Halogenated pyridyl formate derivative and application thereof

Abstract

The invention belongs to the field of medical chemistry, and particularly relates to halogenated pyridyl formate derivatives and application thereof. The halogenated pyridyl formate derivative has a compound shown as a general formula (I) or a general formula (II) or a pharmaceutically acceptable salt thereof, the general formula (I) is # imgabs0, the general formula (II) is # imgabs1, and a series of compounds containing the halogenated pyridyl formate derivative and having a brand new structure are obtained through structural optimization and activity screening. The compound has good Mpro protease inhibitory activity, provides important scientific basis and technical support for research and development of anti-coronavirus drugs, and has good market prospects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to halogenated pyridinecarboxylate derivatives and their applications. Background Art

[0002] Coronaviruses are a group of enveloped, single-stranded, positive-sense RNA viruses that are widely present in nature and can infect a variety of mammals and birds. In recent years, diseases caused by coronaviruses have posed a serious threat to human health. In particular, the outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2) have highlighted the urgency of developing highly effective antiviral drugs. The main protease of coronaviruses (Mpro, also known as 3CLpro) plays a crucial role in the viral replication and transcription processes. Due to its high conservation and substrate specificity, it has become a key target for the development of anti-coronavirus drugs.

[0003] Drug design targeting Mpro mainly falls into two categories: peptidomimetic inhibitors and non-peptidomimetic inhibitors. Both have their own characteristics in terms of structure, mechanism of action, and development potential. Peptidomimetic inhibitors can efficiently bind to the active site of Mpro by mimicking the structure of natural substrates, showing high selectivity and inhibitory activity. However, their peptide bond structure may lead to poor metabolic stability and limited oral bioavailability. Non-peptidomimetic inhibitors, on the other hand, are designed with non-natural chemical skeletons, overcoming the metabolic defects of peptidomimetic compounds and having better pharmacokinetic properties. However, their design is more difficult, and the initial screening activity may be relatively low. Summary of the Invention

[0004] The present invention provides halogenated pyridinecarboxylate derivatives and their applications by studying the crystal structure model of M pro protease and summarizing the structure-activity relationship of M pro inhibitors. Through in-depth analysis of the Mpro crystal structure and by combining computer-aided drug design (CADD) and structure-based drug design (SBDD) strategies, a series of compounds with potential inhibitory activity were screened and optimized. The effectiveness and safety of the candidate compounds were verified through in vitro enzyme activity inhibition experiments, cytotoxicity tests, and studies on the stability of glutathione (GSH).

[0005] To solve the problems of the prior art, the technical solutions adopted by the present invention are as follows:

[0006] A compound having the formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is The formula (II) is

[0007] Among them, ring A is selected from five-membered aromatic heterocycles containing two or three heteroatoms,

[0008] E, M, and G are independently selected from -CR 1 =, -N=, -NR 1 -, -O- or S;

[0009] W and Y are independently selected from -CH=, -CR 1 = or -N=;

[0010] Z is selected from -CR 1 =, -N=, -NR 1 -, -O- or S;

[0011] Ring B is selected from six-membered aromatic rings, four-, five- or six-membered heterocycles, aromatic rings, aromatic heterocycles, 4-8 membered saturated or unsaturated carbocycles;

[0012] X is selected from hydrogen, F, Cl, Br or I;

[0013] R 1 is optionally selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, biphenyl, naphthyl or Het, where alkyl, biphenyl, phenyl, naphthyl and Het may be optionally substituted by the following groups: halogen, -CN, -OH, -CF 3 , OCF 3 , -OR, OCF 3 -SH, -SR, -NH 2 , -NHR, -NR 2 , -NHCOR, -NHSO 2 R, -NRSO 2 R, -COR, -COOR, -CONHR, -CON(R 2 ), -CONH(CH 2 ) 1-10 N(R 2 ), -CONR 2 , -CON(R 2 )O, -CONH(CH 2 ) 1-10 N(R 2 ), -CON(R 2 )NR, -CON(R 2 )NCOOR, -CONH(CH 2 ) 1-10 N(R 2 ), -CONH(CH 2 ) 1-10 N(R 2 ), NCOOR, where R represents hydrogen or alkyl;

[0014] R 2 represents hydrogen, alkyl, halogen, hydroxy, cyano, aryl, Het, -NHR, -OR, -NH(CH 2 ) 1-10 Het, -O(CH 2 ) 1-10 Het, -NH(CH 2 ) 1-10 OR, -O(CH 2 ) 1-10 OR, -NH(CH 2 ) 1-10 NHR, -O(CH 2 ) 1-10 NHR, -CONHR, -NH(CH 2 ) 1-10 NR 2 , -O(CH 2 ) 1-10 NR 2 , -CONHHet, -COOR, -COOHet, -NHCOOR, -NHCOOHet, -NHCONHR or -NHCONHHet, where R represents hydrogen or alkyl;

[0015] The aryl groups are each independently selected from carbocyclic rings of substituted or unsubstituted phenyl, naphthyl or tetrahydronaphthyl, wherein the substitution is that the carbocyclic rings of phenyl, naphthyl or tetrahydronaphthyl are optionally substituted by 1, 2 or 3 substituents, and each substituent is independently selected from alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

[0016] The Het groups are each independently selected from monocyclic heterocycles of piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, morpholinyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl; or are selected from bicyclic heterocycles of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuryl, benzothiophenyl, 2,3-dihydrobenzo[b][1,4]dioxanyl or benzo[d][1,3]dioxolanyl; each monocyclic or bicyclic heterocycle is optionally substituted by 1, 2 or 3 substituents, and each substituent is independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy, or is selected from C 3 -C 8 aliphatic carbocyclic rings, or the following aliphatic heterocycles: pyrrolidinyl, morpholinyl, alkoxymorpholinyl, piperazinyl, piperidinyl, alkylaminopiperidinyl;

[0017] The alkyl group is a straight-chain or branched-chain saturated hydrocarbon group having C1-C6; or a cyclic saturated hydrocarbon group having C3-C6; or a cyclic saturated hydrocarbon group having C3-C6 connected to a straight-chain or branched-chain saturated hydrocarbon group having C1-C6;

[0018] The alkoxy group is a straight-chain or branched-chain saturated hydrocarbon group having C1-C6; or a cyclic saturated hydrocarbon group having C3-C6; or a cyclic saturated hydrocarbon group having C3-C6 connected to a straight-chain or branched-chain saturated hydrocarbon group having C1-C6; where each carbon atom is optionally substituted by oxygen;

[0019] The alkylamino group is a straight-chain or branched-chain saturated hydrocarbon group having C1-C6; or a cyclic saturated hydrocarbon group having C3-C6; or a cyclic saturated hydrocarbon group having C3-C6 connected to a straight-chain or branched-chain saturated hydrocarbon group having C1-C6; where each carbon atom is optionally substituted by nitrogen;

[0020] The halogen is a substituent selected from fluorine, chlorine, bromine or iodine.

[0021] Preferably, ring A is an imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, thiophene ring, isothiazole ring, thiazole ring or triazole ring;

[0022] Ring B is a benzene ring, pyridine, pyridone, hydropyridone, pyrimidine, pyrimidine dione, pyridazine, triazine, tetrazine, imidazole, pyrazole, triazole, thiadiazole, oxadiazole, or a 4-8 membered heterocyclic ring, or a 4-8 membered saturated cycloalkyl or a 4-8 membered ring not containing cycloalkenyl;

[0023] X is F, Cl, Br;

[0024] Z is independently selected from -CR 1 =, -N=, -NR 1 -;

[0025] R 1 is optionally selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, biphenyl or Het, where alkyl, biphenyl, phenyl and Het may be optionally substituted by the following groups: halogen, -CN, -OH, -CF 3 , OCF 3 , -OR, OCF 3 -SH, -SR, -NH 2 , -NHR, -NR 2 , -NHCOR, -NHSO 2 R, -NRSO 2 R, -COR, -COOR, -CONHR, -CON(R 2 ), -CONH(CH 2 ) 1-10 N(R 2 ), -CONR2 , -CON(R 2 )O, -CONH(CH 2 ) 1-10 N(R 2 )O, -CON(R 2 )NR, -CON(R 2 )NCOOR, -CONH(CH 2 ) 1-10 N(R 2 )NR, -CONH(CH 2 ) 1-10 N(R 2 )NCOOR, where R represents hydrogen or alkyl;

[0026] R 2 is selected from hydrogen, halogen, hydroxy, cyano, alkyl, phenyl, Het, -NHR, -OR, -NH(CH 2 ) 1-10 Het, -O(CH 2 ) 1-10 Het, -NH(CH 2 ) 1-10 OR, -O(CH 2 ) 1-10 OR, -NH(CH 2 ) 1-10 NHR, -O(CH 2 ) 1-10 NHR, -CONHR, -NH(CH 2 ) 1-10 NR 2 , -O(CH 2 ) 1-10 NR 2 , -CONHHet, -COOR, -COOHet, -NHCOOR, -NHCOOHet, -NHCONHR or -NHCONHHet, where R represents hydrogen or alkyl.

