Heterocyclic compounds, pharmaceutical compositions, activin type ii receptor inhibitors and uses thereof

Abstract

This application provides a heterocyclic compound, a pharmaceutical composition, an activin type II receptor inhibitor, and their applications. The heterocyclic compound is a compound of Formula I or its racemic, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug. This heterocyclic compound, pharmaceutical composition, and activin type II receptor inhibitor can effectively inhibit activin receptor 2B with high selectivity, showing promising application prospects in the preparation of anti-cachexia drugs, anti-muscle muscular atrophy drugs, or anti-metabolic disease drugs.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical chemistry, and in particular to a heterocyclic compound, a pharmaceutical composition, an activin type II receptor inhibitor, and their applications. Background Technology

[0002] Activin type II receptor (ActRII) is a transmembrane serine / threonine kinase receptor in the transforming growth factor β (TGF-β) receptor superfamily. It mainly includes two subtypes, namely ActRIIA (ACVR2A) and ActRIIB (ACVR2B). The two have overlapping functions, but their expression in specific tissues and their affinity for ligands differ, allowing them to play specific roles in different physiological processes.

[0003] ActRII possesses a cysteine-rich ligand-binding domain and a kinase-active catalytic domain. It forms a ligand-receptor complex by binding to activin, myostatin (GDF8), and GDF11 ligands, further recruiting and binding to the activin type I receptor (ActRI), followed by phosphorylation. This activates downstream signaling pathways such as Smad2 / 3 and MAPK, thereby regulating cell differentiation, embryonic development, organogenesis, hormone synthesis, immune regulation, skeletal muscle mass, and lipid metabolism. Abnormalities in this pathway are highly associated with a variety of diseases, including metabolic and immune disorders, such as musculoskeletal atrophy, obesity, anemia, and pulmonary fibrosis.

[0004] Studies have shown that in adipocytes, activin stores lipids via ActRII, a key driver of obesity; blocking this signaling pathway can promote fat metabolism and aid in weight loss. In muscle cells, the ActRII receptor signaling pathway can inhibit muscle growth and lead to atrophy; blocking activin signaling in skeletal muscle can inhibit this atrophy and promote muscle mass increase. Due to its importance in fat and muscle metabolism, ActRII has become a potential drug target for treating metabolic diseases, muscle atrophy, and even cancer cachexia.

[0005] Cachexia is a multifactorial, progressive, systemic wasting syndrome characterized by extreme weight loss, skeletal muscle atrophy, fat degradation, anemia, chronic obstructive pulmonary disease (COPD), chronic heart failure, and mental deterioration, leading to multiple organ dysfunction. It is often caused by tumors and other serious illnesses such as AIDS, severe trauma, post-surgery, malabsorption, and severe sepsis. Cachexia associated with tumors is the most common, known as cancer cachexia. The main clinical features of cancer cachexia include muscle atrophy and fat degradation, leading to significant weight loss and potentially resulting in multiple organ failure and death in the later stages of the disease. This complication not only weakens the effectiveness of chemotherapy and radiotherapy but also severely impacts the patient's quality of life, significantly shortening the survival time of cancer patients. Reports indicate that cancer cachexia affects nearly 60%–80% of late-stage cancer patients and causes approximately 20%–30% of cancer patients' deaths.

[0006] The pathogenesis of cancer cachexia is extremely complex and largely unclear. Pathogenic factors disrupt metabolism and cause inflammation through various pathways, leading to weakened oxidation processes, accumulation of incomplete oxidation products, and insufficient utilization of nutrients. Currently, most recommended treatments for cachexia are limited to improving appetite and nutritional interventions. The only approved drug for treating cancer cachexia is the ghrelin receptor agonist alamolin, severely limiting treatment options. Inhibiting muscle atrophy and promoting muscle mass increase are currently considered important methods for treating and alleviating cancer cachexia.

