2-amido-substituted aza-heteroaryl compound as HPK1 inhibitor and application of 2-amido-substituted aza-heteroaryl compound

Abstract

The invention discloses a 2-amido substituted aza-heteroaryl compound as well as a pharmaceutical composition and application thereof, the structure of the compound is as shown in formula (I), and the compound also comprises a stereoisomer, a tautomer, a deuterated compound, a pharmaceutically acceptable salt or a mixture of the stereoisomer, the tautomer, the deuterated compound and the pharmaceutically acceptable salt. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compounds disclosed herein. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a 2-amino-substituted nitrogen-heteroaryl compound and a pharmaceutical composition and application thereof, and in particular to a 2-amino-substituted nitrogen-heteroaryl compound which can be prepared as a drug for treating and / or preventing hematopoietic progenitor cell kinase-mediated diseases and a pharmaceutical composition and application thereof. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a serine-threonine protein kinase that belongs to the Ste20-related protein kinase MAP4K family. The MAP4K family also includes glucokinase (GCK, MAP4K2), GPK-like kinase (GLK, MAP4K3), HPK1-GPK-like kinase (HGK, MAP4K4), SPS1 / STE20 homologous kinase (KHS, MAP4K5) and Nck-related kinase (MINK, MAP4K6). HPK1 regulates different functions of a variety of immune cells, and its kinase activity has been shown to be induced upon activation of the T cell receptor (TCR), B cell receptor (BCR), transforming growth factor receptor (TGF-βR) and Gs-coupled PGE2 receptors (EP2 and EP4). Overexpression of HPK1 inhibits TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, indicating that HPK1 is required for the inhibition of the Erk-MAPK pathway.

[0003] In vitro studies have shown that MAP4K1 - / - T cells have a lower TCR activation threshold, can proliferate robustly, and produce increased amounts of Th1 cytokines, MAP4K1 - / - Mice experience more severe autoimmune symptoms. In humans, HPK1 is downregulated in peripheral blood mononuclear cells from patients with psoriasis or arthritis or in T cells from patients with systemic lupus erythematosus (SLE). These results suggest that reduced HPK1 activity may contribute to autoimmunity in patients. Studies have also shown that MAP4K1 - / - HPK1 is a promising target for enhancing anti-tumor immunity.

[0004] In recent years, although several new ATP-competitive and allosteric HPK1 inhibitors have been developed and entered clinical practice, the development of highly efficient, safe, and selective HPK1 inhibitors with excellent activity in cells (inhibiting SLP-76 protein phosphorylation and inducing the release of cytokines such as IL-2) and in vivo has not yet been achieved. Summary of the invention

[0005] Objectives of the invention: The first objective of the present invention is to provide a 2-amino-substituted aza-heteroaryl compound; the second objective is to provide a pharmaceutical composition comprising the compound; the third objective is to provide an application of the compound and its pharmaceutical composition or in combination with other related drugs in the preparation of drugs for the treatment and / or prevention of HPK1-mediated diseases.

[0006] Technical solution: 2-amino substituted aza-heteroaryl compounds having a structure as shown in formula (I) or its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts or mixtures thereof:

[0007]

[0008] in:

[0009] X 1 is selected from C or N atoms;

[0010] Cy 1 Selected from C 3-7 Cycloalkyl, 5- to 10-membered heterocyclic group containing 0, 1, 2, or 3 N, S, or O ring heteroatoms, and each Cy 1 By m R 1 replaced by;

[0011] Cy 2 is selected from 5-10 membered heterocyclic aromatic groups, phenyl groups, containing 0, 1, 2, 3 N, S, O ring heteroatoms, and each Cy 2 By n R 2 replaced by;

[0012] m, n are independently selected from 0, 1, 2 or 3;

[0013] R 1 Selected from H, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 1a , -So2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R1c 、-NR 1a CO2R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO2NR 1b R 1c 、-NR 1a S02R 1b , 3- to 10-membered heterocyclic groups containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic groups containing 0 to 3 N, S, or O ring heteroatoms, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl;

[0014] R 1a , R 1b , R 1c are independently selected from hydrogen, halogen, OH, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, 3- to 10-membered heterocyclic radicals containing 0, 1, 2, 3, 4, or 5 heteroatoms of N, S, or O rings, 5- to 6-membered heterocyclic aromatic radicals containing 0, 1, 2, or 3 heteroatoms of N, S, or O rings, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl;

[0015] R 2 Selected from H, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c 、-NR 2a S02R 2b , 3- to 10-membered heterocyclic groups containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic groups containing 0 to 3 N, S, or O ring heteroatoms, C 1-8 alkyl;

[0016] R 2a , R 2b , R 2c are independently selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, 3- to 10-membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic radicals containing 0, 1, 2, 3 N, S, or O ring heteroatoms, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl;

[0017] L1 is absent, a single bond or selected from -NHR 3a -、-NR 3a R 3b -、-NR 3a CR 3b R 3c -、-OR 3a -、-SR 3a -、-OCR 3a R 3b -、-CONHR 3a -、-CONR 3a R 3b -, -O-, -S-, -SO-, -SO2-, -CO-, -CR 3a R3b -、-NHCONHR 3a -、-NHCONR 3a R 3b -、C 1-8 Alkyl, NH2;

[0018] R 3a , R 3b , R 3c are independently selected from hydrogen, halogen, deuterium, -CN, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, 3- to 10-membered heterocyclic group containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, and 5- to 6-membered heterocyclic aromatic group containing 0, 1, 2, or 3 N, S, or O ring heteroatoms;

[0019] R3 is selected from hydrogen, halogen, -CN, -NH2, C 1-4 Alkyl, C 1-5 Alkoxy, C 1-5 Cycloalkyl.

[0020] The 2-amino substituted aza-heteroaryl compound, X 1 is selected from C or N atoms;

[0021] Cy 1 A 5- to 6-membered heterocyclic group containing one or more heteroatoms of N, S, and O, and each Cy 1 By m R 1 replaced by;

[0022] Cy 2 is selected from 5-6 membered heterocyclic aromatic groups and phenyl groups containing one or more heteroatoms of N, S and O, and each Cy 2 By n R 2 replaced by;

[0023] m, n are independently selected from 0, 1, 2 or 3;

[0024] R 1 Selected from -COR 1a ; R 1a Selected from hydrogen, halogen, OH, -NH-substituted or unsubstituted 6-membered nitrogen heterocycle, -N(CH3)2, -NH-substituted or unsubstituted phenyl, -NHCH3, -NH(CH2) 2～4 NHCOCH3, substituted or unsubstituted 6-membered nitrogen heterocycle, -NH(CH2) 2～4 N(CH3)2, NH2, -OC 1-4 Alkyl; the substitution is halogen, C1-4 Alkyl, NH2 or Boc protected amino group substituted;

[0025] R 2 Selected from H, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c 、-NR 2a S02R 2b , 3- to 10-membered heterocyclic groups containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic groups containing 0 to 3 N, S, or O ring heteroatoms, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl;

[0026] R 2a , R 2b , R 2c are independently selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, 3- to 10-membered heterocyclic radicals containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic radicals containing 0, 1, 2, or 3 N, S, or O ring heteroatoms, C 3-10Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl;

[0027] L1 is absent, a single bond or selected from -O-, -S-, -SO-, -SO2-, -CO-, C 1-4 Alkyl, NH2, -O-(CH2) 1～6 -、-CONH-(CH2) 1～4 -、-NH-(CH2) 1～4 -、-NHCO-(CH2) 1～4 -、NCH3-(CH2) 1～4 -、-S-(CH2) 1～4 -、-SONH-(CH2) 1～4 -、-SOONH-(CH2) 1～4 -、-CO-(CH2) 1～4 -、-CN-(CH2) 1～4 -、-NCH-(CH2) 1～4 -、-NHCO-NCH3(CH2) 1～4 -;

[0028] R 3 Selected from hydrogen, halogen, -CN, -NH2, C 1-4 Alkyl, C 1-5 Alkoxy, C 1-5 Cycloalkyl.

[0029] Further preferably, the 2-amino substituted aza-heteroaryl compound, wherein cy 1 Select from any of the following structures: R 4a Selected from hydrogen, C1-4 alkyl, C1-5 alkoxy, C1-5 cycloalkyl;

[0030] And every Cy 1 0-3 R 1 replaced.

[0031] Preferably, the 2-amino substituted aza-heteroaryl compound has a structure in which Cy 2 Select from any of the following structures:

[0032] Cy 2 Select from any of the following structures:

[0033]

[0034] And every Cy 2 0-3 R 2 replaced.

[0035] Preferably, the 2-amino substituted aza-heteroaryl compound, wherein R 2 Select from the following structures:

[0036]

[0037] More preferably, the 2-amino-substituted aza-heteroaryl compound is selected from any of the following compounds:

[0038]

[0039]

[0040]

[0041] 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, acidic amino acids, and ferulic acid.

[0042] A pharmaceutical composition comprises the 2-amino-substituted aza-heteroaryl compound and a pharmaceutically acceptable carrier.

[0043] The 2-amino substituted aza-heteroaryl compound or the pharmaceutical composition, or use thereof in combination with a PD-1 antibody in the preparation of a drug for preventing and / or treating hematopoietic progenitor cell kinase-mediated diseases.

[0044] The use of the 2-amino substituted aza-heteroaryl compound or the pharmaceutical composition in preparing drugs for treating colon cancer.

[0045] The compound of the general formula (I) of the present invention can be prepared by the following method:

[0046] Reaction diagram 1:

[0047]

[0048] Reaction scheme 1 The synthesis steps are as follows: Dibromo-substituted aromatic amine (I-1) and 1H-pyrazole-4-carboxylic acid ethyl ester are used as raw materials, K2CO3 is used as a base to undergo nucleophilic substitution, and then sodium hydroxide is used for hydrolysis and amide condensation to produce (I-3). Compound (I-4) undergoes nucleophilic substitution with compound (I-5) in DMSO solvent with triethylamine as a base to produce compound (I-6). Compound (I-6) undergoes Suzuki-Miyamoto reaction in the presence of bipyralidone borate and potassium acetate, with dioxane as a solvent and N2 protection to produce compound (I-7). Compound (I-3) and compound (I-7) undergo Suzuki reaction in the presence of Pd(dppf)Cl2 as a catalyst, K2CO3 as a base, N2 protection, with dioxane: water = 4:1 as a solvent to produce compound (I-8).

[0049] Reaction diagram 2:

[0050]

[0051] The synthesis steps of reaction diagram 2 are as follows: dibromo-substituted aromatic amine (II-1) and 1H-pyrazole-4-carboxylic acid ethyl ester (II-2) are used as raw materials, K2CO3 is used as a base to undergo nucleophilic substitution, and then hydrolyzed with sodium hydroxide, and amide condensation is performed to generate (II-3). Compound (II-3) undergoes Suzuki-Miyamoto reaction in the presence of biboric acid pinacol ester and potassium acetate, with dioxane as solvent and N2 protection to obtain compound (II-4). Compound (II-5) undergoes nucleophilic substitution with compound (II-6) in acetonitrile solvent with K2CO3 as a base to generate compound (II-7). Compound (I-7) reacts with compound (II-8) through nucleophilic substitution or Mitsunobu reaction to obtain compound (II-9). Compound (II-4) and compound (II-9) under Pd(dppf)Cl2 as catalyst, K2CO3 as base, under N2 protection conditions, and with dioxane: water = 4:1 as solvent, undergo Suzuki reaction to obtain compound (II-10).

[0052] Reaction diagram 3:

[0053]

[0054] The three steps of the reaction diagram are as follows: the halogenated heterocyclic carboxylic acid (III-1) undergoes amide condensation to generate compound (III-2), compound (III-2) undergoes Suzuki-Miyamoto reaction in the presence of biboric acid pinacol ester and potassium acetate, with dioxane as solvent and N2 protection, and then undergoes Suzuki reaction with dibromo-substituted aromatic amine (III-3) in the presence of Pd(dppf)Cl2 as catalyst, K2CO3 as base, N2 protection, with dioxane: water = 4:1 as solvent to obtain compound (III-4). Compound (III-5) undergoes nucleophilic substitution with compound (III-6) in DMSO solvent with triethylamine as base to obtain compound (OOI-7), and compound (III-6) undergoes Suzuki-Miyamoto reaction in the presence of biboric acid pinacol ester and potassium acetate, with dioxane as solvent and N2 protection to obtain compound (IOI-8). Compound (III-4) and compound (III-8) under Pd(dppf)Cl2 as catalyst, K2CO3 as base, under N2 protection conditions, and with dioxane: water = 4:1 as solvent, undergo Suzuki reaction to obtain compound (III-9).

[0055] The present invention uses skeleton hopping, skeleton fusion strategy and reasonable SAR exploration to develop a new class of effective HPK1 inhibitors, and conducts in vitro / in vivo activity tests on the developed amino-substituted nitrogen-containing heteroaryl HPK1 inhibitors. A new HPK1 inhibitor with strong activity, low toxicity, strong tumor cell killing ability and high safety is obtained, which is expected to achieve targeted treatment of tumors.

[0056] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the compounds have excellent inhibitory activity against HPK1 kinase in vitro, IC 50 The value reaches the nanomolar concentration level; this type of compound has significant inhibitory activity on pSLP-76 in Jurkat cells and significantly promotes IL-2 release; it can significantly inhibit tumor growth in the Balb / c tumor-bearing mouse model. The in vivo and in vitro activities are significantly better than the existing HPK1 kinase small molecule inhibitor drugs, and there is no obvious toxicity. It has a wide range of applications and can be prepared as a drug for the treatment and / or prevention of HPK1 kinase-mediated related diseases, providing a promising candidate drug for solving the drug resistance problem of existing drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 The results are the effects of compound 107 on the tumor volume of mouse colon cancer CT-26 cell transplanted tumors in Balb / c mice;

[0058] Figure 2 The results are as follows: the effect of compound 107 on the body weight of Balb / c mice transplanted with CT-26 cells;

[0059] Figure 3 The results show the effect of compound 107 on the tumor weight of mouse colon cancer CT-26 cell transplanted tumors in Balb / c mice. DETAILED DESCRIPTION

[0060] The technical solution of the present invention is further described below in conjunction with embodiments.

[0061] The experimental methods in the following examples of the present invention, where no specific conditions are specified, are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0062] Example 1: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-(1-methylpiperidin-4-yl)pyrazole-4-carboxamide

[0063]

[0064] Step a: 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylic acid ethyl ester

[0065] In a 100 mL round-bottom flask, 3,5-dibromopyrazin-2-amine (1.0 eq, 1.0 g) and 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 eq, 555 mg) were dissolved in NMP, K2CO3 (2.0 eq, 1.1 g) was added, and the mixture was reacted in an oil bath at 120°C for 4 h. After the reaction, the mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE / EA = 10:1) to obtain 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylic acid ethyl ester as a light yellow solid with a yield of 83%. HRMS (ESI) (m / z): calcd for C 10 H 10 BrN5O2[M+H] + , 312.0018; found, 312.0037.

[0066] Step b: 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylic acid

[0067] In a 100mL round-bottom flask, 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylic acid ethyl ester (1.0eq, 1.0g) was dissolved in CH3OH:H2O=5:1, and NaOH (5.0eq, 640mg) was added in an ice bath, and then the round-bottom flask was transferred to room temperature for reaction for 4h. After the reaction was completed, it was concentrated, the pH was adjusted to 5-6 with HCl, and filtered, washed with ethyl acetate (2mL×1), and washed with water (2mL×3) to obtain 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylic acid as a light yellow solid with a yield of 94%. HRMS(ESI)(m / z):calcd for C8H6BrN5O2[M+H] + , 283.9705; found, 283.9733.

[0068] Step c: 1-(3-amino-6-bromopyrazin-2-yl)-N-(1-methylhexahydropyridin-4-yl)pyrazole-4-carboxamide

[0069] In a 100 mL round-bottom flask, 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxylic acid (1.0 eq, 150 mg), 1-methylhexahydropyridine-4-amine (2 eq, 120 mg), and HATU (1.5 eq, 300 mg) were dissolved in DMF, and DIPEA (2.0 eq. 180 mml) was added. The mixture was reacted at room temperature for 3 h. After the reaction, the mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM / CH3OH=30:1) to obtain 1-(3-amino-6-bromopyrazin-2-yl)-N-(1-methylhexahydropyridine-4-yl)pyrazole-4-carboxamide as a light yellow solid with a yield of 63%. HRMS (ESI) (m / z): calculated for C 14 H 18 BrN7O[M+H] + , 380.0756; found, 380.0768.

