A pyridine compound and its preparation method and pharmaceutical use

Abstract

The present invention belongs to the field of medical technology, and discloses a novel pyridine compound, a preparation method thereof, and a pharmaceutical use thereof. Specifically disclosed are a novel pyridine compound represented by a compound of formula (I), and a pharmaceutically acceptable salt thereof, a preparation method of the compound, and a use thereof in preparing a CDK8 inhibitor, a pharmaceutical preparation containing the compound, and a use of the compound in preparing a drug for preventing and treating tumor-related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to novel pyridine compounds represented by general formula (I), and pharmaceutically acceptable salts thereof; pharmaceutical compositions and preparation methods of these compounds, and uses of these compounds in the preparation of cyclin-dependent kinase 8 (CDK8) inhibitors, and uses of these compounds in the preparation of drugs for preventing or treating CDK8-related diseases. Background Art

[0002] Malignant tumors have become one of the major diseases that seriously threaten human health, and anti-tumor drugs have played a huge role in clinical treatment. However, with the changes in people's living habits, diet, environment and other factors, the incidence and pathogenesis of malignant tumors have also changed significantly. At the same time, long-term use of a certain type of drug has led to drug resistance in tumor cells. Therefore, the demand for anti-tumor drugs with novel structures and new action pathways is increasing day by day, and the research and development of such drugs is imminent.

[0003] Cyclin-dependent kinase 8 (CDK8) is an important component of the Mediator complex. It plays a key role in the function of the Mediator complex after binding to cyclin C to form a dimer. CDK8 is involved in multiple regulatory pathways and is highly expressed in many cancer samples. It is considered a potential target for the treatment of malignant tumors such as colorectal cancer, breast cancer, gastric cancer, ovarian cancer, and melanoma.

[0004] Currently, small molecule inhibitors of CDK8 kinase have been reported, but no drug has been successfully marketed due to many problems such as unstable pharmacokinetic properties and poor selectivity. In view of this, the inventors of this application intend to provide a new safe and effective small molecule anti-tumor drug with molecular targeting. Summary of the invention

[0005] The technical problem solved by the present invention is to provide a novel pyridine compound represented by formula (I), a preparation method thereof, a pharmaceutical composition and use thereof in the preparation of a CDK8 inhibitor, and use thereof in the preparation of a drug for preventing or treating diseases related to hyperuricemia.

[0006] In order to solve the technical problem of the present invention, the present invention adopts the following technical solution:

[0007] The first aspect of the technical solution of the present invention is to provide a novel pyridine compound represented by the following general formula (I) and a pharmaceutically acceptable salt thereof:

[0008]

[0009] in, is selected from a double bond or a single bond; R1 is selected from halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted indazolyl; the substituent is a monosubstituted or polysubstituted group, each of which is independently selected from halogen, -NH2, -OH, C 1- C3 alkyl, C 1- C3 alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro; R2 is selected from -NH2, -OH, -NHNH2, C1-C3 alkoxy, C1-C3 alkylamino, morpholinyl, N-methylpiperazinyl, -(CH2) n COOH, n=1,2,3, -CHR3COOH, R3 is selected from hydrogen, C1-C6 alkyl, C1-C3 hydroxyalkyl.

[0010] Preferred compounds are compounds of formula (IA) and pharmaceutically acceptable salts thereof.

[0011]

[0012] Wherein, R1 is selected from halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted indazolyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from halogen, -NH2, -OH, C 1- C3 alkyl, C 1- C3 alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro; R2 is selected from -NH2, -OH, -NHNH2, C1-C3 alkoxy, C1-C3 alkylamino, morpholinyl, N-methylpiperazinyl, -(CH2) n COOH, n=1,2,3, -CHR3COOH, R3 is selected from hydrogen, C1-C6 alkyl, C1-C3 hydroxyalkyl.

[0013] Preferred compounds are compounds of formula (IB) and pharmaceutically acceptable salts thereof.

[0014]

[0015] Wherein, R1 is selected from halogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolyl, substituted or unsubstituted indazolyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from halogen, -NH2, -OH, C 1- C3 alkyl, C 1-C3 alkoxy, morpholinyl, N-methylpiperazinyl, trifluoromethyl, cyano, nitro; R2 is selected from -NH2, -OH, -NHNH2, C1-C3 alkoxy, C1-C3 alkylamino, morpholinyl, N-methylpiperazinyl, -(CH2) n COOH, n=1,2,3, -CHR3COOH, R3 is selected from hydrogen, C1-C6 alkyl, C1-C3 hydroxyalkyl.

[0016] More preferred compounds are the following compounds and pharmaceutically acceptable salts thereof, characterized in that the compounds are selected from:

[0017]

[0018]

[0019]

[0020] The second aspect of the technical solution of the present invention is to provide a method for synthesizing the compound described in the first aspect, comprising the following steps:

[0021] The compound of general formula (I) is obtained from 3-bromoisonicotinaldehyde as the starting material:

[0022]

[0023] The definitions of R1 and R2 are the same as those described in the first aspect of the technical solution of the present invention.

[0024] The third aspect of the technical solution of the invention is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective dose of any one of the novel pyridine compounds and pharmaceutically acceptable salts thereof described in the first aspect of the invention and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle delivery systems.

[0025] In order to prepare pharmaceutical preparations, the compounds of general formula (I) can be mixed with suitable pharmaceutical carrier materials, aromatics, flavoring agents and pigments by known methods and made into tablets or coated tablets, or suspended or dissolved in water or oil with other additives.

[0026] The compounds of the present invention can be administered orally or parenterally. Oral administration can be tablets, capsules, coatings, and parenteral administration forms include injections and suppositories. These preparations are prepared according to methods well known to those skilled in the art. The adjuvants used to make tablets, capsules, and coatings are conventional adjuvants, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and the solvents used in liquid dosage forms include water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, olive oil, etc. The preparations containing the compounds of the present invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments, etc.

[0027] The fourth aspect of the technical solution of the present invention provides the use of the compound described in the first aspect of the present invention and its pharmaceutically acceptable salt in the preparation of CDK8 inhibitors.

[0028] The fourth aspect of the technical solution of the present invention also provides the use of the novel pyridine compound and its pharmaceutically acceptable salt described in the first aspect in the preparation of a drug for preventing or treating a CDK8-related disease. The CDK8-related disease is selected from tumors and immune-related diseases. The tumor includes rectal cancer, breast cancer, gastric cancer, ovarian cancer, and melanoma.

[0029] Pharmacological studies have shown that the compounds of the general formula (I) of the present invention have the activity of inhibiting CDK8, thereby achieving the purpose of treatment.

[0030] Beneficial technical effects:

[0031] CDK8 inhibitors have inhibitory effects on a variety of tumor strains and may have therapeutic effects on malignant tumors such as colorectal cancer, breast cancer, gastric cancer, ovarian cancer, and melanoma. Poor specificity of action is one of the main challenges currently faced by CDK8 inhibitor research. The compounds of the present invention have the characteristics and advantages of specifically inhibiting CDK8, and are expected to provide new, safe and effective CDK8 inhibitors as small molecule anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 .Selective inhibitory effect of the compound on CDK8 (single concentration inhibition rate of the target compound on the kinase (10 μM)). DETAILED DESCRIPTION

[0033] The invention will be further described below with reference to the embodiments, but these embodiments do not limit the scope of the invention.

[0034] The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) or high resolution mass spectrometry (HRMS). NMR shift (δ) is given in parts per million (ppm). Column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR determination is performed using INOVA-300, the determination solvents are CDCl3, DMSO-d6 and Acetone-d6, the internal standard is TMS, and the chemical shift is given in ppm. MS determination is performed using an Agilent LC / MSD TOF liquid chromatography-mass spectrometer.

[0035] Example 1: Preparation of Compound 1

[0036]

[0037] (1) Synthesis of (E)-ethyl 3-(3-bromopyridin-4-yl)acrylate

[0038] Weigh sodium hydride (content 60%, 520mg) and place it in a dry round-bottom flask, add 5mL of anhydrous tetrahydrofuran, slowly drop phosphonotriethyl ester (2.912g, 13mmol) dissolved in 20mL of anhydrous tetrahydrofuran under ice bath, after the dropwise addition is completed, continue to stir and react for 1h under ice bath. Continue to drop 3-bromo-4-formylpyridine (1.86g, 10mmol) diluted with 25mL of tetrahydrofuran into the above reaction system, after the dropwise addition is completed, stir and react for about 3h at room temperature. After the reaction is completed, evaporate the solvent, extract with ethyl acetate and saturated brine, combine and concentrate the organic layers to obtain a light yellow oil, and obtain a white solid (1.8g, yield 70%) after silica gel column chromatography (petroleum ether: ethyl acetate = 20:1).

[0039] (2) Synthesis of (E)-3-(3-bromopyridin-4-yl)acrylamide

[0040] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (77 mg, 0.3 mmol) was dissolved in 2 mL of 7 M NH3 methanol solution and stirred at room temperature for 24 h, with 2 mL of NH3 methanol solution added during the reaction. After the reaction was completed, the solvent was evaporated and purified by silica gel column chromatography to obtain a white solid (38 mg, yield 50%). 1 H NMR (400MHz, DMSO-d6) δ8.79 (s, 1H), 8.56 (d, J = 5.2Hz, 1H), 7.75 (s, 1H), 7.64 (d,J=5.2Hz,1H),7.55(d,J=15.6Hz,1H),7.40(s,1H),6.83(d,J=15.6Hz,1H); 13C NMR (100MHz, DMSO-d6) δ165.31,152.25,148.87,141.79,134.55,129.45,121.62,121.62; HR-ESI-MS: m / z=226.9824[M+H] + ,calcd for C8H8BrN2O:226.9815.