[0007] The dual effects of inhibiting the ActRII signaling pathway—reducing fat and protecting muscle—make it an attractive target for treating obesity and related metabolic diseases. Bimagrumab, developed by Eli Lilly, is a monoclonal antibody that directly targets ActRIIA and ActRIIB, increasing muscle mass by blocking activin signaling. In a Phase II clinical trial (NCT03005288) in obese patients with type 2 diabetes, results showed an average reduction of 20.5% in total body fat and a 3.6% increase in lean body mass over 48 weeks, along with improvements in glycemic levels and metabolic parameters. LAE-102 from Laikai Pharmaceuticals is also a potent, selective monoclonal antibody targeting ActRIIA, currently in Phase I clinical trials, and is expected to be used to treat obesity, overweight, and metastatic solid tumors.

[0008] Based on the multiple important physiological functions of ActRII, BMS's ActRIIB-Fc fusion protein drug Luspatercept was approved by the FDA on November 8, 2019, and April 3, 2020, respectively, for the treatment of β-thalassemia and anemia caused by myelodysplastic syndrome. Merck's ActRIIA-Fc fusion protein drug Sotatercept was approved by the FDA on March 26, 2024, for the treatment of pulmonary arterial hypertension (PAH) in adults. It dilates the pulmonary artery and remodels vascular structure by restoring the balance between activin and bone morphogenetic protein pathways, significantly improving patients' exercise capacity, hemodynamic parameters, and quality of life, while slowing disease progression.

[0009] Currently, most ActRII-related drugs under development are protein or gene-based drugs. These large molecule drugs are challenging to research, have high overall costs, and face stringent requirements for production, storage, and transportation after market launch. Furthermore, the need for injection administration leads to poor compliance. Therefore, research on ActRII small molecule inhibitors is highly promising. Small molecule ActRII inhibitors address significant unmet clinical needs in treating related diseases such as skeletal muscle atrophy, particularly malignant tumors. Developing ActRII small molecule inhibitors with good inhibitory efficacy and high selectivity has become one of the important research directions in this field. Summary of the Invention

[0010] Based on this, this application provides a heterocyclic compound with good inhibitory effect and high selectivity, a pharmaceutical composition, an activin type II receptor inhibitor, and its application.

[0011] The technical solution proposed in this application is as follows: According to a first aspect of this application, a heterocyclic compound is provided, said heterocyclic compound being a compound of Formula I or a racemic mixture, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug: .

[0012] In the formula, ring A is a 4-8 member aliphatic ring or aliphatic heterocycle, and the number of R1 substituents on ring A is 1-4; Ring B is a 5- to 10-membered aromatic or aromatic heterocyclic ring or a fused ring, and the number of R2 substituents on ring B is 1 to 4. X1, X2, X3, and X4 are each independently selected from N or CR3; Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are each independently selected from N, NH, or CR4; R1 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, cyano, carboxyl, sulfonyl, aminoacyl, carbonyl, and -OR. 11 -OC(=O)N(R) 11 )2、(=O) q 、(=NR 11 ) q 、(=O)(=NR 11 -C(=O)R 11 -C(=O)OR 11 -C(=O)N(R) 11 )2、-C(=O)C(R 11 3. -C(=O)CH=C(R) 11 )2、-C(=O)CH=CH-CH2N(R 11 )2、-C(=O)C(=O)R 11 -C(=O)C(=O)N(R) 11 )2、-C(=S)R 11 -C(=NR) 11 )R 11 -C(=NR) 11 )N(R 11 )2、-N(R 11 )2、-NR 11 C(=O)R 11 -NR 11 C(=NR 11 )N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 C(O)OR 11 -NR 11 S(=O) q R 11 -NR 11 S(=O) q OR 11 -NR 11 S(=O) q SR 11 -NR 11 S(=O) q N(R 11 )2、-N=S(=O)(R 11 2. -S (=O) q R 11 -S(=O) q OR 11 -S(=O) q SR 11 -S(=O) q N(R11 )2、-S(=O)(=NR 11 )R 11 -S(=O)(=NR) 11 )N(R 11 2. C 1~6 Alkyl, C 1~6 alkenyl, C 1~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 alkenyl C 1~6 Alkyl, C 1~6 alkynyl C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, S, and O, and 4-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, S, and O, wherein the above alkyl, alkenyl, alkynyl, acyl, sulfonyl, alkoxy, alkanoyl, cycloalkyl, heterocyclic alkyl, and heterocyclic aryl groups have 1-3 R groups. 11 Substituents; R 11 Independently selected from hydrogen, deuterium, halogen, amino, imino, hydroxyl, mercapto, cyano, carbonyl, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl, benzyl, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, S, and O, -NHC(O)C 1~6 Alkyl group, -NHC(O)C 3~6 cycloalkyl, -NHC(O)C 4~6 Heterocyclic alkyl groups, -NHC(O)NHC 1~6 Alkyl or -NHC(O)OC 1~6 alkyl; q is independently selected from 0, 1, or 2; R2 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, sulfonyl pentafluoride, cyano, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl or containing 1 to 3 4-6 membered heterocycloalkyl groups selected from N, S, and O heteroatoms, or containing 1 to 3 4-6 membered heterocyclic aryl groups selected from N, S, and O heteroatoms; R3 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, sulfonyl pentafluoride, cyano, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, S, and O; R4 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, sulfonyl pentafluoride, cyano, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl or containing 1 to 3 4- to 6-membered heterocycloalkyl atoms selected from N, S, and O heteroatoms.

