marketed drugs and lead compounds. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a fused-ring diaza aromatic skeleton, its synthesis method, and its application. The method uses an electron-deficient nitrogen-containing aromatic compound's N-amino salt and an aldehyde or ketone containing an active methylene group as raw materials. In the presence of an oxidant, the mixture is stirred with a base to form a fused-ring diaza aromatic skeleton compound.

[0006] Since the N-amino salt of the desired electron-deficient azirrolic compound can be obtained in high yield by reacting the electron-deficient azirrolic compound with an electrophilic amination reagent under mild conditions, this invention also provides a method for directly synthesizing fused-ring azirrolic skeleton compounds from electron-deficient azirrolic compounds as raw materials.

[0007] To achieve the above objectives, the present invention provides the following technical solution: This invention discloses a method for synthesizing fused-ring diaza aromatic skeletons. The method involves reacting the N-amino salt of an electron-deficient azirro aromatic compound with an aldehyde or ketone containing an active methylene group in the presence of a base, an oxidant, and an organic solvent at a temperature of -78°C to 150°C to synthesize fused-ring diaza aromatic skeleton compounds.

[0008] Preferably, an electron-deficient aza-aromatic compound is reacted with an electrophilic amination reagent to synthesize the N-amino salt of the electron-deficient aza-aromatic compound in situ. Then, in the presence of a base, an oxidant, and an organic solvent, it is reacted with an aldehyde or ketone containing an active methylene group at -78°C to 150°C for 0.5 h to 80 h to synthesize a fused-ring diaza-aromatic skeleton compound.

[0009] Preferably, the base is one of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene, tetramethylguanidine, Cs2CO3, K2CO3, Na2CO3, Li2CO3, K3PO4, K2HPO3, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, and potassium hexamethyldisilamide; the oxidant is one of peroxide, high-valent iodine reagent, organic nitrogen oxides, and a composite oxidant formed by organic nitrogen oxides and copper / iron salts; the organic solvent is one of toluene, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0010] Preferably, the peroxide is one of tert-butanol peroxide and hydrogen peroxide; the high-valent iodine reagent is one of 2-iodobenzoic acid, Dys-Martin oxidant, diiodobenzene diacetate, and di(trifluoroacetic)iodobenzene; the organic nitrogen oxide is one of tetramethylpiperidine oxide, 4-oxo-2,2,6,6-tetramethyl-4-piperidine oxide, 4-amino-2,2,6,6-tetramethylpiperidine oxide, and 9-azabicyclo[3.3.1]nonane-N-oxy radical; the copper salt / iron salt is one of CuBr, CuI, CuCl, Cu(OTf)2, Cu(CH3CN)4BF4, Cu(CH3CN)4PF6, Cu(CH3CN)4OTf, Fe(NO2)3, Fe(NO2)2, Fe(OTf)3, FeCl2, and FeCl3, and the amount of the copper salt / iron salt is from 0.01 equivalents to 2 equivalents.

[0011] Preferably, the amount of the base is 0.1 to 5 equivalents, the amount of the oxidant is 0.01 to 2 equivalents, and the reaction concentration of the N-amino salt of the electron-deficient nitrogen-containing aromatic compound is 0.01 M to 0.2 M.

[0012] Preferably, the electrophilic amination agent is one of O-benzenesulfonyl hydroxylamine and its substitutes, O-alkylsulfonyl hydroxylamine and its substitutes, O-benzoyl hydroxylamine and its substitutes, and O-nitrobenzenesulfonyl hydroxylamine and its substitutes; wherein, the substitute for O-benzenesulfonyl hydroxylamine is one of O-4-methylbenzenesulfonyl hydroxylamine, O-2-methoxybenzenesulfonyl hydroxylamine, O-4-methoxybenzenesulfonyl hydroxylamine, O-4-bromo-benzenesulfonyl hydroxylamine, O-2-methylbenzenesulfonyl hydroxylamine, O-p-methylbenzenesulfonyl hydroxylamine, O-p-nitrobenzenesulfonyl hydroxylamine, O-2,4,6-trimethylbenzenesulfonyl hydroxylamine, and O-2-bromo-benzenesulfonyl hydroxylamine. The substitute for the O-alkylsulfonyl hydroxylamine is one of O-methylsulfonyl hydroxylamine and O-trifluoromethylsulfonyl hydroxylamine; the substitute for the O-benzoyl hydroxylamine is one of O-benzoyl hydroxylamine, O-4-nitrobenzoyl hydroxylamine, O-2-nitrobenzoyl hydroxylamine, O-2,4-dinitrobenzoyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, and O-o-nitrobenzoyl hydroxylamine; the substitute for the O-nitrophenyl hydroxylamine is one of O-2-nitrophenyl hydroxylamine, O-4-nitrophenyl hydroxylamine, O-o-nitrophenyl hydroxylamine, O-m-nitrophenyl hydroxylamine, O-p-nitrophenyl hydroxylamine, and O-2,4-dinitrophenyl hydroxylamine.

[0013] Preferably, the electron-deficient nitrogen-containing aromatic compound is one of pyridine, quinoline, isoquinoline, phenanthridine, phenanthroline, substituted pyridine, substituted quinoline, substituted isoquinoline, substituted phenanthridine, and substituted phenanthroline; the N-amino salt is one of trifluoromethanesulfonate, alkylsulfonate, arylsulfonate, benzoic acid and its derivatives, phenol and its derivatives, halide, sulfate, and phosphate.

[0014] Accordingly, the method for synthesizing the fused-ring diaza aromatic skeleton described above yields a fused-ring diaza aromatic skeleton with the following general structural formula:

[0015] Among them, R 1 R 2 Each is an independent hydrogen atom, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 It can be one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro.

[0016] Preferably, when R 1 R 2 When each is an independent hydrogen, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 1 R 2 Each can be individually controlled by one or more independent Rs X Substituents of R; and / or, when R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro; 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each can be individually controlled by one or more independent RsX Substituents; R X It is any one of hydrogen atom, alkyl, fluoroalkyl, chloroalkyl, aryl, fluoroaryl, heteroaryl, fluoroheteroaryl, hydroxyl, alkoxy, aryl ether, heteroaryl ether, mercapto, alkyl sulfide, aryl sulfide, heteroaryl sulfide, amino, alkylamino, arylamino, heteroarylamine, ester, acyl, amide, carbonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, sulfonyl, sulfone, and sulfoxide; Or, when R 1 R 2 Each is an independent hydrogen atom, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro, respectively. 1 R 2 Between, and / or, R 3 R 4 Between, and / or, R 4 R 5 Between, and / or, R 5 R 6 Between, and / or, R 6 R 7 Between, and / or, R 7 R 8 Between, and / or, R 8 R 9 Between, and / or, R 9 R 10 These atoms can form rings through carbon chains and heteroatoms.

[0017] Accordingly, the use of the described fused-ring diaza aromatic skeleton in the preparation of drugs for treating gout inflammation, or for fighting Candida albicans or cancer.

[0018] The present invention has the following beneficial effects: ① Under mild conditions, the N-amino salt of electron-deficient nitrogen-containing aromatic compounds is efficiently converted into a fused-ring diaza aromatic skeleton in one step, greatly shortening the synthetic steps and improving the synthetic efficiency. ② This type of reaction exhibits high regioselectivity, thus reducing the difficulty of separation and purification and further improving reaction efficiency. ③ This method can be well applied to the synthesis of other multi-substituted fused-ring diaza aromatic skeletons. ④ This method can directly use electron-deficient nitrogen-containing aromatic compounds as starting materials to synthesize multi-substituted fused-ring diaza aromatic skeletons through a two-step one-pot operation. ⑤ This method can be used to synthesize multiple active drug molecules, greatly simplifying the synthetic route. Detailed Implementation

[0019] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] Unless otherwise specified, the technical means used in the implementation examples are conventional means well known to those skilled in the art.

[0021] 1. This invention discloses a method for synthesizing fused-ring diaza aromatic skeletons. The method involves reacting the N-amino salt of an electron-deficient diaza aromatic compound with an aldehyde or ketone containing an active methylene group in the presence of a base, an oxidant, and an organic solvent at -78°C to 150°C, thereby directly synthesizing a fused-ring diaza aromatic skeleton compound in one step. The reaction concentration of the N-amino salt of the electron-deficient diaza aromatic compound is 0.01 to 0.2 M.

[0022] The general reaction formula is:

[0023] 2. This invention also discloses another method for synthesizing fused-ring diaza aromatic skeletons. An electron-deficient diaza aromatic compound is reacted with an electrophilic amination reagent to synthesize the N-amino salt of the electron-deficient diaza aromatic compound in situ. Then, in the presence of a base, oxidant, and organic solvent, it is reacted with an aldehyde or ketone containing an active methylene group at -78°C to 150°C for 0.5 h to 80 h to synthesize fused-ring diaza aromatic skeleton compounds. This method can directly use electron-deficient diaza aromatic compounds as raw materials to synthesize fused-ring diaza aromatic skeleton compounds in a two-step, one-pot process. The reaction concentration of the N-amino salt of the electron-deficient diaza aromatic compound is 0.01 to 0.2 M.

[0024] The general reaction formula is:

[0025] The oxidizing agent, alkali, and organic solvent used in the two synthesis methods described above are the same. Specifically: The base is an organic or inorganic base, including but not limited to one of the following: triethylamine (TEA or Et3N), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), tetramethylguanidine (TMG), Cs2CO3, K2CO3, Na2CO3, Li2CO3, K3PO4, K2HPO3, sodium methoxide (MeONa), sodium ethoxide (EtONa), sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), lithium tert-butoxide (tBuOLi), lithium hexamethyldisilamide (LiHMDS), sodium hexamethyldisilamide (NaHMDS), and potassium hexamethyldisilamide (KHMDS); the amount of the base used is from 0.1 equivalents to 5 equivalents.

[0026] The oxidant is one of the following: peroxide, high-valent iodine reagent, organic nitrogen oxide, or a composite oxidant formed by organic nitrogen oxide and copper / iron salt (such as CuBr+TEMPO+O2, CuBr+TEMPO+air, ​​etc.); the amount of the oxidant used is 0.01 equivalents to 2 equivalents.