[0070] Step d: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-(1-methylpiperidin-4-yl)pyrazole-4-carboxamide In a 100 mL round-bottom flask, 1-(3-amino-6-bromopyrazin-2-yl)-N-(1-methylpiperidin-4-yl)pyrazole-4-carboxamide (1.0 eq, 200 mg), 4-methyl-1-[4 [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (1.0 eq, 170 mg), K2CO3 (2.5 eq, 180 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 eq, 30 mg) were dissolved in a solvent of dioxane: water = 4:1, and reacted in an oil bath at 100°C for 4 h under N2 protection. After the reaction was completed, it was diluted with water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water (20 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then column chromatographed (DCM / MeOH=20:1) to obtain 3-{[(2-aminopyridin-4-yl)methyl]oxy}-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine as a light yellow solid with a yield of 62.5%. 1 H NMR (300MHz, DMSO-d6) δ9.26 (s, 1H), 8.60 (s, 1H), 8.30 (d, J=7.6Hz, 1H), 8.23 (s, 1H), 7.93 (d, J=8.3Hz, 2H), 7.35 (s, 2H), 7.04 (d, J=8.4Hz, 2H), 3.80 (s, 1H ), 3.23 (d, J = 5.8Hz, 4H), 2.94 (d, J = 11.4Hz, 2H), 2.48 (s, 3H), 2.31 (s, 3H), 2. 25 (s, 4H), 1.92-1.83 (m, 2H), 1.62 (d, J = 12.3Hz, 2H). HRMS (ESI) (m / z): calcd forC 25 H 33 N9O[M+H] + ,476.2808;found,476.2888

[0071] Example 2: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-(1-methylpiperidin-4-yl)pyrazole-4-carboxamide

[0072] The synthesis method refers to the synthesis in Example 1, and the product is a yellow-green solid with a yield of 61.5%. 1H NMR (300MHz, DMSO-d6) δ8.61 (s, 1H), 8.49 (s, 1H), 7.88 (d, J=8.5Hz, 2H), 7.82 (s, 1H), 7.39 (s, 2H), 7. 02 (d, J = 8.5Hz, 2H), 3.18 (d, J = 5.5Hz, 4H), 2.45 (d, J = 4.6Hz, 4H), 2.22 (s, 3H). HRMS (ESI) (m / z): calcd for C 19 H 21 N7O2[M+H] + ,380.1757;found,380.1782

[0073] Example 3: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N,N-dimethylpyrazole-4-carboxamide

[0074] The synthesis method refers to the synthesis in Example 1, and the product is a yellow solid with a yield of 69.5%. 1 H NMR (400MHz, DMSO-d6) δ8.98 (d, J=0.8Hz, 1H), 8.60 (s, 1H), 8.15 (d, J=0.8Hz, 1H), 7.94-7.91 (m, 2H), 7.31 (s, 2H), 7.04- 7.01 (m, 2H), 3.22 (s, 4H), 3.21 (d, J = 5.2Hz, 3H), 3.01 (s, 3H), 2.47 (t, J = 4.5Hz, 4H), 2.24 (s, 3H). HRMS (ESI) (m / z): calcd for C 21 H 26 N8O[M+H] + ,407.2230;found,407.2258

[0075] Example 4: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-(4-fluorophenyl)pyrazole-4-carboxamide

[0076] The synthesis method refers to the synthesis in Example 1, and the product is a yellow solid with a yield of 66%. 1H NMR (300MHz, DMSO-d6) δ10.24 (s, 1H), 9.36 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 7.86 (d, J = 8.5Hz, 2H), 7.71-7.66 (m, 2H), 7.27 ( s, 2H), 7.13 (d, J=8.8Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 3.10 (d, J=5.3Hz, 4H), 2.36 (s, 4H), 2.13 (s, 3H). HRMS (ESI) (m / z): calcd for C 25 H 25 FN8O[M+H] + ,473.2135;found,473.2160

[0077] Example 5: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-(3-fluoropyridin-4-yl)pyrazole-4-carboxamide

[0078] The synthesis method refers to the synthesis in Example 1, and the product is a yellow solid with a yield of 61%. 1 H NMR (300MHz, DMSO-d6) δ10.46 (s, 1H), 9.57 (s, 1H), 8.64 (s, 2H), 8.42 (s, 2H), 8.05-7.99 (m, 1H), 7.95 (d, J=7 .9Hz, 2H), 7.36 (s, 2H), 7.02 (d, J=8.4Hz, 2H), 3.20 (s, 4H), 2.46 (s, 4H), 2.22 (s, 3H).HRMS (ESI) (m / z): calcd for C 24 H 24 FN9O[M+H] + ,474.2088;found,474.2093

[0079] Example 6: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-methylpyrazole-4-carboxamide

[0080] The synthesis method refers to the synthesis in Example 1, and the product is a yellow solid with a yield of 72%. 1H NMR (300MHz, DMSO-d6) δ9.22 (s, 1H), 8.57 (s, 1H), 8.42 (d, J = 5.1Hz, 1H), 8.18 (s, 1H), 7.91 (d, J = 8.4Hz, 2H), 7.33 (s, 2H ), 7.00 (d, J = 8.5Hz, 2H), 3.19 (t, J = 5.0Hz, 4H), 2.76 (d, J = 4.4Hz, 3H), 2.44 (s, 4H), 2.21 (s, 3H). HRMS (ESI) (m / z): calcd for C 20 H24N8O[M+H] + , 393.2073; found, 393.2087

[0081] Example 7: N-[2-(Acetylamino)ethyl]-1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0082] The synthesis method refers to the synthesis in Example 1, and the product is a yellow solid with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 8.61 (s, 1H), 8.57 (t, J = 5.6Hz, 1H), 8.22 (s, 1H), 8.03 (t, J = 5.7Hz, 1H), 7.94 (d, J = 8.6Hz, 2H), 7.35 (s, 2H), 7. 03 (d, J=8.7Hz, 2H), 3.30 (d, J=6.3Hz, 2H), 3.25-3.21 (m, 4H), 3.20 (d, J=3.9Hz, 2H), 2.48 (s, 4H), 2.25 (s, 3H), 1.82 (s, 3H). HRMS (ESI) (m / z): calcd for C 23 H 29 FN9O2[M+H] + ,464.2444;found,464.2462

[0083] Example 8: ({1-[(1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazol-4-yl)carbonyl]-4-methylpiperidin-4-yl}amino)methanoic acid-2-methylpropan-2-yl ester

[0084] The synthesis method refers to the synthesis in Example 1, and the product is a yellow solid with a yield of 78%. 1H NMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.78-7.72 (m, 2H), 7.06 (d, J= 9.2Hz, 1H), 7.03-6.94 (m, 3H), 5.89 (s, 1H), 3.68 (dd, J=6.3, 3.6Hz, 2H), 3.44 (dd, J=6.3, 3.6 Hz, 2H), 3.23 (ddd, J=10.6, 6.1, 3.4Hz, 4H), 2.59 (ddd, J=20.0, 6.1, 3.3Hz, 4H), 2.29 (s, 2H), 1.99 (dd, J=6.2, 3.5Hz, 2H), 1.80 (dd, J=6.3, 3.6Hz, 2H), 1.29 (s, 2H). HRMS (ESI) (m / z): calcd forC 30 H 41 N9O3[M+H] + ,576.3366;found,576.3359

[0085] Example 9: (4-amino-4-methylpiperidin-1-yl)(1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazol-4-yl)methanone

[0086] The synthesis method refers to the synthesis in Example 1. In a 100 ml round-bottom flask, ({1-[(1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazol-4-yl)carbonyl]-4-methylpiperidin-4-yl}amino)methane-2-methylpropan-2-yl ester (1.0 eq, 150 mg) was added. A 4N dioxane solution of hydrochloric acid (10 eq, 0.7 rml) was added thereto. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the mixture was concentrated, filtered, and washed with ethyl acetate (2 mL×1). The result was a yellow solid with a yield of 89%. 1 H NMR (300MHz, DMSO-d6) δ11.21 (s, 1H), 8.96 (s, 1H), 8.62 (s, 1H), 8.43 (s, 3H), 8.10 (s, 1H), 7.96 (d, J=7.4Hz, 2H), 7.08 (d, J= 7.7Hz, 2H), 3.91 (d, J=8.2Hz, 4H), 3.48 (s, 4H), 3.16 (s, 4H), 2.79 (s, 3H), 1.77 (s, 4H), 1.38 (s, 3H). HRMS (ESI) (m / z): calcd forC 25 H 33 N9O[M+H] +,476.2808;found,476.2836

[0087] Example 10: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-N-[3-(dimethylamino)propyl]pyrazole-4-carboxamide

[0088] The synthesis method refers to the synthesis in Example 1, yellow solid, yield 63%, 1 H NMR (400MHz, DMSO-d6) δ9.24 (s, 1H), 8.60 (s, 1H), 8.48 (t, J=5.7Hz, 1H), 8. 21 (s, 1H), 7.96-7.92 (m, 2H), 7.34 (s, 2H), 7.06-7.01 (m, 2H), 3.28 (d, J=6. 6Hz, 2H), 3.22 (t, J=5.0Hz, 4H), 2.48 (t, J=5.1Hz, 4H), 2.32 (t, J=7.1Hz, 2H), 2.24 (s, 3H), 2.18 (s, 6H), 1.67 (q, J=7.1Hz, 2H). HRMS (ESI) (m / z): calcd for C 24 H 33 N9O[M+H] + ,464.2808;found,464.2839

[0089] Example 11: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0090] The synthesis method is based on the synthesis of Example 1, and the product is a light yellow solid with a yield of 72%. 1 H NMR (300MHz, DMSO-d6) δ9.27 (s, 1H), 8.60 (s, 1H), 8.20 (s, 1H), 7.95 (s, 2H), 7.92 (s, 1H), 7.37- 7.33 (m, 2H), 7.02 (d, J = 8.6Hz, 2H), 3.20 (d, J = 5.7Hz, 4H), 2.24 (s, 3H). HRMS (ESI) (m / z): calcd forC 19 H 22 N8O[M+H] + , 379.1917; found, 379.1942

[0091] Example 12: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxylic acid ethyl ester

[0092] The synthesis method refers to the synthesis in Example 1, yellow solid, yield 65%, 1 H NMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 8.32 (d, J = 12.9Hz, 2H), 7.78-7.72 (m, 2 H), 7.06 (d, J=9.2Hz, 1H), 7.00 (d, J=9.2Hz, 1H), 7.00-6.94 (m, 2H), 4.33 (q, J=6.4Hz, 2H), 3.23 (ddd, J=10.6, 6.1, 3.4Hz, 4H), 2.61 (dd, J=6.2, 3.3Hz, 2H), 2.57 (dd, J=6.0, 3.3Hz, 2H), 1.25 (t, J=6.3Hz, 3H). HRMS (ESI) (m / z): calcd for C 21 H 25 N7O2[M+H] + ,409.2103;found,409.2112

[0093] Example 13: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1-methyl-1,2,4-triazacyclopentane-3-carboxamide

[0094]

[0095] Step a: 1-(3-amino-6-bromopyrazin-2-yl)-N-methylmethane hydrazide

[0096] In a 100 mL round-bottom flask, 3-amino-6-bromopyrazine-2-carboxylic acid (1.0 eq, 2.80 g) and methylethazine (3.0 eq, 1.78 g) were dissolved in DCM, and EDCI (1.1 eq, 2.6 g) and pentafluorophenol (1.1 eq, 2.2 g) were added to react at room temperature for 4 h. After the reaction, the mixture was concentrated and column chromatography (PE / EA=2:1) ​​was performed to obtain 1-(3-amino-6-bromopyrazine-2-yl)-N-methylmethane hydrazide ester as a light yellow solid with a yield of 73%. HRMS (ESI) (m / z): calcd for C6H8BrN5O[M+H] + , 245.9912; found, 245.9936.

[0097] Step b: 5-(3-amino-6-bromopyrazin-2-yl)-1-methyl-1,2,4-triazacyclopentane-3-carboxylic acid ethyl ester

[0098] In a 100 mL round-bottom flask, 1-(3-amino-6-bromopyrazin-2-yl)-N-methylmethane hydrazide (1.0 eq, 1 g) was dissolved in toluene, and thiooxamate ethyl ester (1.1 eq, 660 mg) was added and reacted at 100°C oil bath for 10 h. After the reaction, the product was concentrated and column chromatography (PE / EA=4:1) was performed to obtain 5-(3-amino-6-bromopyrazin-2-yl)-1-methyl-1,2,4-triazacyclopentane-3-carboxylic acid ethyl ester as a light yellow solid with a yield of 43%. HRMS (ESI) (m / z): calcd for C 10 H 11 BrN6O2[M+H] + ,327.0127;found,327.0142

[0099] Step c: 5-(3-amino-6-bromopyrazin-2-yl)-1-methyl-1,2,4-triazacyclopentane-3-carboxylic acid

[0100] Synthesis steps refer to Example 1, light yellow solid, yield 89%. HRMS (ESI) (m / z): calculation for C8H7BrN6O2 [M+H] + ,298.9814;found,298.9836

[0101] Step d: 5-(3-amino-6-bromopyrazin-2-yl)-1-methyl-1,2,4-triazacyclopentane-3-carboxamide

[0102] Synthesis steps: Refer to Example 1 to obtain 5-(3-amino-6-bromopyrazin-2-yl)-1-methyl-1,2,4-triazacyclopentane-3-carboxamide as a pale yellow solid with a yield of 61%. RMS (ESI) (m / z): calcd for C8H9BrN7O[M+H] + ,297.9974;found,297.9989

[0103] Step e: Synthesis step: Refer to Example 1 to obtain 5-{3-amino-6-[4-(4-methylpiperazine-1-yl)phenyl]pyrazine-2-yl}-1-methyl-1,2,4-triazacyclopentane-3-carboxamide as a light yellow solid with a yield of 61%. 1H NMR (400MHz, DMSO-d6) δ8.71 (s, 1H), 8.42 (s, 1H), 7.87 (d, J = 8.7Hz, 2H), 7.69 (s, 2H), 7.65 (s, 1H), 7.03 (d, J =8.9Hz, 2H), 4.42 (s, 3H), 3.21 (t, J = 5.0Hz, 4H), 2.46 (t, J = 5.1Hz, 4H), 2.23 (s, 3H). HRMS (ESI) (m / z): calcd for C 19 H 23 N9O[M+H] + , 394.2026; found, 394.2055

[0104] Example 14: Ethyl 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1-methyl-1,2,4-triazacyclopentane-3-carboxylate

[0105] The synthesis method refers to the synthesis of Example 13, light yellow solid, yield 65%, 1 H NMR (400MHz, DMSO-d6) δ7.92-7.86 (m, 1H), 7.32 (s, 1H), 6.96-6.90 (m, 1H), 4.47 (q, J=6.4Hz, 1H), 4.12 (s, 1H), 3.28-3.17 (m , 2H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 1H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 1H), 1.38 (t, J=6.4Hz, 1H). HRMS (ESI) (m / z): calcd for C 21 H 26 N8O2[M+H] + ,423.2212;found,423.2205

[0106] Example 15: Synthesis of 5-{3-amino-6-[4-(4-methylpiperazine-1-yl)phenyl]pyrazine-2-yl}-1-methyl-1,2,4-triazacyclopentane-3-carboxylic acid. Refer to the synthesis of Example 13. Light yellow solid. Yield 65%. 1H NMR (400MHz, DMSO-d6) δ7.92-7.86 (m, 1H), 7.32 (s, 1H), 6.96-6.90 (m, 1H), 4.12 (s, 1H), 3.28-3.17 (m , 2H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 1H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 1H). HRMS (ESI) (m / z): calcd for C 19 H 22 N8O2[M+H] + , 395.1899; found, 395.1902

[0107] Example 16: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}tetrahydropyrrole-3-carboxamide

[0108] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 51%, 1 H NMR (300MHz, DMSO-d6) δ7.90 (s, 1H), 7.76 (d, J=8.6Hz, 2H), 7.44 (s, 1H), 6.97 (s, 1H), 6.94 (s, 2H), 5.72 (s, 2H), 3.63-3.60 (m, 2H), 3. 46 (d, J=4.4Hz, 2H), 3.16 (d, J=5.8Hz, 4H), 2.95 (t, J=7.8Hz, 1H), 2.48 (s, 4H), 2.24 (s, 3H), 2.15-1.99 (m, 2H). HRMS (ESI) (m / z): calcd for C 20 H 27 N7O[M+H] + , 382.2277; found, 382.2291

[0109] Example 17: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}thiophene-2-carboxamide

[0110] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 53%, 1H NMR (400MHz, DMSO-d6) δ8.59 (s, 1H), 7.91-7.83 (m, 3H), 7.28 (d, J=7.0Hz, 1H), 7.04 (d, J=16.9Hz, 3H), 6.96-6.90 (m, 2 H), 3.28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 20 H 22 N6OS[M+H] + ,395.1609;found,395.1615

[0111] Example 18: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1,3,4-thiadiazolidine-2-carboxamide

[0112]

[0113] Stepa: 5-bromo-1,3-thiazolyl-2-carboxamide

[0114] In a 100 mL round-bottom flask, 5-bromothiazole-2-carbonitrile (1.0 eq, 1.0 g) was dissolved in DMSO solvent, and 30% H2O2 (3 ml) and K2CO3 (2.0 eq, 1.1 g) were added under ice bath conditions. The mixture was reacted at room temperature for 10 min. After the reaction, it was diluted with water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EA = 4:1) to obtain 5-bromo-1,3-thiazolyl-2-carboxamide as a white solid with a yield of 76%. HRMS (ESI) (m / z): calcd for C4H3BrN2OS[M+H] + ,206.9149;found,206.9167

[0115] Step b: Synthesis method: refer to Example 1, light yellow solid, yield 68%. HRMS (ESI) (m / z): calculated for C 15 H 18 BrN5[M+H] + ,348.0746;found,348.0753

