Phthaloxizone compounds and pharmaceutical compositions and applications thereof

Abstract

The present invention discloses a phthalazinone compound and a pharmaceutical composition and application thereof. The compound has a structure as shown in formula (I), and further comprises isomers, prodrugs, stable isotope derivatives, pharmaceutically acceptable salts or mixtures thereof. The compound has a significant inhibitory effect on PRMT5 at the enzyme level, and the inhibitory activity is stronger in the presence of MTA, with an inhibition rate of more than 80% at the nanomolar concentration level. At the same time, the inhibitory activity on MTAP-deficient tumor cells is stronger than that of wild-type cells, and the compound has selectivity. The prepared drug can exert its efficacy at both the molecular level and the cellular level, and has a wide range of applications.

Description

Technical Field

[0001] The present invention relates to a phthalazinone compound and a pharmaceutical composition and application thereof, and in particular to a phthalazinone compound having PRMT5 inhibitory activity and a pharmaceutical composition and application thereof. Background Art

[0002] Epigenetic regulation involves the heritable modification of genetic material without changing its nucleotide sequence, and it controls the conformation of chromatin to switch between transcriptional and non-transcriptional activities by selectively and reversibly modifying DNA and proteins (e.g., histones). These covalent modifications can be controlled by enzymes, many of which are associated with specific genetic alterations that can cause human diseases. Arginine methylation is a regulatory type of histone modification and is one of the most common post-translational modifications in mammals.

[0003] Protein arginine methyltransferase (PRMTs) is a type of S-adenosylmethionine (SAM)-dependent methyltransferase that can transfer methyl groups from SAM to the guanidinium nitrogen of arginine residues on histone and non-histone substrates. Based on the product specificity of their transfer, the nine mammalian PRMTs can be divided into three categories, namely type I (PRMT1, 2, 3, 4, 6, 8), type II (PRMT5, 9) and type III (PRMT7), among which PRMT5 is the most promising type II PRMTs, which can catalyze the monomethylation and symmetric dimethylation of arginine residues.

[0004] PRMTs can methylate histones and non-histone substrates, play an important role in a variety of cellular functions, and can affect the gene expression of signal transduction, mRNA splicing and DNA repair through histone methylation. Studies have found that the expression of PRMT5 is upregulated in a variety of human malignant tumors including lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia and malignant glioma. In addition, PRMT5 has been confirmed as an anticancer target for mantle cell lymphoma and glioblastoma. The research on anti-tumor small molecule inhibitors targeting PRMT5 has attracted more and more attention.

[0005] Methylthioadenosine phosphorylase (MTAP) is lost in 40% of glioblastomas, 25% of melanomas, urothelial carcinomas and pancreatic cancers, and 15% of non-small cell lung cancers. MTAP-deficient cells have increased intracellular methylthioadenosine (MTA) concentrations, and MTA is an in vivo inhibitor of PRMT5. Compared with wild-type cells, PRMT5 small molecule inhibitors can significantly inhibit MTAP-deficient cancer cell lines.

[0006] The first generation of PRMT5 inhibitors are mainly divided into SAM non-competitive and SAM competitive inhibitors. Representative drugs include GSK-3326595, JNJ-64619178, PF-06939999, PRT543, and PRT811. They all have non-selective inhibitory activity against PRMT5 and are also associated with dose-limiting thrombocytopenia, anemia, and neutropenia in patients. They have large side effects and low therapeutic index, which limits the application of first-generation PRMT5 inhibitors. The second generation of PRMT5 inhibitors can specifically act on MTAP-deficient tumors, thereby improving tumor selectivity and reducing toxic side effects. At present, there are few studies on the second generation of PRMT5 inhibitors. Representative drugs include MRTX1719, TNG908, and AMG193, all of which are in the early stages of clinical research. Summary of the invention

[0007] Purpose of the invention: The first purpose of the present invention is to provide a phthalazinone compound, the second purpose is to provide a pharmaceutical composition comprising the phthalazinone compound, and the third purpose is to provide an application of the phthalazinone compound and the pharmaceutical composition thereof in the preparation of PRMT5 inhibitor drugs.

[0008] Technical solution: The phthalazinone compound of the present invention has a structure of formula (I), and also includes its isomers, prodrugs, stable isotope derivatives, pharmaceutically acceptable salts or mixtures thereof:

[0009]

[0010] in:

[0011] R 1a , R 1b are independently selected from hydrogen, halogen, C1-C6 alkyl, or R 1a , R 1b Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group or a C2-C6 heterocycloalkyl group; when R 1a , R 1b At the same time, the carbon atom connected thereto is in racemic configuration, R configuration or S configuration, and the C2-C6 heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O or S;

[0012] Ring A is selected from substituted C6~C 10Aryl, substituted C5-C9 heteroaryl, substituted C3-C8 cycloalkyl or substituted C2-C6 heterocycloalkyl; the substituent is selected from at least one of hydrogen, halogen, cyano, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl or nitro; the C5-C9 heteroaryl and C2-C6 heterocycloalkyl contain 1 to 3 heteroatoms selected from N, O or S;

[0013] R 2 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, carboxyl, C1-C3 alkoxycarbonyl, and R 2 The double bond configuration is Z configuration, E configuration or a mixture of the two.

[0014] Preferably, in the structure:

[0015] R 1a , R 1b are independently selected from hydrogen, methyl or ethyl, or R 1a , R 1b Together with the carbon atom to which it is attached, it forms cyclopropane;

[0016] Ring A is selected from substituted benzene ring, pyridazine ring, pyridine ring, pyrimidine ring, thiophene ring, furan ring, pyrrole ring, quinoline ring, quinazoline ring, naphthalene ring; the substituent is selected from at least one hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, hydroxyl, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl or nitro;

[0017] R 2 is a hydrogen atom, and R 2 The double bond configuration is Z configuration, E configuration or a mixture of the two.

[0018] Preferably, in the structure:

[0019] R 1a or R 1b Selected from hydrogen;

[0020] Ring A is selected from substituted benzene ring, pyridine ring, thiophene ring, benzo[d][1,3]dioxole or naphthalene ring; the substituent is selected from at least one hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, hydroxyl, amino or nitro;

[0021] R 2 is a hydrogen atom, and R 2 The double bond configuration is Z configuration.

[0022] Preferably, in the structure:

[0023] R1a or R 1b Selected from hydrogen;

[0024] Ring A is selected from

[0025] R 2 is a hydrogen atom, and R 2 The double bond configuration is Z configuration.

[0026] Preferably, the phthalazinone compound is selected from any of the following compounds:

[0027]

[0028]

[0029]

[0030]

[0031] Furthermore, the pharmaceutically acceptable salt is a salt formed by the phthalazinone compound and any one of the following acids:

[0032] Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

[0033] When the structure of the phthalazinone compound of the present invention is: 1a , R 1b is hydrogen, R 2 is hydrogen, and R 2 When the connected double bond configuration is Z configuration, the preparation method is as follows:

[0034]

[0035] Compound 2 is prepared by reacting compound 1 with compound 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde, wherein the solvent used is selected from methanol, ethanol, dichloromethane, tetrahydrofuran, toluene, 1,4-dioxane, ethyl acetate, acetone, N,N-dimethylformamide or a mixed solvent of any two thereof, preferably ethanol; and the base used is selected from potassium hydroxide, potassium carbonate, potassium acetate, sodium carbonate, piperidine, preferably potassium hydroxide and piperidine.

[0036] Compound 4 is prepared by reacting compound 2 with compound 3, the solvent used is selected from a mixed solvent consisting of any two of toluene, 1,4-dioxane, N,N-dimethylformamide, n-butanol, tert-amyl alcohol, and water, preferably a mixed solvent consisting of tert-amyl alcohol and water; the base used is selected from potassium hydroxide, potassium carbonate, potassium acetate, sodium carbonate, sodium bicarbonate, preferably sodium bicarbonate; the catalyst used is selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (SPhospdG2), preferably SPhospdG2.

[0037] Compound I is prepared by removing Boc protection from compound 4, and the acid used is selected from HCl / Dioxane, HCl / Ethyl acetate or TFA / DCM, preferably HCl / Dioxane.

[0038] Wherein, Ring A is defined as above;

[0039] The corresponding acid is reacted with the phthalazinone compound prepared by the above method to form a salt, thereby obtaining the pharmaceutically acceptable salt.

[0040] The pharmaceutical composition of the present invention comprises the phthalazinone compound and a pharmaceutically acceptable carrier, and is prepared into a common pharmaceutical preparation such as a tablet, capsule, syrup, suspension or injection by adding common pharmaceutical excipients such as flavoring, sweetener, liquid / solid filler, diluent, etc.

[0041] The phthalazinone compound or the pharmaceutical composition thereof described in the present invention is used in the preparation of PRMT5 inhibitor drugs, specifically anti-tumor drugs, more specifically drugs for treating lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia or malignant glioma.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0043] This class of compounds has a novel structure and can significantly inhibit PRMT5 at the enzyme level, and the inhibitory activity is stronger in the presence of MTA (the inhibition rate at a concentration of 100nM is more than 80%); at the same time, the inhibitory activity against MTAP-deficient HCT116 tumor cells (most of the IC 50 values ​​below 1 μM) were stronger than those of wild-type HCT116 tumor cells (most IC 50 value is higher than 1 μM), which is selective. DETAILED DESCRIPTION

[0044] Example 1: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-phenylacrylonitrile (I-1)

[0045] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-phenylacrylonitrile (2-1)

[0046] Benzene acetonitrile 1-1 (124 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carboxaldehyde (200 mg, 1.06 mmol), KOH (120 mg, 2.12 mmol) and 2 mL of EtOH were added to a 25 mL three-necked flask in sequence. The reaction system was reacted at 25 °C for 12 h. TLC monitoring (V 石油醚 :V 乙酸乙酯 =10:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to give 120 mg of a white solid, yield: 38.0%.

[0047] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 7.77-7.71 (m, 2H), 7.58 (s, 1H), 7.56–7.49 (m, 3H), 7.33 (s, 1H), 3.98 (s, 3H).

[0048] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-phenylvinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-1)

[0049] To a 25 mL three-necked flask, add intermediate 2-1 (120 mg, 0.416 mmol), (4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydronaphthyridin-1-yl)methyl)carbamic acid tert-butyl ester 3-1 (200 mg, 0.499 mmol), SPhospdG2 (34.0 mg, 0.0500 mmol), NaHCO3 (70.0 mg, 0.832 mmol), 5 mL of tert-amyl alcohol and 1 mL of water in sequence, stir and dissolve, and the reaction system is reacted under N2 protection at 80 ° C for 6 h, and TLC monitoring (V 二氯甲烷 :V 甲醇=20:1) reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with 5 mL of water, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with 5 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 64.0 mg of a white solid with a yield of 31.9%.

[0050] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.25-8.22 (m, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.95-7.88 (m, 1H). 7.85–7.77(m,2H),7.61–7.49(m,3H),7.45(t,J=5.3Hz,1H),4.39(d,J=5.5Hz,2H),3.98(s,3H),1.38(s,9H).