[0013] In any embodiment, the heterocyclic compound is a compound of Formula II or a racemic, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug. .

[0014] In the formula, W is selected from N, O, SR1 or CR1.

[0015] In any embodiment, the heterocyclic compound is a compound of Formula III or its racemate, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug. .

[0016] In the formula, Z1, Z2, Z3, and Z4 are each independently selected from N, O, S, or CR2.

[0017] In any embodiment, two adjacent R1s on ring A form a 4-7 quintile aliphatic rings or aliphatic heterocycles, and together with ring A, they form a fused ring, a spiral ring, or a bridged ring.

[0018] In any embodiment, the 4-7 member aliphatic ring or aliphatic heterocycle has 1-3 R1 substituents.

[0019] In any embodiment, the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, and heterocycloaryl groups in R2 have 1 to 3 deuterium, halogen, hydroxyl, amino, or C molar groups. 1~6 Alkyl or C 3~6 Cycloalkyl substituents.

[0020] In any embodiment, the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, cycloalkyl, or heterocycloalkyl group in R3 has 1 to 3 deuterium, halogen, hydroxyl, amino, or C molar groups. 1~6 Alkyl or C 3~6 Cycloalkyl substituents.

[0021] In any embodiment, the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, cycloalkyl, or heterocycloalkyl group in R4 has 1 to 3 deuterium, halogen, hydroxyl, amino, or C moiety. 1~6 Alkyl or C 3~6 Cycloalkyl substituents.

[0022] In any implementation, R 11 The hydroxyl, amino, alkyl, alkenyl, alkoxy, alkanoyl, cycloalkyl, and heterocyclic alkyl groups contain 1 to 3 deuterium, halogen, hydroxyl, amino, and C groups. 1~6 Alkyl, C 3~6 cycloalkyl, C 3~6 Heterocyclic alkyl, heterophenyl, or heteroaryl substituents.

[0023] In any embodiment, the heterocyclic compound is any one of the following: , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0024] According to a second aspect of this application, a pharmaceutical composition is provided, comprising the heterocyclic compound of the first aspect of this application.

[0025] According to a third aspect of this application, an activin type II receptor inhibitor is provided, comprising the heterocyclic compound of the first aspect of this application; optionally, the activin type II receptor is activin receptor 2B.