[0116] Step c: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine

[0117] In a 100 mL round-bottom flask, 3-bromo-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-amine (1.0 eq, 200 mg), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (1.5 eq, 440 mg), KOAc (2.5 eq, 220 mg), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 eq, 60 mg) were dissolved in dioxane solvent and reacted in an oil bath at 110° C. under N2 protection for 4 h. After the reaction was completed, the mixture was concentrated, filtered (20 mL × 3), washed with water (2 mL × 3), and dried to obtain 5-[4-(4-methylpiperazine-1-yl)phenyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine as a dark gray solid with a yield of 83%. HRMS (ESI) (m / z): calcd for C 21 H 30 BN5O2[M+H]+, 396.2493; found, 396.2467

[0118] Step d: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1,3,4-thiadiazolidine-2-carboxamide

[0119] The synthesis steps were as in Example 1 to obtain 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1,3,4-thiadiazolidine-2-carboxamide as a light yellow solid with a yield of 59%. 1 H NMR (400MHz, DMSO-d6) δ8.62 (s, 1H), 8.09 (s, 1H), 7.91-7.85 (m, 2H), 7.80 (d, J = 9.0Hz, 1H), 7.45 (d, J = 9.0Hz, 1H), 7.26 (d, J = 9.7Hz, 1H), 7.19 (d, J =9.7Hz, 1H), 6.96-6.90 (m, 2H), 3.28-3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J = 12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 19 H 21 N7OS[M+H]+ ,397.1562;found,397.1569

[0120] Example 19: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1,3-oxazacyclopentane-2-carboxamide

[0121] The synthesis method refers to the synthesis of Example 18, light yellow solid, yield 46%, 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 7.91-7.85 (m, 2H), 7.72 (s, 1H), 7.28 (d, J = 10.1Hz, 1H), 7.13 (d, J = 10.1Hz, 1H), 7.04 (d, J = 9.7Hz, 1H), 6.96 (d, J=9.7Hz, 1H), 6.96-6.90 (m, 2H), 3.28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 19 H 21 N7O2[M+H] + ,380.1790;found,380.1788

[0122] Example 20: 2-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1,3-oxazacyclopentane-5-carboxamide

[0123] The synthesis method refers to the synthesis in Example 18, and the product is a light yellow solid with a yield of 44%. 1 H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 7.92-7.86 (m, 2H), 7.54 (d, J = 10.1Hz, 1H), 7.42 (d, J = 10.1Hz, 1H), 6.98-6.90 (m, 3H), 6.87 (d , J=9.7Hz, 1H), 3.28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 18 H 20 N8O2[M+H] + , 381.1743; found, 381.1736

[0124] Example 21: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1H-pyrazole-3-carboxamide

[0125]

[0126] Stepa: 5-Bromo-1H-pyrazole-3-carboxamide

[0127] In a 100 mL round-bottom flask, 5-bromo-1H-pyrazole-3-carboxylic acid (1.0 eq, 200 mg), ammonia (2 eq, 1.2 ml), and HATU (1.5 eq, 400 mg) were dissolved in DMF, and DIPEA (2.0 eq, 1.0 ml) was added. The mixture was reacted for 3 h at room temperature. After the reaction, the mixture was diluted with water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM / CH3OH=60∶1) to obtain 5-bromo-1H-pyrazole-3-carboxamide as a white solid with a yield of 61%. HRMS (ESI) (m / z): calculated for C4H4BrN3O[M+H] + , 382.1743; found, 382.1736.

[0128] The remaining synthesis steps refer to the synthesis of Example 18, and the product is a pale yellow solid with a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 7.94-7.87 (m, 3H), 7.72 (s, 1H), 7.55 (d, J=9.5Hz, 1H), 6.96-6.90 (m, 2H), 6.59 (s, 2H), 3.28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 19 H 22 N8O[M+H] + , 379.1950; found, 379.1940

[0129] Example 22: 2-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1H-imidazole-5-carboxamide

[0130] The synthesis method refers to the synthesis of Example 21, light yellow solid, yield 46%, 1H NMR (400MHz, DMSO-d6) δ8.71 (s, 1H), 8.32 (s, 1H), 7.94-7.88 (m, 2H), 7.74 (d, J = 7.3Hz, 1H), 7.33 (d, J = 7.3Hz, 1H), 7.10 (d, J = 9.7Hz, 1H ), 6.96-6.88 (m, 3H), 3.28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 19 H 22 N8O[M+H] + , 379.1950; found, 379.1986

[0131] Example 23: 2-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1H-imidazole-4-carboxamide

[0132] The synthesis method refers to the synthesis of Example 21, light yellow solid, yield 41%, 1 H NMR (400MHz, DMSO-d6) δ8.71 (s, 1H), 8.03 (d, J=9.5Hz, 1H), 7.94-7.88 (m, 2H), 7.88 (d, J=6.8Hz, 1H), 7.57 (d, J=9.3Hz, 1H), 7.10 (d, J=9.7H z, 1H), 6.96-6.88 (m, 3H), 3.28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.5, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd forC 19 H 22 N8O[M+H] + , 379.1950; found, 379.1923

[0133] Example 24: 5-{3-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}-1H-pyrrole-2-carboxamide

[0134] The synthesis method refers to the synthesis of Example 21, light yellow solid, yield 41%, 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 7.93-7.87 (m, 3H), 7.63 (d, J=7.3Hz, 1H), 6.96-6.90 (m, 2H), 6.50 (s, 1H), 3 .28-3.17 (m, 4H), 2.80 (ddd, J=12.3, 5.5, 3.9Hz, 2H), 2.57 (ddd, J=12.4, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 20 H 23 N7O[M+H] + , 378.1998; found, 378.1959

[0135] Example 25: 1-(3-amino-6-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0136] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 56%, 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 8.1Hz, 1H), 8.06 (d, J = 8.1Hz, 1H), 7.87-7.81 (m, 2H), 7 .50-7.43 (m, 2H), 7.06 (d, J=9.2Hz, 1H), 7.00 (d, J=9.2Hz, 1H), 3.57 (t, J=1.0Hz, 2H), 2.60-2.50 (m, 8H).HRMS (ESI) (m / z): calcd for C 20 H 24 N8O[M+H]+, 393.2073; found, 393.2095

[0137] Example 26: 1-{3-amino-6-[3-cyano-4-(4-methyl-1,4-diazepan-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0138]

[0139] Step a and Step b are synthesized according to Example 1

[0140] Step c: Synthesis step: Refer to Example 13 to obtain 1-(3-amino-6-bromopyrazin-2-yl)pyrazole-4-carboxamide as a pale yellow solid with a yield of 65%. HRMS (ESI) (m / z): calculated for C8H7BrN6O[M+H]+ , 282.9865; found, 282.9873.

[0141] Step d: Synthesis step: Refer to Example 18 to obtain 1-[3-amino-6-(dihydroxyboryl)pyrazine-2-yl]pyrazole-4-carboxamide as a dark grey solid with a yield of 83%. HRMS (ESI) (m / z): calculated for C8H9BN6O3 [M+H] + , 249.0829; found, 249.0842.

[0142] Step e: 5-bromo-2-(4-methyl-1,4-diazepan-1-yl)benzene-1-carbonitrile

[0143] In a 100 mL round-bottom flask, 5-bromo-2-fluorobenzene-1-carbonitrile (1.0 eq, 1.0 g) and 1-methyl-1,4-diazepane (1.2 eq, 690 mg) were dissolved in DMSO solvent, triethylamine (2.0 eq, 0.67 ml) was added and reacted in an oil bath at 140°C for 12 h. After the reaction was completed, water was added for dilution, ethyl acetate was extracted (20 mL × 3), the organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (PE / EA = 10:1) to obtain 5-bromo-2-(4-methyl-1,4-diazepane-1-yl)benzene-1-carbonitrile as a white solid with a yield of 76%. HRMS (ESI) (m / z): calcd for C 13 H 16 BrN3[M+H] + ,294.0528;found,294.0543

[0144] Step f: The synthesis step was carried out by referring to Example 1 to obtain 1-{3-amino-6-[3-cyano-4-(4-methyl-1,4-diazepan-1-yl)phenyl]pyrazine-2-yl}pyrazole-4-carboxamide as a light yellow solid with a yield of 68%. 1H NMR (300MHz, DMSO-d6) δ8.89 (s, 1H), 8.27 (s, 1H), 7.84 (d, J=2.3Hz, 1H), 7 .81(s, 1H), 7.76(dd, J=9.1, 2.3Hz, 1H), 7.53(s, 1H), 7.05(s, 2H), 6.92(s, 1H), 6.68 (d, J=9.2Hz, 1H), 3.31 (d, J=5.8Hz, 2H), 3.23 (t, J=5.9Hz, 2H), 2 .39(s, 2H), 2.21(s, 2H), 1.93(s, 3H), 1.59(s, 2H).HRMS(ESI)(m / z): calcd for C 21 H 22 N9O[M+H] + ,418.2026;found,418.2037

[0145] Example 27: 2-methylpropan-2-yl 6-{4-[5-amino-6-(4-formamidopyrazol-1-yl)pyrazin-2-yl]-2-cyanophenyl}-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0146] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 58%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 2.3Hz, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1 H), 7.91 (dd, J=8.2, 2.2Hz, 1H), 7.11 (s, 2H), 7.10 (d, J=8.2Hz, 1H), 3.76 (d, J=17.8Hz, 5H), 3.70 (s, 2H).HRMS (ESI) (m / z): calcd for C 25 H 27 N9O3[M+H] + , 502.2270; found, 502.2265.

[0147] Example 28: 7-{4-[5-amino-6-(4-formamidopyrazol-1-yl)pyrazin-2-yl]-2-cyanophenyl}-2,7-diazaspiro[4.4]nonane-2-carboxylic acid-2-methylpropan-2-yl ester

[0148] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 56%. 1H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (d, J = 1.8Hz, 1H), 8.20 (d, J = 1.8Hz, 1H), 8.15 (d, J=1.9Hz, 1H), 8.10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.91 (dd, J=8.1, 1.9Hz, 1H), 7.08 (d, J=8.2Hz, 1H), 3.64-3.54 (m, 2H), 3.54-3.46 (m, 2H), 3.493.40 (m, 2H), 3.3 2 (td, J=3.5, 0.9Hz, 2H), 1.89-1.76 (m, 3H), 1.78-1.70 (m, 1H). HRMS (ESI) (m / z): calcd for C 27 H 31 N9O3[M+H] + ,530.2583;found,530.2555

[0149] Example 29: 1-{3-amino-6-[2-cyano-1-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl-4-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0150] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 67%. 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 9.02-8.90 (m, 2H), 8.67 (s, 1H), 8.26-8.21 (m, 2H), 8.17 (dd, J=9.1, 2.4Hz, 1H), 7.94 (s, 1H), 7.33 (s, 1H), 6.86 (d, J=9.1Hz, 1H), 3 .72 (t, J=7.1Hz, 2H), 3.68-3.57 (m, 2H), 3.34 (q, J=6.4Hz, 2H), 3.23 (h, J=5.9Hz, 2H ), 2.09 (tt, J=9.7, 5.1Hz, 2H), 1.99 (dd, J=13.4, 6.5Hz, 2H). HRMS (ESI) (m / z): calcd for C 22 H 23 N9O[M+H] + ,430.2026;found,430.2059

[0151] Example 30: 1-{3-amino-6-[2-(4-methylpiperazin-1-yl)-1,3-thiazolyl-5-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0152] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.37(s, 2H), 7.32(s, 1H), 3.48(s, 4H), 2.44(s, 4H), 2.24(s, 3H).HRMS(ESI)(m / z): calcd for C 16 H 10 N9OS[M+H] + ,386.1433;found,386.1469

[0153] Example 31: 1-{3-amino-6-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0154] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 63%, 1 H NMR (400MHz, DMSO-d6) δ9.35 (s, 1H), 9.31 (s, 1H), 9.07 (d, J=9.9Hz, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.10 ( s, 1H), 7.98 (s, 1H), 7.33 (s, 1H), 4.54 (d, J=4.7Hz, 1H), 3.40-3.03 (m, 4H), 2.31-2.15 (m, 4H). HRMS (ESI) (m / z): calcd for C 16 H 19 N9O[M+H] + , 354.1713; found, 354.1751

[0155] Example 32: (1S, 5R)-3-{4-[5-amino-6-(4-formamidopyrazol-1-yl)pyrazin-2-yl]-2-cyanophenyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid-2-methylpropan-2-yl ester

[0156] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 67%, 1H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 2.3Hz, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H) , 7.91 (dd, J=8.2, 2.2Hz, 1H), 7.13-7.06 (m, 2H), 4.22-4.15 (m, 2H), 3.65-3.54 (m, 4H), 2.03-1.83 (m, 4H). HRMS (ESI) (m / z): calcd for C 26 H 29 N9O3[M+H] + ,516.2427;found,516.2413

[0157] Example 33: 1-(3-amino-6-{2-cyano-1-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl-4-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0158] The synthesis method refers to the synthesis in Example 9, and the product is a light yellow solid with a yield of 92%. 1 H NMR (300MHz, DMSO-d6) δ9.36 (s, 2H), 9.33 (s, 1H), 8.74 (s, 1H), 8.46 (d, J=2.2Hz, 1H), 8.37-8.31 (m, 1H), 8.23 ​​(s, 1H), 7. 94 (s, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.8Hz, 1H), 4.18 (s, 2H), 3.50-3.38 (m, 4H), 2.22-1.99 (m, 4H). HRMS (ESI) (m / z): calcd for C 21 H 21 N9O[M+H]+, 416.1869; found, 416.1892

[0159] Example 34: 1-{3-amino-6-[2-cyano-1-(4,4-difluorohexahydropyridin-1-yl)phenyl-4-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0160] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 76%, 1H NMR (400MHz, DMSO-d6) δ9.34 (d, J=8.8Hz, 1H), 8.77 (d, J=22.2Hz, 1H), 8.47 (dd, J=28.9, 2.1Hz, 1H), 8.39 8.29 (m, 1H), 8.22 (d, J = 2.5Hz, 1H), 7.93 (s, 1H), 7.62 (d, J = 33.8Hz, 2H), 7.32 (d, J = 8.3Hz, 2H), 3.52-3.33 (m, 4H), 2.19 (tt, J=13.2, 5.3Hz, 4H). HRMS (ESI) (m / z): calcd forC 20 H 18 F2N8O[M+H]+, 425.1752; found, 425.1783

[0161] Example 35: (1R, 5S)-8-{4-[5-amino-6-(4-formamidopyrazol-1-yl)pyrazin-2-yl]-2-cyanophenyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid-2-methylpropan-2-yl ester

[0162] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 68%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.15 (d, J=8.1Hz, 1H), 8.08 -8.02 (m, 2H), 7.80 (dd, J=8.8, 2.2Hz, 1H), 7.10 (d, J=8.7Hz, 1H), 7.06 (d, J=9.2Hz, 1H), 7. 00 (d, J=9.2Hz, 1H), 4.11 (ddddd, J=8.6, 5.7, 4.8, 3.8, 1.9Hz, 2H), 3.81 (d, J=4.8Hz, 2H), 3 .64 (d, J=2.0Hz, 2H), 1.99 (d, J=3.7Hz, 2H), 1.78 (d, J=5.7Hz, 2H). HRMS (ESI) (m / z): calcd forC 26 H 29 N9O3[M+H] + ,516.2427;found,516.2436

[0163] Example 36: 1-(3-amino-6-{2-cyano-1-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl]phenyl-4-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0164] The synthesis method refers to the synthesis of Example 26 and Example 9, yellow solid, yield 92%. 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 8.67 (s, 1H), 8.25 (d, J = 34.2Hz, 2H), 8.16 (d, J = 9.1Hz, 1H), 7.94 (s, 1H), 7.48 (s, 2H), 7.31 (s, 1H), 7.14 (d, J=9.0Hz, 1H), 4.29 (s, 2H), 2.98 (d, J=12.2Hz, 2H), 2.66 (d, J=12.2Hz, 2H), 1.94-1.81 (m, 4H). HRMS (ESI) (m / z): calcd for C 21 H 21 N9O[M+H] + ,415.1869;found,416.1883

[0165] Example 37: 1-(3-amino-6-{3-[(dimethylamino)carbonyl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0166] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 67%. 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 8.1Hz, 1H), 8.09 (t, J = 2.1Hz, 1H), 8.06 (d, J = 8.1Hz, 1H) , 7.75 (dt, J=7.5, 2.2Hz, 1H), 7.73-7.64 (m, 2H), 7.06 (d, J=9.2Hz, 1H), 7.00 (d, J=9.2Hz, 1H), 2.99 (s, 5H).HRMS (ESI) (m / z): calcd for C 17 H 17 N7O2[M+H] + , 352.1444; found, 352.1462

[0167] Example 38: 1-(3-amino-6-{4-amino-3-[(dimethylamino)carbonyl]-2-fluorophenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0168] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 56%, 1H NMR (300MHz, DMSO-d6) δ9.20 (s, 1H), 8.27 (d, J = 43.0Hz, 2H), 7.85 (d, J = 41.4Hz, 2H), 7. 38(s, 2H), 7.29(s, 1H), 6.68(s, 1H), 5.58(s, 2H), 1.23(s, 6H).HRMS(ESI)(m / z): calcd for C 17 H 17 FN8O2[M+H] + ,385.1459;found,385.1473