[0051] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-phenylacrylonitrile (I-1)

[0052] To a 25 mL three-necked flask, intermediate 4-1 (64.0 mg, 0.133 mmol) and 3 mL of dioxane hydrochloride were added in sequence. The reaction system was reacted at 25 °C for 0.5 h. The TLC monitoring (V 石油醚 :V 乙酸乙酯 =1:1) The reaction was complete, filtered, the filter cake was washed with 2 mL of n-hexane, and the filter cake was dried in vacuo to obtain 50.0 mg of a white solid with a yield of 98.9%.

[0053] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.89 (s, 1H), 8.64 (s, 3H). 8.27 (s, 1H), 8.23 ​​(d, J = 8.3Hz, 1H), 8.18 (s, 1H) ,8.06(s,1H),7.94(d,J=8.3Hz,1H),7.82–7.76(m,2H),7.59–7.48(m,3H),4.41-4.39(m,2H),3.97(s,3H).

[0054] 13C NMR(75MHz,DMSO-d6)δ(ppm):159.86,139.03,134.93,132.53,131.12,130.95,130.32, 129.91,128.87,127.47,126.70,125.58,121.97,121.71,119.55,116.57,66.77,38.11.

[0055] HRMS(ESI + ):m / z calcd for C 22 H 18 N6O 383.1620[M+H] + ;found:383.1624

[0056] Example 2: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-methylphenyl)acrylonitrile (I-2)

[0057] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(p-tolyl)acrylonitrile (2-2)

[0058] Using 2-(p-tolyl)acetonitrile 1-2 (139 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 120 mg of a white solid, with a yield of 38.5%.

[0059] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 7.63 (d, J = 8.2 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 3.97 (s, 3H), 2.45 (s, 3H).

[0060] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(p-tolyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-2)

[0061] Using intermediate 2-2 (120 mg, 0.400 mmol) and 3-1 (191 mg, 0.480 mmol) as raw materials, the operation was the same as 4-1 to obtain 60.0 mg of a white solid, with a yield of 30.4%.

[0062] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.20 (d, J = 8.3Hz, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.91-7.84 (m, 1H), 7 .69(d,J=8.1Hz,2H),7.40(t,J=5.7Hz,2H),7.34(d,J=8.1Hz,2H),4.36(d,J=5.1Hz,2H),3.95(s,3H),2.36(s,3H),1.36(s,9H).

[0063] Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(p-tolyl)acrylonitrile (I-2)

[0064] Using intermediate 4-2 (60.0 mg, 0.120 mmol) as raw material, the operation was the same as I-1 to obtain 45.0 mg of white solid, with a yield of 93.9%.

[0065] 1 H NMR(300MHz,DMSO-d6)δ(ppm):12.89(s,1H),8.70(s,3H),8.27-8.15(m,3H),8.10-8.00(m,1H),7.96- 7.84(m,1H),7.69(d,J=7.9Hz,2H),7.34(d,J=7.9Hz,2H),4.51–4.24(m,2H),3.95(s,3H),2.35(s,3H).

[0066] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.87,141.04,139.43,139.36,139.26,135.14,131.10,130.56, 130.09,129.57,129.07,127.56,126.83,125.78,122.22,119.60,116.83,66.96,38.34,21.50.

[0067] HRMS(ESI + ):m / z calcd for C 23 H 20 N6O 397.1777[M+H] + ; found:397.1772.

[0068] Example 3: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(naphthalen-2-yl)acrylonitrile (I-3)

[0069] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(naphthalene-2-yl)acrylonitrile (2-3)

[0070] 2-(Naphthyl)acetonitrile 1-3 (177 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), KOH (120 mg, 2.12 mmol) and 5 mL of EtOH were added to a 25 ml three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 25 °C for 12 h, and the reaction was monitored by TLC (V 石油醚 :V 乙酸乙酯 =10:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to give 120 mg of a white solid with a yield of 33.5%.

[0071] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 8.23 ​​(s, 1H), 7.94 (d, J = 8.7Hz, 2H), 7.92 -7.88(m,1H),7.78-7.75(m,1H),7.62–7.55(m,3H),7.44(s,1H),3.99(s,3H).

[0072] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(naphthalen-2-yl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-3)

[0073] 2-3 (120 mg, 0.355 mmol), intermediate 3-1 (171 mg, 0.426 mmol), SPhospdG2 (26.0 mg, 0.0360 mmol), NaHCO3 (60.0 mg, 0.710 mmol), 10 mL of tert-amyl alcohol and 2 mL of water were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 80 ° C under N2 protection for 12 h, and TLC was monitored (V 石油醚 :V 乙酸乙酯=1:1) the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 10 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 67.0 mg of a white solid with a yield of 35.4%.

[0074] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.3Hz, 1H), 8.15 (s, 1H), 8.12–7.97 (m,5H),7.96-7.90(m,1H),7.63–7.58(m,2H),7.39(t,J=6.0Hz,1H),4.36(d,J=5.7Hz,2H),4.00(s,3H),1.35(s,9H).

[0075] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(naphthalen-2-yl)acrylonitrile (I-3)

[0076] Using intermediate 4-3 (67.0 mg, 0.130 mmol) as raw material, the operation was the same as I-1 to obtain 48.0 mg of white solid, with a yield of 88.2%.

[0077] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.89 (s, 1H), 8.64 (s, 3H), 8.27 (s, 1H), 8.23 ​​(d, J = 8.3Hz, 1H), 8.18 (s, 1H) ),8.06(s,1H),7.97-7.91(m,1H),7.83–7.76(m,2H),7.60–7.47(m,3H),4.44-4.29(m,2H),4.00(s,3H).

[0078] 13C NMR(75MHz,DMSO-d6)δ(ppm):159.80,139.29,139.24,139.07,134.98,134.91,132.61,131.11,130.93,130.43,130. 17,129.91,129.69,129.08,128.90,127.48,126.73,125.64,123.23,122.03,121.71,119.49,116.59,66.79,38.15.

[0079] HRMS(ESI + ):m / z calcd for C 26 H 20 N6O 433.1777[M+H] + ; found:433.1772.

[0080] Example 4: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(benzo[d][1,3]dioxol-5-yl)acrylonitrile (I-4)

[0081] 1. Synthesis of (Z)-2-(Benzo[d][1,3]dioxol-5-yl)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)acrylonitrile (2-4)

[0082] 2-(Benzo[d][1,3]dioxol-5-yl)acetonitrile 1-4 (172 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), KOH (120 mg, 2.12 mmol) and 5 mL of EtOH were added to a 25 mL three-necked flask in sequence and stirred to dissolve. The reaction system was reacted at 25 ° C for 12 h and monitored by TLC (V 石油醚 :V 乙酸乙酯 =10:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to give 120 mg of a white solid with a yield of 35.5%.

[0083] 1H NMR (300MHz, Chloroform-d) δ (ppm): 7.57 (s, 1H), 7.27 (d, J = 1.9Hz, 1H), 7.18 ( d,J=1.9Hz,1H),7.16(s,1H),6.93(d,J=8.2Hz,1H),6.09(s,2H),3.97(s,3H).

[0084] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-(benzo[d][1,3]dioxol-5-yl)-2-cyanovinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-4)

[0085] 2-4 (120 mg, 0.360 mmol), intermediate 3-1 (174 mg, 0.430 mmol), SPhospdG2 (26.0 mg, 0.0400 mmol), NaHCO3 (61.0 mg, 0.720 mmol), 5 mL of tert-amyl alcohol and 1 mL of water were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 80 ° C under N2 protection for 12 h, and the TLC monitoring (V 石油醚 :V 乙酸乙酯 =1:1) reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with 5 mL of water, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with 5 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 63.0 mg of a white solid with a yield of 33.2%.

[0086] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.53 (s, 1H), 8.20 (d, J = 8.3Hz, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.88 (d, J = 8.3Hz, 1H), 7.55 ( s,1H),7.39(t,J=5.4Hz,1H),7.17(d,J=8.2Hz,1H),7.04(d,J=8.1Hz,1H),6.13(s,2H),4.36(d,J=5.8Hz,2H),3.93(s,3H),1.36(s,9H).

[0087] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(benzo[d][1,3]dioxol-5-yl)acrylonitrile (I-4)

[0088] Using intermediate 4-4 (63.0 mg, 0.120 mmol) as raw material, the operation was the same as I-1 to obtain 50.0 mg of white solid, yield: 98.0%.

[0089] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 8.68 (s, 3H), 8.22 (d, J=8.3Hz, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.92 (d, J= 7.8Hz,1H),7.56(d,J=2.0Hz,1H,),7.17(dd,J=8.2,1.9Hz,1H),7.05(d,J=8.1Hz,1H),6.14(s,2H),4.46-4.28(m,2H),3.95(s,3H).

[0090] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.84,149.79,148.98,148.50,139.38,139.19,135.08,131.06,129.01,128. 52,127.52,126.98,125.72,122.13,121.60,119.08,116.76,109.30,108.82,106.33,102.60,66.92,38.24.

[0091] HRMS(ESI + ):m / z calcd for C 23 H 18 N6O3427.1519[M+H] + ; found:427.1508.

[0092] Example 5: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-methoxyphenyl)acrylonitrile (I-5)

[0093] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-methoxyphenyl)acrylonitrile (2-5)

[0094] Using 2-(4-methoxyphenyl)acetonitrile 1-5 (156 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 115 mg of a white solid, with a yield of 32.5%.

[0095] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.73 (d, J = 8.8 Hz, 2H), 7.62 (s, 1H), 7.24 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.02 (s, 3H), 3.95 (s, 3H).

[0096] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(4-methoxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-5)

[0097] Using intermediate 2-5 (115 mg, 0.360 mmol) and intermediate 3-1 (174 mg, 0.430 mmol) as raw materials, the operation was the same as 4-1 to obtain 90.0 mg of a white solid, with a yield of 48.6%.

[0098] 1 H NMR(300MHz, DMSO-d6)δ(ppm):12.55(s,1H),8.23(d,J=8.3Hz,1H),8.13(s,1H),8.08(s,1H),8.05(s,1H),7.91(dd,J=8.3,1.6H z,1H),7.80–7.74(m,2H),7.41(t,J=6.0Hz,1H),7.15–7.09(m,2H),4.39(d,J=5.5Hz,2H),3.97(s,3H),3.85(s,3H),1.39(s,9H).

[0099] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-methoxyphenyl)acrylonitrile (I-5)

[0100] Using intermediate 4-5 (90.0 mg, 0.180 mmol) as raw material, the operation was the same as I-1 to obtain 70.0 mg of white solid, with a yield of 96.6%.

[0101] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 8.65 (s, 3H). 8.23 ​​(d, J = 8.3Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.04 (s ,1H),7.97-7.91(m,1H),7.74(d,J=8.5Hz,2H),7.11(d,J=8.8Hz,2H),4.46-4.32(m,2H),3.95(s,3H),3.82(s,3H).

[0102] 13 C NMR(75MHz,DMSO-d6)δ(ppm):161.40,159.84,139.34,139.28,138.96,135.18,131.06,128.85,128 .36,127.61,127.45,125.53,125.03,121.87,121.41,119.25,116.72,115.27,66.78,55.96,38.04.