[0027] Specifically, the above compounds are:

[0028] 5-chloropyridin-3-yl 1-methyl-1H-pyrazole-4-carboxylate (I-1);

[0029] 5-chloropyridin-3-yl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (I-2);

[0030] 5-chloropyridin-3-yl 1-isopropyl-1H-pyrazole-4-carboxylate (I-3);

[0031] 5-chloropyridin-3-yl 1-phenyl-1H-pyrazole-4-carboxylate (I-4);

[0032] 5-chloropyridin-3-yl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Ⅰ-5);

[0033] 5-chloropyridin-3-yl 1-benzyl-1H-pyrazole-4-carboxylate (Ⅰ-6);

[0034] 5-chloropyridin-3-yl 3-methylisoxazole-5-carboxylate (Ⅰ-7);

[0035] 5-chloropyridin-3-yl 2-methylthiazole-4-carboxylate (Ⅰ-8);

[0036] 5-chloropyridin-3-yl 2-(trifluoromethyl)thiazole-4-carboxylate (Ⅰ-9);

[0037] 5-chloropyridin-3-yl 2-chlorothiazole-4-carboxylate (Ⅰ-10);

[0038] 5-chloropyridin-3-yl 5-methyl-1H-pyrazole-3-carboxylate (Ⅰ-11);

[0039] 5-chloropyridin-3-yl 5-acetyl-1H-pyrazole-3-carboxylate (Ⅰ-12);

[0040] 5-chloropyridin-3-yl 5-cyclopropyl-1H-pyrazole-3-carboxylate (Ⅰ-13);

[0041] 5-chloropyridin-3-yl 1-methyl-1H-imidazole-4-carboxylate (Ⅰ-14);

[0042] 5-chloropyridin-3-yl 1,3-dimethyl-1H-pyrazole-5-carboxylate (Ⅰ-15);

[0043] 5-chloropyridin-3-yl 1-methyl-1H-pyrazole-3-carboxylate (Ⅰ-16);

[0044] 5-chloropyridin-3-yl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate (Ⅰ-17);

[0045] 5-chloropyridin-3-yl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Ⅰ-18);

[0046] 5-chloropyridin-3-yl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (Ⅰ-19);

[0047] 5-chloropyridin-3-yl 1-benzyl-1H-pyrazole-3-carboxylate (Ⅰ-20);

[0048] 5-chloropyridin-3-yl 1-(4-cyanobenzyl)-1H-pyrazole-3-carboxylate (Ⅰ-21);

[0049] 5-chloropyridin-3-yl 1-(3-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxylate (Ⅰ-22);

[0050] 5-chloropyridin-3-yl 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylate (Ⅰ-23);

[0051] 5-bromopyridin-3-yl 2-methylthiazole-4-carboxylate (Ⅰ-24);

[0052] 5-bromopyridin-3-yl 5-methyl-1H-pyrazole-3-carboxylate (Ⅰ-25);

[0053] 5-bromopyridin-3-yl 1-methyl-1H-pyrazole-3-carboxylate (Ⅰ-26);

[0054] 5-bromopyridin-3-yl 1-benzyl-1H-pyrazole-3-carboxylate (Ⅰ-27);

[0055] 5-bromopyridin-3-yl 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylate (Ⅰ-28);

[0056] 5-chloropyridin-3-yl 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (Ⅱ-1);

[0057] 5-chloropyridin-3-yl 4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (Ⅱ-2);

[0058] 5-chloropyridin-3-yl 1-methyl-1H-indazole-3-carboxylate (Ⅱ-3);

[0059] 5-chloropyridin-3-yl 2-methyl-2H-indazole-3-carboxylate (Ⅱ-4);

[0060] 5-chloropyridin-3-yl pyrazolo[1,5-a]pyrimidine-3-carboxylate (Ⅱ-5);

[0061] 5-chloropyridin-3-yl imidazo[1,2-a]pyridine-3-carboxylate (Ⅱ-6);

[0062] 5-chloropyridin-3-yl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (Ⅱ-7);

[0063] 5-chloropyridin-3-yl imidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-8);

[0064] 5-Chloropyridin-3-yl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-9);

[0065] 5-Chloropyridin-3-yl 6-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-10);

[0066] 5-Chloropyridin-3-yl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-11);

[0067] 5-Chloropyridin-3-yl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-12);

[0068] 5-Chloropyridin-3-yl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (Ⅱ-13);

[0069] 5-Chloropyridin-3-yl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate (Ⅱ-14);

[0070] 5-Chloropyridin-3-yl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-15);

[0071] 5-Chloropyridin-3-yl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Ⅱ-16);

[0072] 5-Bromopyridin-3-yl imidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-17);

[0073] 5-Bromopyridin-3-yl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate (Ⅱ-18);

[0074] 5-Bromopyridin-3-yl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-19);

[0075] 5-Bromopyridin-3-yl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-20);

[0076] 5-Bromopyridin-3-yl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-21).

[0077] The specific structures are shown in the table:

[0078]

[0079]

[0080]

[0081] The above pharmaceutically acceptable salts include acid addition salts formed by the compounds of general formula (I) or general formula (II) and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or acid addition salts of inorganic bases containing alkaline metal cations, alkaline earth metal cations, ammonium cations.

[0082] A pharmaceutical composition comprising an effective amount of a compound of general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

[0083] The above compound of general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition is used in the preparation of a medicament for preventing or treating M pro Application in the medicament for protease-dependent diseases.

[0084] As an improvement, the 3CL pro Protease-related diseases are upper respiratory tract infection, lower respiratory tract infection, acute bronchitis, community-acquired pneumonia, viral pneumonia, acute respiratory distress syndrome, acute exacerbation of chronic diseases, acute exacerbation of chronic obstructive pulmonary disease, acute asthma attack, inflammation and immune abnormalities including cytokine release syndrome, multiple organ dysfunction syndrome, cardiovascular system diseases including viral myocarditis, acute heart failure, arrhythmia, deep vein thrombosis, pulmonary embolism, acute encephalopathy and loss of smell / taste, Guillain-Barré syndrome, viral gastroenteritis, acute hepatitis, chronic fatigue syndrome, pulmonary fibrosis, cognitive dysfunction, autonomic dysfunction.

[0085] Specifically, the above M proProtease-dependent diseases include: (1) Respiratory diseases: Upper respiratory tract infections: Common cold caused by it (nasal congestion, fever, chest tightness, runny nose, sore throat), pharyngitis / laryngitis, sinusitis, lower respiratory tract infections, acute bronchitis, community-acquired pneumonia, viral pneumonia, acute respiratory distress syndrome (ARDS), acute exacerbation of chronic diseases, acute exacerbation of chronic obstructive pulmonary disease (COPD), acute asthma attack; (2) Systemic complications (multiple organ involvement): Inflammation and immune abnormalities including cytokine release syndrome ("cytokine storm"), multiple organ dysfunction syndrome (MODS), cardiovascular system diseases including viral myocarditis, acute heart failure, arrhythmia (such as QT interval prolongation), thromboembolic events (deep vein thrombosis, pulmonary embolism), nervous system diseases including acute encephalopathy (such as delirium, epilepsy) and loss of smell / taste, Guillain-Barré syndrome (rare), digestive system diseases including viral gastroenteritis (diarrhea, vomiting) and acute hepatitis; (3) Long-term sequelae: Chronic fatigue syndrome, pulmonary fibrosis (after severe pneumonia), cognitive dysfunction, autonomic nervous system disorders (such as postural tachycardia syndrome).

[0086] The application of the compound represented by the general formula (I) or general formula (II) or its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a drug for inhibiting M pro protease.

[0087] Beneficial effects:

[0088] For the halogenated pyridinecarboxylate derivatives and their applications of the present invention, through in-depth analysis of the M pro crystal structure, combined with computer-aided drug design (CADD) and structure-based drug design (SBDD) strategies, a series of compounds with potential inhibitory activity were screened and optimized. These inhibitors have a small molecular weight, a novel core structure, a protease activity as high as several nanomoles, low cytotoxicity, and good stability in GSH. Through in vitro enzyme activity inhibition experiments, cytotoxicity tests, and studies on the stability of glutathione (GSH), these compounds not only showed significant in vitro enzyme inhibitory activity but also exhibited low cytotoxicity in cell models. Further verified the effectiveness and safety of the candidate compounds. To solve the current drug structure diversity, the brand-new parent nucleus has better potential to expand its chemical space and great potential for further drug development.

[0089] Through structure optimization and activity screening, the present invention synthesized a series of compounds with a brand-new structure containing halogenated pyridinecarboxylate derivatives. The pharmacological test results showed that the compounds of the present invention have good M proThe protease inhibitory activity provides important scientific basis and technical support for the research and development of anti-coronavirus drugs by focusing on the design, synthesis of small molecule inhibitors against coronavirus Mpro and the evaluation of their antiviral activities. Description of the Drawings

[0090] Figure 1 It is about the chemical mechanism and monitoring method of the covalent reaction between the compound with general formula (Ⅰ) or general formula (Ⅱ) and GSH. Detailed Implementation Modes

[0091] For the synthesis method of the compound shown in general formula (Ⅰ) or general formula (II), it can refer to Reagents and conditions: a) 5-chloropyridin-3-ol or 5-bromopyridin-3-ol, EDC·HCl, DMAP, DCM, rt.; b) 5-chloropyridin-3-ol or 5-bromopyridin-3-ol, EDC·HCl, 4-PPy, DCM, rt.; c) 5-chloropyridin-3-ol or 5-bromopyridin-3-ol, DCC, DMAP, DCM, rt. Just select the corresponding raw materials according to the different substituents and their positions.

[0092] Specifically as follows:

[0093] Weigh 100 mg of the corresponding acid substrate into a eggplant-shaped flask, dissolve it with 15 mL of anhydrous dichloromethane, and then successively add 5-chloropyridin-3-ol or 5-chloropyridin-3-ol (1.2 equiv), condensing agent EDC or DCC (1.5 equiv), DMAP or 4-PPy (0.5 equiv), and stir at room temperature for 1 - 12 hours. Detect the completion of the reaction by TLC, pour the reaction solution into a separatory funnel, add 50 mL of water, extract with EA for 3 times, wash the organic layer with saturated brine for 2 times, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and separate by silica gel column chromatography to obtain a white solid, and calculate the yield.

[0094] Reaction formula:

[0095] The melting point was determined by the WRX-4 microscopic melting point apparatus of Shanghai Yice Instrument Equipment Co., Ltd.; 1 HNMR was completed with a JEOL FX90Q Fourier transform nuclear magnetic resonance spectrometer and a BRUKER AM-600 nuclear magnetic resonance spectrometer (TMS as internal standard); MS was determined with a Nicolet 2000 Fourier transform mass spectrometer and a MAT-212 mass spectrometer.