[0041] Example 2: Preparation of Compound 2

[0042]

[0043] (1) Synthesis of (E)-ethyl 3-(3-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)acrylate

[0044] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (512 mg, 2 mmol), p-piperazinylaniline (420 mg, 2.2 mmol), X-phos (95 mg, 0.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), sodium tert-butoxide (269 mg, 2.8 mmol) were placed in a round-bottom flask, and 10 mL of toluene was added. Nitrogen was introduced into the reaction system for 5 min, and then heated to reflux reaction for about 8 h under nitrogen protection. After the reaction was completed, the temperature was cooled to room temperature, the solvent was evaporated, and saturated brine and ethyl acetate were used for extraction. The organic layer was concentrated to obtain a crude product, which was chromatographed on a silica gel column to obtain a solid (366 mg, yield 50%).

[0045] (2) Synthesis of (E)-3-(3-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)acrylamide

[0046] (E)-3-(3-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)acrylate (110 mg, 0.3 mmol) was dissolved in 2 mL of 7 M NH3 methanol solution and stirred at room temperature for 24 h. 2 mL of NH3 methanol solution was added during the reaction. After the reaction was completed, the solvent was evaporated and purified by silica gel column chromatography to obtain a white solid (45 mg, yield 45%). 1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.16(d,J=5.2Hz,1H),7.94(s,1H),7 .61(s,1H),7.55(d,J=16.0Hz,1H),7.46(d,J=5.2Hz,1H),7.21(s,1H),7.0 2(t,J=8.0Hz,1H),6.71(d,J=16.0Hz,1H),6.43-6.47(m,2H),6.27(dd,J= 8.0,1.2Hz,1H),3.05(t,J=4.8Hz,4H),2.42(t,J=4.8Hz,4H),2.20(s,3H); 13 C NMR (100MHz, DMSO-d6) δ166.21,151.99,144.93,143.72,142.65,137.66,133.42,133.16,129.51,125. 93,120.10,107.89,107.23,103.82,54.54,54.54,47.97,47.97,45.66; HR-ESI-MS: m / z=338.1970[M+H] + ,calcd forC 19 H 24 N5O:338.1975.

[0047] Example 3: Preparation of Compound 3

[0048]

[0049] (1) Synthesis of (E)-ethyl 3-(3-((4-fluorophenyl)amino)pyridin-4-yl)acrylate

[0050] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (512 mg, 2 mmol), p-fluoroaniline (244 mg, 2.2 mmol), X-phos (95 mg, 0.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), sodium tert-butoxide (269 mg, 2.8 mmol) were placed in a round-bottom flask, and 10 mL of toluene was added. Nitrogen was introduced into the reaction system for 5 min, and then heated to reflux reaction for about 8 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated, and saturated brine and ethyl acetate were used for extraction. The organic layer was concentrated to obtain a crude product, which was chromatographed on a silica gel column to obtain a solid (300 mg, yield 50%).

[0051] (2) Synthesis of (E)-3-(3-((4-fluorophenyl)amino)pyridin-4-yl)acrylamide

[0052] (E)-3-(3-((4-fluorophenyl)amino)pyridin-4-yl)acrylate (86 mg, 0.3 mmol) was dissolved in 2 mL of 7 M NH3 methanol solution and stirred at room temperature for 24 h. 2 mL of NH3 methanol solution was added during the reaction. After the reaction was completed, the solvent was evaporated and purified by silica gel column chromatography to obtain a white solid (38 mg, yield 45%). 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.17(d,J=4.8Hz,1H),8.05(s,1H),7.61(s,1H),7.56(d,J=15.6Hz ,1H),7.46(d,J=5.2Hz,1H),7.21(s,1H),7.03-7.08(m,2H),6.90-6.96(m,2H),6.72(d,J=15.6Hz,1H); 13 CNMR(100MHz,DMSO-d6)δ166.17,142.85,142.65,140.55,140.54,137.91,133.03,132 .95,126.12,120.18,118.44,118.37,115.87,115.65; HR-ESI-MS: m / z=258.1036[M+H] + ,calcdfor C 14 H 13 FN3O:258.1037.

[0053] Example 4: Preparation of Compound 4

[0054]

[0055] (1) Synthesis of (E)-ethyl 3-(3-(4-fluorophenyl)pyridin-4-yl)acrylate

[0056] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1024 mg, 4 mmol), (4-fluorophenyl) boronic acid (616 mg, 4.4 mmol), Na2CO3 (1272 mg, 12 mmol), (PPh3)2PdCl2 (140 mg, 0.2 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 min. Then, the mixture was heated under reflux in an oil bath under nitrogen protection and reacted overnight. After the reaction was completed, the solvent was evaporated, and the mixture was extracted with saturated brine and ethyl acetate. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (564 mg, yield 52%).

[0057] (2) Synthesis of (E)-3-(3-(4-fluorophenyl)pyridin-4-yl)acrylic acid

[0058] (E)-3-(3-(4-fluorophenyl)pyridin-4-yl)acrylate (678 mg, 2.5 mmol) was dissolved in 10 mL of ethanol and then 7.5 mL of 1N NaOH aqueous solution (7.5 mmol) was added to the system and stirred for about 2 h at room temperature. After the reaction was complete, the organic solvent was evaporated and about 5 mL of distilled water was added to the residue. The residue was completely dissolved. The impurities were first extracted with ethyl acetate to separate the water layer, and 1N HCl aqueous solution was added thereto to adjust the pH to weak acidity. After the adjustment was completed, a large amount of white solid was precipitated, which was filtered and washed with distilled water and dried to obtain a white solid product (528 mg, yield 87%).

[0059] (3) Synthesis of (E)-3-(3-(4-fluorophenyl)pyridin-4-yl)acryloyl-3-methoxyazetidinamine

[0060] (E)-3-(3-(4-fluorophenyl)pyridin-4-yl)acrylic acid (122 mg, 0.5 mmol), 3-methoxyazetidinamine hydrochloride (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.5 mmol) were weighed and dissolved in 5 mL of dichloromethane, and stirred at room temperature for about 6 hours. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain a white solid product (94 mg, yield 60%). 1 H NMR (400MHz, CDCl3) δ8.60(d,J=5.2Hz,1H),8.59(s,1H),7.56(d,J=15.6Hz,1H),7.46(d,J=5.2Hz 1H),7.29-7.32(m,1H),7.27-7.29(m,1H),7.14-7.20(m,2H),6.51(d,J=16.0Hz,1H),4 .36-4.40(m,1H),4.22-4.27(m,2H),4.09-4.11(m,1H),3.94-3.99(m,1H),3.33(s,3H); 13C NMR(100MHz,DMSO-d6)δ164.14,150.66,148.78,139.69,135.30,135.18,132.52,132.49,131.88,1 31.79,122.57,120.47,115.69,115.47,68.41,56.81,55.39,54.66; HR-ESI-MS: m / z=313.1346[M+H] + ,calcd for C 18 H 18 FN2O2:313.1347.

[0061] Example 5: Preparation of Compound 5

[0062]

[0063] (E)-3-(3-(4-fluorophenyl)pyridin-4-yl)acrylic acid is reacted with N-methylpiperazine to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, CDCl3) δ8.59(d,J=5.2Hz,1H),8.57(s,1H),7.54(d,J=15.6Hz,1H),7.46-7.48(m,1H),7.26-7.32( m,2H),7.13-7.18(m,2H),6.91(d,J=15.6Hz,1H),3.70(s,2H),3.58(s,2H),2.41(t,J=15.6Hz,4H),2.31(s,3H); 13 C NMR (100MHz, DMSO-d6) δ163.48,150.67,148.70,139.88,136.65,135.14,132.61,132.58,131.89,131. 81,123.47,120.44,115.67,115.45,55.02,54.25,45.54,44.92,41.57; HR-ESI-MS: m / z=326.1658[M+H] + ,calcd for C 19 H 21 FN3O:326.1663.

[0064] Example 6: Preparation of Compound 6

[0065]

[0066] (1) Synthesis of (E)-ethyl 3-(3-(3,4-dimethoxyphenyl)pyridin-4-yl)acrylate

[0067] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1024 mg, 4 mmol), 3,4-dimethoxyphenylboronic acid (800 mg, 4.4 mmol), Na2CO3 (1272 mg, 12 mmol), (PPh3)2PdCl2 (140 mg, 0.2 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 min. Then, the mixture was heated in an oil bath under nitrogen protection and refluxed to react overnight. After the reaction was completed, the solvent was evaporated, and the mixture was extracted with saturated brine and ethyl acetate. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (677 mg, yield 54%).

[0068] (2) Synthesis of (E)-3-(3-(3,4-dimethoxyphenyl)pyridin-4-yl)acrylic acid

[0069] (E)-3-(3-(3,4-dimethoxyphenyl)pyridin-4-yl) ethyl acrylate (783 mg, 2.5 mmol) was dissolved in 10 mL of ethanol and then 7.5 mL of 1N aqueous NaOH solution (7.5 mmol) was added to the system and stirred for about 2 h at room temperature. After the reaction was complete, the organic solvent was evaporated and about 5 mL of distilled water was added to the residue. The residue was completely dissolved. The impurities were first extracted with ethyl acetate to separate the water layer, and 1N HCl aqueous solution was added thereto to adjust the pH to weak acidity. After the adjustment was completed, a large amount of white solid was precipitated, which was filtered and washed with distilled water and dried to obtain a white solid product (628 mg, yield 89%).