[0103] HRMS(ESI + ):m / z calcd for C 23 H 20 N6O2413.1726[M+H] + ; found:413.1723.

[0104] Example 6: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(m-tolyl)acrylonitrile (I-6)

[0105] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(m-tolyl)acrylonitrile (2-6)

[0106] Using 2-(m-tolyl)acetonitrile 1-6 (140 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 106 mg of a white solid, with a yield of 33.2%.

[0107] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.62 (s, 1H), 7.57 (m, 2H), 7.44 (t, J = 7.9Hz, 1H). 7.36 (m, 2H), 4.01 (s, 3H), 2.50 (s, 3H).

[0108] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(m-tolyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-6)

[0109] Using intermediate 2-6 (106 mg, 0.350 mmol) and intermediate 3-1 (169 mg, 0.420 mmol) as raw materials, the operation was the same as 4-1 to obtain 61.0 mg of white solid, yield: 35.5%.

[0110] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.67 (s, 1H), 8.35 (d, J = 8.6Hz, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.07-7.98 (m ,1H),7.77(s,1H),7.73(d,J=8.1Hz,1H),7.63–7.40(m,3H),4.52(d,J=6.0Hz,2H),4.10(s,3H),2.52(s,3H),1.50(s,9H)

[0111] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(m-tolyl)acrylonitrile (I-6)

[0112] Using intermediate 4-6 (61.0 mg, 0.120 mmol) as raw material, the operation was the same as I-1 to obtain 45.0 mg of white solid, with a yield of 92.4%.

[0113] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.89 (s, 1H), 8.73 (s, 3H), 8.26 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.96-7. 88(m,1H),7.62(s,1H),7.59(d,J=9.2Hz,1H),7.47-7.37(m,1H),7.35-7.27(m,1H),4.46-4.30(m,2H),3.96(s,3H),2.37(s,3H).

[0114] 13C NMR(75MHz,DMSO-d6)δ(ppm):159.80,139.39,139.28,139.07,134.94,132.55,131.60,131.06,130.18,129 .80,128.91,127.45,127.07,125.62,123.93,122.05,121.70,119.57,116.64,66.79,38.14,27.22,21.38.

[0115] HRMS(ESI + ):m / z calcd for C 23 H 20 N6O 397.1777[M+H] + ; found:397.1770.

[0116] Example 7: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(o-tolyl)acrylonitrile (I-7)

[0117] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(o-tolyl)acrylonitrile (2-7)

[0118] Using 2-(o-tolyl)acetonitrile 1-7 (140 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 224 mg of a white solid, with a yield of 70.1%.

[0119] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.58 (s, 1H), 7.43–7.35 (m, 2H), 7.34–7.29 (m, 2H), 6.98 (s, 1H), 3.99 (s, 3H), 2.55 (s, 3H).

[0120] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(o-tolyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-7)

[0121] Using intermediate 2-7 (224 mg, 0.740 mmol) and intermediate 3-1 (357 mg, 0.890 mmol) as raw materials, the operation was the same as 4-1 to obtain 92.0 mg of a white solid, with a yield of 25.5%.

[0122] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.58 (s, 1H), 8.27 (d, J = 8.3Hz, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.96 (d, J = 8.7Hz, 1H), 7.79(s,1H),7.58(d,J=7.2Hz,1H),7.48–7.30(m,4H),4.45(d,J=5.9Hz,2H),3.98(s,3H),2.36(s,3H),1.35(s,9H).

[0123] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(o-tolyl)acrylonitrile (I-7)

[0124] Using intermediate 4-7 (92.0 mg, 0.230 mmol) as raw material, the operation was the same as I-1 to obtain 75.0 mg of white solid, with a yield of 82.6%.

[0125] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.93 (s, 1H), 8.73 (s, 3H), 8.30 (d, J = 8.1Hz, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 8.01 ( d,J=8.4Hz,1H),7.83(s,1H),7.61-7.49(m,1H),7.42–7.30(m,3H),4.54-4.36(m,2H),3.99(s,3H),2.37(s,3H).

[0126] 13 C NMR(75MHz,DMSO-d6)δ(ppm):160.05,139.56,139.51,136.43,135.88,134.72,133.89,131.75, 131.65,130.75,130.25,129.24,127.74,127.68,126.04,122.51,122.09,116.94,67.09,20.39.

[0127] HRMS(ESI + ):m / z calcd for C 23 H 20 N6O 397.1777[M+H] + ; found:397.1768.

[0128] Example 8: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-hydroxyphenyl)acrylonitrile (I-8)

[0129] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-hydroxyphenyl)acrylonitrile (2-8)

[0130] Using the intermediate 2-(4-hydroxyphenyl)acetonitrile 1-8 (142 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 200 mg of a white solid, with a yield of 62.2%.

[0131] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 10.16 (s, 1H), 7.73 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.6Hz, 2H), 6.91 (d, J = 8.6Hz, 2H), 3.87 (s, 3H).

[0132] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(4-hydroxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-8)

[0133] Using intermediate 2-8 (200 mg, 0.660 mmol) and intermediate 3-1 (317 mg, 0.790 mmol) as raw materials, the operation was the same as 4-1 to obtain 79.0 mg of white solid, with a yield of 24.5%.

[0134] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 10.13 (s, 1H), 8.20 (d, J = 8.3Hz, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=8.4Hz,1H),7.63(d,J=8.4Hz,2H),7.42(t,J=5.9Hz,1H),6.89(d,J=8.6Hz,2H),4.37(d,J=6.0Hz,2H),3.92(s,3H),1.36(s,9H).

[0135] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-hydroxyphenyl)acrylonitrile (I-8)

[0136] Using intermediate 4-8 (79.0 mg, 0.160 mmol) as raw material, the operation was the same as I-1 to obtain 55.0 mg of white solid, with a yield of 87.4%.

[0137] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 10.27 (s, 1H), 8.55 (s, 3H), 8.24 (d, J = 8.2Hz, 1H), 8.15 (s, 1H), 8.07 -7.99(m,2H),7.94(d,J=8.2Hz,1H),7.62(d,J=8.4Hz,2H),6.93(d,J=8.3Hz,2H),4.47-4.35(m,2H),3.94(s,3H).

[0138] HRMS(ESI + ):m / z calcd for C 22 H 18 N6O2399.1569[M+H] + ; found:399.1571.

[0139] Example 9: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-fluorophenyl)acrylonitrile (I-9)

[0140] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-hydroxyphenyl)acrylonitrile (2-9)

[0141] Using the intermediate 2-(4-fluorophenyl)acetonitrile 1-9 (142 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 230 mg of a white solid, with a yield of 71.1%.

[0142] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.74–7.65 (m, 2H), 7.56 (s, 1H), 7.24 (s, 1H), 7.19 (t, J = 8.5Hz, 2H), 3.95 (s, 3H).

[0143] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(4-fluorophenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-9)

[0144] Using intermediate 2-9 (230 mg, 0.750 mmol) and intermediate 3-1 (362 mg, 0.900 mmol) as raw materials, the operation was the same as 4-1 to obtain 90.0 mg of a white solid, with a yield of 24.5%.

[0145] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.21 (d, J = 8.9Hz, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8 .01(s,1H),7.94–7.81(m,3H),7.49–7.29(m,3H),4.35(d,J=6.0Hz),3.96(s,3H),1.35(s,9H).

[0146] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-fluorophenyl)acrylonitrile (I-9)

[0147] Using intermediate 4-9 (90.0 mg, 0.180 mmol) as raw material, the operation was the same as I-1 to obtain 70.0 mg of white solid, with a yield of 97.1%.

[0148] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.94 (s, 1H), 8.71 (s, 3H), 8.31 (s, 1H), 8.29 (d, J = 10.1Hz, 1H), 8.23 ​​(s, 1H) ,8.10(s,1H),8.01(d,J=8.3Hz,1H),7.96–7.87(m,2H),7.51-7.39(m,2H),4.66-4.30(m,2H),4.02(s,3H).

[0149] 13C NMR(75MHz,DMSO-d6)δ(ppm):159.84,139.32,139.23,139.10,134.88,131.16,130.53,129.34,129. 30,129.23,128.93,127.55,125.68,122.02,121.72,118.42,117.10,116.80,116.57,66.85,38.22.

[0150] HRMS(ESI + ):m / z calcd for C 22 H 17 FN6O 401.1526[M+H] + ; found:401.1521.

[0151] Example 10: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethylphenyl)acrylonitrile (I-10)

[0152] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethylphenyl)acrylonitrile (2-10)

[0153] Using intermediate 2-(3,5-dimethylphenyl)acetonitrile 1-10 (153 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 250 mg of a white solid, with a yield of 74.7%.

[0154] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.55 (s, 1H), 7.32 (s, 2H), 7.27 (s, 1H), 7.12 (s, 1H), 3.95 (s, 3H), 2.39 (s, 6H).

[0155] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3,5-dimethylphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-10)

[0156] Using intermediate 2-10 (250 mg, 0.790 mmol) and intermediate 3-1 (381 mg, 0.950 mmol) as raw materials, the operation was the same as 4-1 to obtain 96.0 mg of a white solid, with a yield of 23.8%.

[0157] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.21 (d, J = 8.3Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7. 90-7.85(m,1H),7.45-7.36(m,3H),7.15(s,1H),4.38(d,J=6.1Hz,2H),3.95(s,3H),2.34(s,6H),1.37(s,9H).

[0158] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethylphenyl)acrylonitrile (I-10)

[0159] Using intermediate 4-10 (96.0 mg, 0.190 mmol) as raw material, the operation was the same as I-1 to obtain 70.0 mg of white solid, with a yield of 90.7%.

[0160] 1 H NMR(300MHz,DMSO-d6)δ(ppm):13.07(s,1H),8.93(s,3H),8.45-8.33(m,3H),8.23(s,1H),8.06 (d,J=8.2Hz,1H),7.61-7.53(m,2H),7.28(s,1H),4.63-4.52(m,2H),4.12(s,3H),2.48(s,6H).

[0161] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.86,139.31,139.27,139.04,134.97,132.42,132.39, 131.06,129.76,127.42,124.28,121.99,121.68,119.67,116.67,66.78,40.04,21.25.

[0162] HRMS(ESI + ):m / z calcd for C 24 H 22 N6O 411.1933[M+H] + ; found:411.1923.

[0163] Example 11: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(2-methoxyphenyl)acrylonitrile (I-11)

[0164] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(2-methoxyphenyl)acrylonitrile (2-11)

[0165] Using the intermediate 2-(2-methoxyphenyl)acetonitrile 1-11 (156 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 209 mg of a white solid, with a yield of 60.9%.

[0166] 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.59(dd,J=7.7,1.6Hz,1H),7.57(s,1H),7.52(s,1H),7.46(t d,J=8.3,1.7Hz,1H),7.09(td,J=7.6,0.9Hz,1H),7.04(d,J=8.4Hz,1H),3.98(s,3H),3.97(s,3H).