[0027] The peroxides include, but are not limited to, one of tert-butanol peroxide (TBHP) and hydrogen peroxide; the high-valent iodine reagents include, but are not limited to, one of 2-iodobenzoic acid (IBX), Dysmartin oxidant (DMP), iodobenzene diacetate (PIDA), and bis(trifluoroacetic)iodobenzene (PIFA); the organic nitrogen oxides include, but are not limited to, tetramethylpiperidine oxide (TEMPO), 4-oxo-2,2,6,6-tetramethyl-4-piperidine oxide (4-Oxo-TEMPO), and 4-amino-2,2,6,6-tetramethylpiperidine. The copper / iron salt is one of the following: oxide (4-Amino-TEMPO) or 9-azabicyclo[3.3.1]nonane-N-oxygen radical (ABNO); the copper / iron salt includes, but is not limited to, one of CuBr, CuI, CuCl, Cu(OTf)2, Cu(CH3CN)4BF4, Cu(CH3CN)4PF6, Cu(CH3CN)4OTf, Fe(NO2)3, Fe(NO2)2, Fe(OTf)3, FeCl2, and FeCl3, and the amount of the copper / iron salt is from 0.01 equivalents to 2 equivalents.

[0028] The organic solvent is one of toluene, 1,4-dioxane, N,N-dimethylformamide (DMF), acetonitrile (CH3CN), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), diethyl ether, methyl tert-butyl ether, and dimethyl glycol ether (DME).

[0029] In the two synthetic methods described above, the electron-deficient nitrogen-containing aromatic compound is one of pyridine, quinoline, isoquinoline, phenanthridine, phenanthroline, substituted pyridine, substituted quinoline, substituted isoquinoline, substituted phenanthridine, or substituted phenanthroline; the N-amino salt is one of trifluoromethanesulfonate, alkyl sulfonate (such as trifluoromethanesulfonic acid, methanesulfonic acid, p-methylbenzenesulfonic acid, p-nitrobenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, p-bromobenzenesulfonic acid, etc.), aryl sulfonate, benzoic acid and its derivatives (such as p-nitrobenzoic acid, o-nitrobenzoic acid, etc.), phenol and its derivatives (such as o-nitrophenol, p-nitrophenol, m-nitrophenol, 2,4-dinitrophenol, etc.), halide, sulfate, or phosphate. The N-amino salts of the aforementioned electron-deficient nitrogen-containing aromatic compounds can undergo displacement reactions with inorganic acids to form corresponding inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, persulfate, and sulfate. Therefore, the corresponding N-amino inorganic acid salts of electron-deficient aromatic compounds are also within the scope of protection of this invention.

[0030] The electrophilic amination agent is one of O-benzenesulfonyl hydroxylamine and its substitutes, O-alkylsulfonyl hydroxylamine and its substitutes, O-benzoyl hydroxylamine and its substitutes, and O-nitrobenzenesulfonyl hydroxylamine and its substitutes. Specifically, the substitutes for O-benzenesulfonyl hydroxylamine include, but are not limited to, one of O-4-methylbenzenesulfonyl hydroxylamine, O-2-methoxybenzenesulfonyl hydroxylamine, O-4-methoxybenzenesulfonyl hydroxylamine, O-4-bromo-benzenesulfonyl hydroxylamine, O-2-methylbenzenesulfonyl hydroxylamine, O-p-methylbenzenesulfonyl hydroxylamine, O-p-nitrobenzenesulfonyl hydroxylamine, O-2,4,6-trimethylbenzenesulfonyl hydroxylamine, and O-2-bromo-benzenesulfonyl hydroxylamine. The alternatives to the O-alkylsulfonyl hydroxylamine include, but are not limited to, one of O-methylsulfonyl hydroxylamine and O-trifluoromethylsulfonyl hydroxylamine; The alternatives to O-benzoyl hydroxylamine include, but are not limited to, one of O-benzoyl hydroxylamine, O-4-nitrobenzoyl hydroxylamine, O-2-nitrobenzoyl hydroxylamine, O-2,4-dinitrobenzoyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, and O-o-nitrobenzoyl hydroxylamine; The alternatives to O-nitrophenylhydroxylamine include, but are not limited to, one of O-2-nitrophenylhydroxylamine, O-4-nitrophenylhydroxylamine, O-o-nitrophenylhydroxylamine, O-m-nitrophenylhydroxylamine, O-p-nitrophenylhydroxylamine, and O-2,4-dinitrophenylhydroxylamine.

[0031] 3. The general structural formula of the fused-ring diaza aromatic skeleton synthesized by the above-disclosed method is any one of the following:

[0032] Among them, R 1 R 2 Each is an independent hydrogen atom, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 It can be one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro.

[0033] Furthermore, when R 1 R 2 When each is an independent hydrogen, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 1 R 2 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; And / or, when R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro; 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each can be individually controlled by one or more independent Rs X Substituents; R XIt is any one of hydrogen atom, alkyl, fluoroalkyl, chloroalkyl, aryl, fluoroaryl, heteroaryl, fluoroheteroaryl, hydroxyl, alkoxy, aryl ether, heteroaryl ether, mercapto, alkyl sulfide, aryl sulfide, heteroaryl sulfide, amino, alkylamino, arylamino, heteroarylamine, ester, acyl, amide, carbonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, sulfonyl, sulfone, and sulfoxide.

[0034] Furthermore, when R 1 R 2 Each is an independent hydrogen atom, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro, respectively. 1 R 2 Between, and / or, R 3 R 4 Between, and / or, R 4 R 5 Between, and / or, R 5 R 6 Between, and / or, R 6 R 7 Between, and / or, R 7 R 8 Between, and / or, R 8 R 9 Between, and / or, R 9 R 10 Between them, they can form carbon rings, heterocycles, and aromatic carbon rings and heterocycles through carbon chains, heteroatoms, etc. At the same time, after cyclic formation, they can be substituted by substituents such as halogens.

[0035] This invention discloses the application of the aforementioned fused-ring diaza aromatic skeleton in the preparation of drugs for treating gout inflammation, or for fighting Candida albicans or cancer.

[0036] The present invention will be further described below with reference to specific embodiments.

[0037] Example 1 Synthesis of 2,3-diphenylpyrazolo[1,5-a]pyridine-6-ethyl ketone (P1) and 2,3-diphenylpyrazolo[1,5-a]pyridine-4-ethyl ketone (P2)

[0038] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mmol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain P1 and P2 (36.4 mg, yield 78%).

[0039] The reaction equation is:

[0040] The obtained product P1 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 7.79-7.54 (m, 4H), 7.47-7.32 (m, 8H), 2.66 (s, 3H). The obtained product P2 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.61(dd, J =6.9,1.1Hz,1H),7.56-7.49(m,2H),7.43-7.35 (m,3H),7.35-7.31 (m,3H),7.26-7.24 (m,3H),6.84(t,J=7.0Hz, 1H), 1.94 (s,3H). Example 2: Yields of P1 and P2 synthesized under different types of alkalis

[0041] Referring to the synthesis method of Example 1, when the base used was N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP), the product yields are shown in the table below, with target product P1 obtained in yields of 25% and 13%, respectively. When the base used was potassium tert-butoxide (t-BuOK), sodium tert-butoxide (t-BuONa), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), or lithium tert-butoxide (t-BuOLi), the product yields are shown in entries 3-7 of the table below, with target products P1 and P2 obtained in total yields of 77%, 57%, 59%, 28%, and 15%, respectively.

[0042]

[0043] Example 3: Yields of P1 and P2 synthesized with different types of oxidants Referring to the synthesis method in Implementation Regulation 1, when the oxidant Cu(CH3CN)4BF4 (7mol%) / TEMPO (7.5mol%) / O2 is replaced with TEMPO (reaction time 41h), tert-butyl hydrogen peroxide, H2O2, air, and oxygen, the target products P1 and P2 are obtained in total yields of 79%, 11%, 19%, 25%, and 43%, respectively.

[0044] Example 4: Yields of P1 and P2 synthesized in different organic solvents

[0045] Referring to the synthesis method in Implementation Regulation 1, when the organic solvent is replaced with 1,4-dioxane, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, or ethylene glycol dimethyl ether, the target products P1 and P2 are obtained in total yields of 42%, 29%, 42%, 12%, and 10%, respectively.

[0046] Example 5: Yields of P1 and P2 synthesized at different temperatures

[0047] Referring to the synthesis method in Implementation Regulation 1, when 80℃ is replaced with room temperature, the target product P1 is obtained in a yield of 10%; when 80℃ is replaced with 50℃, 60℃, 100℃, or 80℃ (reacting in air for 80 hours), the target products P1 and P2 are obtained in total yields of 50%, 44%, 45%, and 71%, respectively.

[0048] Example 6: Yields of P1 and P2 synthesized at different reaction concentrations

[0049] Referring to the synthesis method in Implementation Regulation 1, when the reaction concentration of 0.1M (mol / L) is replaced with 0.05M and 0.2M, the target products P1 and P2 are obtained with total yields of 47% and 40%, respectively.

[0050] Example 7: Yields of P1 and P2 synthesized with different amounts of alkali

[0051] Referring to the synthesis method of Implementation Regulation 1, when 1 equivalent (eq) of base is replaced with 2 eq, 1.5 eq, and 1.2 eq, the target products P1 and P2 are obtained with total yields of 51%, 50%, and 40%, respectively.

[0052] Example 8 Synthesis of 2,3-tetrahydrocyclohexylpyridinium pyrazolo[1,5-a]pyridine-6-acetone (P3) and 2,3-tetrahydrocyclohexylpyridinium pyrazolo[1,5-a]pyridine-4-acetone (P4)

[0053] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), cyclohexanone (37 mL, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. At 0 °C, 0.3 mmol of alkali was added, and the reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain P3 and P4.

[0054] When the bases used were 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), cesium carbonate (Cs2CO3), sodium methoxide (CH3ONa), tetramethylguanidine (TMG), lithium tert-butoxide (t-BuOLi), and 4-dimethylaminopyridine (DMAP), the yields of the products are shown in entries 1-5 and 8 of the table below, with the target product P3 obtained in yields of 5%, 8%, 7%, 5%, 8%, and 5%, respectively. When the bases used were N,N-diisopropylethylamine (DIPEA), sodium tert-butoxide (t-BuONa), lithium hexamethyldisilamide aminohydroxide (LiHMDS), and potassium tert-butoxide (t-BuOK), the yields of the products are shown in entries 6-7 and 9-10 of the table below, with the target products P3 and P4 obtained in total yields of 8%, 34%, 20%, and 33%, respectively.