[0026] According to a fourth aspect of this application, the use of a heterocyclic compound of the first aspect of this application, a pharmaceutical composition of the second aspect of this application, or an activin type II receptor inhibitor of the third aspect of this application in the preparation of an anti-cachexia drug, an anti-muscle dystrophic drug, or an anti-metabolic disease drug is provided.

[0027] Compared with traditional technologies, this application has at least the following beneficial effects: the heterocyclic compounds, pharmaceutical compositions or activin type II receptor inhibitors of this application can effectively inhibit activin receptor 2B and have high selectivity, and have good application prospects in the preparation of anti-cachexia drugs, anti-muscle dystrophic drugs or anti-metabolic disease drugs. Detailed Implementation

[0028] The technical solution of this application will be clearly and completely described below with reference to the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0029] The "range" disclosed in this application can be defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints. Any endpoint can be independently included or excluded, and they can be combined arbitrarily; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60~120 and 80~110 are listed for a specific parameter, it is expected that ranges of 60~110 and 80~120 are also included. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are also listed, then the following ranges are all expected: 1~3, 1~4, 1~5, 2~3, 2~4, and 2~5. In this application, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0" and "5" have been listed in this document; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, stating that a parameter is an integer ≥2 is equivalent to disclosing that the parameter is, for example, an integer 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc. For instance, stating that a parameter is an integer selected from "2~10" is equivalent to listing the integers 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0030] In this application, the terms "multiple" or "various" are used unless otherwise specified, referring to a quantity greater than or equal to 2. For example, "one or more" means one or more types.

[0031] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0032] In this document, the term "embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment or implementation of this application. The appearance of this phrase in various places throughout the specification does not necessarily refer to the same embodiment, nor is it a separate or alternative embodiment mutually exclusive with other embodiments. It will be explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments. The term "implementation" as used herein has a similar understanding.

[0033] Those skilled in the art will understand that the order in which the steps are written in the methods of various embodiments or examples does not imply a strict execution order and does not constitute any limitation on the implementation process. The detailed execution order of each step should be determined by its function and possible internal logic. Unless otherwise specified, all steps of this application may be performed sequentially or randomly, preferably sequentially. For example, if the method includes steps (a) and (b), it means that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, if the method may also include step (c), it means that step (c) can be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0034] In this application, unless otherwise specified, A (e.g., B) means that B is a non-limiting example of A, and it is understood that A is not limited to B.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. Unless otherwise specifically stated, all raw materials, reagents, instruments, and equipment used herein are commercially available or can be prepared by existing methods.

[0036] Example 1: Synthesis of Intermediate I The reaction equation for synthesizing intermediate I is as follows: .

[0037] The synthesis steps of intermediate I are as follows: Step 1: Synthesis of 5-bromo-3-iodine-1 H -pyrrolo[2,3-b]pyridine (I-2) At 25°C, I-1 (5.0 g, 25.4 mmol) was added sequentially to a 250 mL single-necked flask, followed by 100 mL of DMF solvent. The mixture was cooled to 0°C–5°C, and NIS (6.3 g, 27.9 mmol) was added in portions. The mixture was stirred at 20°C–30°C for 2 h. The reaction was determined to be complete by TLC. A saturated sodium thiosulfate aqueous solution (200 mL) was added, followed by 200 mL of water, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with water (100 mL × 2). The filter cake was dried to give 8.2 g of solid I-2, yield: 100%. LCMS, M / Z (ESI): 323 [M+H]. + .

[0038] Step 2: Synthesis of 5-bromo-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (I-3) At 25°C, I₂ (8.2 g, 25.4 mmol) was added sequentially to a 100 mL single-necked flask, followed by DMF (164 mL) and NaH (1.5 g, 38.1 mmol) at 0°C. The mixture was stirred for 30 min, then TsCl (5.8 g, 30.5 mmol) was added. The mixture was stirred at 20°C–30°C for 16 h. The reaction was determined to be complete by TLC. Ice water (100 mL) was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was washed with water (100 mL × 2). The filter cake was dried to give 10.9 g of solid I₃, yield: 90%. LCMS, M / Z (ESI): 477 [M+H]. + .