[0096] Example 1

[0097] 2-Methyl-4-nitroisoindolin-1-one (I-a) 5-chloropyridin-3-yl 1-methyl-1H-pyrazole-4-carboxylate (Ⅰ-1)

[0098] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-1H-pyrazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (47 mg, 0.12 mmol, yield 24%). It is in the form of a white solid powder. mp 122.8 - 125.8 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.48 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.09–8.04 (m, 2H), 7.65 (t, J = 2.3 Hz, 1H), 4.00 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 160.04, 147.08, 145.79, 141.86, 141.43, 134.41, 131.79, 129.73, 113.04, 39.59. HRMS-EI m / z [M+H] + calcd for C 10 H 9 ClN 3 O 2 + : 238.0378, found: 238.0384.

[0099] Example 2

[0100] 5-Chloropyridin-3-yl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Ⅰ-2)

[0101] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (51 mg, 0.17 mmol, yield 33%). It is in the form of a white solid powder, mp 104.8 - 107.9 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.50 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 7.70 (t, J = 2.2 Hz, 1H), 4.05 (s, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 157.89, 146.77, 146.11 (2C), 141.06 (2C), 137.24, 131.90, 129.48 (2C), 40.13. HRMS-EI m / z [M+H] + calcd for C 11 H 8 ClF 3 N 3 O 2 + : 306.0252, found: 306.0259.

[0102] Example 3

[0103] 5-Chloropyridin-3-yl 1-isopropyl-1H-pyrazole-4-carboxylate (I-3)

[0104] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-isopropyl-1H-pyrazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (75 mg, 0.28 mmol, yield 44%). It is in the form of a white solid powder, mp 92.8 - 94.1 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.48 (dt, J = 4.7, 2.8 Hz, 1H), 8.43 (h, J = 2.0 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 8.07 (t, J = 3.4 Hz, 1H), 7.64 (hept, J = 2.1 Hz, 1H), 4.57 - 4.61 (m, 1H), 1.58 (d, J = 3.7 Hz, 6H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.27, 147.11, 145.78, 141.53, 141.37, 131.70, 131.10, 129.66, 112.29, 54.76, 22.72 (2C). HRMS-EI m / z [M+H] + calcd for C 12 H 13 ClN 3 O 2 + + : 266.0691, found: 266.0698.

[0105] Example 4

[0106] 5-Chloropyridin-3-yl 1-phenyl-1H-pyrazole-4-carboxylate (I-4)

[0107] Prepared according to the reaction formula synthesis steps with a feed amount of 100 mg of 1-phenyl-1H-pyrazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (57 mg, 0.29 mmol, yield 36%). It is in the form of a white solid powder, mp 130.6 - 131.5 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 8.26 (s, 1H), 7.78–7.72 (m, 2H), 7.68 (t, J = 2.2 Hz, 1H), 7.56–7.50 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 160.05, 147.03, 146.03, 142.74, 141.47, 139.11, 131.83, 131.12, 129.78 (2C), 129.67, 128.12, 119.84 (2C),, 114.72. HRMS-EI m / z [M+H] + calcd for C 15 H 11 ClN 3 O 2 + : 300.0534, found: 300.0543.

[0108] Example 5

[0109] 5-Chloropyridin-3-yl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Ⅰ-5)

[0110] Prepared according to the reaction formula synthesis steps with a feed amount of 100 mg of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (79 mg, 0.21 mmol, yield 55%). It is in the form of a white solid powder, mp 82.8 - 83.9 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.53 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 7.71 (t, J = 2.3 Hz, 1H), 7.58–7.53 (m, 3H), 7.47 (d, J = 6.1 Hz, 2H). 1313C NMR (151 MHz, Chloroform-d) δ 158.23, 146.80, 146.34, 142.94, 141.19, 131.87, 130.31, 129.42 (2C), 129.32 (4C), 125.81 (2C), 114.35. HRMS-EI m / z [M+H] + calcd for C 16 H 10 ClF 3 N 3 O 2 + : 368.0408, found: 368.0416.

[0111] Example 6

[0112] 5-Chloropyridin-3-yl 1-benzyl-1H-pyrazole-4-carboxylate (I-6)

[0113] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-benzyl-1H-pyrazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (79 mg, 0.21 mmol, yield 55%). It is in the form of a white solid powder, mp 84.5 - 86.7 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.48 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.62 (t, J = 2.2 Hz, 1H), 7.45–7.35 (m, 3H), 7.33–7.27 (m, 2H), 5.37 (s, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.05, 147.04, 145.83, 141.95, 141.44, 134.73, 133.65, 131.77, 129.68, 129.17 (2C), 128.81, 128.16 (2C), 113.31, 56.78. HRMS-EI m / z [M+H] + calcd for C 16 H 13 ClN 3 O 2 + : 314.0691, found: 314.0696.

[0114] Example 7

[0115] 5-Chloropyridin-3-yl 3-methylisoxazole-5-carboxylate (Ⅰ-7)

[0116] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 3-methylisoxazole-5-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (70 mg, 0.22 mmol, yield 45%). It is in the form of a white solid powder, mp 89.7 - 91.8 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.55 (d, J = 2.0 Hz, 2H), 8.49 (d, J = 2.3 Hz, 2H), 7.71 (t, J = 2.2 Hz, 2H), 7.26 (s, 1H), 7.02 (s, 2H), 2.45 (s, 6H), 0.92–0.81 (m, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 160.97, 158.50, 154.34, 146.95, 146.51, 141.06, 132.18, 129.33, 112.23, 11.64. HRMS-EI m / z [M+H] + calcd for C 10 H 8 ClN 2 O 3 + : 239.0218, found: 239.0226.

[0117] Example 8

[0118] 5-Chloropyridin-3-yl 2-methylthiazole-4-carboxylate (Ⅰ-8)

[0119] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 2-methylthiazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (91 mg, 0.36 mmol, yield 51%). It is in the form of a white solid powder, mp 89.6 - 93.7 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.51 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.29 (s, 1H), 7.67 (t, J = 2.2 Hz, 1H), 2.83 (s, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 167.68, 158.75, 147.13, 146.23, 144.71, 141.47, 131.84, 130.13, 129.63, 19.46. HRMS-EI m / z [M+H] + calcd for C 10 H 8 ClN 2 O 2 S + : 254.9990, found: 254.9996.

[0120] Example 9

[0121] 5-Chloropyridin-3-yl 2-(trifluoromethyl)thiazole-4-carboxylate (I-9)

[0122] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 2-(trifluoromethyl)thiazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (53 mg, 0.17 mmol, yield 34%). It is in the form of a white solid powder, mp 83.9 - 86.3 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.70 (t, J = 2.1 Hz, 1H). 19 19F NMR (565 MHz, Chloroform-d) δ -61.15. 13 13C NMR (151 MHz, Chloroform-d) δ 158.01, 157.38 (d, J = 42.0 Hz, 1C), 147.02, 146.77, 146.55, 141.37, 132.42, 129.54, 120.09, 118.28. HRMS-EI m / z [M+H] + calcd for C 10 H 5 ClN 3 O 2 + : 308.9707, found: 308.9726

[0123] Example 10

[0124] 5-Chloropyridin-3-yl 2-chlorothiazole-4-carboxylate (I-10)

[0125] Prepared according to the reaction synthesis procedure with a feed amount of 100 mg of 2-chlorothiazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (38 mg, 0.14 mmol, yield 23%). It is in the form of a white solid powder, mp 126.6 - 130.2 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.52 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.32 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 157.86, 153.70, 147.09, 146.58, 143.80, 141.37, 132.08, 131.82, 129.59. HRMS-EI m / z [M+H] + calcd for C 9 H 5 Cl 2 N 2 O 2 S + : 274.9443, found: 274.9452.

[0126] Example 11

[0127] 5-Chloropyridin-3-yl 5-methyl-1H-pyrazole-3-carboxylate (Ⅰ-11)

[0128] Prepared according to the reaction synthesis procedure with a feed amount of 100 mg of 5-methyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (38 mg, 0.16 mmol, yield 20%). It is in the form of a white solid powder, mp 120.4 - 123.8 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.50 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.68 (t, J = 2.2 Hz, 1H), 6.81–6.73 (m, 1H), 2.41 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 159.61, 147.25, 146.20, 142.85, 141.52, 141.10, 132.03, 129.80, 108.57, 11.43. HRMS-EI m / z [M+H] + calcd for C 10 H 9ClN 3 O 2 + : 238.0378, found: 238.0387.

[0129] Example 12

[0130] 5-Chloropyridin-3-yl 5-acetyl-1H-pyrazole-3-carboxylate (Ⅰ-12)

[0131] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 5-acetyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (31 mg, 0.12 mmol, yield 18%). It is in the form of a white solid powder, mp 183.1 - 186.7 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.44 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.2 Hz, 1H), 7.68 (q, J = 2.2 Hz, 1H), 7.40 (s, 1H), 2.54 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 158.27, 146.92, 146.08, 141.02, 132.06, 129.75 (2C), 111.60, 26.85. HRMS-EI m / z [M + H] + calcd for C 11 H 9 ClN 3 O 3 + : 266.0327, found: 266.0336.

[0132] Example 13

[0133] 5-Chloropyridin-3-yl 5-cyclopropyl-1H-pyrazole-3-carboxylate (Ⅰ-13)

[0134] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (40 mg, 0.40 mmol, yield 23%). It is in the form of a white solid powder, mp 92.1 - 95.2 °C. 11H NMR (600 MHz, Chloroform-d) δ 9.59 (s, 1H), 8.63 (s, 1H), 7.89 (s, 1H), 6.51 (s, 1H), 1.97 (d, J = 7.6 Hz, 1H), 1.00 (q, J = 5.0 Hz, 2H), 0.78 (q, J = 5.0 Hz, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 159.02, 150.10, 147.55, 146.55, 140.45, 140.00, 134.22, 120.48, 105.26, 8.53 (2C), 6.90. HRMS-EI m / z [M+H] + calcd for C 12 H 11 ClN 3 O 2 + : 264.0534, found: 264.0540.