[0169] Example 39: 1-{3-amino-6-[2-cyano-1-(4-methylpiperazin-1-yl)phenyl-4-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0170] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 75%, 1 H NMR (300MHz, DMSO-d6) δ9.32 (s, 1H), 8.71 (s, 1H), 8.39 (d, J=2.2Hz, 1H), 8.28 (dd, J=8.8, 2.3Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7 .54 (s, 2H), 7.32 (s, 1H), 7.23 (d, J=8.7Hz, 1H), 3.23 (t, J=4.8Hz, 4H), 2.54 (d, J=5.2Hz, 4H), 2.26 (s, 3H).HRMS (ESI) (m / z): calcd for C 20 H 21 N9O[M+H] + ,404.1869;found,404.1891

[0171] Example 40: 1-{3-amino-6-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0172] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 65%, 1 H NMR (300MHz, DMSO-d6) δ9.38 (s, 1H), 9.06 (s, 2H), 8.61 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.48 (s , 2H), 7.34 (s, 1H), 3.85-3.76 (m, 4H), 2.44 (t, J=6.0Hz, 4H), 2.26 (s, 3H).HRMS (ESI) (m / z): calcd forC 17H 20 N 10 O[M+H] + , 381.1822; found, 381.1853

[0173] Example 41: 1-{3-amino-6-[3-(4-methylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0174] The synthesis method refers to the synthesis in Example 1, light yellow solid, yield 64%, 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.65 (ddd, J=8.8, 1.8, 1.1Hz, 1H), 7.30 (dd, J=8.8, 7.3Hz, 1H), 7.14 (t, J=1.9Hz, 1H), 6.89 (ddd, J=7.3, 1.9, 1.2Hz, 1H), 3.28-3.17 (m, 4H), 2.80 (ddd , J=12.3, 5.4, 3.9Hz, 2H), 2.57 (ddd, J=12.5, 5.5, 3.9Hz, 2H). HRMS (ESI) (m / z): calcd for C 19 H22N8O[M+H] + , 379.1950; found, 379.1911

[0175] Example 42: 1-{3-amino-6-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0176] The synthesis method is based on the synthesis of Example 1, and the product is a light yellow solid with a yield of 66%. 1 H NMR (300MHz, DMSO-d6) δ9.34 (s, 1H), 8.87 (s, 1H), 8.60 (s, 1H), 8.18 (d, J=6.7Hz, 2H), 7.94 (s, 1H), 7.40 (s, 2H), 7. 32 (s, 1H), 6.91 (d, J = 9.0Hz, 1H), 3.55 (t, J = 5.0Hz, 4H), 2.40 (d, J = 5.1Hz, 4H), 2.22 (s, 3H). HRMS (ESI) (m / z): calcd for C 18 H 21 N9O[M+H] + , 380.1903; found, 380.1935

[0177] Example 43: 1-{3-amino-6-[4-(hexahydropyridin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0178] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.90-7.85 (m, 2H), 7.11 (s, 2H ), 6.96-6.90 (m, 2H), 3.38 (ddd, J=9.5, 6.0, 3.3Hz, 4H), 1.68 (dddd, J=9.3, 5.3, 4.4, 2.1Hz, 4H), 1.65-1.57 (m, 2H). HRMS (ESI) (m / z): calcd forC 19 H 21 N7O[M+H] + , 364.1841; found, 364.1861

[0179] Example 44: 1-{3-amino-6-[3-cyano-4-(tetrahydro-1H-pyrrol-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0180] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 65%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 2.3Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 8.04 (d, J = 8.0Hz, 1H), 7 .91 (dd, J=8.2, 2.2Hz, 1H), 7.13-7.05 (m, 2H), 3.56 (tt, J=3.4, 1.5Hz, 4H), 1.97 (ddt, J=3.5, 2.3, 1.3Hz, 4H).HRMS (ESI) (m / z): calcd for C 19 H18N8O[M+H] + ,375.1637;found,375.1655

[0181] Example 45: 1-{3-amino-6-[4-(diethylamino)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0182] The synthesis method is based on the synthesis of Example 1, and the product is a light yellow solid with a yield of 68%.1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.85- 7.79 (m, 2H), 7.11 (s, 2H), 6.79-6.73 (m, 2H), 3.31 (q, J=7.1Hz, 4H), 1.16 (t, J=7.0Hz, 6H). HRMS (ESI) (m / z): calcd for C 18 H 21 N7O[M+H] + , 352.1841; found, 352.1866

[0183] Example 46: 1-(3-amino-6-{3-cyano-4-[(3S)-3-fluorotetrahydro-1H-pyrrol-1-yl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0184] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 63%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 2H), 8.30 (s, 2H), 8.20 (s, 2H), 8.15 (d, J=2.3Hz, 2H), 8.10 (d, J=8 .1Hz, 2H), 8.04 (d, J=8.1Hz, 2H), 7.91 (dd, J=8.2, 2.2Hz, 2H), 7.06 (d, J=8.1Hz, 2H), 4.97-4.91 (m, 1H), 4.85 (dq, J=4.3, 2.5Hz, 1H), 3.68 (ddd, J=12.3, 6.9, 5.1Hz, 2H), 3.51-3.47 (m, 2H), 3.44 (dd, J =1.8, 1.1Hz, 2H), 3.45-3.37(m, 2H), 2.23-2.09(m, 2H), 2.05-1.90(m, 2H).HRMS(ESI)(m / z): calcd for C 19 H 17 FN8O[M+H] + ,393.1543;found,393.1596

[0185] Example 47: 1-(3-amino-6-{4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0186] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 67%. 1H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.1Hz, 1H), 8 .04(d, J=8.1Hz, 1H), 7.90-7.85(m, 2H), 7.11(s, 1H), 6.96-6.90(m, 2H), 3.33-3.20(m, 4 H), 2.75-2.61 (m, 6H), 2.44 (ddd, J=12.4, 8.1, 5.4Hz, 2H), 2.37 (p, J=5.4Hz, 1H), 1.77 (d dt, J=12.3, 8.1, 5.3Hz, 2H), 1.58 (ddt, J=12.5, 8.2, 5.5Hz, 2H). HRMS (ESI) (m / z): calcd for C 24 H 31 N9O[M+H] + ,462.2685;found,462.2621

[0187] Example 48: 1-(3-amino-6-{4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0188] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 59%. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.90-7.85 (m, 2H), 7.11 (s, 1H), 6.96-6.90 (m, 2H), 3.58 (qdd, J=12.5, 6.2, 3.9Hz , 4H), 3.33-3.20 (m, 4H), 2.73 (dd, J=6.0, 3.8Hz, 2H), 2.64 (d, J=3.7Hz, 1H), 2.65-2.57 (m, 2H), 1.82 (dtd, J=12.4, 6.2, 4.0Hz, 2H), 1.65 (dtd, J=12.4, 6.2, 4.0Hz, 2H). HRMS (ESI) (m / z): calcd for C 23 H 28 N8O2[M+H] + ,449.2369;found,449.2355

[0189] Example 49: 1-{3-amino-6-[3-cyano-4-(4-cyclopropylpiperazin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0190] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 52%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J=2.3Hz, 1H) , 8.10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.91 (dd, J=8.2, 2.2Hz, 1H), 7.13-7.0 5 (m, 2H), 3.25-3.13 (m, 4H), 2.77 (dd, J=5.9, 3.8Hz, 2H), 2.65 (dd, J=6.0, 3.8Hz, 2H) , 2.50 (p, J=5.7Hz, 1H), 0.76-0.64 (m, 2H), 0.64-0.52 (m, 2H). HRMS (ESI) (m / z): calcd for C 22 H 23 N9O[M+H] + ,430.2059;found,430.2019

[0191] Example 50: 1-(3-amino-6-{3-cyano-4-[(3S)-3,4-dimethylpiperazin-1-yl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0192] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 54%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J=2 .3Hz, 1H), 8.10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.91 (dd, J=8.2, 2.2 Hz, 1H), 7.11 (s, 2H), 7.06 (d, J=8.1Hz, 1H), 3.45-3.29 (m, 4H), 3.04-2.93 ( m, 3H), 2.29 (d, J = 1.4Hz, 3H), 1.15 (d, J = 8.1Hz, 3H). HRMS (ESI) (m / z): calcd for C 21 H 23 N9O[M+H] + ,418.2059;found,418.2044

[0193] Example 51: The synthesis method of 1-(3-amino-6-{3-cyano-4-[(3S)-3-ethyl-4-methylpiperazin-1-yl]phenyl}pyrazin-2-yl)pyrazole-4-carboxamide refers to the synthesis of Example 26, light yellow solid, yield 53%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J=2.2Hz, 1H), 8.10 (d, J=8. 1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.91 (dd, J=8.2, 2.2Hz, 1H), 7.11 (s, 2H), 7.06 (d, J=8.1Hz, 1H), 3.5 3-3.42 (m, 2H), 3.27 (t, J=4.9Hz, 2H), 2.96 (dt, J=12.5, 4.8Hz, 1H), 2.79-2.70 (m, 1H), 2.70-2.62 (m , 1H), 2.29 (d, J=1.4Hz, 3H), 1.69-1.52 (m, 2H), 0.90 (td, J=7.3, 1.5Hz, 3H). HRMS (ESI) (m / z): calcd for C 22 H 25 N9O[M+H] + ,432.2216;found,432.2200

[0194] Example 52: 1-{3-amino-6-[4-(piperazin-1-yl)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0195] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 67%. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.90-7.85 (m , 2H), 7.11 (s, 2H), 6.96-6.90 (m, 2H), 3.35-3.24 (m, 4H), 3.10_2.99 (m, 4H), 1.95 (q, J=3.3Hz, 1H).HRMS (ESI) (m / z): calcd for C 18 H 20 N8O[M+H] + , 365.1794; found, 365.1785

[0196] Example 53: The synthesis method of 1-{3-amino-6-[3-cyano-4-(6-aza-2-oxaspiro[3.3]hept-6-yl)phenyl]pyrazine-2-yl}pyrazole-4-carboxamide refers to the synthesis of Example 26, light yellow solid, yield 65%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 2.3Hz, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.91 (dd, J=8.2, 2.2Hz, 1H), 7.11 (s, 2H), 7.10 (d, J=8.2Hz, 1H), 3.82 (s, 3H), 3.70 (s, 3H). HRMS (ESI) (m / z): calcd for C 18 H 20 N8O[M+H] + ,403.1586;found,403.1544

[0197] Example 54: The synthesis method of 1-{3-amino-6-[3-cyano-4-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)phenyl]pyrazine-2-yl}pyrazole-4-carboxamide refers to the synthesis of Example 26, light yellow solid, yield 62%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.15 (d, J=2.2Hz, 1H), 8.10 (d , J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.91 (dd, J=8.2, 2.2Hz, 1H), 7.11 (s, 2H), 7.10 (d, J=8. 2Hz, 1H), 3.67 (d, J=0.7Hz, 4H), 2.73-2.67 (m, 1H), 2.59-2.52 (m, 2H), 2.49 (ddd, J=12.2, 3.9 , 2.2Hz, 1H), 1.83 (dd, J=4.0, 2.0Hz, 1H), 1.73 (dd, J=4.0, 2.1Hz, 1H). HRMS (ESI) (m / z): calcd for C 22 H 23 N9O[M+H] + ,430.2059;found,430.2020

[0198] Example 55: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)pyrazol-1-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0199] The synthesis method is based on the synthesis of Example 1, and the product is a light yellow solid with a yield of 56%. 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.86 (s, 1H), 7.36 (s, 1 H), 7.17 (s, 2H), 3.31-3.20 (m, 4H), 2.92 (ddd, J=12.3, 5.4, 4.1Hz, 2H), 2.61 (ddd, J=12.3, 5.4, 4.0Hz, 2H). HRMS (ESI) (m / z): calcd for C 16 H 20 N 10 O[M+H] + , 369.1855; found, 369.1849

[0200] Example 56: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)-1H-pyrrol-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0201] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 58%. 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.00 (s, 2H), 6.81 (dd, J = 8.2, 1.6Hz , 1H), 6.56 (d, J=1.8Hz, 1H), 3.17 (ddd, J=5.1, 4.2, 0.8Hz, 4H), 2.90-2.82 (m, 2H), 2.57 (ddd, J=12.3, 5.2, 4.2Hz, 2H). HRMS (ESI) (m / z): calcdfor C 17 H 21 N9O[M+H] + ,403.1586;found,368.1963

[0202] Example 57: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)furan-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0203] The synthesis method is based on the synthesis of Example 1, and the product is a light yellow solid with a yield of 52%. 1H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.17 (d, J = 1.7Hz, 1H), 6. 43 (d, J=1.8Hz, 1H), 3.27-3.16 (m, 4H), 2.92 (ddd, J=12.3, 5.2, 4.1Hz, 2H), 2.61 (ddd, J=12.3, 5.3, 4.0Hz, 2H). HRMS (ESI) (m / z): calcd for C 17 H 20 N8O2[M+H] + , 369.1743; found, 369.1703

[0204] Example 58: 1-{3-amino-6-[5-(4-methylpiperazin-1-yl)furan-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0205] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 54%. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 6.94 (d, J = 5.5Hz, 1H), 6.70 (d, J=5.5Hz, 1H), 3.52 (t, J=4.5Hz, 4H), 2.70-2.64 (m, 1H), 2.64 (d, J=4.5Hz, 1H), 2.59 (dt, J=12.5, 4.5Hz, 2H). HRMS (ESI) (m / z): calcd for C 17 H 20 N8O2[M+H] + , 369.1743; found, 369.1799

[0206] Example 59: 1-{3-amino-6-[5-(4-methylpiperazin-1-yl)thiophen-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0207] The synthesis method refers to the synthesis in Example 1, and the product is a light yellow solid with a yield of 57%. 1H NMR (400MHz, DMSO-d6) δ8.54 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.23 (s, 2H), 7. 07 (d, J=6.6Hz, 1H), 6.60 (d, J=6.6Hz, 1H), 3.53-3.44 (m, 4H), 2.87-2.79 (m, 2H), 2.67-2.60 (m, 2H). HRMS (ESI) (m / z): calcd for C 17 H 20 N8OS[M+H] + ,385.1514;found,385.1549

[0208] Example 60: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)-1,3-thiazolyl-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0209] The synthesis method is based on the synthesis of Example 1, and the product is a light yellow solid with a yield of 53%. 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7. 36 (s, 2H), 6.61 (s, 1H), 3.60 (ddd, J=20.5, 6.5, 3.8Hz, 4H), 2.57 (dt, J=6.6, 3.9Hz, 4H). HRMS (ESI) (m / z): calcd for C 16 H 19 N9OS[M+H] + ,386.1467;found,386.1455

[0210] Example 61: 1-{3-amino-6-[4-(4-methylpiperazin-1-yl)-1,3-thiazolyl-2-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0211]

[0212] Step a: 5-bromo-2-{[2-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}benzene-1-carbonitrile

[0213] In a 100 mL round-bottom flask, 2-(tetrahydro-1H-pyrrol-1-yl)propan-1-ol (1.0 eq, 190 mg) and 5-bromo-2-hydroxybenzonitrile (1.0 eq, 300 mg) were dissolved in acetonitrile solvent, triphenylphosphine (1.2 eq, 460 mg) was added and stirred for 5 min in an ice bath. DIAD (1.2 eq, 0.4 ml) was added and then reacted at room temperature for 4 h. After the reaction was completed, 5-bromo-2-{[2-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}benzene-1-carbonitrile was obtained by column chromatography (PE / EA=6:1) as a white solid with a yield of 68%. HRMS (ESI) (m / z): calculated for C 14 H 17 BrN2O[M+H] + , 309.0524; found, 309.0536

[0214] Step b: Synthesis step reference Example 18, black oily liquid, yield 67%. HRMS (ESI) (m / z): calculated for C 20 H 29 BN2O3[M+H] + ,357.2271;found,357.2293

[0215] Step c: Synthesis step reference Example 1, light yellow solid, yield 68%. HRMS (ESI) (m / z): calculated for C 18 H 20 BrN5O[M+H] + ,402.0851;found,402.0873

[0216] Step d: Synthesis step reference Example 18, black oily liquid, yield 62%. HRMS (ESI) (m / z): calculated for C 24 H 32 BN5O3[M+H] + ,450.2598;found,450.2607

[0217] Step e: Synthesis step reference Example 21, light yellow solid, yield 61%. HRMS (ESI) (m / z): calculated for C4H4BrN3O [M+H] + , 189.9538; found, 189.9567.