[0167] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(2-methoxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-11)

[0168] Using intermediate 2-11 (209 mg, 0.660 mmol) and intermediate 3-1 (316 mg, 0.790 mmol) as raw materials, the operation was the same as 4-1 to obtain 87.0 mg of white solid, with a yield of 25.8%.

[0169] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.98-7.93 (m, 1H), 7.92 (s, 1H), 7.63 (d, J =7.6Hz,1H),7.55-7.46(m,1H),7.41(t,J=5.9Hz,1H),7.20-7.06(m,2H),4.41(d,J=6.0Hz,2H),3.94(s,3H),3.82(s,3H),1.35(s,9H).

[0170] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(2-methoxyphenyl)acrylonitrile (I-11)

[0171] Using intermediate 4-11 (87.0 mg, 0.170 mmol) as raw material, the operation was the same as I-1 to obtain 67.0 mg of white solid, with a yield of 95.6%.

[0172] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.96 (s, 1H), 8.84 (s, 3H), 8.40 (s, 1H), 8.27 (d, J = 8.9Hz, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 8 .0Hz,1H),7.54-7.41(m,2H),7.45(s,1H),7.36(d,J=7.4Hz,1H),7.13(d,J=7.7Hz,1H),4.54-4.35(m,2H),4.02(s,3H),3.89(s,3H).

[0173] 13 C NMR(75MHz,DMSO-d6)δ(ppm):160.26,159.82,139.34,139.25,139.12,134.89,133.96,131.09,130.80, 128.94,127.45,125.65,122.08,121.78,119.27,119.21,116.67,116.61,111.84,66.81,56.01,38.21.

[0174] HRMS(ESI + ):m / z calcd for C 23 H 20 N6O2413.1726[M+H] + ; found:413.1719.

[0175] Example 12: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-methoxyphenyl)acrylonitrile (I-12)

[0176] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-methoxyphenyl)acrylonitrile (2-12)

[0177] Using the intermediate 2-(3-methoxyphenyl)acetonitrile 1-12 (156 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 261 mg of a white solid, with a yield of 77.5%.

[0178] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.56 (s, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.32-7.27 ( m,1H),7.21(t,J=2.2Hz,1H),7.02(dd,J=8.2,1.9Hz,2H),3.96(s,3H),3.88(s,3H).

[0179] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3-methoxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-12)

[0180] Using intermediate 2-12 (261 mg, 0.820 mmol) and intermediate 3-1 (395 mg, 0.980 mmol) as raw materials, the operation was the same as 4-1 to obtain 92.0 mg of a white solid, with a yield of 21.9%.

[0181] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.21 (d, J = 7.5Hz, 2H), 8.11 (s, 1H), 8.01 (s, 1H), 7.93-7.87 (m, 1H), 7.50 –7.37(m,3H),7.30(d,J=7.7Hz,1H),7.13-7.05(m,1H),4.36(d,J=5.9Hz,2H),3.96(s,3H),3.84(s,3H),1.35(s,9H).

[0182] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-methoxyphenyl)acrylonitrile (I-12)

[0183] Using intermediate 4-12 (90.0 mg, 0.180 mmol) as raw material, the operation was the same as I-1 to obtain 70.0 mg of white solid, with a yield of 94.8%.

[0184] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.93 (s, 1H), 8.69 (s, 3H), 8.30 (d, J = 8.2Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.3Hz ,2H),7.97(s,1H),7.62(d,J=6.5Hz,1H),7.56-7.46(m,1H),7.22–7.10(m,2H),4.50-4.37(m,2H),3.97(s,3H),3.86(s,3H).

[0185] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.85,157.13,139.28,139.22,138.91,134.84,134.00,132.37,131.19,130 .35,128.81,127.40,125.60,122.38,121.92,121.73,121.56,117.46,116.58,112.65,66.79,56.39,38.04.

[0186] HRMS(ESI + ):m / z calcd for C 23 H 20 N6O2413.1726[M+H] + ; found:413.1719.

[0187] Example 13: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-ethoxyphenyl)acrylonitrile (I-13)

[0188] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-ethoxyphenyl)acrylonitrile (2-13)

[0189] Using the intermediate 2-(4-ethoxyphenyl)acetonitrile 1-13 (171 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 330 mg of a white solid, with a yield of 94.6%.

[0190] 1H NMR(300MHz,Chloroform-d)δ(ppm):7.69–7.62(m,2H),7.57(s,1H),7.18(s,1H) ),7.03–6.96(m,2H),4.12(q,J=7.0Hz,2H),3.97(s,3H),1.48(t,J=7.0Hz,3H).

[0191] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(4-ethoxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-13)

[0192] Using intermediate 2-13 (330 mg, 0.990 mmol) and intermediate 3-1 (478 mg, 1.19 mmol) as raw materials, the operation was the same as 4-1 to obtain 146 mg of white solid, yield: 28.5%.

[0193] 1 H NMR(400MHz, DMSO-d6)δ(ppm):12.54(s,1H),8.21(d,J=8.3Hz,1H),8.11(s,1H),8.05(s,1H),8.01(s,1H),7.92-7.85(m,1H),7.73(d,J=8.8H z,2H),7.40(t,J=6.0Hz,1H),7.08(d,J=8.9Hz,2H),4.37(d,J=6.0Hz,2H),4.10(q,J=7.0Hz,2H),3.94(s,3H),1.37(s,9H),1.36-1.33(m,3H).

[0194] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-ethoxyphenyl)acrylonitrile (I-13)

[0195] Using intermediate 4-13 (146 mg, 0.280 mmol) as raw material, the operation was the same as I-1 to obtain 110 mg of white solid, with a yield of 93.5%.

[0196] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.92 (s, 1H), 8.69 (s, 3H), 8.26 (d, J = 8.3Hz, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 8 .2Hz,1H),7.76(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),4.46-4.38(m,2H),4.13(q,J=6.9Hz,2H),3.98(s,3H),1.37(t,J=6.9Hz,3H).

[0197] 13 C NMR(75MHz,DMSO-d6)δ(ppm):160.69,139.39,138.92,135.23,131.13,129.60,128.84,128.35,127.47 ,127.38,125.48,124.82,121.83,121.42,119.34,116.70,115.69,114.85,66.77,64.06,37.99,14.90.

[0198] HRMS(ESI + ):m / z calcd for C 24 H 22 N6O2427.1882[M+H] + ; found:427.1877.

[0199] Example 14: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(pyridin-3-yl)acrylonitrile (I-14)

[0200] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(pyridin-3-yl)acrylonitrile (2-14)

[0201] 2-(Pyridin-3-yl)acetonitrile 1-14 (125 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), piperidine (180 mg, 2.12 mmol) and 5 mL of EtOH were added to a 25 mL three-necked flask in sequence and stirred to dissolve. The reaction system was reacted at 25 ° C for 12 h and monitored by TLC (V 石油醚 :V 乙酸乙酯 =3:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V乙酸乙酯 =3:1) to give 250 mg of a white solid with a yield of 81.7%.

[0202] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 8.99 (d, J = 2.4H 1H),8.74(d,J=4.0Hz,1H),8.06–8.02(m,1H),7.60(s,1H),7.51-7.45(m,1H),7.41(s,1H),4.00(s,3H).

[0203] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(pyridin-3-yl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-14)

[0204] 2-14 (250 mg, 0.870 mmol), intermediate 3-1 (416 mg, 1.04 mmol), SPhospdG2 (58.0 mg, 0.0900 mmol), NaHCO3 (145 mg, 1.73 mmol), 5 mL of tert-amyl alcohol and 1 mL of water were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 80 ° C under N2 protection for 12 h, and the TLC monitoring (V 石油醚 :V 乙酸乙酯 =1:1) the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 10 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 90.0 mg of a white solid with a yield of 21.5%.

[0205] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 9.04 (s, 1H), 8.78-8.64 (m, 1H), 8.34 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.21-8.15 (m, 1H), 8 .13(s,1H),8.04(s,1H),7.98-7.91(m,1H),7.63-7.54(m,1H),7.41(t,J=5.5Hz,1H),4.36(d,J=5.9Hz,2H),4.00(s,3H),1.37(s,9H).

[0206] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(pyridin-3-yl)acrylonitrile (I-14)

[0207] Using intermediate 4-14 (90.0 mg, 0.190 mmol) as raw material, the operation was the same as I-1 to obtain 60.0 mg of white solid, with a yield of 84.1%.

[0208] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 9.36 (s, 3H), 8.94 (d, J = 5.2Hz, 1H), 8.72 (d, J = 8.6Hz, 2H), 8.70-8.64 ( m,3H),8.24(d,J=8.4Hz,1H),8.22(s,1H),8.11-8.05(m,1H),8.03(d,J=8.3Hz,1H),4.44-4.26(m,2H),4.02(s,3H).

[0209] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.71,143.86,142.05,141.67,139.48,138.79,137.98,135.89,134. 15,131.94,131.28,129.00,127.59,127.36,125.86,122.45,122.31,115.56,113.38,66.82,38.51.

[0210] HRMS(ESI + ):m / z calcd for C 21 H 17 N7O 384.1573[M+H] + ; found:384.1567.

[0211] Example 15: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-yl)acrylonitrile (I-15)

[0212] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-yl)acrylonitrile (2-15)

[0213] 2-(Pyridyl)acetonitrile 1-15 (125 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), piperidine (180 mg, 2.12 mmol) and 5 mL of EtOH were added to a 25 mL three-necked flask in sequence and stirred to dissolve. The reaction system was reacted at 25 ° C for 12 h and monitored by TLC (V 石油醚 :V 乙酸乙酯 =3:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =3:1) to give 210 mg of a white solid with a yield of 68.6%.

[0214] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 8.67 (d, J = 4.4Hz, 1H), 8.31 (s, 1H), 7.89-7.78 (m, 2H), 7.58 (s, 1H), 7.41-7.34 (m, 1H), 3.98 (s, 3H).

[0215] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(pyridin-2-yl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-15)

[0216] 2-15 (210 mg, 0.730 mmol), intermediate 3-1 (350 mg, 0.870 mmol), SPhospdG2 (49.0 mg, 0.0700 mmol), NaHCO3 (122 mg, 1.45 mmol), 10 mL of tert-amyl alcohol and 2 mL of H2O were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 80 ° C under N2 protection for 12 h, and the reaction was monitored by TLC (V 石油醚 :V 乙酸乙酯 =1:1) the reaction was complete, the reaction solution was concentrated under reduced pressure, 10 mL of water was added to the residue, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 10 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 85.0 mg of a white solid with a yield of 24.2%.

[0217] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.69 (d, J = 4.2Hz, 1H), 8.55 (s, 1H), 8.21 (d, J = 8.3Hz, 1H), 8.12 (s, 1H), 8. 04(s,1H),8.02–7.84(m,3H),7.54–7.49(m,1H),7.36(t,J=5.9Hz,1H),4.37(d,J=6.0Hz,2H),3.99(s,3H),1.36(s,9H).

[0218] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-yl)acrylonitrile (I-15)

[0219] Intermediate 4-15 (85.0 mg, 0.180 mmol) was used as the raw material and the operation was the same as that of I-1 to obtain 65.0 mg of a white solid with a yield of 96.4%.