[0135] Example 14

[0136] 5-Chloropyridin-3-yl 1-methyl-1H-imidazole-4-carboxylate (Ⅰ-14)

[0137] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-1H-imidazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (106 mg, 0.45 mmol, yield 56%). It is in the form of a white solid powder, mp 122.0 - 126.1 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.47 (dd, J = 9.9, 2.1 Hz, 2H), 7.80 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.58 (s, 1H), 3.82 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.05, 147.24, 145.81, 141.61, 139.35, 132.13, 131.68, 129.71, 128.18, 34.08. HRMS-EI m / z [M+H] + calcd for C 10 H 9 ClN 3 O 2 + : 238.0378, found: 238.0386

[0138] Example 15

[0139] 5-Chloropyridin-3-yl 1,3-dimethyl-1H-pyrazole-5-carboxylate (Ⅰ-15)

[0140] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1,3-dimethyl-1H-pyrazole-5-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (88 mg, 0.35 mmol, yield 49%). It is in the form of a white solid powder, mp 96.3 - 98.2 °C. 1 H NMR(600MHz,Chloroform-d)δ8.55–8.50(m,1H),8.44(t,J=2.6Hz,1H),7.66(q,J=2.4Hz,1H),6.84(d,J=2.7Hz,1H),4.21–4.14(m,3H),2.33(d,J=3.3Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ157.31,147.49,146.63,146.26,141.32,131.82,130.76,129.50,111.77,39.32,13.27.HRMS-EI m / z[M+H] + calcd for C 11 H 11 ClN 3 O 2 + :252.0534,found:252.0541.

[0141] Example 16

[0142] 5-Chloropyridin-3-yl 1-methyl-1H-pyrazole-3-carboxylate (Ⅰ-16)

[0143] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (91 mg, 0.38 mmol, yield 48%). It is in the form of a white solid powder, mp 94.0 - 97.9 °C. 1 H NMR(600MHz,Chloroform-d)δ8.49(dd,J=9.9,2.3Hz,2H),7.68(t,J=2.4Hz,1H),7.50(d,J=2.6Hz,1H),6.98(d,J=2.4Hz,1H),4.06(s,3H). 1313C NMR (151 MHz, Chloroform-d) δ 159.67, 147.18, 146.01, 141.61, 141.59, 132.01, 131.79, 129.77, 110.49, 40.02. HRMS-EI m / z [M+H] + calcd for C 10 H 9 ClN 3 O 2 + : 238.0378, found: 238.0384.

[0144] Example 17

[0145] 5-Chloropyridin-3-yl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate (Ⅰ-17)

[0146] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (87 mg, 0.28 mmol, yield 56%). It is in the form of a white solid powder, mp 131.2 - 135.2 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.50 (dd, J = 3.6, 2.2 Hz, 2H), 7.70 (t, J = 2.2 Hz, 1H), 7.53–7.48 (m, 3H), 7.46–7.42 (m, 2H), 7.01 (s, 1H), 4.02 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 159.95, 147.40, 146.17, 145.94, 141.75, 140.78, 131.94, 129.88, 129.56, 129.30, 129.15 (2C), 129.00 (2C), 110.12, 38.73. HRMS-EI m / z [M+H] + calcd for C 16 H 13 ClN 3 O 2 + : 314.0691, found: 314.0699.

[0147] Example 18

[0148] 5-Chloropyridin-3-yl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Ⅰ-18)

[0149] Prepared according to the reaction synthesis steps with a feed amount of 100 mg of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (79 mg, 0.32 mmol, yield 44%). It is a white solid powder, mp 85.3 - 88.3 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.47 (dd, J = 13.8, 2.2 Hz, 2H), 7.67 (dp, J = 3.5, 2.0 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H), 3.93 (s, 3H), 2.37 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 159.94, 147.20, 145.95, 141.68, 140.72, 140.03, 131.71, 129.77, 109.47, 37.24, 11.28. HRMS-EI m / z [M+H] + calcd for C 11 H 11 ClN 3 O 2 + : 252.0534, found: 252.0543.

[0150] Example 19

[0151] 5-chloropyridin-3-yl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (Ⅰ-19)

[0152] Prepared according to the reaction synthesis steps with a feed amount of 100 mg of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (43 mg, mmol, yield 33%). It is a white solid powder, mp 135.6 - 136.8 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.51 (t, J = 2.2 Hz, 2H), 7.71 (t, J = 2.2 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.36–7.31 (m, 3H), 7.14–7.09 (m, 2H), 2.38 (s, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 160.26, 147.08, 146.13, 143.57, 141.78, 136.53, 135.62, 132.95, 131.75, 130.90 (2C), 130.55, 130.34, 129.91, 129.10 (2C), 128.02, 126.50, 120.66, 9.69. HRMS-EI m / z [M+H] + calcd for C 22 H 14 Cl 4 N 3 O 2 + : 491.9835, found: 491.9838.

[0153] Example 20

[0154] 5-Chloropyridin-3-yl 1-benzyl-1H-pyrazole-3-carboxylate (I-20)

[0155] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-benzyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (81 mg, 0.26 mmol, yield 52%). It is in the form of a white solid powder, mp 89.3 - 89.7 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.52–8.42 (m, 2H), 7.69 (t, J = 2.2 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.40–7.34 (m, 3H), 7.30–7.25 (m, 2H), 6.99 (d, J = 2.4 Hz, 1H), 5.45 (s, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 159.76, 147.20, 145.97, 141.55, 134.96, 131.85, 131.22, 129.90, 129.10 (2C), 128.71, 128.03 (2C), 110.77, 57.19. HRMS-EI m / z [M+H] + calcd for C 16 H 13 ClN 3 O 2 + : 314.0691, found: 314.0703.

[0156] Example 21

[0157] 5-Chloropyridin-3-yl 1-(4-cyanobenzyl)-1H-pyrazole-3-carboxylate (Ⅰ-21)

[0158] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-(4-cyanobenzyl)-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (54 mg, 0.16 mmol, yield 36%). It is in the form of a white solid powder, mp 117.5 - 120.3 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.52–8.42 (m, 2H), 7.69 (t, J = 2.2 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.40–7.34 (m, 3H), 7.30–7.25 (m, 2H), 6.99 (d, J = 2.4 Hz, 1H), 5.45 (s, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 159.76, 147.20, 145.97, 141.55, 134.96, 131.85, 131.22, 129.90, 129.10 (2C), 128.71, 128.03 (2C), 110.77, 57.19. HRMS-EI m / z [M+H] + calcd for C 17 H 12 ClN 4 O 2 + : 339.0643, found: 339.0650.

[0159] Example 22

[0160] 5-Chloropyridin-3-yl 1-(3-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxylate (Ⅰ-22)

[0161] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-(3-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (38 mg, 0.09 mmol, yield 27%). It is in the form of a white solid powder, mp 57.3 - 58.8 °C. 11H NMR (600 MHz, Chloroform-d) δ 8.50 (dd, J = 8.2, 2.2 Hz, 2H), 7.71 (t, J = 2.3 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.25–7.21 (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.11 (s, 1H), 7.03 (d, J = 2.4 Hz, 1H), 5.48 (s, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 159.59, 149.64, 147.14, 146.02, 142.00, 141.48, 137.32, 131.90, 131.38, 130.60, 129.89, 126.02, 121.01, 120.31, 111.01, 56.39. HRMS-EI m / z [M+H] + calcd for C 17 H 12 ClF 3 N 3 O 3 + : 398.0514, found: 398.0520.

[0162] Example 23

[0163] 5-Chloropyridin-3-yl 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylate (Ⅰ-23)

[0164] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (41 mg, 0.10 mmol, yield 29%). The form is a white solid powder, mp 114.2 - 116.4 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.49 (dd, J = 12.3, 2.2 Hz, 2H), 7.98–7.92 (m, 2H), 7.69 (t, J = 2.2 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.45–7.41 (m, 2H), 7.05 (d, J = 2.4 Hz, 1H), 5.56 (s, 2H), 3.05 (s, 3H). HRMS-EI m / z [M+H] + calcd forC 17 H 15 ClN 3 O4 S + : 392.0466, found: 2392.0470.

[0165] Example 24

[0166] 5-Bromopyridin-3-yl 2-methylthiazole-4-carboxylate (I-24)

[0167] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 2-methylthiazole-4-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (105 mg, 0.35 mmol, yield 50%). It is in the form of a white solid powder, mp 156.7 - 158.4 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.56 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 7.82 (t, J = 2.1 Hz, 1H), 7.34 (t, J = 2.0 Hz, 1H), 2.79 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 167.92, 158.64, 148.18, 141.59, 141.20, 136.07, 132.54, 130.22, 126.13, 19.28. HRMS-EI m / z [M + H] + calcd for C 10 H 8 BrN 2 O 2 S + : 298.9484, found: 298.9492.

[0168] Example 25

[0169] 5-Bromopyridin-3-yl 5-methyl-1H-pyrazole-3-carboxylate (I-25)

[0170] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 5-methyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (63 mg, 0.22 mmol, yield 28%). It is in the form of a white solid powder, mp 133.6 - 136.6 °C. 11H NMR (600 MHz, Chloroform-d) δ 8.52 (s, 1H), 8.44 (s, 1H), 7.85 (dd, J = 4.7, 2.4 Hz, 1H), 6.66 (d, J = 4.4 Hz, 1H), 2.32 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 163.46, 151.27, 146.07, 145.03, 144.61, 139.13, 137.20, 124.22, 112.08, 70.92, 53.32, 53.18, 53.04, 52.90, 52.75, 52.61, 52.47. HRMS-EI m / z [M+H] + calcd for C 10 H 9 BrN 3 O 2 + : 281.9873, found: 281.9882.