[0218] Step f: The synthesis step was carried out by referring to Example 1 to obtain 5-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazine-2-yl]-2H-pyrazole-3-carboxamide as a light yellow solid with a yield of 54%. 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 8.36 (d, J=1.9Hz, 1H), 7.82 (dd, J=8.8, 1.8Hz, 1H), 7.17 (d, J=8 .8Hz, 1H), 6.67 (d, J=7.5Hz, 1H), 6.60 (d, J=7.5Hz, 1H), 6.36 (s, 2H), 4.09 (t, J=6.5Hz, 2H), 4.05-3. 98 (m, 1H), 3.953.83 (m, 2H), 3.49 (ddd, J=12.6, 7.2, 5.4Hz, 1H), 2.72-2.55 (m, 7H), 2.17-2.08 (m, 1H ), 2.08-1.99 (m, 1H), 1.91 (ddt, J=17.5, 13.1, 6.6Hz, 2H), 1.82-1.74 (m, 4H). HRMS (ESI) (m / z): calcd for C 23 H 29 N7O2[M+H] + ,436.2416;found,436.2400

[0219] Example 62: 5-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]furan-2-carboxamide

[0220] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 51%. 1 H NMR (400MHz, DMSO-d6) δ8.71 (s, 1H), 8.36 (d, J=1.9Hz, 1H), 7.85 (dd, J=8.8, 2. 0Hz, 1H), 7.33 (s, 0H), 7.20 (d, J=8.8Hz, 1H), 7.11 (d, J=5.9Hz, 1H), 6.92 (d, J=8 .6Hz, 1H), 6.86-6.80 (m, 2H), 6.76 (d, J=9.7Hz, 1H), 4.09 (t, J=6.6Hz, 2H), 2.71 -2.55(m, 6H), 1.91(p, J=6.5Hz, 2H), 1.83-1.75(m, 2H).HRMS(ESI)(m / z): calcd for C 23 H 24 N6O3[M+H]+ , 433.1943; found, 433.1996

[0221] Example 63: 2-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1H-imidazole-5-carboxamide

[0222] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 56%. 1 H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 8.32 (s, 1H), 8.15-8.08 (m, 2H), 7.74 (d, J = 7.3Hz, 1H), 7.33 (d, J = 7.3Hz, 1H), 7.15 (s, 1H), 7.15-7.07 (m , 1H), 6.91 (d, J=9.7Hz, 1H), 4.03 (t, J=6.6Hz, 2H), 2.71-2.55 (m, 6H), 1.88 (p, J=6.6Hz, 2H), 1.82-1.75 (m, 2H).HRMS (ESI) (m / z): calcdforC 21 H 25 N7O2[M+H] + ,408.2103;found,408.2123

[0223] Example 64: 5-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1H-pyrazole-3-carboxamide

[0224] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 53%. 1 H NMR (400MHz, DMSO-d6) δ 8.12-8.06 (m, 1H), 7.91 (d, J = 9.5Hz, 1H), 7.55 (d, J = 9.5Hz, 1H), 7.17-7.11 (m, 1H), 6.59 ( s, 1H), 4.03 (t, J=6.6Hz, 1H), 2.71-2.54 (m, 3H), 1.88 (p, J=6.6Hz, 1H), 1.83-1.75 (m, 2H). HRMS (ESI) (m / z): calcd for C 21 H 25 N7O2[M+H] + ,403.1586;found,408.2155

[0225] Example 65: The synthesis method of 1-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazine-2-yl]pyrazole-3-carboxamide refers to the synthesis of Example 61, light yellow solid, yield 54%. 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 1.9Hz, 1H), 7.99 (d, J = 4.8Hz , 1H), 7.82 (dd, J=8.8, 1.8Hz, 1H), 7.45 (d, J=9.5Hz, 1H), 7.17 (dd, J=9.2, 1. 6Hz, 2H), 7.11 (s, 1H), 7.06 (d, J=4.8Hz, 1H), 4.09 (t, J=6.6Hz, 2H), 2.71-2. 54 (m, 6H), 1.91 (p, J = 6.5Hz, 2H), 1.83-1.75 (m, 2H). HRMS (ESI) (m / z): calcd for C 22 H 24 N8O2[M+H] + ,403.1586;found,433.2059

[0226] Example 66: The synthesis method of 2-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazine-2-yl]pyrazole-3-carboxamide refers to the synthesis of Example 61, light yellow solid, yield 58%. 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 1H), 8.36 (d, J=1.9Hz, 1H), 7.83 (dd, J=8.8, 2 .0Hz, 1H), 7.72 (d, J=3.8Hz, 1H), 7.63 (d, J=7.1Hz, 1H), 7.34 (s, 1H), 7.18 (d, J =8.8Hz, 1H), 7.11 (d, J = 3.8Hz, 1H), 6.95 (s, 2H), 4.09 (t, J = 6.6Hz, 2H), 2.71- 2.54 (m, 6H), 1.91 (p, J=6.5Hz, 2H), 1.83-1.75 (m, 4H). HRMS (ESI) (m / z): calcd for C 22 H 24 N8O2[M+H] + ,433.2056;found,433.2056

[0227] Example 67: 4-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1H-pyrrole-2-carboxamide

[0228] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 61%. 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 1H), 8.38 (d, J=1.9Hz, 1H), 7.90 (dd, J=8.8, 1.8Hz, 1H), 7.40 (d, J=1.8Hz, 1H), 7.31 (dd, J=7.3, 1.6Hz, 1H), 7 .20 (d, J=8.8Hz, 1H), 6.80 (s, 2H), 4.09 (t, J=6.6Hz, 2H), 2.71-2.54 (m, 7H), 1.91 (p, J=6.5Hz, 2H), 1.82-1.75 (m, 4H). HRMS (ESI) (m / z): calcd forC23H25N7O2[M+H] + ,432.2103;found,4432.2183

[0229] Example 68: 4-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1H-pyrrole-3-carboxamide

[0230] The synthesis method refers to the synthesis in Example 61, light yellow solid, yield 49%. 1 H NMR (400MHz, DMSO-d6) δ9.07 (t, J=7.3Hz, 1H), 8.78 (s, 1H), 8.38 (d, J=1.9Hz, 1H), 8.0 3 (s, 2H), 7.91 (dd, J=8.8, 2.0Hz, 1H), 7.41 (dd, J=7.1, 1.6Hz, 1H), 7.21 (s, 0H), 6.94 (d d, J=7.6, 1.7Hz, 1H), 6.80 (d, J=9.7Hz, 1H), 6.70 (d, J=9.7Hz, 1H), 4.09 (t, J=6.6Hz, 2H ), 2.71-2.54(m, 6H), 1.91(p, J=6.5Hz, 2H), 1.83-1.75(m, 4H).HRMS(ESI)(m / z): calcd for C 23 H 25 N7O2[M+H] + ,432.2103;found,432.2185

[0231] Example 69: The synthesis method of 5-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazine-2-yl]thiophene-2-carboxamide refers to the synthesis of Example 61, light yellow solid, yield 47%. 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.37 (d, J = 1.9Hz, 1H), 7.90-7.83 (m, 2H), 7.28 (d, J = 7.0Hz, 1H), 7.20 (d, J = 8.8Hz, 1H), 7.0 4 (d, J=16.8Hz, 3H), 4.09 (t, J=6.6Hz, 2H), 2.71-2.54 (m, 6H), 1.91 (p, J=6.5Hz, 2H), 1.83-1.75 (m, 4H). HRMS (ESI) (m / z): calcd forC 23 H 24 N6O2S[M+H] + ,449.1715;found,449.1765

[0232] Example 70: 5-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1,3-thiazolyl-2-carboxamide

[0233] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 51%. 1 H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.11-8.04 (m, 3H), 7.80 (d, J = 9.0Hz, 1H), 7.45 (d, J = 9.0Hz, 1H), 7.26 (d, J = 9.7Hz, 1H), 7.19 (d, J = 9 .7Hz, 1H), 7.17-7.11 (m, 2H), 4.03 (t, J=6.6Hz, 2H), 2.71-2.55 (m, 7H), 1.88 (p, J=6.6Hz, 2H), 1.83-1.75 (m, 2H).HRMS (ESI) (m / z): calcd for C 21 H 24 N6O2S[M+H] + ,425.1715;found,425.1700

[0234] Example 71: 5-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1-methyl-1,2,4-triazacyclopentane-3-carboxamide

[0235] The synthesis method refers to the synthesis of Example 13 and Example 61, and the product is a light yellow solid with a yield of 59%. 1 H NMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 8.11-8.05 (m, 2H), 7.32 (s, 2H), 7.17-7.11 (m, 2H), 6.95 (d, J=10.8Hz, 1H), 6.67 (d, J=10.8 Hz, 1H), 4.09 (s, 2H), 4.03 (t, J=6.6Hz, 2H), 2.71-2.54 (m, 7H), 1.88 (p, J=6.6Hz, 2H), 1.82-1.75 (m, 2H). HRMS (ESI) (m / z): calcd forC 21 H 26 N8O2[M+H] + ,423.2212;found,423.2276

[0236] Example 72: 5-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1-methyl-1,2,4-triazacyclopentane-3-carboxamide

[0237] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 54%. 1 H NMR (400MHz, DMSO-d6) δ8.67 (s, 1H), 8.09-8.03 (m, 2H), 7.72 (s, 1H), 7.28 (d, J = 10.1Hz, 1H), 7.17-7.10 (m, 3H), 7.04 (d, J = 9.7Hz, 1H ), 6.96 (d, J = 9.7Hz, 1H), 4.03 (t, J = 6.6Hz, 2H), 2.71-2.55 (m, 7H), 1.88 (p, J = 6.6Hz, 2H), 1.83-1.75 (m, 2H). HRMS (ESI) (m / z): calcd for C 21 H 24 N6O3[M+H] + ,409.1943;found,409.1943

[0238] Example 73: 5-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]-1,3,4-oxadiazolidine-2-carboxamide

[0239] The synthesis method refers to the synthesis of Example 61, light yellow solid, yield 52%. 1H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.11-8.05 (m, 2H), 7.54 (d, J = 10.1Hz, 1H), 7.42 (d, J = 10.1Hz, 1H), 7.17-7.11 (m, 2H), 6.95 (d, J = 9.7 Hz, 1H), 6.87 (d, J=9.7Hz, 1H), 4.03 (t, J=6.6Hz, 2H), 2.71-2.55 (m, 7H), 1.88 (p, J=6.6Hz, 2H), 1.83-1.75 (m, 2H). HRMS (ESI) (m / z): calcd forC 20 H 23 N7o3[M+H] + ,410.1896;found,410.1896

[0240] Example 74: 1-(3-amino-6-{2-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]-1,3-dimethylbenzene-5-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0241]

[0242] The synthetic method of Step a to Step d is shown in Example 22

[0243] Step e: [(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]acetonitrile

[0244] In a 100mL round-bottom flask, (3R)-3-fluorotetrahydropyrrole hydrochloride (1.0eq, 1.0g) and bromoacetonitrile (1.2eq, 1.05ml) were dissolved in acetonitrile solvent, and K2CO3 (3eq, 4.65g) was added to react at room temperature for 12h. After the reaction was completed, [(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]acetonitrile was obtained by column chromatography (PE / EA=8:1) as a white solid with a yield of 72%. HRMS (ESI) (m / z): calcd for C6H9FN2[M+H] + , 129.0750; found, 129.0778.

[0245] Step f:2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethan-1-amine

[0246] In a 100 mL round-bottom flask, [(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]acetonitrile (1.0 eq, 500 mg) and LiAlH4 (3 eq, 440 mg) were dissolved in THF solvent and reacted at room temperature for 4 h. After the reaction, water was added to dilute under ice bath conditions, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl-1-amine as a white solid with a yield of 72%. HRMS (ESI) (m / z): calculated for C6H 13 FN2[M+H] + , 133.1063; found, 133.1082.

[0247] Step g: Synthesis step refer to Example 1, white solid, yield 68%. HRMS (ESI) (m / z): calculated for C 15 H 20 BrFN2O[M+H] + ,343.0743;found,343.0761

[0248] Step h: Synthesis steps refer to Example 1, light yellow solid, yield 65%. 1 H NMR (300MHz, DMSO-d6) δ9.06 (s, 1H), 8.49 (s, 1H), 8.09 (d, J=5.6Hz, 1H), 7.76 (s, 1H), 7.56 (s, 2H), 7.32 (s, 2H), 7.14 (s, 1H), 5.12-4.86 (m, 1H), 3.18 (s, 2H), 2.70-2.62 (m, 2H), 2.42-2.38 (m, 2H), 2.12 (s, 6H), 1.93 (ddd, J=27.6, 13.9, 7.3Hz, 2H), 1.80-1.54 (m, 2H). HRMS (ESI) (m / z): calcd forC 23 H 27 FN8O2[M+H] + ,468.2275;found,468.2203

[0249] Example 75: 1-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]amino}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide Synthesis method Refer to the synthesis of Example 26, light yellow solid, yield 68%, 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 8.15 (dd, J=8.9, 2.3Hz, 1H), 7.93 (s, 1H), 7.40 (s, 2H), 7.33 (s, 1H) ), 6.86 (d, J = 9.1Hz, 2H), 3.29 (t, J = 6.0Hz, 2H), 2.62 (s, 2H), 2.55 (s, 4H), 1.79 (t, J = 6.4Hz, 2H), 1.76 (q, J = 3.9Hz, 4H). HRMS (ESI) (m / z): calcd for C 22 H 25 N9O[M+H] + ,432.2216;found,432.2289

[0250] Example 76: 1-[3-amino-6-(3,5-dimethyl-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propionyl]amino}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0251] The synthesis method refers to Example 26 and Example 1 to obtain 1-[3-amino-6-(3,5-dimethyl-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propionyl]amino}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide as a light yellow solid with a yield of 68%. 1 HNMR (400MHz, DMSO-d6) δ8.60 (d, J=5.3Hz, 2H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.0Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.54 (s, 2H), 7.11 (s, 2H), 2.76 (t, J=5.8Hz, 2H), 2.72-2.61 (m, 5H), 2.58 (t, J=5.8Hz, 2H), 2.19 (s, 6H), 1.81-1.73 (m, 2H). HRMS (ESI) (m / z): calcd for C 23 H 28 N8O2[M+H]+, 450.2369; found, 450.2339

[0252] Example 77: 1-[3-amino-6-(3,5-dimethyl-4-{methyl[3-(tetrahydro-1H-pyrrol-1-yl)propyl]amino}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0253] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 57%, 1H NMR (400MHz, DMSO-d6) δ8.59 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.42 (s, 2H), 7.11 (s, 2H), 3.32 (s, 1H) ), 3.32 (d, J = 13.0Hz, 1H), 2.96 (s, 2H), 2.64 (ht, J = 4.9, 2.5Hz, 4H), 2.53 (t, J = 6.1Hz, 2H), 2.21 (s, 6H), 1.86-1.77 (m, 4H). HRMS (ESI) (m / z): calcd for C 24 H 32 N8O[M+H]+, 449.2733; found, 449.2785

[0254] Example 78: 1-(3-amino-6-{2-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]-1,3-dimethylbenz-5-yl}-5-methylpyrazin-2-yl)pyrazole-4-carboxamide

[0255] The synthesis method refers to the synthesis of Example 74, light yellow solid, yield 64%, 1 H NMR (400MHz, DMSO-d6) δ8.28 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.55 (s, 1H), 7.41 (t, J = 4.6Hz, 1H), 7.3 1 (d, J=8.8Hz, 1H), 7.18 (d, J=9.0Hz, 1H), 3.53-3.41 (m, 2H), 3.01-2.60 (m, 5H), 2.56 (s, 2H), 2.06-1.84 (m, 1H). HRMS (ESI) (m / z): calcd for C 24 H 29 FN8O2[M+H] + ,481.2431;found,481.2498

[0256] Example 79: 1-(3-amino-5-cyano-6-{2-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]-1,3-dimethylbenz-5-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0257] The synthesis method refers to the synthesis of Example 74, light yellow solid, yield 62%, 1H NMR (400MHz, DMSO-d6) δ8.29 (s, 2H), 8.20 (s, 2H), 8.10 (d, J=8.1Hz, 2H), 8.04 (d, J =8.1Hz, 2H), 7.68 (s, 3H), 7.45-7.38 (m, 4H), 7.35 (d, J = 8.8Hz, 2H), 4.75 (dddd, J = 4 .5, 3.5, 2.7, 1.6Hz, 1H), 4.65 (dddd, J=4.4, 3.5, 2.7, 1.7Hz, 1H), 3.54-3.40 (m, 4H) , 3.01-2.60(m, 12H), 2.12-1.98(m, 2H), 1.98-1.84(m, 2H).HRMS(ESI)(m / z): calcd for C 24 H 26 FN9O2[M+H] + ,492.2227;found,492.2199

[0258] Example 80: 1-(3-amino-5-fluoro-6-{2-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]-1,3-dimethylbenzene-5-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0259] The synthesis method refers to the synthesis of Example 74, light yellow solid, yield 67%, 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 2H), 8.20 (s, 2H), 8.10 (d, J = 8.1Hz, 2H), 8.04 (d, J = 8.1Hz, 2H), 7.5 5 (s, 3H), 7.41 (t, J=4.6Hz, 2H), 4.75 (dddd, J=4.5, 3.5, 2.7, 1.6Hz, 1H), 4.65 (dddd, J=4.4, 3.5, 2. 7, 1.7Hz, 1H), 3.54-3.40 (m, 4H), 2.97 (dd, J=12.3, 1.8Hz, 1H), 2.97-2.86 (m, 4H), 2.89-2.81 (m, 1H ), 2.77 (ddd, J=12.1, 6.7, 4.9Hz, 2H), 2.73-2.60 (m, 4H), 2.12-1.84 (m, 4H). HRMS (ESI) (m / z): calcd for C 23 H 26 F2N8O2[M+H]+, 485.2180; found, 485.2180