[0220] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.89 (s, 1H), 8.70 (s, 3H), 8.63 (s, 1H), 8.23 ​​(d, J = 8.5Hz, 1H), 8.20 (s, 1H) ,8.04(s,1H),8.01(d,J=9.9Hz,2H),7.98-7.88(m,2H).7.58-7.48(m,1H),4.45-4.30(m,2H),3.98(s,3H).

[0221] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.75,149.97,139.28,139.15,139.01,138.91,134.34,133.22, 131.17,128.85,127.48,125.66,125.50,122.23,122.12,122.00,118.98,116.05,66.74,38.33.

[0222] HRMS(ESI + ):m / z calcd for C 21 H 17 N7O 384.1573[M+H] + ; found:384.1565.

[0223] Example 16: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)acrylonitrile (I-16)

[0224] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)acrylonitrile (2-16)

[0225] 2-(Thiophen-3-yl)acetonitrile 1-16 (130 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), KOH (120 mg, 2.12 mmol) and 5 mL of EtOH were added to a 25 mL three-necked flask in sequence and stirred to dissolve. The reaction system was reacted at 25 ° C for 12 h and monitored by TLC (V 石油醚 :V 乙酸乙酯 =10:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to give 240 mg of a white solid with a yield of 70.5%.

[0226] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.76-7.74(m,1H),7.57(s,1H),7.50-7.47(m,1H),7.43-7.40(m,1H),7.21(s,1H),3.97(s,3H).

[0227] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(thien-3-yl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-16)

[0228] 2-16 (240 mg, 0.816 mmol), intermediate 3-1 (393 mg, 0.979 mmol), SPhospdG2 (55.0 mg, 0.0820 mmol), NaHCO3 (137 mg, 1.63 mmol), 10 mL of tert-amyl alcohol and 2 mL of H2O were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 80 ° C under N2 protection for 12 h, and TLC was monitored (V 石油醚 :V 乙酸乙酯=1:1) the reaction was complete, the reaction solution was concentrated under reduced pressure, 10 mL of water was added to the residue, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 10 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 100 mg of a white solid with a yield of 25.5%.

[0229] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.21 (d, J = 8.3Hz, 1H), 8.14-8.08 (m, 2H), 8.01 (s, 1H), 7.92–7.83 (m, 2H),7.80-7.74(m,1H),7.74-7.68(m,1H),7.42(t,J=5.8Hz,1H),4.37(d,J=6.0Hz,2H),3.95(s,3H),1.36(s,9H).

[0230] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)acrylonitrile (I-16)

[0231] Using intermediate 4-16 (95.0 mg, 0.190 mmol) as raw material, the operation was the same as I-1 to obtain 69.0 mg of white solid, with a yield of 91.4%.

[0232] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 8.64 (s, 3H), 8.24 (d, J = 8.3Hz, 1H), 8.20 (s, 1H), 8.18 (s ,1H),8.04(s,1H),7.96-7.86(m,2H),7.88(s,1H),7.83-7.72(m,2H),4.49-4.33(m,2H),3.96(s,3H).

[0233] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.81,139.29,139.24,139.09,135.06,134.73,131.06,129. 52,128.90,128.39,127.48,126.80,125.61,125.47,122.02,121.54,114.62,66.80,38.12.

[0234] HRMS(ESI + ):m / z calcd for C 20 H 16 N6OS 389.1185[M+H] + ; found:389.1178.

[0235] Example 17: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(5-fluoro-2-methylphenyl)acrylonitrile (I-17)

[0236] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(5-fluoro-2-methylphenyl)acrylonitrile (2-17)

[0237] Using the intermediate 2-(5-fluoro-2-methylphenyl)acetonitrile 1-17 (158 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 210 mg of a white solid, with a yield of 62.5%.

[0238] 1 HNMR(400MHz,Chloroform-d)δ(ppm):7.59(s,1H),7.28–7.20(m,1H),7.13–7.07(m,2H),7.00(s,1H),4.00(s,3H),2.51(s,3H).

[0239] 2. Synthesis of tert-butyl (Z)-(7-(5-(2-cyano-2-(5-fluoro-2-methylphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydronaphthyridin-1-yl)methyl)carbamate (4-17)

[0240] Using intermediate 2-17 (210 mg, 0.660 mmol) and intermediate 3-1 (315 mg, 0.790 mmol) as raw materials, the operation was the same as 4-1 to obtain 80.0 mg of white solid, with a yield of 23.7%.

[0241] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.57 (s, 1H), 8.29 (d, J = 8.3Hz, 1H), 8.14 (s, 1H), 7.99 (d, J = 1.9Hz, 2H), 7.88 (s, 1H), 7 .59–7.54(m,1H),7.48–7.34(m,2H),7.32-7.25(m,1H),4.46(d,J=6.0Hz,2H),4.01(s,3H),2.32(s,3H),1.38(s,9H).

[0242] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(5-fluoro-2-methylphenyl)acrylonitrile (I-17)

[0243] Using intermediate 4-17 (80.0 mg, 0.160 mmol) as raw material, the operation was the same as I-1 to obtain 62.0 mg of white solid, with a yield of 96.2%.

[0244] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.94 (s, 1H), 8.68 (s, 3H), 8.32 (d, J = 8.2Hz, 1H), 8.18 (s, 1H), 8.13–8.02 (m, 2H), 7 .91(s,1H),7.55–7.46(m,1H),7.43–7.35(m,1H),7.32–7.22(m,1H),4.52-4.42(m,1H),4.02(s,3H),2.33(s,3H).

[0245] HRMS(ESI + ):m / z calcd for C 23 H 19 FN6O 415.1683[M+H] + ; found:415.1679.

[0246] Example 18: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-chlorophenyl)acrylonitrile (I-18)

[0247] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-chlorophenyl)acrylonitrile (2-18)

[0248] Using the intermediate 2-(4-chlorophenyl)acetonitrile 1-18 (160 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 220 mg of a white solid, with a yield of 64.5%.

[0249] 1 HNMR(400MHz,Chloroform-d)δ(ppm):7.67–7.62(m,2H),7.56(s,1H),7.49–7.44(m,2H),7.29(s,1H),3.96(s,3H).

[0250] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-(4-chlorophenyl)-2-cyanovinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-18)

[0251] Using intermediate 2-18 (220 mg, 0.680 mmol) and intermediate 3-1 (328 mg, 0.820 mmol) as raw materials, the operation was the same as 4-1 to obtain 94.0 mg of a white solid, with a yield of 26.7%.

[0252] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.58 (s, 1H), 8.27 (s, 1H), 8.25 (d, J = 8.7Hz, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.97-7.90 (m, 1H),7.86(d,J=8.6Hz,1H),7.65(d,J=8.6Hz,2H),7.42(t,J=5.9Hz,1H),4.39(d,J=6.0Hz,2H),4.00(s,3H),1.39(s,9H).

[0253] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-chlorophenyl)acrylonitrile (I-18)

[0254] Using intermediate 4-18 (94.0 mg, 0.180 mmol) as raw material, the operation was the same as I-1 to obtain 68.0 mg of white solid, with a yield of 89.6%.

[0255] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.85 (s, 1H), 8.64 (s, 3H), 8.29 (s, 1H), 8.20 (d, J = 8.3Hz, 1H), 8.15 (s, 1H), 8. 02(s,1H),7.91(d,J=8.4Hz,1H),7.79(d,J=8.6Hz,2H),7.59(d,J=8.5Hz,2H),4.41-4.28(m,2H),3.94(s,3H).

[0256] HRMS(ESI + ):m / z calcd for C 22 H 17 ClN6O 417.1231[M+H] + ; found:417.1220.

[0257] Example 19: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3,5-difluorophenyl)acrylonitrile (I-19)

[0258] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3,5-difluorophenyl)acrylonitrile (2-19)

[0259] Using 2-(3,5-difluorophenyl)acetonitrile 1-19 (162 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 220 mg of a white solid, with a yield of 64.2%.

[0260] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.60(s,1H),7.36(s,1H),7.28–7.24(m,1H),6.99-6.93(m,1H),3.99(s,3H).

[0261] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3,5-difluorophenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-19)

[0262] Using intermediate 2-19 (220 mg, 0.680 mmol) and intermediate 3-1 (327 mg, 0.820 mmol) as raw materials, the operation was the same as 4-1 to obtain 91.0 mg of a white solid, with a yield of 25.9%.

[0263] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.60 (s, 1H), 8.41 (s, 1H), 8.28 (d, J = 8.3Hz, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7 .99-7.93(m,1H),7.61(d,J=2.1Hz,2H),7.54–7.39(m,2H),4.40(d,J=6.0Hz,2H),4.03(s,3H),1.40(s,9H).

[0264] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3,5-difluorophenyl)acrylonitrile (I-19)

[0265] Using intermediate 4-19 (91.0 mg, 0.180 mmol) as raw material, the operation was the same as I-1 to obtain 70.0 mg of white solid, with a yield of 95.6%.

[0266] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.92 (s, 1H), 8.68 (s, 3H), 8.47 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.20 (s, 1H) ,8.07(s,1H),7.94(d,J=8.2Hz,1H),7.61–7.53(m,2H),7.50–7.41(m,1H),4.49-4.30(m,2H),4.00(s,3H).

[0267] HRMS(ESI + ):m / z calcd for C 22 H 16 F2N6O 419.1432[M+H] + ; found:419.1426.

[0268] Example 20: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3,4-difluorophenyl)acrylonitrile (I-20)

[0269] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3,4-difluorophenyl)acrylonitrile (2-20)

[0270] 2-(3,4-difluorophenyl)acetonitrile 1-20 (62.0 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), piperidine (180 mg, 2.12 mmol) and 4 mL of EtOH were added to a 25 mL three-necked flask in sequence and stirred to dissolve. The reaction system was reacted at 25 ° C for 12 h and monitored by TLC (V 石油醚 :V 乙酸乙酯 =10:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to give 200 mg of a white solid, yield: 58.3%.

[0271] 1 HNMR(300MHz,Chloroform-d)δ(ppm):7.53(s,1H),7.51–7.40(m,2H),7.33–7.23(m,1H),7.22(s,1H),3.93(s,3H).

[0272] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3,4-difluorophenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-20)

[0273] Using intermediate 2-20 (200 mg, 0.620 mmol) and intermediate 3-1 (297 mg, 0.740 mmol) as raw materials, the operation was the same as 4-1 to obtain 67.0 mg of white solid, with a yield of 20.9%.

[0274] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.52 (s, 1H), 8.23 ​​(s, 1H), 8.21 (d, J = 8.4Hz, 1H), 8.09–7.98 (m, 3H), 7.93 -7.87(m,1H),7.65–7.51(m,2H),7.35(t,J=5.4Hz,1H),4.33(d,J=6.3Hz,2H),3.96(s,3H),1.34(s,9H).

[0275] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3,4-difluorophenyl)acrylonitrile (I-20)

[0276] Using intermediate 4-20 (67.0 mg, 0.130 mmol) as raw material, the operation was the same as I-1 to obtain 51.0 mg of white solid, with a yield of 95.5%.