[0171] Example 26

[0172] 5-Bromopyridin-3-yl 1-methyl-1H-pyrazole-3-carboxylate (Ⅰ-26)

[0173] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (128 mg, 0.45 mmol, yield 57%). It is in the form of a white solid powder, mp 89.5 - 94.2 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.52 (s, 1H), 7.85 (s, 1H), 7.51 (s, 1H), 6.98 (s, 1H), 4.06 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 159.64, 148.09, 147.29, 141.90, 141.61, 132.49, 131.98, 119.96, 110.47, 39.99. HRMS-EI m / z [M+H] + calcd for C 10 H 9 BrN 3 O 2 + : 281.9873, found: 281.9880.

[0174] Example 27

[0175] 5-Bromopyridin-3-yl 1-benzyl-1H-pyrazole-3-carboxylate (Ⅰ-27)

[0176] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-benzyl-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (46 mg, 0.13 mmol, yield 26%). It is in the form of a white solid powder, mp 86.0 - 89.5 °C. 1 H NMR(600MHz,Chloroform-d)δ8.49(d,J=2.0Hz,1H),8.37(d,J=2.4Hz,1H),8.02(s,1H),7.94(s,1H),7.35–7.27(m,3H),7.27–7.21(m,2H),5.29(s,2H). 13 CNMR(151MHz,Chloroform-d)δ160.02,147.88,147.20,141.93,141.75,134.80,133.62,132.40,129.16(2C),128.80,128.15(2C),119.95,113.34,56.80.HRMS-EI m / z[M+H] + calcd for C 16 H 13 BrN 3 O 2 + :358.0186,found:358.0194.

[0177] Example 28

[0178] 5-Bromopyridin-3-yl 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylate (Ⅰ-28)

[0179] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (44 mg, 0.10 mmol, yield 28%). It is in the form of a white solid powder, mp 150.4 - 164.5 °C. 11H NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 12.6 Hz, 2H), 7.89 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 5.40 (s, 2H), 2.98 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 159.84, 148.01, 147.10, 142.43, 141.59, 141.15, 140.85, 134.22, 132.50, 128.64 (2C), 128.23 (2C), 120.00, 113.83, 55.87, 44.42. HRMS-EI m / z [M+H] + calcd for C 17 H 15 BrN 3 O 4 S + : 435.9961, found: 435.9971.

[0180] Example 29

[0181] 5-Chloropyridin-3-yl 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (II-1)

[0182] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (43 mg, 0.16 mmol, yield 25%). It is in the form of a white solid powder, mp 98.6 - 100.0 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.43 (s, 1H), 7.77 (s, 1H), 5.67 (s, 1H), 2.83 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.49 (q, J = 7.3 Hz, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 158.11, 148.25 (2C), 147.01, 141.55, 132.28 (2C), 131.21, 120.08, 30.29, 24.48, 23.92. HRMS-EI m / z [M+H] + calcd for C 12 H11 ClN 3 O 2 + : 264.0534, found: 264.0544.

[0183] Example 30

[0184] 5-Chloropyridin-3-yl 4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (II-2)

[0185] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (32 mg, 0.12 mmol, yield 19%). It is in the form of a white solid powder, mp 101.3 - 103.1 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.49 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.41–8.27 (s, 1H), 7.68 (t, J = 2.3 Hz, 1H), 2.81 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 1.84–1.78 (m, 4H). 13 C NMR (151 MHz, Chloroform-d) δ 159.55, 147.10, 145.89, 141.33, 139.37, 131.89, 129.72, 123.57, 121.01, 22.65, 22.28, 21.72, 21.42. HRMS-EI m / z [M+H] + calcd for C 13 H 13 ClN 3 O 2 + : 278.0691, found: 278.0701.

[0186] Example 31

[0187] 5-Chloropyridin-3-yl 1-methyl-1H-indazole-3-carboxylate (II-3)

[0188] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-methyl-1H-indazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (75 mg, 0.26 mmol, yield 46%). It is in the form of a white solid powder, mp 143.2 - 146.3 °C. 11H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 2.3 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.24 (dd, J = 8.2, 1.0 Hz, 1H), 7.77 (t, J = 2.2 Hz, 1H), 7.57–7.51 (m, 2H), 7.41 (ddd, J = 8.0, 6.1, 1.6 Hz, 1H), 4.26 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.03, 147.19, 146.12, 141.71, 141.24, 132.72, 131.86, 129.93, 127.44, 124.20, 124.03, 121.85, 109.93, 36.81. HRMS-EI m / z [M+H] + calcd for C 14 H 11 ClN 3 O 2 + : 288.0534, found: 288.0542.

[0189] Example 32

[0190] 5-Chloropyridin-3-yl 2-methyl-2H-indazole-3-carboxylate (Ⅱ-4)

[0191] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 2-methyl-2H-indazole-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (78 mg, 0.27 mmol, yield 48%). It is in the form of a white solid powder, mp 122.8 - 124.9 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.56 (t, J = 2.3 Hz, 2H), 8.08 (dt, J = 8.2, 1.2 Hz, 1H), 7.86 (dt, J = 8.6, 1.1 Hz, 1H), 7.77 (t, J = 2.2 Hz, 1H), 7.41 (dd, J = 6.8, 1.2 Hz, 2H), 4.57 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 157.80, 147.44, 146.73, 146.41, 141.46, 131.95, 129.69, 126.72, 126.18, 123.89, 122.21, 120.84, 118.62, 41.83. HRMS-EI m / z [M+H] +Calculated for C 14 H 11 ClN 3 O 2 + : 288.0534, found: 288.0541.

[0192] Example 33

[0193] 5-Chloropyridin-3-yl pyrazolo[1,5-a]pyrimidine-3-carboxylate (II-5)

[0194] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (90 mg, 0.33 mmol, yield 54%). In the form of a white solid powder, mp 225.0 - 228.1 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.94 (td, J = 7.1, 1.8 Hz, 1H), 8.89 (tt, J = 4.2, 2.2 Hz, 1H), 8.75 (d, J = 7.0 Hz, 1H), 8.49 (dt, J = 17.0, 3.5 Hz, 2H), 7.80 (dq, J = 4.5, 2.2 Hz, 1H), 7.36 (d, J = 4.5 Hz, 1H), 7.22 (td, J = 7.1, 4.1 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 163.47, 157.64, 152.20, 151.28, 149.42, 145.33, 140.74, 135.93, 134.21 (2C), 114.62 (2C), 104.83. HRMS-EI m / z [M+H] + Calculated for C 12 H 8 ClN 4 O 2 + : 275.0330, found: 275.0340.

[0195] Example 34

[0196] 5-Chloropyridin-3-yl imidazo[1,2-a]pyridine-3-carboxylate (II-6)

[0197] Prepared according to the reaction synthesis procedure with a feed amount of 100 mg of imidazo[1,2-a]pyridine-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (66 mg, 0.24 mmol, yield 39%). It is in the form of a white solid powder, mp 147.4 - 148.5 °C. 1 H NMR (600 MHz, Chloroform-d) δ 9.27 (d, J = 6.8 Hz, 1H), 8.56 (s, 1H), 8.52 (dd, J = 7.9, 2.1 Hz, 2H), 7.84 (d, J = 8.9 Hz, 1H), 7.72 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 6.9 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 157.83, 147.02, 146.21, 143.39, 141.66, 132.03, 129.77, 129.16, 128.00, 118.32, 115.45. HRMS-EI m / z [M+H] + calcd for C 13 H 9 ClN 3 O 2 + : 274.0378, found: 274.0387.

[0198] Example 35

[0199] 5-Chloropyridin-3-yl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (Ⅱ-7)

[0200] Prepared according to the reaction synthesis procedure with a feed amount of 100 mg of 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (67 mg, 0.23 mmol, yield 41%). It is in the form of a white solid powder, mp 118.0 - 120.1 °C. H NMR (600 MHz, Chloroform-d) δ 9.28 (dt, J = 7.0, 1.2 Hz, 1H), 8.52 (dd, J = 13.5, 2.2 Hz, 2H), 7.79–7.66 (m, 2H), 7.51 (dd, J = 7.0, 1.3 Hz, 1H), 7.09 (td, J = 6.9, 1.3 Hz, 1H), 2.84 (s, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 158.58, 158.58, 154.94, 148.10, 147.02, 146.15, 141.69, 132.04, 129.91, 129.28, 128.32, 117.10, 114.82, 17.22. HRMS-EI m / z [M+H] + calcd for C 14 H 11 ClN 3 O 2 + : 288.0534, found: 288.0543.

[0201] Example 36

[0202] 5-Chloropyridin-3-yl imidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-8)

[0203] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of imidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (47 mg, 0.17 mmol, yield 28%). In the form of a white solid powder, mp 177.7 - 178.9 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.52 (dd, J = 6.4, 2.2 Hz, 2H), 8.37 (s, 1H), 8.20 (d, J = 6.9 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.73 (t, J = 2.3 Hz, 1H), 7.33 (ddd, J = 9.4, 6.7, 1.2 Hz, 1H), 6.96 (t, J = 6.8 Hz, 1H). 13 13C NMR (151 MHz, Chloroform-d) δ 194.71, 160.91, 147.41, 146.26, 141.74, 134.98, 131.96, 129.83, 127.01, 126.40, 119.49, 118.64, 114.67. HRMS-EI m / z [M+H] + calcd for C 13 H 9 ClN 3 O 2 + : 274.0378, found: 274.0385.