[0055] The reaction equation is as follows:

[0056] The obtained product P3 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ 8.99(s,1H),7.56(dd, J =9.3, 1.6 Hz, 1H), 7.32 (dd, J =9.3,0.9Hz,1H),2.90(t, J =6.2Hz,2H),2.73(t, J =6.2Hz,2H),2.58(s,3H),1.96-1.90(m,1H),1.90-1.84(m,1H). The obtained product P4 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.47(d, J =6.9Hz, 1H), 7.50(d, J=7.0Hz,1H),6.64(s,1H),2.63(s,4H), 1.91-1.86(m,2H),1.85-1.79(m,2H). Example 9 Synthesis of 2-(2-fluorophenyl)-3-phenylpyrazolo[1,5-a]pyridine-6-ethyl ketone (P5)

[0057] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(2-fluorophenyl)-2-acetophenone (64.3 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P5 (48.6 mg, yield 98%).

[0058] The reaction equation is:

[0059] The obtained product P5 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.16(s,1H),7.74-7.64(m,2H),7.50(td, J =7.4,1.8Hz, 1H),7.42-7.33(m,3 H),7.33-7.27(m,3H),7.21-7.15(m,1H),7.09(dd, J =10.1,8.3Hz,1H),2.63(s,3H). Example 10 Synthesis of 2,4-diphenylpyrazole[1,5-a]pyridine-6-carboxynitrile (P6)

[0060] At room temperature, 1-amino-3-cyanopyridine 2,4,6-trimethylbenzenesulfonate (48.4 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P6 (25 mg, yield 57%).

[0061] The reaction equation is:

[0062] The obtained product P6 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.86 (s, 1H), 7.59 (dd, J = 10.5, 8.3 Hz, 3H), 7.42 (t, J = 7.4 Hz, 2H), 7.35 (dt, J = 16.0, 7.6 Hz, 7H), 7.16 (d, J = 9.2 Hz, 1H). Example 11 Synthesis of 2-((2-(4-chlorophenoxy)-2-methylpropionyl)oxy)ethyl 2,3-diphenylpyrazolo[1,5-a]pyridine-6-carboxylic acid ester (P7)

[0063] At room temperature, 1-amino-3-((2-((2-(4-chlorophenoxy)-2-methylpropionyl)oxy)ethoxy)methyl)pyridine 2,4,6-trimethylbenzenesulfonate (86.7 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P7 (35.8 mg, yield 43%).

[0064] The reaction equation is:

[0065] The obtained product P7 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.12-9.08(m,1H),7.65-7.59(m,2H),7.53-7.47(m,2H), 7.42-7.38 (m,2H),7.38-7.32(m,7H),7.11-7.06(m,2H),6.78-6.72(m,2H),4.58-4.50(m,4H),1.60(s,7H). Example 12 Synthesis of 2-thiazol-3-phenylpyrazole[1,5-a]pyridine-6-ethyl ketone (P8)

[0066] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 2-phenyl-1-thiophene-ethyl ketone (60.7 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P8 (55.1 mg, yield 99%).

[0067] The reaction equation is:

[0068] The obtained product P8 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ 9.13(s,1H),7.69-7.63(m,1H),7.53-7.39(m,7H),7.35(d, J =5.1Hz, 1H), 7.17(t, J =3.0Hz, 1H), 6.98(q, J =3.6, 3.1 Hz, 1H), 2.63 (d, J =2.2Hz, 3H). Example 13 Synthesis of 2,3-dihydrocyclopentylpyrazolo[3,4]pyrazolo[1,5-a]pyridine-6-acetone (P9) and 2,3-dihydrocyclopentylpyrazolo[3,4]pyrazolo[1,5-a]pyridine-4-acetone (P10)

[0069] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), cyclopentanone (52 mL, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P9 and P10 (16.8 mg, yield 56%, ratio P9:P10 = 2:1).

[0070] The reaction equation is:

[0071] The obtained product P9 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.02(s,1H),7.57(dd, J =9.4, 1.6 Hz, 1H), 7.30 (d, J =9.3 Hz, 1H), 2.96 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H), 2.58 (s, 3H), 2.57 – 2.52 (m, 2H). The obtained product P10 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.50 (d, J = 6.9 Hz, 1H), 7.64 (dd, J = 7.1, 1.0 Hz, 1H), 6.61(t, J = 7.0Hz, 1H), 3.21(t, J = 7.2 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H),2.61(s,3H),2.48(p, J = 7.4 Hz, 2H). Example 14 Synthesis of 2,3-(2,2-difluoro)cyclohexylpyrazolo[1,5-a]pyridine-6-acetone (P11) and 2,3-(2,2-difluoro)cyclohexylpyrazolo[1,5-a]pyridine-4-acetone (P12)

[0072] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 4,4-difluorocyclohexanone (40.2 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P11 and P12 (22.2 mg, yield 59%, P11:P12 = 4:1).

[0073] The reaction equation is:

[0074] The obtained product P11 was measured using an NMR spectrometer, and the obtained NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.00(s,1H),7.63(dd, J =9.3, 1.6 Hz, 1H), 7.32 (dd, J =9.3,0.9Hz,1H), 3.25(t, J =13.9Hz,3H),3.13(t, J =6.8Hz,3H),2.59(s,4H),2.36(tt, J =13.5, 6.8 Hz, 3H). The obtained product P12 was measured using an NMR spectrometer, and the obtained NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.49(dd, J =6.9, 1.1 Hz, 1H), 7.63 (dd, J =7.1,1.1Hz,1H),6.72(t, J=7.0 Hz, 1H), 3.50(t, J =14.8Hz,1H),3.11(t,J=6.9Hz,1H),2.63(s,2H),2.32(dt,J=13.4, 6.6Hz,1H). Example 15 Synthesis of 2-naphthyl-3-phenylpyrazole[1,5-a]pyridine-6-ethyl ketone (P13)

[0075] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-naphthyl-2-phenyl-ethyl ketone (74.1 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P13 (24.8 mg, yield 46%).

[0076] The reaction equation is:

[0077] The obtained product P13 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.19(s,1H),8.15(s,1H),7.89–7.75(m,4H),7.69(d, J =8.6Hz,2H),7.59(dd, J =9.5,2.2Hz,1H),7.54–7.45(m,2H),7.39(d, J =6.7Hz, 5H), 2.65(d, J =2.1Hz, 3H). Example 16 Synthesis of 9-chloro-1,2-diphenylpyrazolo[5,1-a]isoquinoline (P14)

[0078] At room temperature, 2-amino-6-chloroisoquinoline pyridine 2,4,6-trimethylbenzenesulfonate (56.7 mg, 0.15 mmol), phenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain P14 (27.8 mg, yield 52%).

[0079] The reaction equation is:

[0080] The obtained product P14 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.31(d, J =7.4Hz, 1H), 7.66(d, J =2.2Hz,1H),7.55-7.51(m,3H),7.50-7.45 (m,3H),7.43(dd, J =7.6,1.9Hz,2H),7.26(dd,J=6.8,3.8Hz,4H),7.20(dd,J=8.8,2.2Hz,1H). Example 17 Synthesis of 2,3-diphenylpyrazolo[1,5-f]phenanthridine (P15)

[0081] At room temperature, 5-aminophenanthridinepyridine 2,4,6-trimethylbenzenesulfonate (59.1 mg, 0.15 mmol), phenyl ethyl ketone (48.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain P15 (42.6 mg, yield 77%).

[0082] The reaction equation is:

[0083] The obtained product P15 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.77(dd, J =8.2,1.2Hz,1H),8.39(t, J =7.4Hz,2H),7.70–7.64(m,1H), 7.61(ddd, J =6.8,5.1,1.5Hz,3H),7.53–7.45(m,7H),7.32–7.22(m,5H). Example 18 Synthesis of 2-methyl-3-p-methoxyphenylpyrazole[1,5-a]pyridine-6-ethyl ketone (P16)

[0084] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 4-p-methoxyphenyl-2-propanone (49.3 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P16 (26.8 mg, yield 64%).

[0085] The reaction equation is:

[0086] The obtained product P16 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.02(s,1H),7.60(dd, J =9.3, 1.6 Hz, 1H), 7.48 (d, J =9.4Hz,1H), 7.39–7.34(m,2H),7.06–7.00(m,2H),3.87(s,3H),2.60(s,3H),2.54(s,3H). Example 19 Synthesis of ethyl 2-phenylpyrazole[1,5-a]pyridine-6-carboxylate (P17) and ethyl 2-phenylpyrazole[1,5-a]pyridine-4-carboxylate (P18)

[0087] At room temperature, 1-amino-3-ethoxycarbonylpyridine 2,4,6-trimethylbenzenesulfonate (55 mg, 0.15 mmol), acetophenone (35 mL, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7.5 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P17 (14.2 mg) and P18 (21 mg, total yield 53%).

[0088] The reaction equation is:

[0089] The obtained product P17 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ 9.23 (s, J =1.4Hz,1H),8.01-7.94(m,2H),7.65(dd, J =9.3, 1.5 Hz, 1H), 7.51 (d, J =9.3Hz, 1H), 7.47(dd, J =8.3,6.9Hz,2H),7.43-7.38(m,1H),4.42(q, J =7.1Hz,2H),1.42(t, J =7.2Hz, 3H). The obtained product P18 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.64(d, J =6.9Hz, 1H), 8.01(d, J =7.6Hz,2H),7.97(d, J =7.1Hz, 1H), 7.47(t, J =7.6Hz,2H),7.43(s,1H),7.39(s,1H),6.81(s,1H),4.49(d, J =7.2Hz, 1H), 1.48(t, J =7.1Hz, 3H). Example 20 Synthesis of 3,4-diphenylpyrazolo[1,5-a]pyridine (P19) and 3,6-diphenylpyrazolo[1,5-a]pyridine (P20) At room temperature, 1-amino-3-phenylpyridine 2,4,6-trimethylbenzenesulfonate (55.5 mg, 0.15 mmol), phenylacetaldehyde (35 mL, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 mL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain P19 and P20 (21.1 mg, total yield 52%).

[0090] The reaction equation is:

[0091] The obtained product P19 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.72(dd,J=1.7,0.9Hz,1H),8.18(s,1H),7.89(dd,J=9.2,0.9Hz,1H), 7.65–7.60(m,4H),7.50(dd,J=8.5,3.0Hz,2H),7.49–7.47(m,2H),7.47–7.46(m,1H). The obtained product P20 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR(600MHz, CDCl3) δ 8.54(dd,J=7.0,1.1Hz,1H),8.04(s,1H),7.18-7.12(m,1H),7.09(dd,J=6.7, 1.4Hz,3H),7.05(td,J=7.4,1.7Hz,3H),6.99(dd,J=8.3,6.8Hz,2H),6.91–6.85(m,3H). Example 21 Synthesis of 1-(2-(4-methoxy-3-nitrophenyl)-3-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-6-yl)ethyl-1-one (P21)

[0092] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(4-methoxy-3-nitrophenyl)-2-(3,4,5-trimethoxyphenyl)ethyl-1-one (108.3 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P21 (27.1 mg, yield 37%).