[0070] (3) Synthesis of (E)-3-(3-(3,4-dimethoxyphenyl)pyridin-4-yl)acryloyl-3-methoxyazetidinamine

[0071] (E)-3-(3-(3,4-dimethoxyphenyl)pyridin-4-yl)acrylic acid is reacted with 3-methoxyazetidinamine hydrochloride. The synthesis method and operation are the same as those of compound 4. 1H NMR (400MHz, CDCl3) δ8.63(s,1H),8.57(d,J=5.2Hz,1H),7.65(d,J=15.6Hz,1H),7.46(d,J=5.2Hz,1H),6.96(d,J=8.0Hz,1H),6.83-6.87(m,2 H),6.52(d,J=15.6Hz,1H),4.37-4.41(m,1H),4.24-4.27(m,2H),4.10- 4.13(m,1H),3.96-4.00(m,1H),3.93(s,3H),3.90(s,3H),3.33(s,3H); 13 C NMR(100MHz,DMSO-d6)δ164.32,150.74,148.80,148.64,148.17,139.48,136.10,135.96,128.39,122.31, 121.89,120.38,113.40,111.77,68.42,56.81,55.58,55.55,55.39,54.66; HR-ESI-MS: m / z=355.1651[M+H] + ,calcd for C 20 H 23 N2O4:355.1652.

[0072] Example 7: Preparation of Compound 7

[0073]

[0074] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1024 mg, 4 mmol), 2-naphthaleneboronic acid (757 mg, 4.4 mmol), Na2CO3 (1272 mg, 12 mmol), (PPh3)2PdCl2 (140 mg, 0.2 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 min. Then, the mixture was heated in an oil bath under nitrogen protection and refluxed to react overnight. After the reaction was completed, the solvent was evaporated, and the mixture was extracted with saturated brine and ethyl acetate. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (800 mg, yield 53%). 1H NMR(500MHz, DMSO-d6)δ8.74(s,1H),8.68(d,J=4.4Hz,1H),8.08(d,J=6.8Hz,1H),8.05–8.00(m,2H),7.98(s,1H),7.94(d,J=4.4Hz,1H),7 .63–7.61(m,2H),7.52(d,J=12.8Hz,1H),7.52(dd,J=6.8,1.6Hz,1H),6.90(d,J=12.8Hz,1H),4.14(q,J=5.6Hz,2H),1.19(t,J=5.6Hz,3H); 13 C NMR (125MHz, DMSO-d6) δ165.62,151.05,149.00,139.95,138.87,136.43,133.48,132.81,132.36,128.99,128 .21,128.20,127.71,127.67,126.91,126.88,123.42,120.49,60.49,14.10; HR-ESI-MS: m / z=304.13345[M+H] + ,calcdfor C 20 H 18 O2N:304.13375.

[0075] Example 8: Preparation of Compound 8

[0076]

[0077] (E)-3-(3-(naphthalene-2-yl)pyridin-4-yl)ethyl acrylate (758 mg, 2.5 mmol) was dissolved in 5 mL of ethanol and 5 mL of tetrahydrofuran, and then 7.5 mL of 1N aqueous NaOH solution (7.5 mmol) was added to the system, and the reaction was stirred at room temperature for about 2 h. After the reaction was complete, the organic solvent was evaporated, and about 5 mL of distilled water was added to the residue, and the residue was completely dissolved. It was first extracted with ethyl acetate to remove some impurities, and the water layer was separated. 1N HCl aqueous solution was added thereto to adjust the pH to weak acidity. After the adjustment was completed, a large amount of white solid was precipitated, which was filtered and washed with distilled water, and dried to obtain a white solid (600 mg, yield 87%). 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.71(s,1H),8.67(d,J=5.2Hz,1H),8.08(d,J=8.4Hz,1H),8.00-8.04(m,2H),7.97(s ,1H),7.92(d,J=5.2Hz,1H),7.59-7.64(m,2H),7.52(dd,J=8.4,1.6Hz,1H),7.46(d,J=16.0Hz,1H),6.79(d,J=15.6Hz,1H); 13 C NMR(100MHz,DMSO-d6)δ166.82,150.92,148.91,139.29,139.06,136.29,133.52,132.74,132.27,128 .83,128.11,128.11,127.62,127.58,126.78,126.77,124.53,120.36; HR-ESI-MS: m / z=276.1019[M+H] + ,calcd for C 18 H 14 O2N:276.1019.

[0078] Example 9: Preparation of Compound 9

[0079]

[0080] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid is reacted with methanol to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.67(d,J=5.2Hz,1H),8.06(d,J=8.0Hz,1H),7.98-8.02(m,2H),7.95 (s,1H),7.91(d,J=5.2Hz,1H),7.59-7.61(m,2H),7.55-7.44(m,2H),6.87(d,J=16.0Hz,1H),3.65(s,3H); 13C NMR(100MHz,DMSO-d6)δ165.96,150.98,148.93,139.95,138.80,136.35,133.42,132.74,132.29,128.86 ,128.14,128.12,127.62,127.56,126.82,126.79,123.10,120.44,51.75; HR-ESI-MS: m / z=290.1173[M+H] + ,calcd for C 19 H 16 NO2:290.1176.

[0081] Example 10: Preparation of Compound 10

[0082]

[0083] The compound 1 is prepared by reacting a methanol solution of (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)ethyl acrylate NH3. The synthesis method and operation are the same as those of compound 1. 1 H NMR (400MHz, Acetone-d6) δ8.69(s,1H),8.63(d,J=5.2Hz,1H),8.05(d,J=8.4Hz,1H),7.98-8.03(m,2H),7.94(d,J=1.6Hz,1H),7.69(d, J=5.2Hz,1H),7.57-7.61(m,2H),7.55(d,J=15.2Hz,1H),7.53(dd,J=8.4,2.0Hz,1H),7.07(s,1H),6.91(d,J=16.0Hz,1H),6.47(s,1H); 13 C NMR(100MHz,DMSO-d6)δ166.16,151.40,149.41,140.44,136.68,135.37,134.22,133.25,132.75,129 .18,128.59,128.54,128.09,128.09,127.93,127.19,127.19,120.35; HR-ESI-MS: m / z=275.1178[M+H] + ,calcd for C 18 H 15 N2O:275.1179.

[0084] Example 11: Preparation of Compound 11

[0085]

[0086] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid is reacted with methylamine hydrochloride to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),8.63(d,J=5.2Hz,1H),7.93(d,J=8.8Hz,1H),7.87-7.92(m,2H),7.81(s,1H),7.59(s,1H),7. 52-7.57(m,2H),7.49(d,J=5.2Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),6.47(d,J=15.6Hz,1H),5.62(s,1H),2.88(d,J=4.8Hz,3H); 13 C NMR(100MHz,DMSO-d6)δ164.41,150.09,148.08,140.94,136.41,133.92,133.44,132.73,132.31,128.75 ,128.11,128.09,127.68,127.61,127.54,126.79,126.74,120.23,25.66; HR-ESI-MS: m / z=289.1334[M+H] + ,calcd for C 19 H 17 N2O:289.1335.

[0087] Example 12: Preparation of Compound 12

[0088]

[0089] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid is reacted with cyclopropylamine to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, CDCl3) δ8.71 (s, 1H), 8.62 (d, J = 5.3Hz, 1H), 7.95 (s, 1H), 7.89 (dt,J=6.9,3.8Hz,2H),7.81(s,1H),7.60(d,J=15.7Hz,1H),7.55(m,2H),7. 50(d,J=5.3Hz,1H),7.42(dd,J=8.4,1.7Hz,1H),6.44(d,J=15.7Hz,1H),5.7 4(s,1H),2.82-2.76(m,1H),0.80(dt,J=6.9,5.5Hz,2H),0.56-0.51(m,2H); 13C NMR(125MHz,DMSO-d6)δ165.09,150.98,149.00,140.00,136.25,134.22,133.78,132.81,132.32,128.75,128.1 8,128.12,127.69,127.68,127.02,126.80,126.78,119.83,22.58,5.87,5.87; HR-ESI-MS: m / z=315.15018[M+H] + ,calcd for C 21 H 19 ON2:315.14919.

[0090] Example 13: Preparation of Compound 13

[0091]

[0092] (E)-3-(3-(naphthalene-2-yl)pyridin-4-yl)acrylic acid (138 mg, 0.5 mmol), 3-aminoalanine methyl ester (84 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain a white solid product (110 mg, yield 61%). The white solid (110 mg, 0.5 mmol) was dissolved in anhydrous ethanol, and 2 ml of 1 M NaOH aqueous solution was added dropwise, and the reaction was stirred at room temperature for about 2 h. After the reaction was completed, the reaction solution was evaporated under reduced pressure, dissolved in distilled water, washed with ethyl acetate, and the aqueous phase was adjusted to pH 5 with 1M HCl aqueous solution. A white solid precipitated and was filtered to obtain a white solid (85 mg, yield 82%). 1 H NMR (400MHz, DMSO-d6) δ8.72 (s, 1H), 8.70 (d, J = 5.3Hz, 1H), 8.38 (t, J = 5.6Hz, 1H),8.07(d,J=8.5Hz,1H),8.02(td,J=6.9,4.4Hz,2H),7.96(s,1H),7.74(d, J=5.3Hz,1H),7.65-7.59(m,2H),7.50(dd,J=8.4,1.7Hz,1H),7.34(d,J=15.7 Hz,1H),6.91(d,J=15.7Hz,1H),3.33(q,J=6.6Hz,2H),2.42(t,J=6.7Hz,2H); 13C NMR (125MHz, DMSO-d6) δ172.91,164.02,150.17,148.13,140.91,136.56,134.19,133.48,132.79,132.37,128.83 ,128.20,128.17,127.70,127.66,127.64,126.88,126.83,120.20,35.03,33.69; HR-ESI-MS: m / z=347.13937[M+H] + ,calcd for C 21 H 19 O3N2:347.13902.