[0204] Example 37

[0205] 5-Chloropyridin-3-yl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-9)

[0206] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 7-methylimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (57 mg, 0.20 mmol, yield 35%). It is in the form of a white solid powder, mp 166.1 - 168.5 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.50 (dd, J = 4.0, 2.2 Hz, 2H), 8.30 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.71 (t, J = 2.2 Hz, 1H), 7.48 (s, 1H), 6.79 (dd, J = 7.0, 1.6 Hz, 1H), 2.45 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 160.85, 147.41, 146.29, 146.19, 141.70, 138.53, 134.54, 131.94, 129.83, 125.49, 118.28, 117.64, 117.23, 21.70. HRMS-EI m / z [M+H] + calcd for C 14 H 11 ClN 3 O 2 + : 288.0534, found: 288.0547.

[0207] Example 38

[0208] 5-Chloropyridin-3-yl 6-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-10)

[0209] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 6-methylimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (62 mg, 0.22 mmol, yield 38%). It is in the form of a white solid powder, mp 160.1 - 163.9 °C. 11H NMR (600 MHz, Chloroform-d) δ 8.50 (dd, J = 4.1, 2.1 Hz, 2H), 8.28 (s, 1H), 7.97 (q, J = 1.4 Hz, 1H), 7.71 (t, J = 2.2 Hz, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.19 (dd, J = 9.3, 1.7 Hz, 1H), 2.37 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.84, 147.41, 146.16, 144.93, 141.67, 134.45, 131.95, 130.65, 129.82, 124.73, 123.81, 118.46, 118.31, 18.35. HRMS-EI m / z [M+Na] + calcd for C 14 H 10 ClN 3 O 2 Na + : 310.0354, found: 310.0360.

[0210] Example 39

[0211] 5-Chloropyridin-3-yl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-11)

[0212] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (63 mg, 0.18 mmol, yield 43%). It is in the form of a white solid powder, mp 174.5 - 177.2 °C. 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.98 (s, 1H), 8.75 (s, 1H), 8.62 (dd, J = 14.4, 2.2 Hz, 2H), 8.15 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 9.6 Hz, 1H), 7.55 (dd, J = 9.7, 2.0 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d 6 ) δ 160.26, 147.05, 145.80, 143.36, 142.05, 134.05, 130.84, 130.31, 130.16, 127.77, 119.88, 119.10, 108.00. HRMS-EI m / z [M+H] +Calculated for C 13 H 8 BrClN 3 O 2 + : 351.9483, found: 351.9491.

[0213] Example 40

[0214] 5-Chloropyridin-3-yl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (II-12)

[0215] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (49 mg, 0.16 mmol, yield 31%). In the form of a white solid powder, mp 168.3 - 172.8 °C. 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.92 (s, 1H), 8.77 (s, 1H), 8.62 (dd, J = 15.1, 2.2 Hz, 2H), 8.16 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 9.7 Hz, 1H), 7.49 (dd, J = 9.7, 2.1 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d 6 ) δ 160.24, 147.03, 145.79, 143.32, 142.04, 134.27, 130.83, 130.14, 128.28, 125.67, 120.89, 120.12, 118.92. HRMS-EI m / z [M+H] + Calculated for C 13 H 8 Cl 2 N 3 O 2 + : 307.9988, found: 307.9998.

[0216] Example 41

[0217] 5-Chloropyridin-3-yl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (II-13)

[0218] Prepared according to the reaction synthesis procedure with a feed amount of 100 mg of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (61 mg, 0.23 mmol, yield 35%). It is a white solid powder, mp 103.6 - 107.6 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.47 (dd, J = 6.9, 2.2 Hz, 2H), 7.67 (t, J = 2.2 Hz, 1H), 6.69 (s, 1H), 4.26 (t, J = 7.4 Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H), 2.68 (p, J = 7.4 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 160.11, 147.51, 147.43, 146.01, 145.64, 131.87, 129.86, 103.57, 48.57, 26.19, 23.09. HRMS-EI m / z [M+H] + calcd for C 12 H 11 ClN 3 O 2 + : 264.0534, found: 264.0538.

[0219] Example 42

[0220] 5-Chloropyridin-3-yl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate (Ⅱ-14)

[0221] Prepared according to the reaction synthesis procedure with a feed amount of 100 mg of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (32 mg, 0.12 mmol, yield 19%). It is a white solid powder, mp 40.2 - 43.1 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.46 (dd, J = 11.3, 2.1 Hz, 2H), 7.66 (d, J = 2.2 Hz, 1H), 6.68 (s, 1H), 4.27 (t, J = 6.2 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 2.12–2.08 (m, 2H), 1.92 (p, J = 6.2 Hz, 2H). 1313C NMR (151 MHz, Chloroform-d) δ 147.45, 145.97, 141.72, 141.31, 140.76, 131.90, 129.93, 107.38, 49.09, 23.31, 22.77, 20.24. HRMS-EI m / z [M+H] + calcd for C 13 H 13 ClN 3 O 2 + : 278.0691, found: 278.0698.

[0222] Example 43

[0223] 5-Chloropyridin-3-yl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-15)

[0224] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (64 mg, 0.22 mmol, yield 39%). It is in the form of a white solid powder, mp 132.8 - 134.1 °C. 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.61 (dd, J = 7.4, 2.2 Hz, 2H), 8.14 (t, J = 2.4 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.38 (dd, J = 9.2, 6.7 Hz, 1H), 6.92 (d, J = 6.8 Hz, 1H), 2.67 (s, 3H). 13 13C NMR (151 MHz, DMSO-d 6 ) δ 160.70, 147.20, 145.72, 145.44, 142.07, 136.47, 133.52, 130.89, 130.14, 127.41, 117.57, 115.44, 112.92, 18.07. HRMS-EI m / z [M+H] + calcd for C 14 H 11 ClN 3 O 2 + : 288.0534, found: 288.0544.

[0225] Example 44

[0226] 5-Chloropyridin-3-yl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Ⅱ-16)

[0227] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (33 mg, 0.06 mmol, yield 26%). It is in the form of a white solid powder, mp 121.5 - 125.3 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.52 (dd, J = 9.6, 2.1 Hz, 2H), 8.24 (d, J = 8.9 Hz, 2H), 7.71 (t, J = 2.1 Hz, 1H), 7.54–7.47 (m, 4H), 6.99–6.95 (m, 2H), 4.24 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.42 (t, J = 6.6 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 160.57, 159.64, 147.28, 146.52, 141.61, 137.40, 132.22, 132.03, 129.75, 126.95, 125.48, 124.45, 114.10, 55.72, 50.76, 21.59. 13 C NMR (151 MHz, Chloroform-d) δ 160.57, 159.64, 156.81, 147.28, 147.05, 146.52, 145.43, 141.61, 137.40, 133.17, 132.22, 132.03, 129.75, 128.54, 126.95(2C), 125.48(2C), 124.45(2C), 114.10(2C), 55.72, 50.76, 21.59. HRMS-EI m / z [M+H] + calcd forC 25 H 19 ClN 5 O 6 + : 520.1018, found: 520.1021.

[0228] Example 45

[0229] 5-Bromopyridin-3-yl imidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-17)

[0230] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of imidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (67 mg, 0.21 mmol, yield 34%). It is a white solid powder, mp 162.4 - 164.5 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.61 (d, J = 1.9 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J = 7.2 Hz, 1H), 7.88 (t, J = 2.1 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.38–7.31 (m, 1H), 6.96 (s, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 160.72, 148.21, 147.32, 145.69, 141.91, 134.75, 132.40, 126.89, 126.27, 119.96, 119.30, 118.50, 114.53. HRMS-EI m / z [M+H] + calcd for C 12 H 8 BrN 3 O 2 Na + : 339.9692, found: 339.9703.

[0231] Example 46

[0232] 5-Bromopyridin-3-yl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate (Ⅱ-18)

[0233] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (37 mg, 0.12 mmol, yield 19%). It is a white solid powder, mp 105.1 - 107.1 °C. 11H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.82 (t, J = 2.2 Hz, 1H), 6.69 (s, 1H), 4.28 (t, J = 6.2 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.15–2.08 (m, 2H), 1.94 (s, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.14, 148.01, 147.37, 142.00, 141.14, 140.64, 132.48, 119.89, 107.24, 48.97, 23.20, 22.64, 20.13. HRMS-EI m / z [M+H] + calcd for C 13 H 13 BrN 3 O 2 + : 322.0186, found: 322.0193.

[0234] Example 47

[0235] 5-Bromopyridin-3-yl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-19)

[0236] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 6-chloroimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (81 mg, 0.23 mmol, yield 45%). It is in the form of a white solid powder, mp 145.1 - 146.8 °C. 1 1H NMR (600 MHz, Chloroform-d) δ 8.61 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.34 (s, 1H), 8.30–8.25 (m, 1H), 7.87 (t, J = 2.2 Hz, 1H), 7.70 (d, J = 9.6 Hz, 1H), 7.32 (dd, J = 9.7, 2.0 Hz, 1H). 13 13C NMR (151 MHz, Chloroform-d) δ 160.26, 148.30, 147.20, 144.02, 141.74, 135.53, 132.39, 128.83, 124.03, 123.15, 120.04, 119.56, 118.53. HRMS-EI m / z [M+H] + calcd for C13 H 8 BrClN 3 O 2 + : 351.9483, found: 351.9492.

[0237] Example 48

[0238] 5-Bromopyridin-3-yl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-20)

[0239] Prepared according to the synthetic steps of the reaction formula with a feed amount of 100 mg of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (74 mg, 0.22 mmol, yield 39%). It is in the form of a white solid powder, mp 135.2 - 137.1 °C. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.64 (d, J = 0.9 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.15 (t, J = 2.2 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.29–7.26 (m, 1H), 6.82 (dt, J = 7.0, 1.2 Hz, 1H), 2.56 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 161.20, 148.32, 147.76, 145.90, 142.79, 136.98, 134.01, 133.32, 127.89, 120.02, 118.09, 115.93, 113.39, 18.56. HRMS-EI m / z [M+H] + calcd for C 14 H 11 BrN 3 O 2 + : 332.0029, found: 332.0039.