[0277] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 8.68 (s, 3H), 8.35 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.1 9(s,1H),8.12–8.00(m,2H),7.98-7.90(m,1H),7.69–7.54(m,2H),4.43-4.30(m,2H),3.98(s,3H).

[0278] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.77,139.24,139.05,134.48,131.61,131.12,128.79,127. 47,125.55,124.21,121.82,118.96,118.72,117.10,116.08,115.97,115.71,66.68,38.08.

[0279] HRMS(ESI + ):m / z calcd for C 22 H 16 F2N6O 441.1251[M+Na] + ; found:441.1241.

[0280] Example 21: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-methoxy-4-methylphenyl)acrylonitrile (I-21)

[0281] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-methoxy-4-methylphenyl)acrylonitrile (2-21): Using 2-(3-methoxy-4-methylphenyl)acetonitrile 1-21 (171 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 155 mg of a white solid, with a yield of 44.1%.

[0282] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.56 (s, 1H), 7.26 (s, 1H), 7.22 (s, 2H), 7.10 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 2.27 (s, 3H).

[0283] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3-methoxy-4-methylphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-21)

[0284] Using intermediate 2-21 (200 mg, 0.600 mmol) and intermediate 3-1 (286 mg, 0.710 mmol) as raw materials, the operation was the same as 4-1 to obtain 56.0 mg of white solid, with a yield of 23.1%.

[0285] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.25 (d, J = 8.3Hz, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.96-7.92 (m, 1H), 7.46 (s, 1H) ,7.42(t,J=5.8Hz,1H),7.31(d,J=7.8Hz,1H),7.25-.19(m,1H),4.39(d,J=5.9Hz,2H),3.98(s,3H),3.93(s,3H),2.23(s,3H),1.38(s,9H).

[0286] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-methoxy-4-methylphenyl)acrylonitrile (I-21)

[0287] Using intermediate 4-21 (56.0 mg, 0.110 mmol) as raw material, the operation was the same as I-1 to obtain 40.0 mg of white solid, with a yield of 88.2%.

[0288] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.88 (s, 1H), 8.72 (s, 3H), 8.31 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.93 (d, J =8.3Hz,1H),7.39(s,1H),7.27(d,J=7.8Hz,1H),7.19(d,J=7.2Hz,1H),4.43-4.29(m,2H),3.96(s,3H),3.90(s,3H),2.18(s,3H).

[0289] 13 C NMR(75MHz,DMSO-d6)δ(ppm):148.08,139.25,139.07,134.79,131.01,130.74,129.61,128. 83,127.43,125.61,121.97,121.59,120.01,119.91,118.45,116.48,111.85,66.74,56.85.

[0290] HRMS(ESI + ):m / z calcd for C 24 H 22 N6O2427.1882[M+H] + ; found:427.1874.

[0291] Example 22: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-fluoro-5-methoxyphenyl)acrylonitrile (I-22)

[0292] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-fluoro-5-methoxyphenyl)acrylonitrile (2-22)

[0293] Using 2-(3-fluoro-5-methoxyphenyl)acetonitrile 1-22 (175 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 200 mg of a white solid, with a yield of 56.2%.

[0294] 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.57(s,1H),7.31(s,1H),7.05–6.98(m,2H),6.76-6.70(m,1H),3.96(s,3H),3.87(s,3H).

[0295] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3-fluoro-5-methoxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-22)

[0296] Using intermediate 2-22 (155 mg, 0.470 mmol) and intermediate 3-1 (225 mg, 0.560 mmol) as raw materials, the operation was the same as 4-1 to obtain 76.0 mg of a white solid, with a yield of 30.9%.

[0297] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.29 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 8.3Hz, 1H), 7.46 -7.31(m,1H),7.25(d,J=9.6Hz,1H),7.17(s,1H),7.02(d,J=10.7Hz,1H),4.36(d,J=5.9Hz,2H),3.96(s,3H),3.84(s,3H),1.36(s,9H).

[0298] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-fluoro-5-methoxyphenyl)acrylonitrile (I-22)

[0299] Using intermediate 4-22 (76.0 mg, 0.140 mmol) as raw material, the operation was the same as I-1 to obtain 52.0 mg of white solid, with a yield of 84.4%.

[0300] 1H NMR (300MHz, DMSO-d6) δ (ppm): 8.66 (s, 1H), 8.33 (s, 3H), 8.24 (d, J = 8.3Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.96 (d, J =8.9Hz,1H),7.70–7.61(m,1H),7.42–7.33(m,1H),7.31–7.21(m,1H),4.43-4.30(m,1H),3.97(s,3H),3.96(s,3H).

[0301] 13 C NMR(75MHz,DMSO-d6)δ(ppm):161.29,161.13,159.24,138.99,138.86,138.52,133.99,131.98,130 .50,128.53,126.96,125.33,121.84,121.14,115.82,108.80,105.46,105.14,66.36,56.14,55.63.

[0302] HRMS(ESI + ):m / z calcd for C 23 H 19 FN6O2431.1632[M+H] + ; found:431.1626.

[0303] Example 23: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-methoxyphenyl)acrylonitrile (I-23)

[0304] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-methoxyphenyl)acrylonitrile (2-23)

[0305] Using intermediate 2-(4-fluoro-3-methoxyphenyl)acetonitrile 1-23 (175 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 247 mg of white solid, yield: 69.4%.

[0306] 1H NMR(300MHz,Chloroform-d)δ(ppm):7.57(s,1H),7.30-7.27(m,1H),7.25-7.22(m,2H),7.22–7.14(m,1H),3.98(s,3H),3.96(s,3H).

[0307] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(4-fluoro-3-methoxyphenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-23)

[0308] Using intermediate 2-23 (247 mg, 0.740 mmol) and intermediate 3-1 (354 mg, 0.880 mmol) as raw materials, the operation was the same as 4-1 to obtain 80.0 mg of a white solid, with a yield of 20.5%.

[0309] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.53 (s, 1H), 8.23 ​​(d, J = 8.5Hz, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.92 (d, J = 9.5Hz, 1 H),7.68(d,J=8.0Hz,1H),7.43–7.34(m,2H),7.28–7.24(m,1H),4.35(d,J=6.0Hz,2H),3.96(s,3H),3.95(s,3H),1.35(s,9H).

[0310] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-fluoro-3-methoxyphenyl)acrylonitrile (I-23)

[0311] Using intermediate 4-23 (80.0 mg, 0.150 mmol) as raw material, the operation was the same as I-1 to obtain 56.0 mg of white solid, with a yield of 86.3%.

[0312] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.89 (s, 1H), 8.66 (s, 3H), 8.33 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7. 96(d,J=8.4Hz,1H),7.70-7.60(m,1H),7.48-7.33(m,1H),7.28–7.24(m,1H),4.46-4.26(m,2H),3.97(s,3H),3.96(s,3H).

[0313] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.57,151.31,148.14,147.99,139.17,138.99,134.71,130.9 1,130.70,129.56,127.27,125.50,121.89,121.51,118.34,117.00,116.76,116.39,111.76.

[0314] HRMS(ESI + ):m / z calcd for C 23 H 19 FN6O2431.1632[M+H] + ; found:431.1629.

[0315] Example 24: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-(tert-butyl)phenyl)acrylonitrile (I-24)

[0316] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-(tert-butyl)phenyl)acrylonitrile (2-24)

[0317] Using 2-(4-(tert-butyl)phenyl)acetonitrile 1-24 (183 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 338 mg of a white solid, with a yield of 92.8%.

[0318] 1HNMR(300MHz,Chloroform-d)δ(ppm):7.94–7.88(m,2H),7.82(s,1H),7.80–7.73(m,2H),7.54(s,1H),4.21(s,3H),1.62(s,9H).

[0319] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-(4-(tert-butyl)phenyl)-2-cyanovinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-24)

[0320] Using intermediate 2-24 (338 mg, 0.980 mmol) and intermediate 3-1 (473 mg, 1.18 mmol) as raw materials, the operation was the same as 4-1 to obtain 110 mg of white solid, with a yield of 20.8%.

[0321] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.64 (s, 1H), 8.31 (d, J = 8.3Hz, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.02-7.97 (m, 1H), 7 .83(d,J=8.4Hz,2H),7.65(d,J=8.5Hz,2H),7.51(t,J=6.1Hz,1H),4.49(d,J=5.9Hz,2H),4.05(s,3H),1.46(s,9H),1.40(s,9H).

[0322] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-(tert-butyl)phenyl)acrylonitrile (I-24)

[0323] Using intermediate 4-24 (110 mg, 0.200 mmol) as raw material, the operation was the same as I-1 to obtain 80.0 mg of white solid, with a yield of 89.3%.

[0324] 1 H NMR(300MHz,DMSO-d6)δ(ppm):12.88(s,1H),8.72(s,3H),8.24–8.21(m,2H),8.08(s,1H),7.96-7.8 9(m,1H),7.72(d,J=8.5Hz,2H),7.55(d,J=8.6Hz,2H),4.47-4.33(m,2H),3.95(s,3H),1.29(s,9H).

[0325] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.99,154.09,139.46,135.16,130.06,129.57,129.08,127.5 9,126.87,126.71,121.76,119.60,116.77,66.94,60.59,38.22,35.18,31.44,31.44,14.64.

[0326] HRMS(ESI + ):m / z calcd for C 26 H 26 N6O 439.2246[M+H] + ; found:439.2235.

[0327] Example 25: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-fluorophenyl)acrylonitrile (I-25)

[0328] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-fluoro-5-methylphenyl)acrylonitrile (2-25)

[0329] Using 2-(3-fluoro-5-methylphenyl)acetonitrile 1-25 (125 mg, 0.840 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (158 mg, 0.840 mmol) as raw materials, the operation was the same as 2-1 to obtain 145 mg of a white solid, with a yield of 54.2%.

[0330] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.56 (s, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.23-7.17 (m, 1H), 7.00 (d, J = 9.1Hz, 1H), 3.96 (s, 3H), 2.44 (s, 3H).

[0331] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(3-fluorophenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-25)

[0332] Using intermediate 2-25 (145 mg, 0.450 mmol) and intermediate 3-1 (218 mg, 0.540 mmol) as raw materials, the operation was the same as 4-1 to obtain 50.0 mg of a white solid, with a yield of 21.5%.

[0333] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.27 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.89 (dd, J = 8.3, 1.6Hz, 1H),7.55(d,J=9.9Hz,1H),7.42-7.63(m,2H),7.21(d,J=9.6Hz,1H),4.36(d,J=5.9Hz,1H),3.96(s,3H),2.38(s,3H),1.34(s,9H).

[0334] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-fluorophenyl)acrylonitrile (I-25)

[0335] Using intermediate 4-25 (50.0 mg, 0.100 mmol) as raw material, the operation was the same as I-1 to obtain 35.0 mg of white solid, with a yield of 86.9%.

[0336] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.91 (s, 1H), 8.74 (s, 3H), 8.37 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7. 91(d,J=8.3Hz,1H),7.54(d,J=9.9Hz,1H),7.39(s,1H),7.19(d,J=8.8Hz,1H),4.45-4.32(m,2H),3.97(s,3H),2.37(s,3H).