[0093] The reaction equation is:

[0094] The obtained product P21 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.14(s,1H),7.92(d, J =2.2Hz, 1H), 7.72(dd, J =9.4,1.6Hz,1H), 7.52-7.47 (m,2H),7.13(d, J =8.7Hz,1H),6.82(s,2H),3.99(s,3H),3.87(s,3H),3.73(s,6H),2.63(s,3H). Example 22 Synthesis of 3-phenylpyrazolo[1,5-f]phenanthridine (P22)

[0095] At room temperature, 5-aminophenanthrene 2,4,6-trimethylbenzenesulfonate (59.1 mg, 0.15 mmol), phenylacetaldehyde (34 mL, 0.3 mmol), TEMPO (28.1 mg, 0.18 mol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 mL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain P22 (24.5 mg, yield 56%).

[0096] The reaction equation is:

[0097] The obtained product P22 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.64 (dd, J = 8.2, 1.3 Hz, 1H), 8.42 – 8.33 (m,2H), 8.00 (dd, J = 8.1, 1.3 Hz, 1H), 7.93 (s, 1H), 7.66 (ddd, J = 8.4, 7.1, 1.3Hz, 1H), 7.59 – 7.53 (m, 3H), 7.53 – 7.48 (m, 3H), 7.47 – 7.42 (m, 1H). Example 23 Synthesis of 3-phenylpyrazolo[1,5-a][1,10]phenanthroline (P23) At room temperature, 1-amino-1,10-phenanthroline 2,4,6-trimethylbenzenesulfonate (59.3 mg, 0.15 mmol), phenylacetaldehyde (35 mL, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 mL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain P23 (27 mg, yield 61%).

[0098] The reaction equation is:

[0099] The obtained product P23 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.45 (dd, J =4.3,1.9Hz,1H),8.61(s,1H),8.31(dd, J =8.2, 1.8Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.80 (d, J =8.4 Hz, 1H), 7.70 – 7.66 (m, 2H), 7.65 – 7.60 (m, 2H), 7.50 (t, J= 7.7 Hz, 2H), 7.38 – 7.33 (m, 1H). Example 24 Synthesis of 3-chloropropylpyrazole[1,5-a]pyridine-6-ethyl ketone (P24)

[0100] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-chloropentanal (35 mL, 0.3 mmol), TEMPO (28.1 mg, 0.18 mol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 mL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P24 (31.7 mg, yield 90%).

[0101] The reaction equation is:

[0102] The obtained product P24 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3)δ9.05(d, J =1.6Hz,1H),7.95(s,1H),7.60(dd, J =9.3, 1.6 Hz, 1H), 7.49 (dd, J = 9.3, 0.9 Hz, 1H), 3.53 (t, J =6.2Hz,2H),2.91(t, J =7.3Hz,2H),2.59(s,3H),2.14-2.06(m,2H). Example 25 Synthesis of ethyl 3-glucosyl-pyrazolo[1,5-a]pyridine-6-carboxylate (P25) At room temperature, 1-amino-3-ethoxycarbonylpyridine 2,4,6-trimethylbenzenesulfonate (55 mg, 0.15 mmol), glucosylacetaldehyde (112 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 mL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain P25 (32.1 mg, yield 41%).

[0103] The reaction equation is:

[0104] The obtained product P25 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.21(t, J =1.2Hz, 1H), 8.38(d, J =0.6Hz,1H),7.70(t, J =1.2Hz,2H), 5.76–5.72(m,1H),5.72-5.68(m,1H),5.36(dd, J =10.4, 6.1 Hz, 1H), 5.11 (dd, J =10.1,9.1Hz,1H),4.41(q, J =7.1Hz, 2H), 4.14(dd, J =12.3,5.2Hz,1H),3.94(dd, J =12.3,2.3Hz,1H),2.07(s,3H),2.03(s,3H),2.01(s,3H),1.96 (s,3H),1.41(t, J =7.1Hz, 3H). Example 26 Synthesis of 3(5-deoxyfuranose)pyrazolo[1,5-a]pyridine-6-acetone (P26) At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 5-deoxyfuranose ribose acetaldehyde (91 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and CH3ONa (8 mg, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain P26 (37.3 mg, yield 69%).

[0105] The reaction equation is:

[0106] The obtained product P26 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1H NMR(600 MHz, CDCl3) δ 9.06(s,1H),8.08(s,1H),7.70-7.58(m,2H),5.63-5.55(m,2H),5.16 (dd,J= 7.4,4.6Hz,1H),4.39(p,J=6.5Hz,1H),2.61(s,3H),2.08(s,3H),1.85(s,3H),1.40(d,J=6.3Hz,3H). Example 27 Two-step one-pot synthesis of 2,3-diphenylpyrazole[1,5-a]pyr-6-ethyl ketone (P1)

[0107] 3-Acetylpyridine (0.61 g, 5 mmol) was added to a solution of hydroxylamine methanesulfonate (MesNH2) (approximately 0.063 M in dichloromethane) and stirred for 10 minutes. The resulting mixture was then heated to reflux in an oil bath, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, the solvent was removed by rotary evaporation. The residue was suspended in 30 mL of toluene, and phenyl ethyl ketone (1.96 g, 10 mmol), copper tetraacetonitrile tetrafluoroborate (117.75 mg, 0.35 mmol), and 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO, 58.59 mg, 0.375 mmol) were added, followed by attaching an oxygen balloon. The reaction mixture was cooled to 0 °C, and then lithium bis(trimethylsilyl)amino (LiHMDS, 5 mL, 5 mmol) was added dropwise. The resulting mixture was stirred at room temperature, then heated to 80 °C, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by rapid column chromatography (FCC, petroleum ether: ethyl acetate = 15:1-8:1) to obtain 962.3 mg (62% yield) of product P1.

[0108] The reaction equation is:

[0109] Example 28 Synthesis of 2,3-diphenylpyrazolo[1,5-a]pyridine-6-ethyl ketone (P1) at -78°C At -78°C, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), LiHMDS (150 mL, 0.15 mmol), and toluene (1.5 mL) were added to a reaction tube. After stirring for 1 h, the mixture was moved to room temperature, and 1,2-diphenyl ethyl ketone (58.9 mg, 0.15 mmol) was added. After stirring for 15 min, TEMPO (1.8 mg, 7.5 mol%) and Cu(CH3CN)4BF4 (3.3 mg, 7 mol%) were added. An oxygen bulb was inserted, and the reaction mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8:1) to obtain P1 (15.5 mg, yield 33%).

[0110] The reaction equation is:

[0111] Or synthesize according to the following methods At -78°C, 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), LiHMDS (300 mL, 0.3 mmol), and toluene (1.5 mL) were added to a reaction tube. After stirring for 1 h, the mixture was moved to room temperature, and 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), TEMPO (1.8 mg, 7.5 mol%), and Cu(CH3CN)4BF4 (3.3 mg, 7 mol%) were added. An oxygen bulb was inserted, and the reaction mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8:1) to obtain 2,3-diphenylpyrazolo[1,5-a]pyridine-6-ethyl ketone P1 (22.4 mg, yield 48%).

[0112] The reaction equation is:

[0113] This method can greatly shorten the synthetic routes of some drugs and bioactive molecules. One example is given below.

[0114] 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylonitrile has been developed as a targeted inhibitor of Yck2, exhibiting high potency and favorable drug-like properties. Targeting Yck2 is a promising strategy against Candida albicans, the most common cause of life-threatening fungal infections. Even with current treatments, the mortality rate of these infections exceeds 40%, highlighting a significant unmet medical need for novel antifungal drugs. Previously reported synthetic routes involved the cyclization of 3-iodo-N-aminopyridinium with ethyl 4-fluorophenylpropynate (reaction formula below), followed by alkaline hydrolysis / decarboxylation, N-bromosuccinimide (NBS)-mediated bromination, cuprous cyanide (CuCN)-based cyanation, and palladium-catalyzed Suzuki coupling. After five transformations, the overall yield of target product 9 was only 1.9% (Cowen, LE et al, Cell Chemical Biology (2020, 27, 269; Nature Communications, 2025, 16, 2156). This lengthy synthetic sequence suffers from problems such as low efficiency, harsh reaction conditions, use of highly toxic reagents (CuCN), and poor regioselectivity in certain steps.

[0115]

[0116] In stark contrast, the synthetic method of this invention enables the direct one-step synthesis of the same molecule, significantly increasing the yield to 47%, and possesses unique regioselectivity control. This contrast powerfully underscores the practical value of our method in efficiently constructing drug-related scaffolds. Specific embodiments are as follows: Example 29 Synthesis of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylonitrile (P27)

[0117] At room temperature, 1-amino-3-cyanopyridine 2,4,6-trimethylbenzenesulfonate (48 mg, 0.15 mmol), 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethyl ketone (64.5 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 mL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P27 (22.1 mg, yield 47%).

[0118] The reaction equation is:

[0119] The obtained product P27 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.89 (s, 1H), 8.65 (d, J = 5.0 Hz, 2H), 7.66(d, J =9.2 Hz,1H), 7.55 – 7.49 (m, 2H), 7.30 (dd, J = 12.6, 7.1 Hz, 3H), 7.09 (t, J =8.4 Hz, 2H). Example 30 Synthesis of 3-(((tert-butyldimethylsilyl)oxy)methyl)pyrazolo[1,5-a]pyridine-6-ethyl ketone (P28)

[0120] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 3-((tert-butyldimethylsilyl)oxy)propionaldehyde (56.4 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P28 (32.9 mg, yield 70%).

[0121] The reaction equation is:

[0122] The obtained product P28 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.07 (t, J = 1.3 Hz,1H),8.03(s,1H),7.64(dd, J =9.4, 1.5 Hz, 1H), 7.59(dd, J =9.3,0.9Hz,1H),4.89(s,2H),2.60(s,3H),0.90(s,9H),0.09(s,6H). Example 31 Synthesis of 2-((6-acetylpyrazolo[1,5-a]pyridin-3-yl)methyl)isoindoline-1,3-dione (P29)

[0123] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 3-(1,3-dioxoisoindolin-2-yl)propionaldehyde (60.9 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P29 (23.3 mg, yield 48%).