[0240] Example 49

[0241] 5-Bromopyridin-3-yl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (Ⅱ-21)

[0242] Prepared according to the reaction synthesis steps with a feed amount of 100 mg of 7-methylimidazo[1,2-a]pyridin-2-carboxylic acid. Purified by column chromatography (EA / PE: 20% - 100%) to obtain the target compound (60 mg, 0.18 mmol, yield 33%). It is in the form of a white solid powder, mp 149.5 - 152.0 °C. 1 H NMR (600 MHz, Chloroform-d) δ 8.64 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 0.8 Hz, 1H), 8.02 (q, J = 1.3 Hz, 1H), 7.91 (t, J = 2.2 Hz, 1H), 7.67 (d, J = 9.4 Hz, 1H), 7.24 (dd, J = 9.4, 1.7 Hz, 1H), 2.42 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 160.70, 148.14, 147.35, 144.80, 141.86, 132.46, 130.53, 125.94, 124.61, 123.68, 120.00, 118.31, 118.19, 18.24. HRMS-EI m / z [M+H] + calcd for C 14 H 10 BrN 3 O 2 Na + : 353.9849, found: 353.9858.

[0243] Example 50

[0244] Experimental study on the activity of some compounds against M pro protease

[0245] (I). Anti-SARS-CoV-2 M pro protease activity test

[0246] The protease activity of the compound was evaluated by fluorescence resonance energy transfer (FRET) method. The Beyotime novel coronavirus screening kit (https: / / www.beyotime.com / product / P0315M.htm) was used, and the test process referred to the instruction manual of the kit (P0315M).

[0247] The specific experimental operations are as follows:

[0248] 1. Sample determination: a. Prepare Assay Reagent according to the number of samples. Each sample requires 92 μL of Assay buffer + 1 μL of 2019 - nCov M pro / 3CL pro ; b. Use a 96 - well black plate to set up a blank control group (93 μL of Assay buffer + 5 μL of sample solvent), a 100% enzyme activity control group (93 μL of Assay Reagent + 5 μL of sample solvent), a PF - 07321332 group (93 μL of Assay Reagent + 5 μL of the sample to be tested), an Ebselen group (93 μL of Assay Reagent + 5 μL of the sample to be tested), and a compound group (93 μL of Assay Reagent + 5 μL of the sample to be tested). Two replicates were set for each single concentration; c. Quickly add 2 μL of Substrate to each well, mix well, and incubate at 37 °C for 5 minutes. At 20 minutes, use a multifunctional microplate reader (Thermo Fisher 3020 - 426) to perform fluorescence measurement (excitation wavelength is 340 nm, emission wavelength is 490 nm) to obtain the fluorescence value.

[0249] 2. Calculation: a. Calculate the average fluorescence value of each sample well and record them as RFU 空白对照 、RFU 100％酶活性对照 、RFU Ebselen阳性对照 、RFU 样品 ; b. Calculate the inhibition percentage of each sample. The calculation formula is as follows: Inhibition rate (%) = (RFU 100％酶活性对照 - RFU 样品 ) / (RFU 100％酶活性对照 - RFU 空白对照 ) × 100%. Use GraphPad Prism 8 to calculate the inhibition rate and IC 50 value.

[0250] Compound cytotoxicity test: 1. Resuscitate 2 types of cells with the corresponding culture medium and maintain cell growth until the logarithmic growth phase. Digest adherent cells with trypsin and collect cells by centrifugation at 1000 rpm for 5 minutes. After centrifugation, discard the supernatant and resuspend the cells with an appropriate amount of culture medium. 2. Take the above cell suspension and perform cell counting using a cell counting chamber; according to the required number of tests, plate the cells. Add a certain amount of cell suspension to each well in a 96 - well plate. The final cell density is: 4000 Hela cells / well, 6000 HUVEC cells / well. Incubate at 37 °C, 5% CO 2, After culturing cells for 24 h under 95% humidity conditions, compounds with corresponding concentrations were administered, and control groups were set up (medium-only group, medium + cell group, medium + cell + DMSO group). Three replicates were set for each concentration. After culturing in an incubator for 24 h / 72 h, 20 μL of MTT was added in the dark. After 4 h, a multifunctional microplate reader (Thermo Fisher 3020-426) was used for measurement (wavelength: 490 nm), and GraphPad Prism 8 was used to calculate the cell survival rate.

[0251] Table 1 Experimental results of protease activity and cytotoxicity of some representative Series I compounds

[0252]

[0253] Note a : Protease activity was independently tested twice; b : Independently repeated three times; c : Not tested

[0254] Table 2 Experimental results of protease activity and cytotoxicity of some representative Series II compounds

[0255]

[0256]

[0257] Note a : Protease activity was independently tested twice; b : Independently repeated three times; c : Not tested

[0258] The in vitro antitumor activity of the target compound was determined. The results showed that the compounds of the present invention had excellent M pro protease activity and good cell safety, and could be used for the preparation of drugs for the prevention and treatment of diseases caused by coronavirus infection.

[0259] (2) Evaluation of the stability test of the compound against glutathione (GSH)

[0260] GSH is the main intracellular reducing agent and antioxidant, participating in various biological processes, including drug metabolism and detoxification. Evaluating the reactivity of compounds with GSH helps predict their stability and potential toxicity in vivo. The reactivity of GSH with compounds can provide information about the potential reactivity of the compounds, which is crucial for understanding their mechanism of action and possible side effects. By understanding the reactivity of compounds with GSH, the molecular structure can be optimized to improve their stability and efficacy in vivo. By identifying compounds that remain stable in the presence of GSH, they are more likely to exhibit good pharmacokinetic properties in vivo. By reducing the potential reactivity of compounds with other thiol-containing molecules in cells, off-target effects and toxicity can be reduced. Improve safety: Ensure that compounds do not produce harmful metabolites due to reactions with endogenous substances such as GSH in vivo.

[0261] Specific steps:

[0262] 1. Prepare samples: Dissolve the compound in an appropriate solvent to prepare solutions of different concentrations (such as 100 μM). Prepare a GSH solution, usually at a concentration of 1 mM.

[0263] 2. Reaction setup: Mix the compound solution with the GSH solution at 37 °C, ensuring that the total volume is the same. The reaction time is usually set to 1 hour and then freeze-dried to simulate the in vivo environment.

[0264] 3. Monitor the reaction: Use ultraviolet thin-layer chromatography technology to monitor the degradation of the compound during the reaction. Calculate the remaining amount of the compound by comparing the spot concentrations before and after the reaction.

[0265] 4. Data analysis: Calculate the percentage of stability of the compound in the presence of GSH. Analyze the data to determine the reactivity of the compound with GSH and evaluate its stability.

[0266] 5. Result analysis: Compounds with high stability usually have a higher remaining amount, indicating that they may have better pharmacokinetic properties in vivo. Compounds with low stability may require further structural optimization to improve their stability in vivo.

[0267] Table 3 Results of the GSH stability experiment for some representative compounds

[0268]

[0269] Note a : The stability calculation was repeated with independent tests twice;

[0270] Through in vitro activity tests of M pro protease, it was shown that the compounds of the present invention have significant Mpro enzyme activity. There are multiple compound activities IC 50The value is two-digit nM. The most representative compound Ⅱ-12 has an IC 50 of 1 nM, has relatively low cytotoxicity to cells, good stability to GSH, and a high stability rate of up to 95% at a high concentration of 1 mM GSH and 100 μM. Since M pro plays a key role in the viral life cycle and is supported by in vitro protease inhibition activity experiments, the compounds of the present invention can be used in drugs for preventing or treating diseases related to M pro inhibitors, especially antiviral drugs.

[0271] The present invention and its embodiments are schematically described above. The description is not restrictive. Only one of the embodiments of the present invention is shown in the drawings, and the actual structure is not limited thereto. Therefore, if those of ordinary skill in the art are inspired by it and design similar structural modes and embodiments without creative efforts without departing from the gist of the present invention, they shall fall within the protection scope of the present invention.