[0093] Example 14: Preparation of Compound 14

[0094]

[0095] (E)-3-(3-(naphthalene-2-yl)pyridin-4-yl)acrylic acid (138 mg, 0.5 mmol), L-valine ethyl ester hydrochloride (109 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain a light yellow oil. The light yellow oil (116 mg, 0.3 mmol) was dissolved in anhydrous ethanol, and 2 ml of 1 M NaOH aqueous solution was added dropwise, and the reaction was stirred at room temperature for about 2 h. After the reaction was completed, the reaction solution was evaporated under reduced pressure, dissolved in distilled water, washed with ethyl acetate, and the aqueous phase was adjusted to pH 5 with 1M HCl aqueous solution. A white solid precipitated and was filtered to obtain a white solid (110 mg, yield 73%). 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.68(s,1H),8.38(d,J=8.5Hz,1H),8.06(d,J=8 .6Hz,1H),8.01(ddd,J=9.6,4.7,3.3Hz,2H),7.95(d,J=1.7Hz,1H),7.68(d,J=5.3Hz, 1H),7.63-7.59(m,2H),7.50(dd,J=8.4,1.8Hz,1H),7.35(d,J=15.8Hz,1H),7.12(d, J=15.7Hz,1H),4.21(dd,J=8.5,5.6Hz,1H),2.13–2.04(m,1H),0.89(t,J=6.9Hz,6H);13 C NMR(100MHz,DMSO-d6)δ172.66,164.12,150.89,148.87,139.74,136.21,134.67,133.61,132.65,132.17,128.61,128.0 0,127.97,127.52,127.52,126.71,126.63,126.63,119.51,57.25,29.81,19.01,17.85; HR-ESI-MS: m / z=375.17050[M+H] + ,calcd for C 23 H 23 O3N2:375.17032.

[0096] Example 15: Preparation of Compound 15

[0097]

[0098] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid is reacted with dimethylamine hydrochloride to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, Acetone-d6) δ8.68(s,1H),8.62(d,J=5.2Hz,1H),8.04(d,J=8.4Hz,1H),7.97-8.02(m,2H),7.94(d,J=1.6Hz,1H),7.83(d, J=5.2Hz,1H),7.57-7.61(m,2H),7.55(d,J=15.2Hz,1H),7.52(dd,J=8.4,2.0Hz,1H),7.36(d,J=15.4Hz,1H),3.18(s,3H),2.91(s,3H); 13 C NMR(100MHz,DMSO-d6)δ164.66,150.82,148.70,140.02,136.38,136.33,133.78,132.69,132.19,128.69,12 8.04,128.00,127.59,127.56,126.70,126.66,123.72,120.44,36.82,35.28; HR-ESI-MS: m / z=303.1491[M+H] + ,calcdfor C 20 H 19 N2O:303.1492.

[0099] Example 16: Preparation of Compound 16

[0100]

[0101] The compound 4 is prepared by reacting (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid with 3-methoxyazetidinamine hydrochloride. The synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, CDCl3) δ8.71 (s, 1H), 8.64 (d, J = 5.2Hz, 1H), 7.93 (d, J = 8.4Hz, 1H), 7.86-7.92(m,2H),7.80(d,J=1.2Hz,1H),7.59(d,J=15.6Hz,1H),7.51-7.56(m,2 H),7.50(d,J=5.2Hz,1H),7.42(dd,J=8.4,1.6Hz,1H),6.49(d,J=15.6Hz,1H),4. 26-4.30(m,1H),4.16-4.25(m,2H),3.99-4.02(m,1H),3.93(m,1H),3.28(s,3H); 13 C NMR(100MHz,DMSO-d6)δ164.17,150.76,148.70,139.83,136.26,135.43,133.68,132.72,132.26,128.72,128.08,1 28.07,127.60,127.58,126.75,126.73,122.51,120.46,68.39,56.82,55.37,54.65; HR-ESI-MS: m / z=345.1597[M+H] + ,calcd for C 22 H 21 N2O2:345.1598.

[0102] Example 17: Preparation of Compound 17

[0103]

[0104] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid is reacted with morpholine to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1H NMR (400MHz, CDCl3) δ8.71(s,1H),8.64(d,J=5.2Hz,1H),7.94(d,J=8.4Hz,1H),7.86-7.91(m,2H),7.81(d,J=1.2Hz,1H),7.60(d,J=15.6Hz ,1H),7.53-7.57(m,2H),7.51(d,J=5.2Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),6.81(d,J=15.6Hz,1H),3.65(s,4H),3.57(s,2H),3.42(s,2H); 13 C NMR(100MHz,DMSO-d6)δ163.65,150.85,148.72,139.93,136.99,136.2,133.80,132.73,132.23,128.71,128.08,12 8.05,127.64,127.60,126.71,126.71,123.11,120.41,66.30,66.01,45.57,42.05; HR-ESI-MS: m / z=345.1598[M+H] + ,calcd for C 22 H 21 N2O2:345.1598.

[0105] Example 18: Preparation of Compound 18

[0106]

[0107] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid is reacted with N-methylpiperazine to obtain the compound. Its synthesis method and operation are the same as those of compound 4. 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),8.64(d,J=5.2Hz,1H),7.94(d,J=8.6Hz,1H),7.91-7.87(m,2H),7.81(s,1H),7.56-7.53(m,3H),7.5 2(d,J=5.2Hz,1H),7.43(dd,J=8.3,1.7Hz,1H),6.87(d,J=15.6Hz,1H),3.67(s,2H),3.48(s,2H),2.35(d,J=27.7Hz,4H),2.29(s,3H); 13C NMR (125MHz, DMSO-d6) δ163.39,150.75,148.62,139.84,136.74,136.10,133.72,132.63,132.13,128.61,127.99,127.9 6,127.56,127.51,126.62,126.62,123.26,120.34,54.91,54.13,45.44,44.80,41.44; HR-ESI-MS: m / z=358.19046[M+H] + ,calcd for C 23 H 24 ON3:358.19139.

[0108] Example 19: Preparation of Compound 19

[0109]

[0110] The compound 4 is prepared by reacting (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylic acid with L-proline methyl ester hydrochloride. The synthesis method and operation are the same as those of compound 4. 1 H NMR(400MHz,DMSO-d6)δ8.68(d,J=5.2Hz,2H),8.08-7.80(m,6H),7.60(dd,J=7.2,2.4Hz,2H),7.49(d,J=10.0Hz, 1H),7.42-7.34(m,1H),7.29-7.04(m,1H),4.96-4.21(m,1H),3.75(m,2H),2.20-2.11(m,1H),2.00-1.76(m,3H); 13 C NMR(100MHz,DMSO-d6)δ172.53,162.65,150.45,148.46,139.69,136.21,135.96,133.58,132.51,132.03,128.30,127.7 1,127.71,127.23,127.14,126.30,126.30,124.49,120.16,58.42,46.34,28.37,23.92; HR-ESI-MS: m / z=373.15472[M+H] + ,calcd for C 23 H 21 O3N2:373.15467.

[0111] Example 20: Preparation of Compound 20

[0112]

[0113] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1228 mg, 4.8 mmol), 1-methylindazole-5-boric acid (845 mg, 4.8 mmol), Na2CO3 (2035 mg, 19.2 mmol), (PPh3)2PdCl2 (168 mg, 0.24 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 times. Then, the mixture was heated in an oil bath under nitrogen protection and refluxed for 12 h. After the reaction was completed, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with distilled water. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (870 mg, yield 59%). 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.63 (d, J = 5.2Hz, 1H), 8.15 (s, 1H), 7.89 (d,J=5.2Hz,1H),7.79(d,J=8.7Hz,1H),7.78(d,J=0.8Hz,1H),7.49(d,J=16.0 Hz,1H),7.39(dd,J=8.6,1.6Hz,1H),6.86(d,J=16.0Hz,1H),4.17-4.12(q,7. 2Hz, 2H), 4.12 (s, 3H), 1.20 (t, J=7.1Hz, 3H). HR-ESI-MS: m / z=308.13956[M+H] + ,calcd forC 18 H 18 O2N3:308.13935.

[0114] Example 21: Preparation of Compound 21

[0115]

[0116] (E)-3-(3-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)acrylate (615 mg, 2.0 mmol) was dissolved in 20 ml of anhydrous ethanol, and 3 ml of 1 M NaOH aqueous solution was added dropwise, and stirred at room temperature for 4 h. After the reaction was completed, the solvent was evaporated, distilled water was added to dissolve, and ethyl acetate was washed. The aqueous layer was adjusted to pH 5 with 1 M HCl aqueous solution to precipitate a light yellow solid (470 mg, yield 84%). 1H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.61(d,J=5.2Hz,1H),8.14(d,J=0.9Hz,1H),7.84(d,J=5.2Hz,1H),7 .80-7.77(m,1H),7.77-7.76(m,1H),7.41-7.38(m,1H),7.37-7.35(m,1H),6.77-6.72(m,1H),4.11(s,3H); 13 C NMR(125MHz,DMSO-d6)δ167.01,150.99,148.37,139.22,138.96,138.62,136.59,132.70,128 .11,127.90,125.14,123.51,121.87,120.16,109.83,35.41; HR-ESI-MS: m / z=280.10889[M+H] + ,calcd for C 16 H 14 O2N3:280.10805.