[0260] Example 81: 1-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]sulfanyl}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0261] The synthesis method refers to the synthesis of Example 26, light yellow solid, yield 59%, 1 H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.0Hz, 1H), 8.07-8.00 (m, 2H), 7.75 (dd, J=7.8, 2.3Hz, 1H), 7.52 (d, J=7.8Hz, 1H), 7.11 (s, 2H), 2.99 (t, J=6.7Hz, 2H), 2.69-2.58 (m, 4H), 2.55 (t, J=5.8Hz, 2H), 1.82-1.74 (m, 5H). HRMS (ESI) (m / z): calcd forC 22 H 24 N8OS[M+H]+, 449.1827; found, 449.1827

[0262] Example 82: 1-(2-amino-5-{2-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]-1,3-dimethylbenzene-5-yl}pyridin-3-yl)pyrazole-4-carboxamide

[0263] The synthesis method refers to the synthesis of Example 74, light yellow solid, yield 67%, 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 8.31 (d, J = 2.0Hz, 1H), 8.19 (d, J = 2.0Hz, 1 H), 8.13 (s, 1H), 7.75 (s, 1H), 7.41 (t, J=4.6Hz, 1H), 6.52 (d, J=7.7Hz, 1H), 6.4 5(d, J=7.7Hz, 1H), 3.54-3.40(m, 2H), 3.01-2.91(m, 1H), 2.94-2.88(m, 1H), 2. 90-2.67(m, 2H), 2.69-2.60(m, 1H), 2.12-1.84(m, 2H).HRMS(ESI)(m / z): calcd for C 24 H 28 FN7O2[M+H]+, 466.2322; found, 466.2344

[0264] Example 83: 1-(3-amino-5-chloro-6-{2-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]-1,3-dimethylbenz-5-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0265] The synthesis method refers to the synthesis of Example 74, light yellow solid, yield 65%, 1 H NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 8.29 (s, 1H), 8.15 (d, J=8.0Hz, 1H), 8.06 (d, J=8. 0Hz, 1H), 7.48 (s, 2H), 7.40 (t, J=4.6Hz, 1H), 4.70 (dddd, J=4.5, 3.6, 2.7, 1.8Hz, 1H), 3 .49-3.33(m, 2H), 3.05-2.94(m, 2H), 2.93-2.87(m, 1H), 2.71(ddd, J=9.6, 6.7, 4.9Hz, 1H), 2.68-2.54 (m, 2H), 2.09 (ddd, J=7.3, 4.9, 2.6Hz, 1H), 1.92 (dt, J=6.7, 4.7Hz, 1H).

[0266] Example 84: 1-{3-amino-6-[2-({3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propyl}amino)-1,3-dimethylbenz-5-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0267] The synthesis method refers to the synthesis of Example 74, light yellow solid, yield 52%, 1 H NMR (400MHz, DMSO-d6) δ8.65 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.79 (s, 2H), 7.11 (s, 2H), 4.88 (t , J=4.9Hz, 1H), 4.61 (t, J=4.8Hz, 1H), 4.52 (t, J=4.9Hz, 1H), 3.01 (q, J=5.2Hz, 2H), 2.81-2.71 (m, 4H), 2.40 (s, 6H).HRMS (ESI) (m / z): calcdfor C 22 H 27 FN8O2S[M+H]+, 487.1995; found, 487.1995

[0268] Example 85: 1-(3-amino-6-{1-[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)dioxylidene-λ6-thio]-2-methylphenyl-4-yl}pyrazin-2-yl)pyrazole-4-carboxamide

[0269]

[0270] Step a: 4-bromo-N-{2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}-2,6-dimethylbenzenesulfonamide

[0271] In a 100 mL round-bottom flask, 4-bromo-2,6-dimethylbenzenesulfonyl chloride (1.0 eq, 1.0 g), 2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl-1-amine (1.2 eq, 560 mg), and NaOH (1 eq, 140 mg) were dissolved in DCM and reacted at room temperature for 3 h. After the reaction, water was added to dilute, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM / CH3OH=30:1) to obtain 4-bromo-N-{2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}-2,6-dimethylbenzenesulfonamide as a white solid with a yield of 58%. HRMS(ESI)(m / z):calcd for C 14 H 20 BrFN2O2S[M+H]+, 379.0413; found, 379.0436

[0272] The remaining synthesis steps refer to the synthesis of Example 74, and the product is a light yellow solid with a yield of 54%. 1H NMR (400MHz, DMSO-d6) δ8.67 (s, 1H), 8.30 (s, 2H), 8.20 (s, 2H), 8.10 (d, J = 8.0Hz, 2H), 8.04 (d, J = 8.0Hz, 1 H), 7.92 (d, J=1.2Hz, 3H), 7.88 (dt, J=1.5, 0.8Hz, 2H), 7.07 (t, J=6.2Hz, 2H), 4.74 (dddd, J=4.4, 3.5, 2.7, 1.7Hz, 1H), 4.65 (dddd, J=4.4, 3.6, 2.7, 1.8Hz, 1H), 3.32-3.16 (m, 4H), 3.01-2.85 (m, 5H), 2.87-2.81 (m, 1H), 2.77 (ddd, J=12.1, 6.7, 4.9Hz, 2H), 2.66 (s, 5H), 2.65 (td, J=5.5, 0.8Hz, 4H), 2.12-1.98 (m, 2H), 1.98 1.84(m,2H).HRMS(ESI)(m / z):calcd for C 21 H 25 FN8O3S[M+H]+, 489.1788; found, 489.1703

[0273] Example 86: 1-[3-amino-6-(2-{4-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]-1-oxydebutylene}-1,3-dimethylbenz-5-yl)pyrazin-2-yl]pyrazole-4-carboxamide

[0274]

[0275] Step a: 1-(4-bromo-2,6-dimethylphenyl)-4-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]butan-1-one

[0276] In a 100 mL round-bottom flask, 5-bromo-2-fluoro-1,3-dimethylbenzene (1.0 eq, 500 mg), 4-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]butyric acid (1.2 eq, 520 mg), and H2SO4 (1 eq, 0.13 ml) were dissolved in DCM and reacted at room temperature for 3 h. After the reaction, water was added for dilution, and ethyl acetate was used for extraction (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM / CH3OH=30:1) to obtain 1-(4-bromo-2,6-dimethylphenyl)-4-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]butan-1-one as a white solid with a yield of 52%. HRMS (ESI) (m / z): calcd for C16 H 21 BrFNO[M+H] + , 341.0791; found, 341.0768.

[0277] The rest of the synthesis method refers to the synthesis of Example 74, light yellow solid, yield 56%, 1 H NMR (400MHz, DMSO-d6) δ8.65 (s, 2H), 8.30 (s, 2H), 8.20 (s, 2H), 8.10 (d, J = 8.1Hz, 2H), 8.04 (d, J = 8.1Hz, 2H), 7 .61 (s, 4H), 4.76 (dddd, J=4.4, 3.6, 2.7, 1.6Hz, 1H), 4.67 (dddd, J=4.4, 3.5, 2.7, 1.6Hz, 1H), 3.11-3.00 (m, 2H ), 2.97-2.90(m, 2H), 2.94-2.85(m, 5H), 2.88-2.81(m, 1H), 2.83-2.75(m, 2H), 2.68-2.56(m, 4H), 2.12-1.96( m, 2H), 1.99-1.91 (m, 1H), 1.95-1.86 (m, 2H), 1.87 (t, J=2.4Hz, 1H), 1.88-1.78 (m, 2H). HRMS (ESI) (m / z): calcd for C 24 H 30 FN7O[M+H]+, 452.2529; found, 452.2485

[0278] Example 87: 1-[3-amino-6-(2-{4-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]butyl}-1,3-dimethylbenzene-5-yl)pyrazin-2-yl]pyrazole-4-carboxamide

[0279]

[0280] Stepa: (3R)-1-[4-(4-bromo-2,6-dimethylphenyl)butyl]-3-fluorotetrahydropyrrole

[0281] In a 100 mL round-bottom flask, lithium aluminum hydride (3 eq, 170 mg) was dissolved in THF, and then 1-(4-bromo-2,6-dimethylphenyl)-4-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]butan-1-one (1.0 eq, 500 mg) was added under ice bath conditions and reacted at room temperature for 3 h. After the reaction was completed, water was added for dilution, and ethyl acetate was used for extraction (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM / CH3OH=30:1) to obtain (3R)-1-[4-(4-bromo-2,6-dimethylphenyl)butyl]-3-fluorotetrahydropyrrole as a white solid with a yield of 89%. HRMS(ESI)(m / z):calcd for C 16 H 23 BrFN[M+H]+, 328.0998; found, 328.1007 The remaining synthesis steps refer to the synthesis of Example 74, light yellow solid, yield 53%, 1 H NMR (400MHz, DMSO-d6) δ8.62 (s, 2H), 8.30 (s, 2H), 8.20 (s, 2H), 8.10 (d, J=8.0Hz, 2H), 8.04 (d , J=8.0Hz, 2H), 7.11 (s, 3H), 4.76 (dddd, J=4.5, 3.6, 2.7, 1.6Hz, 1H), 4.67 (dddd, J=4.4, 3.5, 2 .7, 1.6Hz, 1H), 3.11-3.06(m, 1H), 3.06-3.00(m, 1H), 2.96-2.73(m, 7H), 2.76-2.64(m, 4H), 2 .60-2.50(m, 4H), 2.28(s, 12H), 2.12-1.85(m, 5H), 1.64-1.51(m, 9H).HRMS(ESI)(m / z): calcd for C 24 H 28 FN7O2[M+H]+, 466.2322; found, 466.2359

[0282] Example 88: 1-[3-amino-6-(2-{[(E)-{2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}azide]methyl}-1,3-dimethylbenzene-5-yl)pyrazin-2-yl]pyrazole-4-carboxamide

[0283]

[0284] Step a: (1E)-1-(4-bromo-2,6-dimethylphenyl)-N-{2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}methanimine In a 100 mL round-bottom flask, dissolve 4-bromo-2,6-dimethylbenzaldehyde (1.0 eq, 500 mg), 2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethan-1-amine (1.0 eq, 300 mg), and B(OCH2CF3)3 (1.0 eq, 350 mg) in THF and react at room temperature for 2 h. After the reaction, water was added for dilution, and ethyl acetate was used for extraction (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EA = 4:1) to obtain (1E)-1-(4-bromo-2,6-dimethylphenyl)-N-{2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}methanimine as a white solid with a yield of 54%. HRMS (ESI) (m / z): calcd for C 15 H 20 BrFN2[M+H]+, 327.0794; found, 327.0769

[0285] The remaining synthesis steps refer to the synthesis of Example 74, and the product is a light yellow solid with a yield of 56%. 1 H NMR (400MHz, DMSO-d6) δ8.61 (s, 1H), 8.29 (d, J = 6.6Hz, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 8.04 (d, J = 8.0Hz, 1H) , 7.62 (s, 1H), 3.62 (t, J=7.1Hz, 1H), 3.11-3.00 (m, 1H), 2.98-2.69 (m, 4H), 2.12-1.84 (m, 2H).HRMS (ESI) (m / z): calcd for C 23 H 27 FN8O[M+H]+, 451.2325; found, 451.2365

[0286] Example 89: 1-{3-amino-6-[2-({3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propyl}amino)-1,3-dimethylbenz-5-yl]pyrazin-2-yl}pyrazole-4-carboxamide

[0287]

[0288] Step a: Synthesis steps refer to Example 74, and 3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propan-1-ol was obtained as a white solid with a yield of 72%. HRMS (ESI) (m / z): calculated for C7H 14 FNO[M+H]+, 148.1059; found, 148.1073

[0289] Step b: 3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propanal

[0290] In a 100 mL round-bottom flask, 3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propan-1-ol (1.0 eq, 500 mg) was dissolved in DCM solvent, and DMP (2.0 eq, 2.9 g) was added to react at room temperature for 12 h. After the reaction was completed, 3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propanal was obtained by column chromatography (PE / EA=10:1) as a white solid with a yield of 57%. HRMS (ESI) (m / z): calculated for C7H 12 FNO[M+H]+, 146.0903; found, 146.0936

[0291] Step c: Synthesis step reference Example 88, white solid, yield 54%. HRMS (ESI) (m / z): calculated for C 15 H 20 BrFN2[M+H]+, 327.0794; found, 327.0769

[0292] The remaining synthesis steps refer to the synthesis of Example 74, and the product is a light yellow solid with a yield of 58%. 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 2H), 8.30 (s, 2H), 8.20 (s, 2H), 8.10 (d, J=8.0Hz, 2H), 8.04 (d, J=8.0Hz, 2H), 7.61-7.53 (m, 6H), 4.76 (dddd, J=4.5, 3.7, 2.7, 1.7Hz, 1H), 4.67 (dddd, J= 4.4, 3.5, 2.7, 1.6Hz, 1H), 3.11-3.00 (m, 2H), 2.94-2.83 (m, 3H), 2.86-2.78 (m, 1H), 2.81-2. 74(m, 1H), 2.78-2.68(m, 5H), 2.71-2.61(m, 5H), 2.12-1.85(m, 4H).HRMS(ESI)(m / z): calcd for C 23 H 27FN8O[M+H]+, 451.2325; found, 451.2313

[0293] Example 90: 1-[3-amino-6-(4-{[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)carbonyl]amino}-3,5-dimethylphenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0294]

[0295] Stepa: N-(4-bromo-2,6-dimethylphenyl)-1-({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)methaneamide

[0296] In a 100 mL round-bottom flask, 4-bromo-2,6-dimethylaniline (1.0 eq, 500 mg) and DIPEA (0.2 eq, 0.09 ml) were dissolved in dry DCM solution, triphosgene (0.33 eq, 240 mg) was added thereto in an ice bath, stirred for 5 min, and then 2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethan-1-amine (1.0 eq, 330 mg) was added and heated at room temperature. After the reaction was completed for 12 hours under the conditions, water was added for dilution, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with water (20 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM / CH3OH=30:1) to obtain N-(4-bromo-2,6-dimethylphenyl)-1-({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}amino)methaneamide as a white solid with a yield of 76%. HRMS (ESI) (m / z): calculated for C 15 H 21 BrFN3O[M+H]+, 358.0852; found, 358.0873

[0297] The remaining synthesis steps refer to the synthesis of Example 74, and the product is a pale yellow solid with a yield of 54%. 1H NMR (400MHz, DMSO-d6) δ8.60 (s, 2H), 8.30 (s, 2H), 8.20 (s, 2H), 8.10 (d, J=8.0Hz, 2H), 8.04 (d, J=8. 0Hz, 2H), 7.52 (s, 4H), 7.21 (s, 2H), 7.05 (t, J=3.7Hz, 2H), 4.85 (dddd, J=4.4, 3.6, 2.7, 1.9Hz, 1H), 4 .75 (dddd, J=4.6, 3.8, 2.7, 1.8Hz, 1H), 4.06 (d, J=3.7Hz, 4H), 3.22-3.15 (m, 1H), 3.19-3.10 (m, 1H), 2.99-2.89(m, 3H), 2.90-2.78(m, 4H), 2.13-2.00(m, 2H), 2.00-1.86(m, 2H).HRMS(ESI)(m / z): calcd for C 22 H 26 FN9O2[M+H]+, 468.2227; found, 468.2209

[0298] Example 91: 1-[3-amino-6-(4-{[({2-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]ethyl}(methyl)amino)carbonyl]amino}-3,5-dimethylphenyl)pyrazine-2-yl]pyrazole-4-carboxamide Synthesis method Refer to the synthesis of Example 74, light yellow solid, yield 58%, 1 H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.30 (s, 2H), 8.20 (s, 2H), 8.10 (d, J=8.1Hz, 2H), 8.04 (d, J=8. 1Hz, 2H), 7.52 (s, 3H), 7.36 (s, 1H), 4.80-4.74 (m, 1H), 4.71-4.65 (m, 1H), 4.05 (d, J=1.8Hz, 4H), 3.2 2-3.16 (m, 1H), 3.16-3.10 (m, 1H), 2.98 (ddd, J=12.1, 6.7, 4.9Hz, 2H), 2.95 (s, 6H), 2.94-2.82 (m, 2H ), 2.78 (ddd, J=12.2, 6.7, 4.9Hz, 2H), 2.13-1.99 (m, 2H), 1.99-1.85 (m, 2H). HRMS (ESI) (m / z): calcd forC 23 H 28 FN9O2[M+H]+, 482.2384; found, 482.2363

[0299] Example 92: 1-[3-amino-6-(3-cyano-4-{[2-(tetrahydro-1H-pyrrol-1-yl)ethyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0300] The synthesis steps refer to Example 22, Example 61, and Example 1 to obtain 1-[3-amino-6-(3-cyano-4-{[2-(tetrahydro-1H-pyrrol-1-yl)ethyl]oxy}phenyl)pyrazine-2-yl]pyrazole-4-carboxamide as a light yellow solid with a yield of 68%. 1 HNMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.74 (s, 1H), 8.44 (d, J=2.3Hz, 1H), 8.37 (dd, J=8.9, 2.4Hz, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.56 (s, 2H ), 7.37 (d, J = 9.0Hz, 1H), 7.33 (d, J = 4.1Hz, 1H), 4.33 (t, J = 5.7Hz, 2H), 2.94 (s, 2H), 2.66 (s, 4H), 1.75-1.70 (m, 4H). HRMS (ESI) (m / z): calcd for C 21 H 22 N8o2[M+H]+, 419.1866; found, 419.1892