Claims

1. A compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is The general formula (II) is Wherein, ring A is selected from a five-membered aromatic heterocycle containing two or three heteroatoms, E, M, G are independently selected from -CR 1 =, -N =, -NR 1 -, -O- or S; W and Y are independently selected from -CH=, -CR 1 = or -N =; Z is selected from -CR 1 =, -N =, -NR 1 -, -O- or S; Ring B is selected from a six-membered aromatic ring, a four-, five- or six-membered heterocyclic ring, an aromatic ring, an aromatic heterocyclic ring, a 4-8-membered saturated or unsaturated carbon ring; X is selected from hydrogen, F, Cl, Br or I; R 1 is optionally selected from hydrogen, alkyl, alkenyl, alkynyl, phenyl, biphenyl, naphthyl or Het, wherein alkyl, biphenyl, phenyl, naphthyl and Het may be optionally substituted by halogen, -CN, -OH, -CF3, OCF3, -OR, OCF3, -SH, -SR, -NH2, -NHR, -NR2, -NHCOR, -NHSO2R, -NRSO2R, -COR, -COOR, -CONHR, -CON(R2), -CONH(CH2) 1-10 N(R2), -CONR2, -CON(R2)O, -CONH(CH2) 1-10 N(R2)O, -CON(R2)NR, -CON(R2)NCOOR, -CONH(CH2) 1-10 N(R2)NR, -CONH(CH2) 1-10 N(R2)NCOOR, R represents hydrogen or alkyl; R 2 represents hydrogen, alkyl, halogen, hydroxyl, cyano, aryl, Het, -NHR, -OR, -NH(CH2) 1-10 Het, -O(CH2) 1- 10 Het, -NH(CH2) 1-10 OR, -O(CH2) 1-10 OR, -NH(CH2) 1-10 NHR, -O(CH2) 1-10 NHR, -CONHR, -NH(CH2) 1- 10 NR2, -O(CH2) 1-10 NR2, -CONHHet, -COOR, -COOHet, -NHCOOR, -NHCOOHet, -NHCONHR or -NHCONHHet, R represents hydrogen or alkyl; The aryl groups are selected from substituted or unsubstituted phenyl, naphthyl or tetrahydronaphthyl carbocyclic rings, wherein the substituted phenyl, naphthyl or tetrahydronaphthyl carbocyclic rings are optionally substituted by 1, 2 or 3 substituents, each of which is independently selected from alkyl, cyano, halogen, haloalkyl, hydroxyl, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het; The Het is selected from the group consisting of piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl monocyclic heterocyclic rings; or selected from the group consisting of quinolyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo[b][1,4]dioxane or benzo[d][1,3]dioxolanyl bicyclic heterocycle; each monocyclic or bicyclic heterocycle is optionally substituted by 1, 2 or 3 substituents, each substituent is independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy, or selected from C3-C8 aliphatic carbocycle, or the following aliphatic heterocycles: tetrahydropyrrolyl, morpholinyl, alkoxymorpholinyl, piperazinyl, piperidinyl, alkylaminopiperidinyl; The alkyl group is a C1-C6 straight-chain or branched saturated hydrocarbon group; or a C3-C6 cyclic saturated hydrocarbon group; or a C3-C6 cyclic saturated hydrocarbon group connected to a C1-C6 straight-chain or branched saturated hydrocarbon group; The alkoxy group is a straight or branched saturated hydrocarbon group having C1-C6; or a cyclic saturated hydrocarbon group having C3-C6; or A cyclic saturated hydrocarbon group having C3-C6 connected to a straight or branched saturated hydrocarbon group having C1-C6; wherein each carbon atom is optionally substituted by oxygen; The alkylamino group is a straight or branched saturated hydrocarbon group having C1-C6; or a cyclic saturated hydrocarbon group having C3-C6; or A cyclic saturated hydrocarbon group having C3-C6 connected to a straight or branched saturated hydrocarbon group having C1-C6; wherein each carbon atom is optionally substituted by nitrogen; The halogen is selected from fluorine, chlorine, bromine or iodine substituents.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a thiophene ring, an isothiazole ring, a thiazole ring or a triazole ring; Ring B is a benzene ring, pyridine, pyridone, hydrogenated pyridone, pyrimidine, pyrimidinedione, pyridazine, triazine, tetrazine, imidazole, pyrazole, triazole, thiadiazole, oxadiazole, or a 4-8 membered heterocycle, or a 4-8 membered saturated cycloalkyl or a 4-8 membered non-cycloalkenyl group; X is F, Cl, Br; Z is independently selected from -CR 1 =, -N =, -NR 1 -; R 1 Any one of hydrogen, alkyl, alkenyl, alkynyl, phenyl, biphenyl or Het, wherein alkyl, biphenyl, phenyl and Het may be optionally substituted by halogen, -CN, -OH, -CF3, OCF3, -OR, OCF3, -SH, -SR, -NH2, -NHR, -NR2, -NHCOR, -NHSO2R, -NRSO2R, -COR, -COOR, -CONHR, -CON(R2), -CONH(CH2) 1-10 N(R2), -CONR2, -CON(R2)O, -CONH(CH2) 1-10 N(R2)O, -CON(R2)NR, -CON(R2)NCOOR, -CONH(CH2) 1-10 N(R2)NR, -CONH(CH2) 1-10 N(R2)NCOOR, R represents hydrogen or alkyl; R 2 Selected from hydrogen, halogen, hydroxy, cyano, alkyl, phenyl, Het, -NHR, -OR, -NH(CH2) 1-10 Het, -O(CH2) 1- 10 Het, -NH(CH2) 1-10 OR, -O(CH2) 1-10 OR, -NH(CH2) 1-10 NHR, -O(CH2) 1-10 NHR, -CONHR, -NH(CH2) 1- 10 NR2, -O(CH2) 1-10 NR2, -CONHHet, -COOR, -COOHet, -NHCOOR, -NHCOOHet, -NHCONHR or -NHCONHHet, R represents hydrogen or alkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is specifically: 5-Chloropyridin-3-yl 1-methyl-1H-pyrazole-4-carboxylate (Ⅰ-1); 5-Chloropyridin-3-yl 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (I-2); 5-Chloropyridin-3-yl 1-isopropyl-1H-pyrazole-4-carboxylate (Ⅰ-3); 5-Chloropyridin-3-yl 1-phenyl-1H-pyrazole-4-carboxylate (Ⅰ-4); 5-Chloropyridin-3-yl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (I-5); 5-Chloropyridin-3-yl 1-benzyl-1H-pyrazole-4-carboxylate (Ⅰ-6); 5-Chloropyridin-3-yl 3-methylisoxazole-5-carboxylate (Ⅰ-7); 5-Chloropyridin-3-yl 2-methylthiazole-4-carboxylate (I-8); 5-Chloropyridin-3-yl 2-(trifluoromethyl)thiazole-4-carboxylate (I-9); 5-Chloropyridin-3-yl 2-chlorothiazole-4-carboxylate (Ⅰ-10); 5-Chloropyridin-3-yl 5-methyl-1H-pyrazole-3-carboxylate (I-11); 5-Chloropyridin-3-yl 5-acetyl-1H-pyrazole-3-carboxylate (I-12); 5-Chloropyridin-3-yl 5-cyclopropyl-1H-pyrazole-3-carboxylate (I-13); 5-Chloropyridin-3-yl 1-methyl-1H-imidazole-4-carboxylate (I-14); 5-Chloropyridin-3-yl 1,3-dimethyl-1H-pyrazole-5-carboxylate (Ⅰ-15); 5-Chloropyridin-3-yl 1-methyl-1H-pyrazole-3-carboxylate (Ⅰ-16); 5-Chloropyridin-3-yl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate (I-17); 5-Chloropyridin-3-yl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (I-18); 5-Chloropyridin-3-yl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (Ⅰ-19); 5-Chloropyridin-3-yl 1-benzyl-1H-pyrazole-3-carboxylate (Ⅰ-20); 5-Chloropyridin-3-yl 1-(4-cyanobenzyl)-1H-pyrazole-3-carboxylate (Ⅰ-21); 5-Chloropyridin-3-yl 1-(3-(trifluoromethoxy)benzyl)-1H-pyrazole-3-carboxylate (I-22); 5-Chloropyridin-3-yl 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylate (I-23); 5-Bromopyridin-3-yl 2-methylthiazole-4-carboxylate (I-24); 5-Bromopyridin-3-yl 5-methyl-1H-pyrazole-3-carboxylate (I-25); 5-Bromopyridin-3-yl 1-methyl-1H-pyrazole-3-carboxylate (Ⅰ-26); 5-Bromopyridin-3-yl 1-benzyl-1H-pyrazole-3-carboxylate (Ⅰ-27); 5-Bromopyridin-3-yl 1-(4-(methylsulfonyl)benzyl)-1H-pyrazole-3-carboxylate (I-28); 5-Chloropyridin-3-yl 1,4,5,6-tetrahydrocyclopentane[c]pyrazole-3-carboxylate (II-1); 5-Chloropyridin-3-yl 4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (II-2); 5-Chloropyridin-3-yl 1-methyl-1H-indazole-3-carboxylate (II-3); 5-Chloropyridin-3-yl 2-methyl-2H-indazole-3-carboxylate (II-4); 5-Chloropyridin-3-ylpyrazolo[1,5-a]pyrimidine-3-carboxylate (II-5); 5-Chloropyridin-3-ylimidazo[1,2-a]pyridine-3-carboxylate (II-6); 5-Chloropyridin-3-yl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (II-7); 5-Chloropyridin-3-ylimidazo[1,2-a]pyridine-2-carboxylate (II-8); 5-Chloropyridin-3-yl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (II-9); 5-Chloropyridin-3-yl 6-methylimidazo[1,2-a]pyridine-2-carboxylate (II-10); 5-Chloropyridin-3-yl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (II-11); 5-Chloropyridin-3-yl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (II-12); 5-Chloropyridin-3-yl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (II-13); 5-Chloropyridin-3-yl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate (II-14); 5-Chloropyridin-3-yl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (II-15); 5-Chloropyridin-3-yl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (II-16); 5-Bromopyridin-3-ylimidazo[1,2-a]pyridine-2-carboxylate (II-17); 5-Bromopyridin-3-yl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylate (II-18); 5-Bromopyridin-3-yl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (II-19); 5-Bromopyridin-3-yl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (II-20); 5-Bromopyridin-3-yl 7-methylimidazo[1,2-a]pyridine-2-carboxylate (II-21).

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salts include acid addition salts formed between the compound of formula (I) or the compound of formula (II) and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or acid salts of inorganic bases containing basic metal cations, alkaline earth metal cations, and ammonium cation salts.

5. A pharmaceutical composition, characterized in that The active ingredients of the pharmaceutical composition are the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. A method for the prevention or treatment of 3CL-related diseases based on the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the drug combination according to claim 5 pro Pharmaceutical applications for proteolytic enzyme-related diseases.

7. The use according to claim 6, characterized in that: The 3CL pro Proteolytic enzyme-related diseases include upper respiratory tract infection, lower respiratory tract infection, acute bronchitis, community-acquired pneumonia, viral pneumonia, acute respiratory distress syndrome, acute exacerbation of chronic diseases, acute exacerbation of chronic obstructive pulmonary disease, acute asthma attack, inflammation and immune abnormalities including cytokine release syndrome, multiple organ dysfunction syndrome, cardiovascular system diseases including viral myocarditis, acute heart failure, arrhythmia, deep vein thrombosis, pulmonary embolism, acute encephalopathy and loss of smell / taste, Guillain-Barré syndrome, viral gastroenteritis, acute hepatitis, chronic fatigue syndrome, pulmonary fibrosis, cognitive dysfunction, and autonomic dysfunction.

8. A method for preparing a drug for inhibiting M based on the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or the drug combination according to claim 5 pro Application of proteases in medicine.

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