[0124] The reaction equation is:

[0125] The obtained product P29 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.05(s,1H),8.23(s,1H),7.93(dd, J =9.4, 0.9 Hz, 1H), 7.82 (dd, J =5.5,3.1 Hz,2H),7.71(dd, J =9.4, 1.6 Hz, 1H), 7.69 (dd, J =5.5,3.0Hz,2H),4.99(s,2H),2.59(s,3H). Example 32 Synthesis of 3-ribosyl-pyrazolo[1,5-a]pyridine-6-ethyl ketone (P30)

[0126] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), ribosylacetaldehyde (56.4 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and CH3ONa (8 mg, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to obtain P30 (44.2 mg, yield 53%).

[0127] The reaction equation is:

[0128] The obtained product P30 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.09(d, J =1.5Hz,1H),8.10(s,1H),7.73–7.62(m,2H),5.63(t, J =4.2Hz, 1H), 5.59(d, J =3.6Hz, 1H), 5.50(dd, J =7.6, 4.6Hz, 1H), 4.49(ddd, J =7.8,4.8,3.2Hz,1H),4.41(dd, J =12.1,3.2Hz, 1H),4.24(dd, J =12.1,4.9Hz,1H),2.63(s,3H),2.14(s,3H),2.09(s,4H),1.91(s,3H). Example 33 Synthesis of 3-galactosyl-pyrazolo[1,5-a]pyridine-6-ethyl ketone (P31)

[0129] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), galactosylacetaldehyde (169.9 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P31 (52.4 mg, yield 53%).

[0130] The reaction equation is:

[0131] The obtained product P31 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ 9.08 (t, J =1.2Hz, 1H), 8.51(s, 1H), 7.78(d, J=9.4Hz, 1H), 7.54(dd, J =9.4, 1.6 Hz, 1H), 7.36 (dd, J =7.8,1.8Hz,2H),7.33-7.31(m,5H),7.30-7.26(m,4H),7.25-7.20(m,3H),5.54(d, J =5.0Hz, 1H), 5.05(d, J =10.8Hz, 1H), 4.86(d, J =10.8Hz, 1H), 4.80(dd, J =17.9,11.2Hz,2H),4.72(d, J =11.6Hz, 1H), 4.59 (d, J =11.9Hz, 1H), 4.44(dd, J =11.3,3.1Hz,2H),4.09-4.03(m,2H),3.68(dd, J =9.9, 7.9Hz, 1H), 3.62(dd, J =10.5, 4.3 Hz, 1H), 3.56 (dd, J =10.4, 2.1Hz, 1H), 3.31(ddd, J = 10.1, 4.3, 2.1 Hz, 1 H), 2.60 (s, 3H). Example 34 Synthesis of 1-(3-phenyl-2-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-6-yl)acetone (P32)

[0132] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 2-phenyl-1-(4-(trifluoromethyl)phenyl)ethyl-1-one (79.2 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P32 (41.1 mg, yield 72%).

[0133] The reaction equation is:

[0134] The obtained product P32 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.15(t, J =1.2Hz, 1H), 7.74(d, J =8.2Hz,2H),7.69(dd, J = 9.4, 1.5 Hz, 1H), 7.60 (d, J =8.2Hz,2H),7.55(d, J =9.4Hz, 1H), 7.44(dd, J =8.1,6.3Hz,2H),7.41-7.37(m,1H),7.36-7.31(m,2H),2.65(s,3H). Example 35 Synthesis of 1-(2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)acetone (P33)

[0135] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethyl-1-one (64.5 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P33 (36.4 mg, yield 73%).

[0136] The reaction equation is:

[0137] The obtained product P33 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.15(t,J=1.2Hz,1H),8.73–8.47(m,2H),7.77(dd,J=9.3, 1.6 Hz,1H),7.62 (dd,J=9.4,0.9Hz,1H),7.28–7.26(m,2H),7.08(t,J=8.7Hz,2H),2.65(s,3H). Example 36 Synthesis of 7-fluoro-2,3-diphenylpyrazolo[1,5-a]quinoline (P34)

[0138] At room temperature, 1-amino-6-fluoroquinoline 2,4,6-trimethylbenzenesulfonate (54.3 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to obtain P34 (22.9 mg, yield 47%).

[0139] The reaction equation is:

[0140] The obtained product P34 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.66 (dd, J = 9.9, 4.9 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.45 (d, J = 9.3 Hz, 1H), 7.42 – 7.36 (m, 6H), 7.36 – 7.29 (m, 5H). Example 37 Synthesis of 1-(3-((1-methyl-1H-pyrrolo-2-yl)(phenyl)methyl)pyrazolo[1,5-a]pyridine-6-ethyl ketone (P35)

[0141] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 3-(1-methyl-1H-pyrrolo-2-yl)-3-phenylpropanal (38.4 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P35 (32.2 mg, yield 65%).

[0142] The reaction equation is:

[0143] The obtained product P35 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.07(s,1H),7.77(s,1H),7.50(dd,J=9.4,1.6Hz,1H),7.33-7.29(m,2H),7.25 (d,J=7.4Hz,1H),7.18–7.15(m,2H),6.96(dd,J=9.4,0.9Hz,1H),6.64–6.62(m,1H),6.04(dd,J=3.6,2.7Hz, 1H),5.59(ddd,J=3.7,1.9,0.9Hz,1H),5.56(s,1H),3.38(s,3H),2.59(s,3H). Example 38 Synthesis of 1-(2-(4-fluorophenyl)-3-phenylpyrazolo[1,5-a]pyridin-6-yl)acetone (P36)

[0144] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(4-fluorophenyl)-2-acetophenone (64.23 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P36 (38.1 mg, yield 77%).

[0145] The reaction equation is:

[0146] The obtained product P36 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.13-9.10 (m, 1H), 7.66 (dd, J = 9.3, 1.6 Hz, 1H), 7.61-7.56 (m, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.38-7.31 (m, 3H), 7.06 –6.99 (m, 2H), 2.62 (s, 3H). Example 39 Synthesis of 1-(2-(4-chlorophenyl)-3-phenylpyrazolo[1,5-a]pyridin-6-yl)acetone (P37)

[0147] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(4-chlorophenyl)-2-acetophenone (69.1 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P37 (35.8 mg, yield 69%).

[0148] The reaction equation is:

[0149] The obtained product P37 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.15(t,J=1.2Hz,1H),7.69(dd,J=9.4,1.6Hz,1H),7.61-7.53(m,3 H),7.45 (dd,J=8.0,6.4Hz,2H),7.41–7.38(m,1H),7.38–7.31(m,4H),2.66(s,3H). Example 40 Synthesis of 1-(2-(4-bromophenyl)-3-phenylpyrazolo[1,5-a]pyridin-6-yl)acetone (P38)

[0150] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(4-bromophenyl)-2-acetophenone (82.2 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P38 (49.1 mg, yield 84%).

[0151] The reaction equation is:

[0152] The obtained product P38 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.16 – 9.12 (m, 1H), 7.69 (dd, J = 9.4, 1.6Hz, 1H), 7.58 – 7.50 (m, 1H), 7.50 – 7.38 (m, 6H), 2.65 (s, 3H). Example 41 Synthesis of 1-(2-(4-methylphenyl)-3-phenylpyrazolo[1,5-a]pyridin-6-yl)acetone (P39)

[0153] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1-(4-methylphenyl)-2-acetophenone (63.03 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P39 (18.6 mg, yield 38%).

[0154] The reaction equation is:

[0155] The obtained product P39 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.17(s,1H),7.68(dd,J=9.4,1.5Hz,1H),7.59–7.50(m, 3H),7.44(dd,J =8.2,6.6Hz,2H),7.38(d,J=6.9Hz,3H),7.18(d,J=7.9Hz,2H),2.65(s,3H),2.39 (s, 3H). Example 42 Synthesis of 1-(2-(4-methoxyphenyl)-3-phenylpyrazolo[1,5-a]pyridin-6-yl)acetone (P40)

[0156] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P40 (29.8 mg, yield 58%).

[0157] The reaction equation is:

[0158] The obtained product P40 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 7.64 (dd, J = 9.4, 2.4 Hz, 1H), 7.55 (dd, J = 8.9, 2.5 Hz, 2H), 7.51 (dd, J = 9.4, 2.3 Hz, 1H), 7.45 – 7.39(m, 2H), 7.36 (d, J = 7.1 Hz, 4H), 6.92 – 6.84 (m, 2H), 3.82 (d, J = 2.3 Hz, 3H), 2.62 (s, 3H). Example 43 Synthesis of ethyl 2,3-diphenylpyrazolo[1,5-a]pyridine-6-carboxylate (P41)

[0159] At room temperature, 1-amino-3-ethoxycarbonylpyridine 2,4,6-trimethylbenzenesulfonate (54.9 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P41 (30.8 mg, yield 60%).

[0160] The reaction equation is:

[0161] The obtained product P41 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 7.72 – 7.61 (m, 3H), 7.56 (d, J= 9.3 Hz, 1H), 7.47 – 7.33 (m, 9H), 4.45 (q, J = 7.1 Hz, 2H), 1.45 (t, J =7.1 Hz, 3H). Example 44 Synthesis of N,N-diethyl-2,3-diphenylpyrazolo[1,5-a]pyridine-6-sulfonamide (P42)

[0162] At room temperature, 1-amino-3-sulfonamide pyridine 2,4,6-trimethylbenzenesulfonate (64.4 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to obtain P42 (32.8 mg, yield 54%).

[0163] The reaction equation is:

[0164] The obtained product P42 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.62 (t, J = 8.0 Hz, 3H), 7.43 (d, J = 7.0 Hz, 2H), 7.37 (q, J = 4.6 Hz, 8H), 3.35 (q, J = 7.1 Hz, 4H), 1.23(t, J = 7.1 Hz, 6H). Example 45 Synthesis of N,N-diethyl-2,3-diphenylpyrazolo[1,5-a]pyridine-6-carboxamide (P43)

[0165] At room temperature, 1-amino-3-carboxamidopyridine 2,4,6-trimethylbenzenesulfonate (59.0 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P43 (37.7 mg, yield 68%).

[0166] The reaction equation is:

[0167] The obtained product P43 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.60(s,1H),7.61(dd,J=6.5,3.0Hz,2H),7.57(d,J=9.1Hz, 1H),7.40(t,J= 7.5Hz,2H),7.36(d,J=7.4Hz,2H),7.35–7.31(m,5H),3.50(s,4H),1.25(t,J=7.1Hz, 6H). Example 46 Synthesis of 2,3-diphenylpyrazolo[1,5-a]pyridine-6-benzophenone (P44)

[0168] At room temperature, 1-amino-3-benzoylpyridine 2,4,6-trimethylbenzenesulfonate (59.7 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P44 (31.4 mg, yield 58%).