[0337] 13C NMR(75MHz,DMSO-d6)δ(ppm):165.52,162.28,160.83,143.45,143.34,140.36,140.22,135.64,135.50,132.67, 132.16,129.97,128.52,126.72,124.63,123.14,122.99,119.06,117.37,111.71,111.40,67.83,39.25,22.30.

[0338] HRMS(ESI + ):m / z calcd for C 23 H 19 FN6O 415.1683[M+H] + ; found:415.1679.

[0339] Example 26: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-chloro-3-fluorophenyl)acrylonitrile (I-26)

[0340] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(4-chloro-3-fluorophenyl)acrylonitrile (2-26)

[0341] Using 2-(4-chloro-3-fluorophenyl)acetonitrile 1-26 (180 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 280 mg of a white solid, with a yield of 77.7%.

[0342] 1 HNMR(300MHz,Chloroform-d)δ(ppm):7.60(s,1H),7.58–7.54(m,1H),7.53–7.45(m,2H),7.33(s,1H),3.99(s,3H).

[0343] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-(4-chloro-3-fluorophenyl)-2-cyanovinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-26)

[0344] Using intermediate 2-26 (115 mg, 0.360 mmol) and intermediate 3-1 (174 mg, 0.430 mmol) as raw materials, the operation was the same as 4-1 to obtain 96.0 mg of a white solid, with a yield of 21.8%.

[0345] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.56 (s, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.11 (s, 1H)), 8.04 (s, 1H), 8.01 (d, J = 8.6Hz, 1H), 7. 93(d,J=8.3Hz,1H),7.79-7.75(m,1H),7.58(d,J=8.9Hz,1H),7.38(t,J=6.8Hz,1H),4.36(d,J=6.1Hz,2H),3.99(s,3H),1.37(s,9H).

[0346] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(4-chloro-3-fluorophenyl)acrylonitrile (I-26)

[0347] Using intermediate 4-26 (96.0 mg, 0.180 mmol) as raw material, the operation was the same as I-1 to obtain 72.0 mg of white solid, with a yield of 92.3%.

[0348] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.91 (s, 1H), 8.66 (s, 3H), 8.42 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.19 (s, 1H), 8.06 (s ,1H),8.03-7.99(m,1H),7.97-7.93(m,1H),7.78-7.74(m,1H),7.60-7.54(m,1H),4.42-4.32(m,2H),3.99(s,3H).

[0349] 13C NMR (75MHz, DMSO-d6) δ (ppm): 159.60 (d, J = 17.8Hz), 156.20, 139.24, 139.11, 139.00, 134.39, 133.62 (d, J = 7.8Hz), 132.32, 131.90 ,131.10,128.81,127.47,125.61,124.35–123.85(m),121.96,121.78,116.87(d,J=2.4Hz),116.00,115.04,114.72,66.71,38.17.

[0350] HRMS(ESI + ):m / z calcd for C 22 H 16 ClFN6O 435.1136[M+H] + ; found:435.1132.

[0351] Example 27: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-chloro-5-fluorophenyl)acrylonitrile (I-27)

[0352] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-chloro-5-fluorophenyl)acrylonitrile (2-27)

[0353] Using 2-(2-chloro-4-fluorophenyl)acetonitrile 1-27 (125 mg, 0.740 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (139 mg, 0.740 mmol) as raw materials, the operation was the same as 2-1 to obtain 210 mg of a white solid, with a yield of 83.7%.

[0354] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.60 (s, 1H), 7.55-7.52 (m, 1H), 7.38-7.33 (m, 2H), 7.27-7.22 (m, 1H), 3.99 (s, 3H).

[0355] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-(3-chloro-5-fluorophenyl)-2-cyanovinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-27)

[0356] Using intermediate 2-27 (297 mg, 0.740 mmol) and intermediate 3-1 (210 mg, 0.620 mmol) as raw materials, the operation was the same as 4-1 to obtain 69.0 mg of white solid, with a yield of 20.9%.

[0357] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.37 (s, 1H), 8.23 ​​(d, J = 8.3Hz, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.92 (d ,J=8.4Hz,1H),7.71(s,1H),7.69–7.59(m,2H),7.41–7.34(m,1H),4.35(d,J=5.8Hz,2H),3.98(s,3H),1.35(s,9H).

[0358] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-chloro-5-fluorophenyl)acrylonitrile (I-27)

[0359] Using intermediate 4-27 (69.0 mg, 0.130 mmol) as raw material, the operation was the same as I-1 to obtain 45.0 mg of white solid, with a yield of 80.2%.

[0360] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.91 (s, 1H), 8.67 (s, 3H), 8.47 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.19 (s, 1H) ),8.07(s,1H),7.97-7.92(m,1H),7.73-7.67(m,2H),7.65-7.60(m,1H),4.45-4.35(m,2H),3.99(s,3H).

[0361] 13 C NMR (75MHz, DMSO-d6) δ (ppm): 162.78 (d, J = 248.6Hz), 159.74, 139.33, 139.28, 139.02, 136.22 (d, J = 9.4Hz), 135.47 (d, J = 11.3Hz), 134.27, 13 3.33,131.17,128.93,127.50,125.73,123.00,122.19,118.17,117.83,116.16(d,J=27.8Hz),112.79(d,J=24.1Hz),66.77,38.29.HRMS(ESI+ ):m / z calcd for C 22 H 16 ClFN6O 435.1136[M+H] + ; found:435.1129.

[0362] Example 28: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-chlorophenyl)acrylonitrile (I-28)

[0363] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-chlorophenyl)acrylonitrile (2-28)

[0364] Using intermediate 2-(3-chlorophenyl)acetonitrile 1-28 (160 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 175 mg of a white solid, with a yield of 51.3%.

[0365] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.62–7.58 (m, 1H), 7.51 (dt, J = 6.4, 2.0 Hz, 1H), 7.48 (s, 1H), 7.40–7.33 (m, 2H), 7.23 (s, 1H), 3.87 (s, 3H).

[0366] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-(3-chlorophenyl)-2-cyanovinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (4-28)

[0367] Using intermediate 2-28 (175 mg, 0.540 mmol) and intermediate 3-1 (260 mg, 0.650 mmol) as raw materials, the operation was the same as 4-1 to obtain 72.0 mg of white solid, with a yield of 26.6%.

[0368] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.55 (s, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.94-7.88 (m,1H),7.71–7.66(m,1H),7.61–7.52(m,2H),7.41(t,J=6.0Hz,1H),4.37(d,J=5.9Hz,2H),3.98(s,3H),1.36(s,9H).

[0369] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-chlorophenyl)acrylonitrile (I-28)

[0370] Using intermediate 4-28 (72.0 mg, 0.140 mmol) as raw material, the operation was the same as I-1 to obtain 51.0 mg of white solid, with a yield of 87.8%.

[0371] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.91 (s, 1H), 8.74 (s, 3H), 8.40 (s, 1H), 8.22 (d, J = 10.1Hz, 2H), 8.0 8(s,1H),7.96-7.90(m,2H),7.73-7.67(m,1H),7.59-7.53(m,2H),4.46-4.35(m,2H),3.98(s,3H).

[0372] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.67,139.17,139.01,134.43,131.75,131.54,131.00,130. 41,128.76,127.31,126.08,125.49,125.38,121.91,121.83,117.56,116.11,66.61,38.05.

[0373] HRMS(ESI + ):m / z calcd for C 22 H 17 ClN6O 417.1231[M+H] + ; found:417.1223.

[0374] Example 29: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-fluorophenyl)acrylonitrile (I-29)

[0375] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-fluorophenyl)acrylonitrile (2-29)

[0376] Using 2-(3-fluorophenyl)acetonitrile 1-29 (142 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 254 mg of a white solid, with a yield of 78.4%.

[0377] 1 HNMR(300MHz,Chloroform-d)δ(ppm):7.57(s,1H),7.54–7.46(m,2H),7.44–7.38(m,2H),7.33(s,1H),7.23–7.15(m,1H),3.97(s,3H).

[0378] 2. Synthesis of tert-butyl (Z)-(7-(5-(2-cyano-2-(3-fluorophenyl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydronaphthyridin-1-yl)methyl)carbamate (4-29)

[0379] Using intermediate 2-29 (254 mg, 0.830 mmol) and intermediate 3-1 (400 mg, 0.990 mmol) as raw materials, the operation was the same as 4-1 to obtain 120 mg of white solid, with a yield of 28.9%.

[0380] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.54 (s, 1H), 8.29 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.93-7. 87(m,1H),7.81–7.71(m,1H),7.62–7.52(m,2H),7.43–7.31(m,2H),4.36(d,J=6.0Hz,2H),3.97(s,3H),1.35(s,9H).

[0381] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-fluorophenyl)acrylonitrile (I-29)

[0382] Using intermediate 4-29 (120 mg, 0.120 mmol) as raw material, the operation was the same as I-1 to obtain 72.0 mg of white solid, with a yield of 75.5%.

[0383] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.91 (s, 1H), 8.67 (s, 3H), 8.38 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 8.20 (s, 1H), 8.07 (s, 1H) ),7.94(d,J=8.3Hz,1H),7.77(d,J=10.1Hz,1H),7.66–7.53(m,2H),7.42–7.32(m,1H),4.46-4.32(m,2H),3.99(s,3H).

[0384] 13 C NMR (75MHz, DMSO-d6) δ (ppm): 162.92 (d, J = 244.8Hz), 159.81, 139.31, 139.17, 134.93 (d, J = 8.5Hz), 134.59, 132.02 (d, J = 8.5Hz), 131.85, 131.18, 12 8.92,127.52,125.69,123.16(d,J=1.9Hz),122.08,121.97,117.94(d,J=2 .6Hz), 117.73 (d, J = 22.4Hz), 116.30, 113.41 (d, J = 24.0Hz), 66.80, 38.22.

[0385] HRMS(ESI + ):m / z calcd for C 22 H 17 FN6O 401.1526[M+H] + ; found:401.1519.

[0386] Example 30: Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-phenoxyphenyl)acrylonitrile (I-30)

[0387] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(3-phenoxyphenyl)acrylonitrile (2-30)

[0388] Using 2-(3-phenoxyphenyl)acetonitrile 1-30 (221 mg, 1.06 mmol) and 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol) as raw materials, the operation was the same as 2-1 to obtain 170 mg of a white solid, with a yield of 42.2%.

[0389] 1 H NMR(300MHz,Chloroform-d)δ(ppm):7.52(s,1H),7.44–7.32(m,4H),7.24(s,1H) ,7.23(s,1H),7.13(t,J=7.4Hz,1H),7.09–7.02(m,2H),7.01(s,1H),3.91(s,3H).

[0390] 2. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-phenoxyphenyl)acrylonitrile (4-30)

[0391] Using intermediate 2-30 (145 mg, 0.450 mmol) and intermediate 3-1 (218 mg, 0.540 mmol) as raw materials, the operation was the same as 4-1 to obtain 50.0 mg of a white solid, with a yield of 21.5%.