[0117] Example 22: Preparation of Compound 22

[0118]

[0119] (E)-3-(3-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)acrylic acid (140 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain a light yellow solid (100 mg, yield 68%). 1H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.61(d,J=0.8Hz,1H),8.18,(d,J=4.4Hz,1H),8.13(d,J=0.9Hz,1H),7.78(dt,J=8.6,0.9Hz,1H),7.75(dd,J=1. 6,0.8Hz,1H),7.64(d,J=5.3Hz,1H),7.36(dd,J=8.6,1.6Hz,1H),7.28(d, J=15.7Hz,1H),6.78(d,J=15.7Hz,1H),4.11(s,3H),2.66(d,J=4.4Hz,3H); 13 C NMR(125MHz,DMSO-d6)δ164.45,150.98,148.40,139.89,138.94,136.47,134.28,132.69,128.24 ,127.90,126.74,123.50,121.77,119.73,109.80,35.41,25.56; HR-ESI-MS: m / z=293.13940[M+H] + ,calcd forC 17 H 17 ON4:293.13969.

[0120] Example 23: Preparation of Compound 23

[0121]

[0122] (E)-3-(3-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)acrylic acid (140 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (110 mg, yield 63%). 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.62(s,1H),8.14(d,J=0.9Hz,1H),7.98(d,J=5.3Hz,1H),7.78(dt,J=8.7,0.9Hz,1H),7.76(dd,J=1 .6,0.8Hz,1H),7.47(d,J=15.4Hz,1H),7.40-7.35(m,2H),4.11(s,3H),3.74-3.67(m,2H),3.59(dd,J=8.1,4.0Hz,4H),3.52-3.46(m,2H); 13 C NMR(100MHz,DMSO-d6)δ163.57,150.75,147.98,140.08,138.95,137.08,136.63,132.68,128.22,127.93,1 23.50,122.80,121.82,120.35,109.80,66.22,65.95,45.48,41.96,35.41; HR-ESI-MS: m / z=349.16483[M+H] + ,calcd forC 20 H 21 O2N4:349.16590.

[0123] Example 24: Preparation of Compound 24

[0124]

[0125] (E)-3-(3-(1-methyl-1H-indazol-6-yl)pyridin-4-yl)acrylic acid (140 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (105 mg, yield 70%). 1H NMR (400MHz, DMSO-d6) δ8.66-8.64(m,2H),8.65(d,J=0.7Hz,1H),8.14(d,J=0.9Hz,1H),7.86(dd,J=8.3,0.8Hz,1H),7.71(q,J=0.9Hz, 1H),7.68-7.65(m,1H),7.29(d,J=15.8Hz,1H),7.06(dd,J=8.3,1.4Hz,1H),6.78(d,J=15.8Hz,1H),4.08(s,3H),2.65(d,J=4.7Hz,3H); 13 C NMR(125MHz,DMSO-d6)δ164.40,150.84,148.80,139.93,139.51,136.47,134.06,134.01,132.33 ,126.93,122.77,122.53,120.68,119.62,110.54,35.34,25.56; HR-ESI-MS: m / z=293.13937[M+H] + ,calcd for C 17 H 17 ON4:293.13969.

[0126] Example 25: Preparation of Compound 25

[0127]

[0128] (E)-3-(3-(1-methyl-1H-indazol-6-yl)pyridin-4-yl)acrylic acid (140 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (160 mg, yield 92%). 1H NMR (400MHz, DMSO-d6) δ8.67-8.65(m,2H),8.14(d,J=0.9Hz,1H),7.99(d,J=5.3Hz,1H),7.87(dd,J=8.3,0.8Hz,1H),7.71(d,J=1.1Hz,1H),7.4 7(d,J=15.4Hz,1H),7.37(d,J=15.4Hz,1H),7.07(dd,J=8.3,1.4Hz,1H) ,4.08(s,3H),3.72-3.66(m,2H),3.61-3.54(m,4H),3.52-3.46(m,2H); 13 C NMR(125MHz,DMSO-d6)δ163.57,150.81,148.60,139.87,139.49,136.94,136.54,134.05,132.33,122.90,1 22.76,122.56,120.69,120.18,110.61,66.22,65.93,45.47,41.95,35.34; HR-ESI-MS: m / z=349.16684[M+H] + ,calcd forC 20 H 21 O2N4:349.16590.

[0129] Example 26: Preparation of Compound 26

[0130]

[0131] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1228 mg, 4.8 mmol), indole-5-boric acid (773 mg, 4.8 mmol), Na2CO3 (2035 mg, 19.2 mmol), (PPh3)2PdCl2 (168 mg, 0.24 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 times. Then, the mixture was heated in an oil bath under nitrogen protection and refluxed for 12 h. After the reaction was completed, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with distilled water. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (700 mg, yield 50%). 1H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.64(s,1H),8.59(d,J=5.2Hz,1H),7.86(d, J=5.2Hz,1H),7.56(d,J=16.0Hz,1H),7.54(s,1H),7.53(d,J=4.4Hz,1H),7.46(t, J=2.8Hz,1H),7.06(dd,J=8.4,1.6Hz,1H),6.84(d,J=16.0Hz,1H),6.53-6.51(m,1 H), 4.14 (q, J=7.2Hz, 2H), 1.20 (t, J=7.2Hz, 3H). HR-ESI-MS: m / z=293.12799[M+H] + ,calcd for C 18 H 17 O2N2:293.12845.

[0132] Example 27: Preparation of Compound 27

[0133]

[0134] (E)-3-(3-(1H-indol-5-yl)pyridin-4-yl)acrylate (585 mg, 2.0 mmol) was dissolved in 20 ml of anhydrous ethanol, and 6 ml of 1 M NaOH aqueous solution was added dropwise, and stirred at room temperature for 10 h. After the reaction was completed, the solvent was evaporated, distilled water was added to dissolve, and ethyl acetate was washed. The aqueous layer was adjusted to pH 5 with 1 M HCl aqueous solution to precipitate a light yellow solid (225 mg, yield 85%). 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.45(s,1H),8.44(d,J=5.2Hz,1H)7.81(d,J=5.6Hz,1H),7.50(d,J=5.6Hz, 1H),7.48(s,1H),7.42(t,J=2.4Hz,1H),7.05(d,J=9.2Hz,1H),7.02(s,1H),6.73(d,J=16.0Hz,1H),6.52(s,1H); 13 C NMR (125MHz, DMSO-d6) δ169.69,151.51,148.21,142.53,137.88,136.29,135.98,131.38,128. 34,128.13,126.87,123.59,121.80,120.24,111.98,101.98; HR-ESI-MS: m / z=265.09689[M+H] +,calcd forC 16 H 13 O2N2:265.09715.

[0135] Example 28: Preparation of Compound 28

[0136]

[0137] (E)-3-(3-(1H-indol-5-yl)pyridin-4-yl)acrylic acid (140 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (80 mg, yield 58%). 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.59(s,1H),8.57(d,J=5.2Hz,1H),8.17(q,J=4.8Hz,1H),7.61(d,J=5.2Hz,1H),7.53-7.51(m,2H),7 .45(t,J=2.8Hz,1H),7.36(d,J=15.6Hz,1H),7.04(dd,J=8.4,1.6Hz,1H),6.77(d,J=15.6Hz,1H),6.51-6.50(m,1H),2.66(d,J=4.8Hz,3H); 13 C NMR(125MHz,DMSO-d6)δ164.58,151.02,147.74,139.67,137.70,135.34,134.77,127.65,126.61, 126.35,126.18,122.83,121.23,119.56,111.40,101.32,25.56; HR-ESI-MS: m / z=278.12817[M+H] + ,calcd for C 17 H 16 ON3:278.12879.

[0138] Example 29: Preparation of Compound 29

[0139]

[0140] (E)-3-(3-(1H-indol-5-yl)pyridin-4-yl)acrylic acid (132 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (100 mg, yield 60%). 1 HNMR (400MHz, DMSO-d6) δ11.32(s,1H),8.67(s,1H),8.64(d,J=5.2Hz,1H),8.05(d,J=5.2Hz,1H),7.54(s,1H),7.53-7.52(m,1 H),7.48-7.45(m,3H),7.06(dd,J=8.4,1.6Hz,1H),6.52-6.51(m,1H),3.71-3.70(m,2H),3.62-3.55(m,4H),3.50-3.49(m,2H); 13 C NMR (125MHz, DMSO-d6) δ163.54,149.52,146.01,141.28,138.29,137.17,135.43,127.65,126.50,126.12,12 3.10,122.81,121.37,120.83,111.48,101.35,66.22,65.93,45.48,41.96; HR-ESI-MS: m / z=334.15463[M+H] + ,calcd for C 20 H 20 O2N3:334.15500.