[0169] The reaction equation is:

[0170] The obtained product P44 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.96(d,J=1.5Hz,1H),7.86–7.81(m,2H),7.71(dt,J=9.3, 1.4Hz,1H),7.66- 7.59(m,4H),7.54(t,J=7.5Hz,2H),7.43(t,J=7.6Hz,2H),7.41–7.31(m, 6H). Example 47 Synthesis of methyl 4-methyl-2,3-diphenylpyrazolo[1,5-a]pyridine-6-carboxylic acid ester (P45)

[0171] At room temperature, 1-amino-3-methyl-5-acetylpyridine 2,4,6-trimethylbenzenesulfonate (52.5 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P45 (46.7 mg, yield 91%).

[0172] The reaction equation is:

[0173] The obtained product P45 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.03(s,1H),7.46–7.40(m,2H),7.32–7.24(m,6H),7.17 (d,J=6.0Hz, 3H),3.86(s,3H),1.97(s,3H). Example 48 Synthesis of methyl 7-methyl-2,3-diphenylpyrazolo[1,5-a]pyridine-6-carboxylic acid ester (P46)

[0174] At room temperature, 1-amino-2-methyl-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (52.5 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P46 (45.7 mg, yield 55%).

[0175] The reaction equation is:

[0176] The obtained product P46 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.68–7.63(m,3H),7.44(s,1H),7.43–7.38(m,2H),7.38–7.35 (m, 2H), 7.35–7.31(m,4H),3.95(s,3H),3.26(s,3H). Example 49 Synthesis of 1-(2-(4-trifluoromethylphenyl)-3-phenylpyrazolo[1,5-a]pyridin-6-yl)acetone (P47)

[0177] At room temperature, 1-amino-3-trifluoromethylpyridine 2,4,6-trimethylbenzenesulfonate (54.3 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain P47 (10.7 mg, yield 22%).

[0178] The reaction equation is:

[0179] The obtained product P47 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.84 (s, 1H), 7.65 – 7.57 (m, 3H), 7.42 (t, J= 7.5 Hz, 2H), 7.35 (d, J = 7.5 Hz, 7H), 7.23 (d, J = 9.4 Hz, 1H). Example 50 Synthesis of 2,3-diphenylpyrazolo[1,5-a]quinoline (P48)

[0180] At room temperature, 1-aminoquinoline 2,4,6-trimethylbenzenesulfonate (51.6 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to obtain P48 (21.6 mg, yield 45%).

[0181] The reaction equation is:

[0182] The obtained product P48 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.69(d,J=8.4Hz,1H),7.74(dd,J=7.9,1.4Hz, 1H),7.68 (tdd,J=8.4,6.6, 1.7Hz,3H),7.45–7.42(m,2H),7.41–7.38(m,5H),7.34(qt,J=5.3,1.8Hz,4H). Example 51 Synthesis of 7-methoxy-2,3-diphenylpyrazolo[1,5-a]quinoline (P49)

[0183] At room temperature, 1-amino-6-methoxyquinoline 2,4,6-trimethylbenzenesulfonate (56.1 mg, 0.15 mmol), 1,2-diphenyl ethyl ketone (58.9 mg, 0.3 mmol), TEMPO (1.8 mg, 7.5 mol%), Cu(CH3CN)4BF4 (3.3 mg, 7 mol%), and toluene (1.5 mL) were added to a reaction tube. An oxygen bulb was inserted, and LiHMDS (150 μL, 0.15 mmol) was added at 0 °C. The reaction solution was stirred at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P49 (36.8 mg, yield 70%).

[0184] The reaction equation is:

[0185] The obtained product P49 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.61 (d, J = 9.1 Hz, 1H), 7.70 – 7.66 (m,2H), 7.46 – 7.37 (m, 5H), 7.36 – 7.28 (m, 6H), 7.15 (d, J = 2.8 Hz, 1H), 3.92(s, 3H). Example 52 Synthesis of 1-(3-ethyl)pyrazolo[1,5-a]pyridine-6-ethyl ketone (P50)

[0186] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), n-butyraldehyde (21.6 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P50 (14.8 mg, yield 53%).

[0187] The reaction equation is:

[0188] The obtained product P50 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1H NMR (600 MHz, CDCl3) δ 9.05(d,J=1.5Hz,1H),7.95(s,1H),7.58(dd,J=9.3,1.5Hz, 1H), 7.45(d,J= 9.3Hz,1H),2.75(q,J=7.6Hz,2H),2.60(s,3H),1.30(t,J=7.6Hz,3H). Example 53 Synthesis of 4-(6-aldehyde)propylpyrazolo[1,5-a]pyridine-6-ethyl ketone (P51)

[0189] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), hexamethylenedialdehyde (34.2 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P51 (13.8 mg, yield 40%).

[0190] The reaction equation is:

[0191] The obtained product P51 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.78(s,1H),9.07(s,1H),7.95(s,1H),7.62(d,J=9.3Hz,1H),7.47(d,J=9.3 Hz,1H),2.78(t,J=7.6Hz,2H),2.61(d,J=1.7Hz,3H),2.51(t,J=7.2Hz,2H),2.01(p,J=7.4Hz,2H). Example 54 Synthesis of pyrazolo[1,5-a]pyridine-6-ethyl ketone (P52)

[0192] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), acetaldehyde (13.2 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P52 (10.3 mg, yield 43%).

[0193] The reaction equation is:

[0194] The obtained product P52 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.13(p,J=0.9Hz,1H),8.10(d,J=2.2Hz,1H),7.66(dd,J= 9.3,1.6Hz,1H), 7.56(dd,J=9.3,0.9Hz,1H), 6.61 – 6.56 (m, 1H), 2.62 (s,3H). Example 55 Synthesis of ethyl 3-phenylpyrazolo[1,5-a]pyridine-6-carboxylate (P53)

[0195] At room temperature, 1-amino-3-ethoxycarbonylpyridine 2,4,6-trimethylbenzenesulfonate (54.9 mg, 0.15 mmol), phenylacetaldehyde (36.1 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain P53 (36.6 mg, yield 92%).

[0196] The reaction equation is:

[0197] The obtained product P53 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1H NMR (600 MHz, CDCl3) δ 9.22(dd,J=1.5,0.9Hz,1H),8.27(s,1H),7.80(dd,J=9.4,0.9Hz,1H),7.70(dd, J=9.4,1.5Hz,1H),7.61-7.57(m,2H),7.50-7.44(m,2H),7.35-7.31(m,1H),4.43(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H). Example 56 Synthesis of 3-phenylpyrazolo[1,5-a]pyridine-4-methyl ether (P54)

[0198] At room temperature, 1-amino-3-methoxypyridine 2,4,6-trimethylbenzenesulfonate (48.6 mg, 0.15 mmol), phenylacetaldehyde (36.1 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P54 (28.0 mg, yield 53%).

[0199] The reaction equation is:

[0200] The obtained product P54 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.15(dd,J=7.0,0.8Hz,1H),7.95(s,1H),7.60-7.56(m,2H),7.42- 7.37(m,2 H),7.32–7.27(m,1H),6.68(t,J=7.2Hz,1H),6.40(d,J=7.6Hz,1H),3.85(s,3H). Example 57 Synthesis of 3-phenylpyrazolo[1,5-a]pyridine-4-bromo-6-ethyl ketone (P55)

[0201] At room temperature, 1-amino-3-bromo-5-acetylpyridine 2,4,6-trimethylbenzenesulfonate (62.1 mg, 0.15 mmol), phenylacetaldehyde (36.1 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P55 (44.6 mg, yield 95%).

[0202] The reaction equation is:

[0203] The obtained product P55 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.12 (d, J = 1.4 Hz, 1H), 8.11 (s, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.47 – 7.43 (m, 2H), 7.41 (dtd, J = 6.8, 4.8, 1.8 Hz, 3H), 2.63 (s, 3H). Example 58 Synthesis of 3-phenylpyrazolo[1,5-a]pyridine (P56)

[0204] At room temperature, 1-aminopyridine 2,4,6-trimethylbenzenesulfonate (44.1 mg, 0.15 mmol), phenylacetaldehyde (36.1 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to obtain P56 (10.5 mg, yield 36%).

[0205] The reaction equation is:

[0206] The obtained product P56 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1H NMR (600 MHz, CDCl3) δ 8.50(dt,J=7.0,1.1Hz,1H),8.15(s,1H),7.83(dt,J=9.1, 1.2Hz,1H),7.63–7.56(m,2H),7.50–7.44(m,2H),7.30(tt,J=7.3,1.3Hz,1H), 7.18(ddd, J = 9.0, 6.7, 1.1 Hz, 1H), 6.79 (td, J = 6.8, 1.3 Hz, 1H). Example 59 Synthesis of 1-(3-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)pyrazolo[1,5-a]pyridin-6-yl)acetone (P57)

[0207] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetaldehyde (102.3 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P57 (44 mg, yield 64%).

[0208] The reaction equation is:

[0209] The obtained product P57 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.25(s,1H),7.76(d,J=8.4Hz,2H),7.52(d,J=8.6Hz,2H),6.95(d,J=9.0Hz,1 H),6.78(d,J=2.5Hz,1H),3.75(s,3H),2.67(s,3H),2.38(s,3H). Example 60 Synthesis of (5S,8R,9S,10S,13R,14S,17R)-17-((R)-1-(6-acetylpyrazolo[1,5-a]pyridin-3-yl)propyl-2-yl)-10,13-dimethyldodecylhydro-3H-cyclopentan[a]phenanthrene-3,7,12(2H,4H)-trione (P58)

[0210] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), (R)-4-((5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7,12-trioxohexadecylhydro-1H-cyclopentadien[a]phenanthrene-17-yl)pentanal (115.9 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P58 (79.3 mg, yield 99%).