[0301] Example 93: 1-[3-amino-6-(3-cyano-4-{[4-(tetrahydro-1H-pyrrol-1-yl)butyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0302] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 54%, 1-[3-amino-6-(3-cyano-4-{[4-(tetrahydro-1H-pyrrol-1-yl)butyl]oxy}phenyl)pyrazine-2-yl]pyrazole-4-carboxamide 1 H NMR (400MHz, DMSO-d6) δ9.34 (d, J=0.8Hz, 1H), 8.74 (s, 1H), 8-45 (d, J=2.4H z, 1H), 8.37 (dd, J=8.9, 2.4Hz, 1H), 8.23 ​​(s, 1H), 7.92 (s, 1H), 7.56 (s, 2H), 7 .37-7.32(m, 2H), 4.24(t, J=6.2Hz, 2H), 2.75(s, 4H), 2.68(p, J=2.0Hz, 2H) ,1.88-1.82(m,2H),1.78(s,4H),1.74-1.68(m,2H).HRMS(ESI)(m / z):calcd for C 23 H26 N8O2[M+H]+, 447.2179; found, 447.2193

[0303] Example 94: 1-[3-amino-6-(3-cyano-4-{[6-(tetrahydro-1H-pyrrol-1-yl)hexyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0304] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 65%, 1 H NMR (300MHz, DMSO-d6) δ9.31 (s, 1H), 8.70 (s, 1H), 8.40 (d, J=2.3Hz, 1H), 8.32 (dd, J=8.9, 2. 4Hz, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.53 (s, 2H), 7.30 (d, J=8.7Hz, 2H), 4.16 (t, J=6.3Hz, 2H) , 2.39 (d, J = 6.4Hz, 4H), 2.36-2.32 (m, 2H), 1.73 (q, J = 6.8Hz, 2H), 1.65-1.60 (m, 4H), 1.45 (d , J=6.3Hz, 2H), 1.40 (d, J=7.9Hz, 2H), 1.34 (q, J=8.6, 6.0Hz, 2H).HRMS (ESI) (m / z): calcdfor C 22 H 24 N8O2[M+H]+, 475.2492; found, 475.2483

[0305] Example 95: 1-[3-amino-6-(3-cyano-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0306] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 68%, 1 H NMR (300MHz, DMSO-d6) δ9.33 (d, J=0.8Hz, 1H), 8.72 (s, 1H), 8.43 (d, J=2.3Hz, 1H), 8.35 (dd, J=8.9, 2.4Hz, 1H), 8.21 (d, J=0.8Hz, 1H), 7.91 (s, 1 H), 7.55 (s, 2H), 7.34 (d, J=8.9Hz, 2H), 4.25 (t, J=6.2Hz, 2H), 2.61 (s, 2H), 2.53 (s, 4H), 1.98-1.92 (m, 2H), 1.70 (s, 4H). HRMS (ESI) (m / z): calcd for C 23 H28 FN9O2[M+H]+, 433.2022; found, 433.2053

[0307] Example 96: 1-[3-amino-6-(3-fluoro-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0308] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 72%, 1H NMR (300MHz, DMSO-d6) δ9.44 (s, 1H), 8.80 (s, 1H), 8.32 (s, 1H), 8.08 (dd, J = 13.1, 2.1 Hz, 2H), 7.98 (d, J = 8.6 Hz, 1H), 7.63 (s, 2H), 7.46 (s, 1H), 7.36 (t, J = 8.8 Hz, 1H), 4.27 (t, J = 6.3 Hz, 2H), 2.84 (s, 2H), 2.10-2.02 (m, 2H), 1.83 (s, 4H). HRMS (ESI) (m / z): calculated for C 21 H 24 FN7O2[M+H]+, 426.1976; found, 426.1991

[0309] Example 97: 1-[3-amino-6-(2-methoxy-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0310] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 70%, 1 H NMR (400MHz, DMSO-d6) δ9.18 (d, J=0.8Hz, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 7 .91 (s, 1H), 7.83 (d, J = 8.3Hz, 1H), 7.32 (s, 2H), 7.28 (s, 1H), 6.68 (d, J = 2.3 Hz, 2H), 4.09 (t, J=6.4Hz, 2H), 3.88 (s, 3H), 2.58 (t, J=7.1Hz, 2H), 2.48 (s, 4H), 1.93 (d, J=6.8Hz, 2H), 1.70 (p, J=3.1Hz, 4H). HRMS (ESI) (m / z): calcd for C 22 H 27 N7O3[M+H]+, 438.2175; found, 438.2193

[0311] Example 98: 1-[3-amino-6-(3-methyl-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0312] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 69%, 1 H NMR (300MHz, DMSO-d6) δ9.27 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 7.1Hz, 2H), 7.41 (s, 2H), 7.37 (s, 1H), 6.98 (d, J = 8.5Hz, 1H) , 4.04 (t, J=6.2Hz, 2H), 2.58 (t, J=7.1Hz, 2H), 2.46 (d, J=5.7Hz, 4H), 2.23 (s, 3H), 1.95-1.88 (m, 2H), 1.68 (t, J=5.0Hz, 4H). HRMS (ESI) (m / z): calcd for C 22 H 27 N7O2[M+H]+, 422.2226; found, 422.2253

[0313] Example 99: 1-[3-amino-6-(3,5-dimethyl-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0314] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 62%, 1 H NMR (300MHz, DMSO-d6) δ9.33(s, 1H), 8.71(s, 1H), 8.31(s, 1H), 8.05(s, 1H), 7.82(s, 2H), 7.53(s, 2H), 7.44(s , 1H), 3.90 (t, J=6.2Hz, 2H), 2.72 (s, 2H), 2.40 (s, 6H), 2.07-1.97 (m, 2H), 1.79 (s, 4H). HRMS (ESI) (m / z): calcd for C 23 H 29 N7O2[M+H]+, 436.2383; found, 436.2391

[0315] Example 100: 1-[3-amino-6-(3-methoxy-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0316] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 73%, 1 H NMR (300MHz, DMSO-d6) δ9.27 (s, 1H), 8.70 (s, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.65 (d, J = 8.0Hz, 2H), 7.45 (s, 2H), 7.36 (s, 1H), 7.07 (d, J=8.3Hz, 1H), 4.08 (t, J=6.4Hz, 2H), 3.92 (s, 3H), 1.96 (s, 2H), 1.74 (s, 4H).HRMS (ESI) (m / z): calcd for C 22 H 27 N7O3[M+H]+, 438.2175; found, 438.2189

[0317] Example 101: 1-[3-amino-6-(3-chloro-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0318] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 75%, 1 H NMR (300MHz, DMSO-d6) δ9.29 (s, 1H), 8.68 (s, 1H), 8.17 (d, J = 23.4Hz, 2H), 8.01 (d, J = 8.8Hz, 1H), 7.96 (s, 1H), 7.50 (s , 2H), 7.34 (s, 1H), 7.23 (d, J=8.8Hz, 1H), 4.16 (s, 2H), 2.63 (s, 4H), 1.95 (s, 2H), 1.70 (s, 4H).HRMS (ESI) (m / z): calcd for C 21 H 24 ClN7O2[M+H]+, 442.1680; found, 442.1693

[0319] Example 102: 1-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}-3-(trifluoromethyl)phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0320] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 73%, 1H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 8.72 (s, 1H), 8.30 (dd, J=8.7, 2.3Hz, 1H), 8.21 (s, 2H), 7.94 (s, 1H), 7.51 (s, 2H), 7.39-7.31 (m, 2H), 4.20 (t, J=6.1Hz, 2H), 2.58 (s, 2H), 1.91 (q, J=4.9, 2.9Hz, 2H), 1.68 (s, 4H).HRMS (ESI) (m / z): calcd for C 22 H 24 F3N7O2[M+H]+, 496.1944; found, 496.1963

[0321] Example 103: 1-[3-amino-6-(4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0322] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 53%, 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 8.06-8.01 (m, 2H), 7.96 (s, 1H), 7.42 (s, 2H), 7.33 (s, 1H), 7.06- 7.02 (m, 2H), 4.08 (t, J = 6.3Hz, 2H), 2.63 (s, 4H), 1.98-1.92 (m, 2H), 1.91 (s, 2H), 1.71 (d, J = 5.2Hz, 4H). HRMS (ESI) (m / z): calcd for C 21 H 25 N7O2[M+H]+, 408.2070; found, 408.2093

[0323] Example 104: 1-[3-amino-6-(3-formyl-4-{[3-(tetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0324] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 48%, 1H NMR (400MHz, DMSO-d6) δ10.44 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 8.34 (d, J= 8.4Hz, 1H), 8.30 (d, J=2.2Hz, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.49 (s, 2H), 7 .33(d, J=7.7Hz, 2H), 4.25(t, J=6.1Hz, 2H), 3.55-3.27(m, 4H), 2.66(s, 2H) , 2.00 (dd, J=8.9, 4.7Hz, 2H), 1.72 (d, J=5.2Hz, 4H). HRMS (ESI) (m / z): calcd for C 22 H 25 N7O3[M+H]+, 436.2019; found, 436.2034

[0325] Example 105: 1-[3-amino-6-(4-{[3-(diethylamino)propyl]oxy}-3,5-dimethylphenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0326] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 58%, 1 H NMR (300MHz, DMSO-d6) δ9.24 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.73 (s, 2H), 7.44 (s, 2H), 7.35 (s, 1H), 3.80 (t, J=6.2Hz, 2H), 2.31 (s, 6H), 1.89 (s, 2H), 1.00 (s, 6H). HRMS (ESI) (m / z): calcdfor C 23 H 31 N7O2[M+H]+, 438.2539; found, 438.2553

[0327] Example 106: 1-(3-amino-6-{4-[(3-methoxypropyl)oxy]-3,5-dimethylphenyl}pyrazin-2-yl)pyrazole-4-carboxamide

[0328] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 58%, 1H NMR (300MHz, DMSO-d6) δ9.24 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.73 (s, 2H), 7.44 (s, 2H), 7.35 (s, 1H) , 3.81 (t, J=6.1Hz, 2H), 3.56 (t, J=6.2Hz, 2H), 3.28 (s, 3H), 2.30 (s, 6H), 2.03-1.93 (m, 2H).HRMS (ESI) (m / z): calcd for C 20 H 24 N6O3[M+H] + , 397.1910; found, 397.1932

[0329] Example 107: 1-{3-amino-6-[4-({3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propyl}oxy)-3,5-dimethylphenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0330] The synthesis steps refer to Example 26, Example 89, Example 92, and Example 1 to obtain 1-{3-amino-6-[4-({3-[(3R)-3-fluorotetrahydro-1H-pyrrol-1-yl]propyl}oxy)-3,5-dimethylphenyl]pyrazine-2-yl}pyrazole-4-carboxamide as a light yellow solid with a yield of 62%. 1 H NMR (300MHz, DMSO-d6) δ9.24 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.72 (s, 2H), 7.44 (s, 2H), 7.35 (s, 1H), 5.20 (d, J=56.0Hz, 1H), 3.81 (t, J=6.3Hz, 2H), 2.82 (s, 2H), 2.65 (s, 2H), 2.31 (s, 6H), 1.92 (s, 2H).HRMS (ESI) (m / z): calcdfor C 23 H 28 FN7O2[M+H] + ,454.2289; found, 454.2289

[0331] Example 108: 1-[3-amino-6-(3,5-dimethyl-4-{[3-(1,4-oxazepine-4-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0332] The synthesis method refers to the synthesis of Example 92, light yellow solid, yield 56%, 1H NMR (300MHz, DMSO-d6) δ9.24 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.72 (s, 2H), 7.44 (s, 2H), 7.35 (s, 1H), 3.79 ( t, J=5.9Hz, 2H), 3.61-3.55 (m, 4H), 2.52 (s, 2H), 2.38 (s, 4H), 2.30 (s, 6H), 1.90 (t, J=6.7Hz, 2H). HRMS (ESI) (m / z): calcd for C 23 H 29 N7O3[M+H] + ,452.2332;found,452.2356

[0333] Example 109: 1-{3-amino-6-[3-cyano-4-({3-[(3S)-3-methyltetrahydro-1H-pyrrol-1-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0334] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 58%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 7.11 (s, 2H), 4.09 (t, J=6.5Hz, 2H), 2.77 (ddd, J=12.4, 6.7, 4.7Hz, 1H), 2.70-2.63 (m, 1H), 2.63-2.51 (m, 4H), 1.90 (ddp, J=19.9, 13.2, 6.7Hz, 2H ), 1.81-1.66 (m, 2H), 1.52 (dddd, J=11.6, 6.2, 4.8, 2.8Hz, 1H), 0.91 (d, J=6.9Hz, 3H). HRMS (ESI) (m / z): calcd for C 23 H 26 N8O2[M+H] + ,447.2212;found,447.2256

[0335] Example 110: 1-{3-amino-6-[3-cyano-4-({3-[(3R)-3-(hydroxymethyl)tetrahydro-1H-pyrrol-1-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0336] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 53%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 4.09 (t, J=6.5Hz, 2H), 3.4 5 (dd, J=5.9, 5.1Hz, 2H), 3.36 (dd, J=5.9, 5.3Hz, 1H), 2.82-2.71 (m, 2H), 2.63-2.49 (m, 4H), 2.07-1.98 (m , 1H), 1.90 (ddp, J=19.9, 13.2, 6.7Hz, 2H), 1.81-1.72 (m, 1H), 1.61-1.51 (m, 1H). HRMS (ESI) (m / z): calcd for C 23 H 26 N8O3[M+H] + ,463.2161;found,463.2172

[0337] Example 111: 1-[3-amino-6-(3-cyano-4-{[3-(4-methyl-1,4-diazepan-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0338] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 61%, 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7. 18 (d, J=8.8Hz, 1H), 7.11 (s, 2H), 4.09 (t, J=6.5Hz, 2H), 2.65 (t, J=6.5Hz, 2H), 2. 57-2.41 (m, 8H), 1.91 (p, J=6.5Hz, 2H), 1.77-1.65 (m, 2H). HRMS (ESI) (m / z): calcd for C 24 H29N9O2[M+H] + ,476.2478;found,476.2455

[0339] Example 112: 1-{3-amino-6-[3-cyano-4-({3-[(1S,5R)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0340] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 59%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.0 4 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 4.10 (td, J=6.1, 2.3Hz, 2H), 2.87-2.79 (m , 2H), 2.76 (dd, J=12.3, 4.4Hz, 2H), 2.72-2.59 (m, 4H), 1.94 (tdd, J=12.9, 6.8, 6.0Hz, 1H), 1.87 (ddd, J=13.1, 6. 8, 6.2Hz, 1H), 1.82 (ddd, J=4.1, 2.5, 1.4Hz, 1H), 1.83-1.75 (m, 1H), 1.73-1.61 (m, 2H). HRMS (ESI) (rm / z): calcd forC 25 H 29 N9O2[M+H] + ,488.2478;found,488.2478

[0341] Example 113: 1-{3-amino-6-[3-cyano-4-({3-[(3S)-3-hydroxytetrahydro-1H-pyrrol-1-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0342] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 57%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 4.09 (t, J=6.5Hz, 2H), 3.4 5 (dd, J=5.9, 5.1Hz, 2H), 3.36 (dd, J=5.9, 5.3Hz, 1H), 2.82-2.71 (m, 2H), 2.63-2.49 (m, 4H), 2.07-1.98 (m , 1H), 1.90 (ddp, J=19.9, 13.2, 6.7Hz, 2H), 1.81-1.72 (m, 1H), 1.61-1.51 (m, 1H). HRMS (ESI) (m / z): calcd for C 23 H 26 N8O3[M+H] + ,463.2161;found,463.2199

[0343] Example 114: 1-{3-amino-6-[3-cyano-4-({3-[(1S,5R)-3-methyl-3,7-diazabicyclo[3.1.1]hept-7-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0344] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 64%, 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 7.11 (s, 2H), 4.10 (td, J=6.1, 2.3Hz , 2H), 3.16 (dtt, J=21.2, 6.7, 1.8Hz, 2H), 2.75-2.66 (m, 2H), 2.69-2.62 (m, 2H), 2.57 (dd, J=12.5, 1.8Hz, 2H), 1.96 (ddt, J=12.5, 10.8, 6.6Hz, 2H), 1.93-1.81 (m, 1H), 1.67 (dt, J=12.3, 6.6Hz, 1H). HRMS (ESI) (m / z): calcd for C 24 H 27 N9O2[M+H] + ,474.2321;found,474.2357