[0141] Example 30: Preparation of Compound 30

[0142]

[0143] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1228 mg, 4.8 mmol), indole-6-boronic acid pinacol ester (1215 mg, 5.0 mmol), Na2CO3 (2035 mg, 19.2 mmol), (PPh3)2PdCl2 (168 mg, 0.24 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 times. Then, the mixture was heated under reflux in an oil bath under nitrogen protection for 12 h. After the reaction was completed, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with distilled water. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (1000 mg, yield 71%). 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.66(s,1H),8.60(d,J=5.2Hz,1H),7.87(d, J=5.2Hz,1H),7.68(d,J=8.0Hz,1H),7.57(d,J=16.0Hz,1H),7.46(t,J=2.4Hz,1H), 7.38(s,1H),6.98(dd,J=8.0,1.6Hz,1H),6.85(d,J=16.0Hz,1H),6.53(t,J=2.4Hz, 1H), 4.14 (q, J=7.2Hz, 2H), 1.20 (t, J=7.2Hz, 3H); HR-ESI-MS: m / z=293.12872[M+H] + ,calcd for C 18 H 17 O2N2:293.12845.

[0144] Example 31: Preparation of Compound 31

[0145]

[0146] (E)-3-(3-(1H-indol-6-yl)pyridin-4-yl)acrylate (585 mg, 2.0 mmol) was dissolved in 20 ml of anhydrous ethanol, and 4 ml of 1 M NaOH aqueous solution was added dropwise, and stirred at room temperature for 6 h. After the reaction was completed, the solvent was evaporated, distilled water was added to dissolve, and ethyl acetate was washed. The aqueous layer was adjusted to pH 5 with 1 M HCl aqueous solution to precipitate a light yellow solid (423 mg, yield 80%). 1H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.47(s,1H),8.46(d,J=5.2Hz,1H),7.64(d,J=1.6Hz,1H),7.62(d,J=5.2Hz,1H),7.41(t,J=2.4 Hz,1H),7.33(s,1H),7.07,(dd,J=15.6,1.2Hz,1H),6.95(dd,J=8.0,1.6Hz,1H),6.56(dd,J=15.6,1.2Hz,1H),6.49(t,J=2.4Hz,1H); 13 C NMR(125MHz,DMSO-d6)δ169.07,150.65,147.58,141.71,136.89,135.69,135.47,130.71,129.35, 126.98,126.18,120.73,119.80,119.55,112.54,100.83; HR-ESI-MS: m / z=265.09796[M+H]+,calcd for C 16 H 13 O2N2:265.09715.

[0147] Example 32: Preparation of Compound 32

[0148]

[0149] (E)-3-(3-(1H-indol-6-yl)pyridin-4-yl)acrylic acid (140 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (78 mg, yield 57%). 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.61(s,1H),8.58(d,J=5.2Hz,1H),8.18(q,J=4.4Hz,1H),7.66(d,J=8.4Hz,1H),7.62(d,J=5.2Hz,1H),7.4 5(m,1H),7.38(d,J=15.6Hz,1H),7.36-7.35(m,1H),6.97(dd,J=8.4,1.6 Hz,1H),6.78(d,J=15.6Hz,1H),6.52-6.51(m,1H),2.67(d,J=4.4Hz,3H); 13 C NMR(125MHz,DMSO-d6)δ164.56,150.97,147.94,139.64,137.42,135.67,134.81,128.60,127.24, 126.50,126.27,120.77,120.03,119.67,112.66,100.93,25.57; HR-ESI-MS: m / z=278.12878[M+H] + ,calcd for C 17 H 16 ON3:278.12879.

[0150] Example 33: Preparation of Compound 33

[0151]

[0152] (E)-3-(3-(1H-indol-6-yl)pyridin-4-yl)acrylic acid (132 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (50 mg, yield 30%). 1HNMR (400MHz, CDCl3) δ8.69(s,1H),8.60(s,1H),8.54(s,1H),7.70(d,J=8.0Hz,1H),7.64(d,J=15.6Hz,1H),7.52(d,J=5.2Hz,1H),7.33(s, 1H),7.29-7.27(m,1H),7.05(d,J=8.0Hz,1H),6.83(d,J=15.6Hz,1H), 6.59(s,1H),3.71-3.62(m,4H),3.64-3.59(m,2H),3.50-3.44(m,2H); 13 C NMR (125MHz, CDCl3) δ164.75,151.19,147.62,141.21,139.18,138.24,135.82,129.72,127.76,125.55,122 .41,121.75,120.94,120.79,112.47,102.50,66.74,66.66,46.26,42.39; HR-ESI-MS: m / z=334.15472[M+H] + ,calcd for C 20 H 20 O2N3:334.15500.

[0153] Example 34: Preparation of Compound 34

[0154]

[0155] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1228 mg, 4.8 mmol), 1-methylindole-5-boric acid (962 mg, 5.5 mmol), Na2CO3 (2035 mg, 19.2 mmol), (PPh3)2PdCl2 (168 mg, 0.24 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 times. Then, the mixture was heated in an oil bath under nitrogen protection and refluxed for 12 h. After the reaction was completed, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with distilled water. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (1000 mg, yield 71%). 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.59(d,J=5.2Hz,1H),7.86(d,J=5.2Hz,1H),7.59 (d,J=8.4Hz,1H),7.55(d,J=1.6Hz,1H),7.54(d,J=16.0Hz,1H),7.44(d,J=3.2,0.8Hz,1 H),7.12(dd,J=8.4,1.6Hz,1H),6.84(d,J=16.0Hz,1H),6.51(dd,J=3.2,0.8Hz,1H),4.1 4(q,J=7.2Hz,2H),3.86(s,3H),1.20(t,J=7.2Hz,3H); HR-ESI-MS: m / z=307.14426[M+H] + ,calcd for C 19 H 19 O2N2:307.14410.

[0156] Example 35: Preparation of Compound 35

[0157]

[0158] (E)-3-(3-(1-methyl-1H-indol-5-yl)pyridin-4-yl)acrylate (613 mg, 2.0 mmol) was dissolved in 20 ml of anhydrous ethanol, and 4 ml of 1 M NaOH aqueous solution was added dropwise, and stirred at room temperature for 6 h. After the reaction was completed, the solvent was evaporated, distilled water was added to dissolve, and ethyl acetate was washed. The aqueous layer was adjusted to pH 5 with 1 M HCl aqueous solution to precipitate a light yellow solid (334 mg, yield 60%). 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.57(d,J=5.2Hz,1H),7.81(d,J=5.2Hz,1H),7.58(d,J=8.4Hz,1H),7.53(d,J=1.2Hz,1H),7.4 4(d,J=16.0Hz,1H),7.43(d,J=3.2Hz,1H),7.11(d,J=8.4,Hz,1H),6.72(d,J=16.0Hz,1H),6.51(dd,J=3.2,1.2Hz,1H),3.86(s,3H); 13C NMR(125MHz,DMSO-d6)δ167.08,151.06,147.85,138.98,137.65,135.87,130.68,128.04,126.63, 122.90,122.90,121.53,121.53,120.03,109.81,100.60,32.51; HR-ESI-MS: m / z=279.11383[M+H] + ,calcd for C 17 H 15 O2N2:279.11280.

[0159] Example 36: Preparation of Compound 36

[0160]

[0161] (E)-3-(3-(1-methyl-1H-indol-5-yl)pyridin-4-yl)acrylic acid (139 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (130 mg, yield 90%). 1 H NMR (400MHz, DMSO-d6) δ8.65 (s, 1H), 8.62 (d, J = 5.2Hz, 1H), 8.20 (q, J = 4.4Hz, 1H),7.70(d,J=5.2Hz,1H),7.58(d,J=8.4Hz,1H),7.54(d,J=2.0Hz,1H),7.44( d,J=3.2Hz,1H),7.35(d,J=15.6Hz,1H),7.11(dd,J=8.4,2.0Hz,1H),6.81(d,J =15.6Hz,1H),6.51(dd,J=2.8,0.8Hz,1H),3.86(s,3H),2.67(d,J=4.4Hz,3H); 13C NMR (125MHz, DMSO-d6) δ164.44,149.85,146.66,141.01,137.93,135.92,134.40,130.71,128.01,126 .98,126.32,122.86,121.54,120.12,109.84,100.63,32.51,25.58; HR-ESI-MS: m / z=292.14410[M+H] + ,calcd for C 18 H 18 ON3:292.14444.

[0162] Example 37: Preparation of Compound 37

[0163]

[0164] (E)-3-(3-(1-methyl-1H-indol-5-yl)pyridin-4-yl)acrylic acid (139 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (110 mg, yield 63%). 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 8.62 (d, J = 4.8Hz, 1H), 7.60 (d, J = 15.6Hz, 1H), 7.56-7.54 (m, 2H), 7.40 (d, J = 8.4Hz, 1H), 7.14-7.1 2(m,2H),6.85(d,J=15.6Hz,1H),6.52(dd,J=3.2,0.8Hz,1H),3.84(s,3H),3.69-3.64(m,4H),3.64-3.60(m,2H),3.52-3.48(m,2H); 13 C NMR (125MHz, CDCl3) δ164.68,151.09,147.31,141.81,139.05,138.78,136.41,129.97,128.64,126.96,123.4 6,122.48,122.14,120.86,109.52,101.38,66.7,66.69,46.28,42.38,33.00; HR-ESI-MS: m / z=348.16931[M+H]+ ,calcd for C 21 H 22 O2N3:348.17065.