[0211] The reaction equation is:

[0212] The obtained product P58 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.03(t,J=1.2Hz,1H),7.90(s,1H),7.57(dd,J=9.4,1.5Hz,1H),7.43(dd, J=9.3,0.9Hz,1H),2.93-2.89(m,3H),2.83(t,J=12.7Hz,1H),2.58(s,3H),2.42(dd,J=14.4,10.0Hz,1H), 2.38-2.29(m,2H),2.27(dd,J=14.7,5.3Hz,1H),2.24-2.17(m,3H),2.16–2.09(m,3H),2.02(dd,J=13.3,2.3 Hz,1H),1.97-1.91(m,1H),1.87(dd,J=11.5,7.0Hz,1H),1.64-1.56(m,1H),1.53-1.47(m,2H),1.38(s,3H), 1.36-1.29(m,1H),1.08(s,3H),0.76(d,J=6.6Hz,3H). Example 61 Synthesis of 1-(3-((4,5-diphenyloxazol-2-yl)methyl)pyrazolo[1,5-a]pyridine)-6-ethyl ketone (P59)

[0213] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), 3-(4,5-diphenyloxazol-2-yl)propionaldehyde (83.1 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P59 (25 mg, yield 42%).

[0214] The reaction equation is:

[0215] The obtained product P59 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.10(t, J =1.2Hz,1H),8.18(s,1H),7.69(dd, J =6.8,1.2Hz, 2H),7.64–7.59(m,2H),7.55–7.50(m,2H),7.38–7.30(m,4H),4.34(s,2H), 2.62(s, 3H). Example 62 Synthesis of 3-glucosylpyrazolo[1,5-a]pyridine-6-acetone (P60)

[0216] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), glucosylacetaldehyde (112.2 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P60 (44.2 mg, yield 53%).

[0217] The reaction equation is:

[0218] The obtained product P60 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1H NMR (400 MHz, CDCl3) δ 9.09(d, J =1.5Hz,1H),8.10(s,1H),7.73–7.62(m,2H),5.63(t, J =4.2Hz, 1H), 5.59(d, J =3.6Hz, 1H), 5.50(dd, J =7.6, 4.6Hz, 1H), 4.49(ddd, J =7.8,4.8,3.2Hz,1H),4.41(dd, J =12.1,3.2Hz, 1H),4.24(dd, J =12.1,4.9Hz,1H),2.63(s,3H),2.14(s,3H),2.09(s,4H),1.91(s,3H). Example 63 Synthesis of 3-mannosylpyrazolo[1,5-a]pyridine-6-acetone (P61)

[0219] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), mannosylacetaldehyde (112.2 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P61 (26.4 mg, yield 36%).

[0220] The reaction equation is:

[0221] The obtained product P61 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.13(s,1H),8.28(s,1H),7.79-7.70(m,2H),5.96(t, J =2.8Hz, 1H), 5.40 (d, J =2.3Hz, 1H), 5.35(t, J =9.4Hz, 1H), 5.30(dd, J =9.6, 3.2 Hz, 1H), 4.26 (dd, J=12.2,6.4Hz,1H),4.06(dd, J =12.2,2.4Hz,1H),3.61(ddd, J =9.0,6.3,2.4Hz,1H),2.62(s,3H),2.20(s,3H),2.06(d, J =6.6Hz, 6H), 1.99(s, 3H). Example 64 Synthesis of 3-galactosylpyrazolo[1,5-a]pyridine-6-ethyl ketone (P62)

[0222] At room temperature, 1-amino-3-acetylpyridine 2,4,6-trimethylbenzenesulfonate (50.5 mg, 0.15 mmol), galactosylacetaldehyde (112.2 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P62 (49.3 mg, yield 67%).

[0223] The reaction equation is:

[0224] The obtained product P62 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ 9.11(d, J =1.3Hz, 1H), 8.32(s, 1H), 7.72(d, J =0.9Hz,1H),7.71(d, J = 1.5Hz, 1 H), 5.78(d, J =5.4Hz, 1H), 5.55(d, J =3.3Hz, 1H), 5.39(dd, J =3.3,1.7Hz,1H),4.28-4.22(m,1H),4.13-4.08(m, 1H),4.04(dd, J =11.5, 5.3Hz, 1H), 3.75(ddd, J =7.2,5.3,1.8Hz,1H),2.62(s,4H),2.17(s,3H),2.05(s, J =3.4Hz, 6H), 1.93(s, 3H). Example 65 Synthesis of methyl 3-glucosyl-4-methylpyrazolo[1,5-a]pyridine-6-carboxylic acid (P63)

[0225] At room temperature, 1-amino-3-methyl-5-acetylpyridine 2,4,6-trimethylbenzenesulfonate (54.9 mg, 0.15 mmol), 3-(1-methyl-1H-pyrrolo-2-yl)-3-phenylpropanal (155.5 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P63 (31.6 mg, yield 32%).

[0226] The reaction equation is:

[0227] The obtained product P63 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 9.06(d, J =1.4Hz,1H),8.44(s,1H),7.43–7.38(m,4H),7.37-7.29(m, 6H), 7.29-7.26(m,1H),7.26–7.18(m,8H),5.53(d, J =6.4Hz, 1H), 5.12(d, J =10.7Hz, 1H), 4.91(dd, J =31.3,10.8 Hz,2H),4.74(d, J =11.8Hz, 1H), 4.60(dd, J =29.6,11.4Hz,2H),4.31(t, J =9.0Hz,1H),4.17-4.05(m,3H),3.96(s,3H),3.55(dd, J =10.1,8.4Hz,1H),3.35(ddd, J =10.1,5.3,2.5Hz,1H),1.94(s,3H). Example 66 Synthesis of N,N-diethyl-3-glucosyl-pyrazolo[1,5-a]pyridine-6-sulfonamide (P64)

[0228] At room temperature, 1-amino-3-sulfonylpyridine 2,4,6-trimethylbenzenesulfonate (64.4 mg, 0.15 mmol), glucosylacetaldehyde (169.9 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P64 (55.6 mg, yield 48%).

[0229] The reaction equation is:

[0230] The obtained product P64 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR(600MHz, CDCl3) δ 9.04-8.98(m,1H),8.55(s,1H),7.87(dd, J =9.3,0.9Hz,1H),7.39-7.37(m,2H), 7.34(t, J =1.6Hz, 3H), 7.31(d, J =6.4Hz, 8H), 7.25(p, J =1.1Hz,2H),7.21(dd, J =9.4,1.7Hz,1H),7.11-7.09(m, 2H),5.55(d, J =4.8Hz, 1H), 5.06(d, J =10.8Hz, 1H), 4.87(d, J =10.8Hz,1H),4.85-4.81(m,2H),4.80(s,1H), 4.74(d, J =11.6Hz, 1H), 4.58(d, J =11.9Hz, 1H), 4.47(d, J =1.8Hz,1H),4.45(s,1H),4.07-4.05(m,2H),3.63(d, J =4.6Hz, 1H), 3.59(dd, J =10.4, 2.1Hz, 1H), 3.34(ddd, J =10.0,4.6,2.1Hz,1H),3.28(qd, J=7.1,1.1Hz,4H), 1.19(t, J =7.1Hz, 6H). Example 67 Synthesis of 3-glucosylpyrazolo[1,5-a]quinoline (P65)

[0231] At room temperature, 1-aminoquinoline 2,4,6-trimethylbenzenesulfonate (51.6 mg, 0.15 mmol), glucosylacetaldehyde (169.9 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P65 (30.8 mg, yield 30%).

[0232] The reaction equation is:

[0233] The obtained product P65 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ 8.60 (d, J =8.4Hz, 1H), 8.49(s, 1H), 7.75(d, J =7.9Hz,1H),7.73-7.65(m,2H), 7.46(t, J =7.5Hz, 1H), 7.39(d, J =7.2Hz,2H),7.36-7.28(m,13H),7.24(d, J =7.3Hz,3H),7.14-7.06(m,2H), 5.64(d, J =5.8Hz, 1H), 5.09(d, J =10.7Hz,1H),4.89-4.85(m,2H),4.79(q, J =11.6Hz,2H),4.61(d, J =11.9Hz, 1H),4.48-4.44(m,2H),4.20(t, J =9.2Hz, 1H), 4.10(dd, J =9.8, 5.9 Hz, 1H), 3.74 (t, J =9.3Hz, 1H), 3.66(dd, J=10.6, 4.1 Hz, 1H), 3.59 (dd, J =10.5,2.1Hz,1H),3.46-3.41(m,1H). Example 68 Synthesis of 6-(trifluoromethyl)-3-glucosyl-pyrazolo[1,5-a]pyridine (P66)

[0234] At room temperature, 1-amino-3-trifluoromethylpyridine 2,4,6-trimethylbenzenesulfonate (54.3 mg, 0.15 mmol), glucosylacetaldehyde (169.9 mg, 0.3 mmol), TEMPO (28.1 mg, 0.18 mmol), and toluene (1.5 mL) were added to a reaction tube. DIPEA (49 μL, 0.3 mmol) was then added at 0 °C. The reaction solution was stirred at 50 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain P66 (84.3 mg, yield 67%).

[0235] The reaction equation is:

[0236] The obtained product P66 was measured using an NMR spectrometer, and the resulting NMR data are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.78(q, J =1.4Hz, 1H), 8.51(s, 1H), 7.87(d, J =9.3Hz,1H),7.38- 7.36(m,2H), 7.34-7.31(m,5H),7.31-7.28(m,5H),7.24(qd, J =4.3, 2.3Hz, 3H), 7.10(dd, J = 7.5, 2.1 Hz, 2H), 7.06 (dd, J = 9.4, 1.7 Hz, 1H), 5.55 (d, J =5.1Hz, 1H), 5.06(d, J =10.8Hz,1H),4.89-4.78(m,3H),4.73(d, J =11.6Hz, 1H), 4.57(d, J =11.8Hz, 1H), 4.45(dd, J =11.3,8.2Hz,2H),4.10-4.04(m,2H),3.69-3.61(m,2H),3.58(dd, J=10.4, 2.1Hz, 1H), 3.32(ddd, J =10.0, 4.6, 2.1 Hz, 1H). Example 69 Activity Test - Inhibition Rate of Gout Inflammatory Factors

[0237] An in vitro gout inflammation model was established by stimulating mouse macrophages J774A.1 cells with a combination of lipopolysaccharide and adenosine triphosphate. The release level of interleukin-1β (IL-1β) in the cell supernatant was detected using enzyme-linked immunosorbent assay (ELISA) to evaluate the degree of inflammatory response. Due to space limitations, only a selection of compounds from each formula were used for activity testing. The main evaluation index was the release of the inflammatory factor IL-1β, and the inhibition rate is shown in Table 1. The results showed that the selected compounds P14, P24, P27, P28, P29, P30, P31, and P32 significantly inhibited the release level of IL-1β at a concentration of 20 μM, indicating a certain therapeutic effect on gout-induced inflammation.