[0392] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.56 (s, 1H), 8.24 (s, 1H), 8.22 (d, J = 8.4Hz, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.93–7.84 (m, 1H), 7 .56–7.50(m,3H),7.46-7.38(m,3H),7.17(t,J=7.4Hz,1H),7.13-7.03(m,3H),4.34(d,J=5.6Hz,2H),3.96(s,3H),1.34(s,9H).

[0393] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydronaphthyridin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(3-phenoxyphenyl)acrylonitrile (I-30)

[0394] Using intermediate 4-30 (59.0 mg, 0.0400 mmol) as raw material, the operation was the same as I-1 to obtain 17.0 mg of white solid, with a yield of 90.5%.

[0395] 1H NMR (300MHz, DMSO-d6) δ (ppm): 12.92 (s, 1H), 8.72 (s, 3H), 8.33 (s, 1H), 8.22 (d, J = 8.5Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.91 (d, J = 8 .5Hz,1H),7.60-7.52(m,2H),7.49(s,1H),7.45-7.37(m,2H),7.21-7.12(m,1H),7.11-7.03(m,3H),4.48-4.29(m,2H),3.96(s,3H).

[0396] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.84,157.88,156.30,139.36,139.22,134.72,134.51,131.68,131.21,130.76, 128.93,127.46,125.63,124.62,122.11,121.89,121.70,120.36,119.45,118.53,116.51,116.44,66.78,38.18.

[0397] HRMS(ESI + ):m / z calcd for C 28 H 22 N6O2475.1882[M+H] + ; found:475.1871.

[0398] Example 31: Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acrylonitrile (I-31)

[0399] 1. Synthesis of (Z)-3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acrylonitrile (2-31)

[0400] 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile 1-31 (209 mg, 1.06 mmol), 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (200 mg, 1.06 mmol), KOH (120 mg, 2.12 mmol) and 5 mL of EtOH were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 25 ° C for 12 h, and TLC was monitored (V 石油醚 :V乙酸乙酯 =10:1) the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to give 270 mg of a white solid with a yield of 69.4%.

[0401] 1 H NMR (300MHz, Chloroform-d) δ (ppm): 7.56 (s, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 7.18 (d, J = 8.4Hz, 1H), 3.95 (s, 3H).

[0402] 2. Synthesis of tert-butyl (Z)-((7-(5-(2-cyano-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)vinyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydronaphthyridin-1-yl)methyl)carbamate (4-31)

[0403] 2-31 (270 mg, 0.730 mmol), intermediate 3-1 (354 mg, 0.880 mmol), SPhospdG2 (49.0 mg, 0.0700 mmol), NaHCO3 (123 mg, 1.47 mmol), 10 mL of tert-amyl alcohol and 2 mL of water were added to a 25 mL three-necked flask in sequence, and the mixture was stirred to dissolve. The reaction system was reacted at 80 ° C under N2 protection for 12 h, and the TLC monitoring (V 石油醚 :V 乙酸乙酯 =1:1) reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was diluted with 5 mL of water, extracted with ethyl acetate (5 mL×3), the organic phases were combined, washed with 5 mL of saturated NaCl, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =1:1) to give 107 mg of a white solid with a yield of 26.5%.

[0404] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.56 (s, 1H), 8.22 (s, 1H), 8.21 (d, J = 8.1Hz, 1H), 8.09 (s, 1H), 8.04-7.99 (m, 2H ),7.94–7.89(m,1H),7.59–7.50(m,2H),7.40(t,J=5.7Hz,1H),4.34(d,J=5.8Hz,2H),3.96(s,3H),1.34(s,9H).

[0405] 3. Synthesis of (Z)-3-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acrylonitrile (I-31)

[0406] Using intermediate 4-31 (107 mg, 0.190 mmol) as raw material, the operation was the same as I-1 to obtain 85.0 mg of white solid, with a yield of 97.5%.

[0407] 1 H NMR (300MHz, DMSO-d6) δ (ppm): 12.90 (s, 1H), 8.70 (s, 3H), 8.34 (s, 1H), 8.21 (d, J = 8.6Hz, 1H), 8.1 9(s,1H),8.11-8.04(m,2H),7.98-7.89(m,1H),7.60-7.50(m,1H),4.45-4.31(m,2H),3.97(s,3H).

[0408] 13 C NMR(75MHz,DMSO-d6)δ(ppm):159.61,144.21,143.87,139.20,139.04,138.98,134.49,131.54,131.22, 130.92,129.57,128.78,127.34,125.53,123.96,121.68,117.68,116.21,111.03,108.33,66.65,38.08.

[0409] HRMS(ESI + ):m / z calcd for C 23 H 16 F2N6O3463.1330[M+H] + ; found:463.1324.

[0410] Example 32: Study on PRMT5 inhibitory activity of some compounds of the present invention

[0411] 1. Experimental reagents

[0412] PRMT5(Active Motif,Cat.No.31921)[ 3H]-SAM(PerkinElmer,Cat.No.NET155V001MC)SAM(Sigma,Cat.No.A7007-100MG)SAH(Sigma,Cat.No.A9384-25MG)MTA(Sigma,D5011-100MG)OptiPlate(384-well,white)(Perkin Elmer, Cat. No. 6007299) 384-well Flashplate (Perkin Elmer, Cat. No. SMP410A001PK)

[0413] 2. Experimental methods

[0414] (1) Prepare 1x detection buffer (modified Tris buffer);

[0415] (2) Compound serial dilution: Compounds were transferred to the test plate by Echo in 100% DMSO, and the final concentration fraction of DMSO was 1%;

[0416] (3) PRMT5: Prepare enzyme and [ 3 H]-SAM mixed solution (PRMT5+MTA: prepare enzyme, [ 3 H]-SAM and MTA mixed solution);

[0417] (4) Prepare substrate solution in 1x assay buffer;

[0418] (5) PRMT5: 15 μL enzyme and [ 3 H]-SAM mixed solution was transferred to the test plate (PRMT5+MTA: 15 μL enzyme, [ 3 H]-SAM and MTA mixed solution was transferred to the test plate);

[0419] (6) Add 10 μL of substrate solution to each well to start the reaction and 10 μL of 1x detection buffer as a blank control;

[0420] (7) Incubate at room temperature for 90 min;

[0421] (8) Add cold SAM to 1x detection buffer to make a stop solution;

[0422] (9) Add 5 μL of stop solution to each well to stop the reaction;

[0423] (10) Transfer 25 μL per well to Flashplate;

[0424] (11) Incubate at room temperature for at least 1 h;

[0425] (12) Flashplate detection through Microbeta;

[0426] (13) Data processing: Fit the data in Excel and use formula (1): inh% = (Max-Signal) / (Max-Min)*100 to obtain the inhibition value; use formula (2): Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)*HillSlope) to get IC 50 Values ​​where Y is the inhibition rate and X is the compound concentration.

[0427] 3. Experimental results

[0428]

[0429]

[0430] a : A: Inhibitionrate%@100nM≥90%, B: 80%≤Inhibitionrate%@100nM<90%, C: Inhibitionrate%@100nM<80%.

[0431] Example 33: Evaluation of in vitro cellular SDMA activity of some compounds of the present invention

[0432] 1. Experimental reagents

[0433] Protease inhibitors were purchased from MCE; phosphatase inhibitor II was purchased from MCE; BCA kit was purchased from Beyotime Co., Ltd.; PVDF membrane was purchased from Millipore, USA; ECL was purchased from Nanjing Novezan Biotechnology Co., Ltd.; SDMA antibody was purchased from CST, catalog number 13222S; β-Tubulin was purchased from CST, catalog number 2146S; HRP-conjugated secondary antibody was purchased from CST; PRMT5 antibody was purchased from Abcam, catalog number ab109451.

[0434] 2. Experimental methods

[0435] Compounds were administered at the expected concentration and for the expected time in the MV-4-11 cell line. After washing twice with PBS, cells were lysed with RIPA buffer, protease inhibitors, and phosphatase inhibitor II for 1 h. The mixture was centrifuged at 12,000 rpm for 15 min. Total protein content was quantified by BCA kit, protein was diluted to a uniform concentration, 6× Loading Buffer was added, protein was denatured at 100°C, and then transferred to -80°C for storage until analysis. Equivalent protein was electrophoresed by 8-10% SDS-PAGE and then transferred to PVDF membrane. Subsequently, the membrane was blocked with 5% (w / v) skim milk for 1-2 h. Proteins were detected with primary antibodies, followed by HRP-conjugated secondary antibodies and visualized with ECL as HRP substrate. Target blots were detected using a chemiluminescence system. Grayscale analysis was performed using Image J software.

[0436] 3. Experimental results

[0437]

[0438] a :A:IC 50 <100nM, B:100nM≤IC 50 <1μM, C:IC 50 ≥1.0μM;

[0439] b :D:IC 50 ≥10μM, E:1μM≤IC 50 <10μM, F:IC 50 <1μM.

Claims

1. A phthalazinone compound, characterized in that: Having the structure of formula (I), and also including pharmaceutically acceptable salts thereof: in: R 1a , R 1b are independently selected from hydrogen, halogen, C1-C6 alkyl; when R 1a , R 1b At different times, the carbon atom connected thereto is in racemic configuration, R configuration or S configuration; Ring A is selected from substituted benzene ring, pyridine ring, thiophene ring, naphthalene ring; the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl or nitro; R 2 is selected from hydrogen, halogen, C1-C6 alkyl, and R 2 The double bond configuration is Z configuration, E configuration or a mixture of the two.

2. The phthalazinone compound according to claim 1, characterized in that In the structure: R 1a , R 1b are independently selected from hydrogen, methyl or ethyl; Ring A is selected from substituted benzene ring, pyridine ring, thiophene ring, naphthalene ring; the substituent is selected from at least one hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, hydroxyl, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl or nitro; R 2 is a hydrogen atom, and R 2 The double bond configuration is Z configuration, E configuration or a mixture of the two.

3. The phthalazinone compound according to claim 1, characterized in that: In the structure: R 1a or R 1b Selected from hydrogen; Ring A is selected from substituted benzene ring, pyridine ring, thiophene ring, benzo[d][1,3]dioxole or naphthalene ring; the substituent is selected from at least one hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, hydroxyl, amino or nitro; R 2 is a hydrogen atom, and R 2 The double bond configuration is Z configuration.

4. The phthalazinone compound according to claim 1, characterized in that: In the structure: R 1a or R 1b Selected from hydrogen; Ring A is selected from R 2 is a hydrogen atom, and R 2 The double bond configuration is Z configuration.

5. The phthalazinone compound according to claim 1, characterized in that: Select any of the following compounds:

6. The phthalazinone compound according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by the compound and any one of the following acids: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

7. A pharmaceutical composition, characterized in that The invention comprises the phthalazinone compound according to claim 1 and a pharmaceutically acceptable carrier.

8. Use of the phthalazinone compound according to claim 1 or the pharmaceutical composition according to claim 7 in the preparation of a PRMT5 inhibitor drug.

9. The use according to claim 8, characterized in that: The drug is an anti-tumor drug.

10. The use according to claim 9, characterized in that: The medicine is a medicine for treating lung cancer, ovarian cancer, colorectal cancer, breast cancer, melanoma, leukemia or malignant glioma.

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