[0165] Example 38: Preparation of Compound 38

[0166]

[0167] (E)-3-(3-(quinolin-6-yl)pyridin-4-yl)acrylic acid (138 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (80 mg, yield 55%). 1 HNMR(400MHz,DMSO-d6)δ8.99(dd,J=4.4,1.6Hz,1H),8.69(s,1H),8.68(d,J=5.2Hz ,1H),8.45(dd,J=8.4,1.2Hz,1H),8.20(q,J=4.8Hz,1H),8.14(d,J=8.8Hz,1H),8.03 (d,J=1.6Hz,1H),7.74(dd,J=8.8,2.0Hz,1H),7.69(d,J=5.2Hz,1H),7.62(dd,J=8. 4,4.4Hz,1H),7.30(d,J=16.0Hz,1H),6.81(d,J=16.0Hz,1H),2.65(d,J=4.8Hz,3H); 13 C NMR (125MHz, DMSO-d6) δ164.34,151.17,150.80,149.10,146.93,139.96,136.22,135.43,134.28,133 .83,131.10,129.01,128.92,127.64,127.31,122.04,119.86,25.57; HR-ESI-MS: m / z=290.12762[M+H] + ,calcd for C 18 H 16 ON3:290.12879.

[0168] Example 39: Preparation of Compound 39

[0169]

[0170] (E)-3-(3-(quinolin-6-yl)pyridin-4-yl)acrylic acid (138 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (80 mg, yield 46%). 1 HNMR(400MHz,DMSO-d6)δ8.99(dd,J=4.4,2.0Hz,1H),8.70(s,1H),8.69(d,J=5.2Hz, 1H),8.44(dd,J=8.8,2.0Hz,1H),8.15(d,J=8.4Hz,1H),8.03(s,1H),8.03(d,J=8.4H z,1H),7.75(dd,J=8.8,2.0Hz,1H),7.63(dd,J=8.4,4.4Hz,1H),7.50(d,J=15.6Hz,1 H),7.39(d,J=15.6Hz,1H),3.72-3.69(m,2H),3.61-3.55(m,4H),3.51-3.47(m,2H); 13 C NMR (125MHz, DMSO-d6) δ163.48,151.19,150.77,148.89,146.90,139.87,136.69,136.20,135.52,134.31,131.1 4,129.00,128.96,127.61,123.21,122.06,120.35,66.21,65.92,45.47,41.96; HR-ESI-MS: m / z=346.15396[M+H] + ,calcd for C 21 H 20 O2N3:346.15500.

[0171] Example 40: Preparation of Compound 40

[0172]

[0173] (E)-3-(3-(quinolin-7-yl)pyridin-4-yl)acrylic acid (138 mg, 0.5 mmol), methylamine hydrochloride (40.5 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (90 mg, yield 62%). 1 HNMR (400MHz, DMSO-d6) δ8.99(dd,J=4.0,1.6Hz,1H),8.71(s,1H),8.69(d,J=5.2Hz,1H),8.50-8.46(m,1H),8.21(q,J=5.2Hz,1H),8.14(d,J= 8.4Hz,1H),8.01-7.99(m,1H),7.70(d,J=5.2Hz,1H),7.64-7.61(m,2H),7.32(d,J=15.6Hz,1H),6.81(d,J=15.6Hz,1H),2.66(d,J=4.4Hz,3H); 13 C NMR (125MHz, DMSO-d6) δ164.35,151.27,150.73,149.15,147.24,139.98,137.27,135.86,135.35,133 .95,129.57,128.39,128.12,127.33,127.20,122.00,119.98,25.57; HR-ESI-MS: m / z=290.12878[M+H] + ,calcd for C 18 H 16 ON3:290.12879.

[0174] Example 41: Preparation of Compound 41

[0175]

[0176] (E)-3-(3-(quinolin-7-yl)pyridin-4-yl)acrylic acid (138 mg, 0.5 mmol), morpholine (52 mg, 0.6 mmol), HATU (228 mg, 0.6 mmol), DIEA (129 mg, 1.0 mmol) were dissolved in 10 mL of dichloromethane and stirred at room temperature for about 6 h. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate solution, 0.5 N hydrochloric acid solution, and saturated brine, respectively, and the organic layer was concentrated to obtain a crude product, which was subjected to silica gel column chromatography to obtain a light yellow solid (112 mg, yield 65%). 1 HNMR(400MHz,DMSO-d6)δ8.99(dd,J=4.4,1.6Hz,1H),8.71(d,J=0.8Hz,1H),8.69(dd, J=5.2,0.8Hz,1H),8.50-8.46(m,1H),8.14(d,J=8.4Hz,1H),8.02(d,J=5.2Hz,1H),8. 00-7.99(m,1H),7.63(dd,J=8.4,3.2Hz,1H),7.62(d,J=8.4Hz,1H),7.50(d,J=15.6Hz ,1H),7.42(d,J=15.6Hz,1H),3.75-3.67(m,2H),3.63-3.53(m,4H),3.52-3.45(m,2H); 13 C NMR (125MHz, DMSO-d6) δ163.47,151.30,150.70,148.94,147.20,139.87,137.31,136.76,135.87,135.44,129.6 2,128.40,128.17,127.17,123.24,122.01,120.45,66.21,65.91,45.47,41.96; HR-ESI-MS: m / z=346.15503[M+H] + ,calcd for C 21 H 20 O2N3:346.15500.

[0177] Example 42: Preparation of Compound 42

[0178]

[0179] (1) Ethyl (E)-3-(3-(1H-indazol-5-yl)pyridin-4-yl)acrylate

[0180] (E)-3-(3-bromopyridin-4-yl) ethyl acrylate (1228 mg, 4.8 mmol), 1H-indole-5-boronic acid pinacol ester (1342 mg, 5.5 mmol), Na2CO3 (2035 mg, 19.2 mmol), (PPh3)2PdCl2 (168 mg, 0.24 mmol), dissolved in a mixed solution of toluene, ethanol and water (volume ratio = 1:1:0.2), nitrogen was introduced into the mixed system for 5 times. Then, the mixture was heated under reflux in an oil bath under nitrogen protection for 12 h. After the reaction was completed, the solvent was evaporated, ethyl acetate was added, and the mixture was washed with distilled water. The organic layers were combined and concentrated to obtain a solid crude product. The crude product was eluted by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (1014 mg, yield 72%).

[0181] (2) (E)-3-(3-(1H-indazol-5-yl)pyridin-4-yl)acrylic acid

[0182] (E)-3-(3-(1H-indazol-5-yl)pyridin-4-yl)acrylate (586 mg, 2.0 mmol) was dissolved in 20 ml of anhydrous ethanol, and 4 ml of 1 M NaOH aqueous solution was added dropwise, and stirred at room temperature for 6 h. After the reaction was completed, the solvent was evaporated, distilled water was added to dissolve, and ethyl acetate was washed. The aqueous layer was adjusted to pH 5 with 1 M HCl aqueous solution to precipitate a light yellow solid (329 mg, yield 62%).

[0183] (3) (E)-3-(3-(1H-indazol-5-yl)pyridin-4-yl)acryloyl-3-methoxycyclobutylamine

[0184] The compound 4 was prepared by the reaction of (E)-3-(3-(1H-indazol-5-yl)pyridin-4-yl)acrylic acid and 3-methoxycyclobutylamine hydrochloride. The method and operation were the same as those for compound 4. 1 H NMR (400MHz, CDCl3) δ10.92 (s, 1H), 8.66 (s, 1H), 8.62 (d, J = 5.2Hz, 1H), 8.07 (d ,J=1.2Hz,1H),7.68(d,J=16.0Hz,1H),7.67-7.68(m,1H),7.51(d,J=5.6Hz,1H ),7.46-7.49(m,1H),7.28(d,J=1.6Hz,1H),6.57(d,J=15.6Hz,1H),4.36-4.42 (m,1H),4.20-4.31(m,2H),4.06-4.16(m,1H),3.95-4.00(m,1H),3.32(s,3H); 13C NMR(100MHz,DMSO-d6)δ164.25,151.05,148.29,139.71,139.37,136.81,135.75,133.80,128.21,127.9 5,122.98,122.10,121.71,120.37,110.37,68.40,56.81,55.38,54.65; HR-ESI-MS: m / z=335.1503[M+H] + ,calcd for C 19 H 19 O2N4:335.1503.

[0185] Example 43: Preparation of Compound 43

[0186]

[0187] (1) Synthesis of ethyl 3-(3-(naphthalene-2-yl)pyridin-4-yl)propionate

[0188] (E)-3-(3-(naphthalene-2-yl)pyridin-4-yl)acrylate (464 mg, 1.53 mmol) was dissolved in 5 mL of ethanol, Pd / C (44 mg, 10%) was added, and a normal pressure hydrogen balloon was added to replace the gas in the bottle three times, and then stirred at room temperature for about 3 hours. After the reaction was completed, palladium carbon was filtered out by diatomaceous earth, the filter cake was washed with methanol several times, the filtrate was concentrated under reduced pressure, and a white solid (443 mg, yield 95%) was obtained by normal phase column chromatography.