[0238] Table 1. Inhibition rate of some compounds on gout inflammatory factors compound VX765 P14 P24 P27 P28 P29 P30 P31 P32 Cell inhibition rate / % 87 69 35 52 32 39 49 53 54 Example 70 Activity Test - Candida albicans Activity Inhibition Rate

[0239] The inhibitory effects of ketoconazole on Candida albicans activity were evaluated using a broth enrichment method with ketoconazole as a positive control. Due to space limitations, only a subset of compounds for each formula were selected for activity testing. The results are shown in Table 2 below. The activity tests revealed that compounds P11, P27, P33, P34, and P35 exhibited varying degrees of inhibitory effects on Candida albicans at 100 μM.

[0240] Table 2. Inhibition rates of some compounds against Candida albicans compound Ketoconazole P11 P27 P33 P34 P35 Activity inhibition rate / % 98.95 57.64 99.64 73.64 29.44 62.16 Example 71 Activity Test - Cell Proliferation Inhibition Rate

[0241] The inhibitory activity of the compounds on cell proliferation was evaluated using the Cell Counting Kit (CCK-8) method. The stock solution concentration was 10 mM, with cisplatin as a positive control. The main cell types tested were human lung cancer cells (A549), human gastric cancer cells (MKN-45), human colon cancer cells (HCT 116), human cervical cancer cells (HeLa), human chronic myeloid leukemia cells (K-562), human gallbladder cancer cells (GBC-SD), normal human hepatocytes (L-02), human liver cancer cells (HepG2), human thyroid cancer cells (CAL-62), and human embryonic kidney cells (293T). The inhibition rate values ​​determined by single-concentration activity screening are shown in Table 3 (where the concentration of cisplatin was 50 μM and the concentration of other compounds was 20 μM).

[0242] Table 3. Inhibition rate of some compounds on cell proliferation compound Cisplatin P5 P8 P11 P33 P35 P43 P47 P53 P54 P55 293T 85.21% 28.17% 22.18% 3.41% 19.44% 7.49% 45.23% 1.81% 4.95% -4.68% 7.49% CAL-62 81.11% 17.25% 22.69% 10.39% 17.49% 14.66% 12.32% 9.41% 13.37% 7.28% 18.23% HepG2 75.42% 3.73% 20.15% 4.06% 15.02% 4.70% 11.36% 16.40% 19.36% 3.88% 7.24% L-02 93.01% 17.26% 10.44% 6.34% 1.64% 8.04% 32.02% 15.93% 46.25% -0.50% 4.86% GBC-SD 70.37% 5.43% 5.26% 9.49% 19.95% 7.21% 11.07% 3.77% 11.42% 3.39% 16.41% K-562 57.25% 28.97% 22.69% 22.63% 3.38% 24.63% 63.19% 23.51% 10.24% 33.93% 18.55% HeLa 95.67% 6.08% 5.27% 18.32% 17.76% 20.22% 3.94% 9.99% 20.75% 20.15% 10.76% HCT 116 72.90% 12.25% 11.20% 17.13% 23.87% 21.80% 10.48% 4.19% 30.52% 17.43% 18.81% MKN-45 85.67% 5.44% 5.20% 4.56% 3.52% 7.01% 34.20% 6.41% 23.59% 15.62% 44.88% A549 75.13% 5.78% 3.04% 5.88% 24.02% 2.34% 2.13% -0.67% 3.35% 3.14% 2.47% The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synthesizing a fused-ring diaza aromatic skeleton, characterized in that: By reacting the N-amino salt of an electron-deficient nitrogen-containing aromatic compound with an aldehyde or ketone containing an active methylene group in the presence of a base, oxidant, and organic solvent at a temperature of -78°C to 150°C, a fused-ring diaza aromatic skeleton compound can be synthesized.

2. The method for synthesizing a fused-ring diaza aromatic skeleton according to claim 1, characterized in that: Electron-deficient nitrogen-containing aromatic compounds are reacted with electrophilic amination reagents to synthesize N-amino salts of electron-deficient nitrogen-containing aromatic compounds in situ. Then, in the presence of alkali, oxidant, and organic solvent, they are reacted with aldehydes or ketones containing active methylene groups at -78°C to 150°C for 0.5 h to 80 h to synthesize fused-ring diaza-containing aromatic skeleton compounds.

3. The method for synthesizing a fused-ring diaza aromatic skeleton according to claim 1 or 2, characterized in that: The base is one of the following: triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, 1,5-diazabicyclo[4.3.0]-5-nonene, tetramethylguanidine, Cs2CO3, K2CO3, Na2CO3, Li2CO3, K3PO4, K2HPO3, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, and potassium hexamethyldisilamide. The oxidant is one of peroxide, high-valent iodine reagent, organic nitrogen oxide, or a composite oxidant formed by organic nitrogen oxide and copper / iron salt; The organic solvent is one of toluene, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

4. The method for synthesizing a fused-ring diaza aromatic skeleton according to claim 3, characterized in that: The peroxide is one of tert-butanol peroxide and hydrogen peroxide; the high-valent iodine reagent is one of 2-iodobenzoic acid, Dys-Martin oxidant, diacetic iodobenzene, and di(trifluoroacetic)iodobenzene; the organic nitrogen oxide is one of tetramethylpiperidine oxide, 4-oxo-2,2,6,6-tetramethyl-4-piperidine oxide, 4-amino-2,2,6,6-tetramethylpiperidine oxide, and 9-azabicyclo[3.3.1]nonane-N-oxy radical; the copper salt / iron salt is one of CuBr, CuI, CuCl, Cu(OTf)2, Cu(CH3CN)4BF4, Cu(CH3CN)4PF6, Cu(CH3CN)4OTf, Fe(NO2)3, Fe(NO2)2, Fe(OTf)3, FeCl2, and FeCl3, and the amount of the copper salt / iron salt is 0.01 equivalents to 2 equivalents.

5. The method for synthesizing a fused-ring diaza aromatic skeleton according to claim 3, characterized in that: The amount of the base used is 0.1 to 5 equivalents, the amount of the oxidant used is 0.01 to 2 equivalents, and the reaction concentration of the N-amino salt of the electron-deficient nitrogen-containing aromatic compound is 0.01 M to 0.2 M.

6. The method for synthesizing a fused-ring diaza aromatic skeleton according to claim 2, characterized in that: The electrophilic amination agent is one of O-benzenesulfonyl hydroxylamine and its substitutes, O-alkylsulfonyl hydroxylamine and its substitutes, O-benzoyl hydroxylamine and its substitutes, and O-nitrophenylhydroxylamine and its substitutes; The substitute for O-benzenesulfonyl hydroxylamine is one of O-4-methylbenzenesulfonyl hydroxylamine, O-2-methoxybenzenesulfonyl hydroxylamine, O-4-methoxybenzenesulfonyl hydroxylamine, O-4-bromo-benzenesulfonyl hydroxylamine, O-2-methylbenzenesulfonyl hydroxylamine, O-p-methylbenzenesulfonyl hydroxylamine, O-p-nitrobenzenesulfonyl hydroxylamine, O-2,4,6-trimethylbenzenesulfonyl hydroxylamine, and O-2-bromo-benzenesulfonyl hydroxylamine. The alternative to the O-alkylsulfonyl hydroxylamine is one of O-methylsulfonyl hydroxylamine and O-trifluoromethylsulfonyl hydroxylamine; The alternative to the O-benzoyl hydroxylamine is one of O-benzoyl hydroxylamine, O-4-nitrobenzoyl hydroxylamine, O-2-nitrobenzoyl hydroxylamine, O-2,4-dinitrobenzoyl hydroxylamine, O-p-nitrobenzoyl hydroxylamine, and O-o-nitrobenzoyl hydroxylamine. The alternative to O-nitrophenylhydroxylamine is one of O-2-nitrophenylhydroxylamine, O-4-nitrophenylhydroxylamine, O-o-nitrophenylhydroxylamine, O-m-nitrophenylhydroxylamine, O-p-nitrophenylhydroxylamine, and O-2,4-dinitrophenylhydroxylamine.

7. The method for synthesizing a fused-ring diaza aromatic skeleton according to claim 1 or 2, characterized in that: The electron-deficient nitrogen-containing aromatic compound is one of pyridine, quinoline, isoquinoline, phenanthridine, phenanthroline, substituted pyridine, substituted quinoline, substituted isoquinoline, substituted phenanthridine, and substituted phenanthroline; the N-amino salt is one of trifluoromethanesulfonate, alkylsulfonate, arylsulfonate, benzoic acid and its derivatives, phenol and its derivatives, halide, sulfate, and phosphate.

8. A fused-ring diaza aromatic skeleton synthesized by the method according to any one of claims 1-7, characterized in that: The structural formula of the fused-ring diaza-aromatic skeleton is any one of the following: Among them, R 1 R 2 Each is an independent hydrogen atom, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 It can be one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro.

9. A fused-ring diaza aromatic skeleton according to claim 8, characterized in that: When R 1 R 2 When each is an independent hydrogen, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 1 R 2 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; And / or, when R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro; 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each can be individually controlled by one or more independent Rs X Substituents of the substituents; R X It is any one of hydrogen atom, alkyl, fluoroalkyl, chloroalkyl, aryl, fluoroaryl, heteroaryl, fluoroheteroaryl, hydroxyl, alkoxy, aryl ether, heteroaryl ether, mercapto, alkyl sulfide, aryl sulfide, heteroaryl sulfide, amino, alkylamino, arylamino, heteroarylamine, ester, acyl, amide, carbonyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, sulfonyl, sulfone, and sulfoxide; Or, when R 1 R 2 Each is an independent hydrogen atom, aromatic group, heteroaryl group, alkyl group, or cycloalkyl group, or any combination of two of them; R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 When R is one or any combination of hydrogen, halogen, alkyl, alkoxy, aromatic, heteroaryl, alkylcarbonyl, arylcarbonyl, ester, amide, sulfonamide, trifluoromethyl, and nitro, respectively. 1 R 2 Between, and / or, R 3 R 4 Between, and / or, R 4 R 5 Between, and / or, R 5 R 6 Between, and / or, R 6 R 7 Between, and / or, R 7 R 8 Between, and / or, R 8 R 9 Between, and / or, R 9 R 10 These atoms can form rings through carbon chains and heteroatoms.

10. The use of the fused-ring diaza aromatic skeleton of claim 8 or 9 in the preparation of a drug for treating gout inflammation, or for fighting Candida albicans, or for cancer.

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