[0345] Example 115: 1-{3-amino-6-[3-cyano-4-({3-[(2R)-2-hydroxy-1-methylpiperazin-4-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0346] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 58%, 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1 H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 7.11 (s, 2H), 4.56 (dddd, J=6.8, 5.3, 3.1, 1.5Hz, 1H), 4.09 (t, J=6.6Hz, 2 H), 3.83 (d, J=6.6Hz, 1H), 3.00 (ddd, J=12.5, 6.3, 3.7Hz, 1H), 2.82 (ddd, J=12.3, 6.2, 3.6Hz, 1H), 2.77-2.66 (m, 2H), 2.66-2.58 (m, 3H), 2.50 (ddd, J=12.3, 6.2, 3.5Hz, 1H), 2.43 (d, J=1.4Hz, 3H), 1.89 (ddt, J=19.8, 13.2, 6.6Hz, 2H). HRMS (ESI) (m / z): calcd for C 23 H 27 N9O3[M+H] + ,478.2270;found,478.2246

[0347] Example 116: 1-{3-amino-6-[3-cyano-4-({3-[(2R,6S)-1,2,6-trimethylpiperazin-4-yl]propyl}oxy)phenyl]pyrazin-2-yl}pyrazole-4-carboxamide

[0348] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 49%, 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1H z, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 7.11 (s, 2H), 4.09 (td , J=6.5, 0.7Hz, 2H), 2.88 (ddddd, J=15.0, 9.6, 6.8, 2.9, 1.5Hz, 2H), 2.78 (dd, J=12.4, 5.6Hz, 2H), 2.69 -2.59 (m, 4H), 2.31 (t, J = 1.5Hz, 3H), 1.98-1.84 (m, 2H), 1.12 (d, J = 8.1Hz, 6H). HRMS (ESI) (m / z): calcd for C 25 H 31 N9O2[M+H] + ,490.2634;found,490.2663

[0349] Example 117: 1-[3-amino-6-(3-cyano-4-{[3-(3-cyanotetrahydro-1H-pyrrol-1-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0350] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 65%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d , J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 4.09 (td, J=6.5, 0.7Hz, 2H), 3.07 (tt, J=3.8, 2.8Hz, 1H), 3.04-2.97 (m, 1H), 2.84-2.72 (m, 2H), 2.6 8-2.58 (m, 3H), 1.98-1.82 (m, 3H), 1.72 (ddt, J=12.7, 5.5, 3.7Hz, 1H). HRMS (ESI) (m / z): calcd for C 23 H 23 N9O2[M+H] + ,458.2008;found,458.2023

[0351] Example 118: 1-[3-amino-6-(3-cyano-4-{[3-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0352] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 67%, 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J=2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8 .10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8H z, 1H), 7.11 (s, 2H), 4.13-4.05 (m, 2H), 2.66-2.43 (m, 11H), 2.28 (s, 2H), 1.99-1.83 (m, 2 H), 1.72 (dddd, J=11.4, 7.5, 4.8, 3.0Hz, 2H), 1.64-1.56 (m, 2H). HRMS (ESI) (m / z): calcd for C 26 H 31 N9O2[M+H] + ,502.2634;found,502.2656

[0353] Example 119: 1-[3-amino-6-(3-cyano-4-{[3-(2-methyl-2,7-diazaspiro[4.4]non-7-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0354] The synthesis method refers to the synthesis of Example 107, light yellow solid, yield 65%, 1H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J=2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8 .10 (d, J=8.1Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8H z, 1H), 7.11 (s, 2H), 4.13-4.05 (m, 2H), 2.66-2.43 (m, 11H), 2.28 (s, 2H), 1.99-1.83 (m, 2 H), 1.72 (dddd, J=11.4, 7.5, 4.8, 3.0Hz, 2H), 1.64-1.56 (m, 2H). HRMS (ESI) (m / z): calcd for C 26 H 31 N9O2[M+H] + ,502.2634;found,502.2623

[0355] Example 120: 1-[3-amino-6-(3-cyano-4-{[3-(2-methyl-2,7-diazaspiro[3.5]non-7-yl)propyl]oxy}phenyl)pyrazin-2-yl]pyrazole-4-carboxamide

[0356] The synthesis method is based on the synthesis of Example 107, with a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ8.66 (s, 1H), 8.36 (d, J = 2.3Hz, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.1Hz , 1H), 8.04 (d, J=8.1Hz, 1H), 7.82 (dd, J=8.8, 2.2Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 7.11 (s, 2H), 4.09 (t, J =6.6Hz, 2H), 2.79 (s, 2H), 2.71-2.62 (m, 4H), 2.56 (dd, J = 5.5, 2.7Hz, 2H), 2.50 (dd, J = 5.5, 2.7Hz, 2H), 1.91 (p, J=6.6Hz, 2H), 1.73 (dd, J=5.4, 2.7Hz, 2H), 1.65 (dd, J=5.4, 2.7Hz, 2H). HRMS (ESI) (m / z): calcd for C 26 H 31 N9O2[M+H] + ,502.2634;found,502.2659

[0357] Inhibition of HPK1 kinase and SLP-76 protein phosphorylation activity by compounds

[0358] 1. Experimental materials and instruments

[0359]

[0360] 2. Experimental methods

[0361] (1) In vitro kinase inhibitory activity assay of HPK1

[0362] Transfer 2 μL of kinase sample in duplicate from the wells of the kinase prep row to the wells of a 384-well plate, adding 2 μL of 1× kinase buffer to the first well only for a no enzyme control. Transfer 1 μL of inhibitor sample in duplicate from the inhibitor titration prep row to the corresponding wells of the assay row, mix, and incubate at room temperature for 10 minutes. Transfer 2 μL of the corresponding 2.5× ATP / substrate mix from the ATP / substrate prep row wells to the same assay row in the presence of the kinase / inhibitor mix. Centrifuge the plate, mix for 2 minutes, and then incubate the kinase reaction at room temperature for 60 minutes or as desired. Add 5 μL of ADP-Glo TM The kinase reaction was stopped with reagent. Incubate 384 white plates (Corning @ 3824) at room temperature for 40 minutes. Add 10 μL of kinase detection reagent (Promega V6930) and incubate at room temperature for 30-60 minutes. Measure luminescence with a Tecan SPARK plate reader, inhibition % = (specific signal (control) - specific signal (inhibition)) / (specific signal (control)) × 100%. Use Prism (Graph Pad) to fit the dose-response curve and calculate the IC 50 value.

[0363] (2) Detection of SLP76 phosphorylation inhibitory activity

[0364] Jurkat cells were seeded at a density of 1 million per well in 6-well plates in 1 mL RPMI 1640 containing 10% FBS. Jurkat cells were incubated with different concentrations of compounds for 2 h, and then stimulated with anti-human CD3 antibody (5 μg / mL) and anti-human CD28 antibody (2 μg / mL) for 10 min. The cells were then collected and washed twice with cold PBS. The cell pellet was resuspended in 80 μL of lysis buffer, and the cell lysate was centrifuged at 20,000 g for 30 min at 4 °C. The protein concentration was determined using a BCA protein assay kit (Beyotime, P0010). Western blot was performed on cell lysates using primary antibodies against SLP-76 (Proteintech, 12728), phosphorylated SLP-76 (Cell Signaling Technology, 14745), and GAPDH (Proteintech, 10494). Images were captured by an imaging system (Tanon). Image J was used to quantitatively analyze the intensity of protein bands.

[0365] 3. Experimental results

[0366] Table 1. Inhibitory activity of the compounds in each example

[0367]

[0368]

[0369] IC s0 : A≤100nM, 100nM<B≤500nM, 1000nM<C; ND: no detection.

[0370] As can be seen from Table 1, the compounds designed in the present invention have high inhibitory activity on both HPK1 kinase and SLP-76 protein phosphorylation, and the inhibitory activity is significantly better than that of the HPK1 inhibitor positive drug BGB-15025 reported in the literature.

[0371] Embodiment 121

[0372] Experimental study on the efficacy of mouse colon cancer CT-26 cell transplanted tumors in Balb / c mice

[0373] 1. Experimental methods

[0374] The cultured mouse colon cancer CT-26 cell suspension was collected at a concentration of 1×10 7 Each mouse was inoculated with 0.1 ml of the solution into the subcutaneous tissue of the right armpit. The diameter of the transplanted tumor was measured with a vernier caliper. The tumor grew to 100 mm 3The animals were randomly divided into groups at 1:10 p.m. and 1:10 p.m. At the same time, the mice in each group began to receive medication. After the experiment, the mice were immediately killed and the tumors were surgically removed and weighed. The animal weight and tumor volume were recorded once on days 0, 3, 7, 9, 14, and 17;

[0375] The calculation formula of tumor volume (TV) is: TV = 1 / 2 × a × b 2 , where a and b represent the length and width respectively.

[0376] The relative tumor volume (RTV) was calculated based on the measurement results. The calculation formula is:

[0377] RTV=V t / V0, where V0 is the tumor volume measured at the time of administration (i.e., d0); V t The tumor volume at each measurement.

[0378] Evaluation index of antitumor activity: relative tumor proliferation rate T / C (%), calculated by the following formula:

[0379] T / C(%)=T RTV / C RTV ×100,T RTV :RTV in treatment group; C RTV : Model group RTV.

[0380] Evaluation index of anti-tumor activity: tumor growth inhibition rate (%), calculated by the following formula:

[0381] Tumor growth inhibition rate = (average tumor weight of model group - average tumor weight of drug-treated group) / average tumor weight of model group × 100%

[0382] Statistical analysis: The mean was expressed as X±SD, and the t-test was used for inter-group analysis. SPSS (Staffstical Package for the Social Science) 17.0 was used for statistical analysis of the results.

[0383] 2. Experimental results

[0384] Depend on Figures 1 to 3It can be seen that the HPK1 inhibitor Example 107 of the present invention can significantly inhibit tumor growth in the CT-26 tumor model of Balb / c mice. Under the same dosage conditions, the in vivo tumor inhibition effect of Example 107 is equivalent to that of the clinical compound BGB-15025. From the experimental data, it can be seen that the pharmaceutical composition of Example 107 and PD-1 antibody of the present invention is significantly superior to the single drug use of Example 107 and BGB-15025. More advantageously, Example 107 of the present invention does not have a significant effect on the weight of mice at a dosage concentration that significantly inhibits tumor growth, showing the good safety of the compound.

[0385] In summary, the compounds designed in the present invention exhibit excellent HPK1 and pSLP-76 inhibitory activity in vitro and can significantly inhibit tumor growth in vivo. According to the excellent properties exhibited by the example compounds in the present invention, the compounds found in the present invention and the PD-1 antibody composition can be used as clinical candidate drugs to provide support for further new drug development.

Claims

1. A 2-amino substituted aza-heteroaryl compound, characterized in that: Having a structure as shown in formula (I) or its stereoisomers, tautomers, deuterated compounds, pharmaceutically acceptable salts or mixtures thereof: in: X 1 is selected from C or N atoms; Cy 1 Selected from C 3-7 Cycloalkyl, 5- to 10-membered heterocyclic group containing 0, 1, 2, or 3 N, S, or O ring heteroatoms, and each Cy 1 By m R 1 replaced by; Cy 2 is selected from 5-10 membered heterocyclic aromatic groups, phenyl groups, and each Cy 2 By n R 2 replaced by; m, n are independently selected from 0, 1, 2 or 3; R 1 Selected from H, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 1a 、-SO2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO2R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO2NR 1b R 1c 、-NR 1a S02R 1b , 3- to 10-membered heterocyclic groups containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic groups containing 0 to 3 N, S, or O ring heteroatoms, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl; R 1a , R 1b , R 1c are independently selected from hydrogen, halogen, OH, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, 3- to 10-membered heterocyclic radicals containing 0, 1, 2, 3, 4, or 5 heteroatoms of N, S, or O rings, 5- to 6-membered heterocyclic aromatic radicals containing 0, 1, 2, or 3 heteroatoms of N, S, or O rings, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl; R 2 Selected from H, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-C02R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c 、-NR 2a S02R 2b , 3- to 10-membered heterocyclic groups containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic groups containing 0 to 3 N, S, or O ring heteroatoms, and 3- to 10-membered heterocyclic groups substituted with 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms. 1-8 alkyl; R 2a , R 2b , R 2c are independently selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, 3- to 10-membered heterocyclic radicals containing 0, 1, 2, 3, 4, or 5 heteroatoms of N, S, or O rings, 5- to 6-membered heterocyclic aromatic radicals containing 0, 1, 2, or 3 heteroatoms of N, S, or O rings, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl; L1 is absent, a single bond or selected from -NHR 3a -、-NR 3a R 3b -、-NR 3a CR 3b R 3c -、-OR 3a -、-SR 3a -、-OCR 3a R 3b -、-CONHR 3a -、-CONR 3a R 3b -, -O-, -S-, -SO-, -SO2-, -CO-, -CR 3a R 3b -、-NHCONHR 3a -、-NHCONR 3a R 3b -、C 1-8 Alkyl, NH2; R 3a , R 3b , R 3c are independently selected from hydrogen, halogen, deuterium, -CN, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, 3- to 10-membered heterocyclic group containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, and 5- to 6-membered heterocyclic aromatic group containing 0, 1, 2, or 3 N, S, or O ring heteroatoms; R 3 Selected from hydrogen, halogen, -CN, -NH2, C 1-4 Alkyl, C 1-5 Alkoxy, C 1-5 Cycloalkyl.

2. The 2-amino substituted aza-heteroaryl compound according to claim 1, characterized in that: X 1 is selected from C or N atoms; Cy 1 A 5- to 6-membered heterocyclic group containing one or more heteroatoms of N, S, and O, and each Cy 1 By m R 1 replaced by; Cy 2 is selected from 5-6 membered heterocyclic aromatic groups and phenyl groups containing one or more heteroatoms of N, S and O, and each Cy 2 By n R 2 replaced by; m, n are independently selected from 0, 1, 2 or 3; R 1 Selected from -COR 1a ; R 1a Selected from hydrogen, halogen, OH, -NH-substituted or unsubstituted 6-membered nitrogen heterocycle, -N(CH3)2, -NH-substituted or unsubstituted phenyl, -NHCH3, -NH(CH2) 2～4 NHCOCH3, substituted or unsubstituted 6-membered nitrogen heterocycle, -NH(CH2) 2～4 N(CH3)2, NH2, -OC 1-4 Alkyl; the substitution is halogen, C 1-4 Alkyl, NH2 or Boc protected amino group substituted; R 2 Selected from H, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c 、-NR 2a SOO2R 2b , 3- to 10-membered heterocyclic groups containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic groups containing 0 to 3 N, S, or O ring heteroatoms, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl; R 2a , R 2b , R 2c are independently selected from hydrogen, halogen, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 3-7 Cycloalkyl, -NH2, -CN, -NO2, 3- to 10-membered heterocyclic radicals containing 0, 1, 2, 3, 4, or 5 N, S, or O ring heteroatoms, 5- to 6-membered heterocyclic aromatic radicals containing 0, 1, 2, or 3 N, S, or O ring heteroatoms, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted with 3 to 10 membered heterocyclic radicals containing 0, 1, 2, 3, 4, 5 N, S, O ring heteroatoms 1-8 alkyl; L1 is absent, a single bond or selected from -O-, -S-, -SO-, -SO2-, -CO-, C 1-4 Alkyl, NH2, -O-(CH2) 1～6 -、-CONH-(CH2) 1～4 -、-NH-(CH2) 1～4 -、-NHCO-(CH2) 1～4 -、NCH3-(CH2) 1～4 -、-S-(CH2) 1～4 -、-SONH-(CH2) 1～4 -, -SOONH-(CH2) 1～4 -、-CO-(CH2) 1～4 -、-CN-(CH2) 1～4 -、-NCH-(CH2) 1～4 -、-NHCO-NCH3(CH2) 1～4 -; R 3 Selected from hydrogen, halogen, -CN, -NH2, C 1-4 Alkyl, C 1-5 Alkoxy, C 1-5 Cycloalkyl.

3. The 2-amino substituted aza-heteroaryl compound according to any one of claims 1 to 2, characterized in that: cy 1 Select from any of the following structures: R4 a选 Hydrogen, C1-4 alkyl, C1-5 alkoxy, C1-5 cycloalkyl; And every Cy 1 0-3 R 1 replaced.

4. The 2-amino substituted aza-heteroaryl compound according to any one of claims 1 to 3, characterized in that: In the structure: in: Cy 2 Select from any of the following structures: R 4b Selected from hydrogen, C1-4 alkyl, C1-5 alkoxy, C1-5 cycloalkyl; And every Cy 2 0-3 R 2 replaced.

5. The 2-amino-substituted aza-heteroaryl compound according to any one of claims 1 to 4, characterized in that: In the structure, R 2 Select from the following structures:

6. The 2-amino-substituted aza-heteroaryl compound according to any one of claims 1 to 5, characterized in that: A compound selected from any of the following:

7. The 2-amino substituted aza-heteroaryl 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, acidic amino acids, ferulic acid.

8. A pharmaceutical composition, characterized in that It comprises the 2-amino substituted aza-heteroaryl compound according to claim 1 and a pharmaceutically acceptable carrier.

9. The 2-amino substituted aza-heteroaryl compound according to claim 1 or the pharmaceutical composition according to claim 8, or use thereof in combination with a PD-1 antibody in the preparation of a drug for preventing and / or treating hematopoietic progenitor cell kinase-mediated diseases.

10. Use of the 2-amino substituted aza-heteroaryl compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating colon cancer.

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