[0189] (2) Synthesis of 3-(3-(naphthalene-2-yl)pyridin-4-yl)propionic acid

[0190] Ethyl 3-(3-(naphthalene-2-yl)pyridin-4-yl)propanoate (610 mg, 2.0 mmol) was dissolved in 20 ml of anhydrous ethanol, and 4 ml of 1 M NaOH aqueous solution was added dropwise, and stirred at room temperature for 6 h. After the reaction was completed, the solvent was evaporated, distilled water was added to dissolve, and ethyl acetate was washed. The aqueous layer was adjusted to pH 5 with 1 M HCl aqueous solution to precipitate a light yellow solid (338 mg, yield 61%). 1 H NMR(400MHz,DMSO-d6)δ12.21(br s,1H),8.52(d,J=5.2Hz,1H),8.46(s,1H),8.03(d,J=8.4Hz,1H),8.01-7.98(m,2H),7.94(s,1H),7.58(q ,J=3.2Hz,2H),7.55(d,J=8.4Hz,1H),7.43(d,J=4.8Hz,1H),2.87(t,J=8.0Hz,2H),2.47(t,J=8.0Hz,2H);13 C NMR (125MHz, DMSO-d6) δ173.37,149.82,148.61,147.11,137.04,134.91,132.86,132.16,128.05,128 .05,127.94,127.63,127.33,126.55,126.46,123.54,33.27,27.09; HR-ESI-MS: m / z=278.11853[M+H] + ,calcd for C 18 H 16 O2N:278.11756.

[0191] Example 44: Preparation of Compound 44

[0192]

[0193] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylate was obtained by reduction reaction. The synthesis method and operation were the same as those of compound 43. 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=5.2Hz,1H),8.46(s,1H),8.03(d,J=8.4Hz,1H),8.01-7.98(m,2H),7.93(s,1H),7.58(d,J=8.8Hz,1H ),7.58(d,J=2.8Hz,1H),7.55(dd,J=8.4,1.6Hz,1H),7.43(d,J=5.2Hz,1H),3.49(s,3H),2.90(t,J=8.0Hz,2H),2.58(t,J=8.0Hz,2H); 13 C NMR(125MHz,DMSO-d6)δ172.14,149.74,148.52,146.60,136.91,134.70,132.73,132.03,127.95,127.92 ,127.83,127.50,127.20,126.44,126.36,123.39,51.27,32.76,26.75; HR-ESI-MS: m / z=292.13425[M+H] + ,calcd for C 19 H 18 O2N:292.13321.

[0194] Example 45: Preparation of Compound 45

[0195]

[0196] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylamide is obtained by reduction reaction. The synthesis method and operation are the same as those of compound 43. 1 H NMR(500MHz,DMSO-d6)δ8.52(d,J=4.0Hz,1H),8.45(s,1H),8.02(d,J=6.8Hz,1H),8.01 -7.97(m,2H),7.93(d,J=0.8Hz,1H),7.74(d,J=4.0Hz,1H),7.58(d,J=6.8Hz,1H),7.58( dd,J=2.4,0.8Hz,1H),7.54(dd,J=6.8,1.6Hz,1H),7.38(d,J=4.0Hz,1H),2.85(t,J=6. 4Hz, 2H), 2.49 (d, J=4.0Hz, 3H), 2.31 (t, J=6.4Hz, 2H); HR-ESI-MS: m / z=291.15018[M+H] + ,calcd for C 19 H 19 ON2:291.14919.

[0197] Example 46: Preparation of Compound 46

[0198]

[0199] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acryloylmorpholine is obtained by reduction reaction. The synthesis method and operation are the same as those of compound 43. 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=5.2Hz,1H),8.45(s,1H),8.03(d,J=8.4Hz,1H),8.00( d,J=10.8Hz,1H),8.00(d,J=3.2Hz,1H),7.94(d,J=0.8Hz,1H),7.54(d,J=10.8Hz,1H),7. 54(d,J=3.2,0.8Hz,1H),7.55(dd,J=8.4,1.6Hz,1H),7.46(d,J=5.2Hz,1H),3.43(t,J=4. 8Hz,2H),3.34-3.30(m,4H),3.19(t,J=4.8Hz,2H),2.88-2.81(m,2H),2.57-2.51(m,2H); 13C NMR(125MHz,DMSO-d6)δ169.54,149.74,148.58,147.68,137.07,134.98,132.85,132.14,128.10,128.03,127.95,1 27.63,127.46,126.59,126.49,123.86,65.99,65.90,45.15,41.39,32.21,27.39; HR-ESI-MS: m / z=347.17636[M+H] + ,calcd for C 22 H 23 O2N2:347.17540.

[0200] Example 47: Preparation of Compound 47

[0201]

[0202] (E)-3-(3-(naphthalen-2-yl)pyridin-4-yl)acrylate (30 mg, 0.1 mmol) and hydrazine hydrate (25 mg, 5 mmol) were dissolved in 5 mL of ethanol, and the reaction system was heated to reflux for about 4 hours. After the reaction was completed, the solvent was evaporated and washed with a small amount of ethyl acetate to obtain a white flocculent solid (15 mg, yield 51%). 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),8.50(d,J=5.2Hz,1H),8.44(s,1H),8.01(d,J=8.8Hz,1H),7.96-7.99(m,2H),7.91(d,J=1.2 Hz,1H),7.55-7.59(m,2H),7.53(dd,J=8.4,1.6Hz,1H),7.37(d,J=4.8Hz,1H),4.09(s,2H),2.82-2.86(m,2H),2.25-2.29(m,2H); 13 C NMR(100MHz,DMSO-d6)δ170.20,149.80,148.52,147.38,136.96,134.84,132.82,132.13,128.05,12 8.02,127.87,127.57,127.36,126.49,126.40,123.46,33.10,27.57; HR-ESI-MS: m / z=292.1444[M+H] + ,calcdfor C 18 H 18 ON3:292.1444.

[0203] Pharmacological experiments:

[0204] Example 1: In vitro kinase inhibitory activity test

[0205] The compound was diluted 100 times with DMSO solution, mixed with buffer solution (50mM HEPES pH 7.5, 0.01% BRIJ-35, 10mM MgCl2, 1mM EGTA), a mixture of kinase and antibody, and Tracer, shaken for 30s, and then incubated at room temperature for 60min. The Emission Ratio (ER, AF647 Emission (665nm) to Europium Emission (615nm)) was then read on a microplate reader and analyzed. IC 50 In the test, the compound was diluted in a 3-fold gradient, and a total of 10 concentrations were tested. A blank control was set in the test, and sorafenib was used as a reference for the positive control. The results are given as the percentage of "the difference between the ER of the blank control and the ER of the test sample" and "the difference between the ER of the blank control and the ER of the positive control". The larger the percentage, the better the compound binds to the kinase. Table 1 shows the in vitro inhibitory activity results of the CDK8 kinase of the compounds of the present invention.

[0206] Table 1

[0207]

[0208]

[0209] ND: Not Determined, not tested.

[0210] Example 2: In vitro kinase selectivity activity test

[0211] The present invention selected 13 representative effective inhibitors to test the selectivity of 12 kinases. Among them, 4 are CDK subtypes, including CDK2, CDK6, CDK7 and CDK9; the other 8 are Aurora A, BRAF, EGFR, FGFR1, FLT3, JAK1, PDGFRA and GSK3A. The kinase selectivity of the 13 compounds selected by the present invention was determined at a concentration of 10 μM. As shown in Table 2 and Figure 1 As shown, the 13 compounds described in the present invention all showed selective inhibition of CDK8.

[0212] Table 2 Inhibitory effects of 13 compounds of the present invention on 13 kinases

[0213]

[0214] CDK: Cyclin dependent kinase; BRAF: v-raf murine sarcomaviral oncogene homolog B1; Aurora A: Aurora kinase A; EGFR: epidermal growth factor receptor; PDGFRα: platelet-derived growth factor receptor α; JAK1: Janus kinase 1; FGFR1: fibroblast growth factor receptor-1; GSK3α: glycogen synthase kinase 3α; FLT3: Fms-like tyrosine kinase 3.

[0215] Example 3: In vitro anti-tumor cell activity test

[0216] The present invention uses the SRB method to test the cytotoxic activity of 31 compounds with good activity at the molecular level. The cell tumor lines selected are A549, MDA-MB-231, KB, KB-VIN and MCF-7, and the test results are shown in Table 2. First, the cell suspension treated with trypsin is added to a 96-well plate with a cell density of 4000-11000 cells / well. Then, the diluted compound solution is added and mixed with the cells. After incubation for three days, the adhered cells are fixed with 10% trichloroacetic acid after an ice bath and stained with 0.04% sulforhodamine B. The absorbance value at 515nm is measured using an enzyme reader (ELx800, BioTek). IC 50 The values ​​were obtained by averaging the results of three independent experiments.

[0217] Table 2

[0218]

Claims

1. A pyridine compound represented by the following general formula (IA) and a pharmaceutically acceptable salt thereof, in, R1 is selected from halogen, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted indolyl, quinolyl, substituted or unsubstituted indazolyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from halogen, C 1- C3 alkyl, C 1- C3 alkoxy; R2 is selected from C1-C3 alkylamino, morpholinyl, and N-methylpiperazinyl.

2. A compound having the following structure and a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

3. The method for preparing the compound according to claim 1, characterized in that: The following steps are involved: The compound of general formula (IA) is obtained from 3-bromoisonicotinaldehyde as the starting material: R1 and R2 are as defined in claim 1.

4. A pharmaceutical composition comprising an effective dose of any one of the compounds according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier thereof.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle delivery systems.

6. Use of the compound according to any one of claims 1 to 2 and a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating CDK8-related diseases.

7. The use according to claim 6, characterized in that: The CDK8-related disease is selected from tumors and immune-related diseases.

8. Use according to claim 7, characterized in that The tumors include colorectal cancer, breast cancer, gastric cancer, ovarian cancer, and melanoma.

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