[0039] Step 3: Synthesis of 3-(1H-pyrazol-3-yl)-5-bromo-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (I-5) At 25 °C, I-3 (3.0 g, 6.29 mmol), I-4 (1.8 g, 9.43 mmol), Pd(dppf)Cl2 (230 mg, 0.314 mmol), and K2CO3 (2.6 g, 18.86 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (40 mL) and water (10 mL) were added. The mixture was purged three times with nitrogen, and under nitrogen protection, the temperature was raised to 105 °C and the reaction was allowed to proceed for 16 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 1.9 g of solid I-5, yield: 72.4%. LCMS, M / Z (ESI): 417 [M+H]. + .

[0040] Step 4: Synthesis of 3-(1H-pyrazol-3-yl)-5-bromo-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (intermediate I) At 25 °C, I-5 (1.6 g, 3.83 mmol), THF (40 mL), DHP (645 mg, 7.67 mmol), and p-toluenesulfonic acid hydrate (219 mg, 1.15 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was heated to 70 °C and reacted for 2 h. The reaction was determined to be complete by TLC, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1, 3 / 1) to give 1.3 g of solid intermediate I, yield: 67.6%, LCMS, M / Z (ESI): 501 [M+H]. + .

[0041] Example 2: Synthesis of compound XY2501-2 The reaction equation for the synthesis of compound XY2501-2 is as follows: .

[0042] The synthetic steps of compound XY2501-2 are as follows: Step 1: Synthesize tert-butyl 8-(4-bromophenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl-3-carboxylic acid (XY2501-2-3) At 25°C, XY2501-2-1 (2.0 g, 7.07 mmol), XY2501-2-2 (1.0 g, 4.71 mmol), Pd2(dba)3 (431 mg, 0.471 mmol), and Xantphos (272 mg, 0.471 mmol) were added sequentially to a 100 mL single-necked flask. t BuONa (905 mg, 9.42 mmol) was added to solvent 1,4-dioxane (20 mL), purged three times with nitrogen, and heated to 80 °C under nitrogen protection, with stirring for 16 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1), the reaction was stopped, cooled to room temperature, filtered, and the filter cake was washed with EA (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1) to give 1.7 g of solid XY2501-2-3, yield: 98.3%, LCMS, M / Z (ESI): 367 [M+H]. + .

[0043] Step 2: Synthesis of 8-(4-bromophenyl)-3,8-diazabicyclo[3.2.1]octane (XY2501-2-4) At 25°C, XY2501-2-3 (1.5 g, 4.08 mmol) was added sequentially to a 100 mL single-necked flask, followed by DCM (45 mL). The mixture was cooled to 0–5°C, and TFA (15 mL) was slowly added. The temperature was then raised to 25°C, and the mixture was stirred for 2 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure. The crude product was adjusted to pH 7–8 with a saturated NaHCO3 aqueous solution. The aqueous phase was extracted with EA (50 mL × 2). The organic phases were combined and washed sequentially with water (50 mL × 2) and a saturated NaCl solution (50 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 970 mg of solid XY2501-2-4, yield: 88.9%. LCMS, M / Z (ESI): 267 [M+H]. + .

[0044] Step 3: Synthesis of 8-(4-bromophenyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane (XY2501-2-5) At 25°C, XY2501-2-4 (970 mg, 3.63 mmol) was added sequentially to a 100 mL single-necked flask, followed by methanol (20 mL), paraformaldehyde (327 mg, 10.89 mmol), AcOH (218 mg, 3.63 mmol), and NaBH3CN (685 mg, 10.89 mmol). The mixture was heated to 70°C and stirred for 16 h. The reaction was determined to be complete by LCMS. The pH was adjusted to 7-8 by adding saturated NaHCO3 aqueous solution. The aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 1.0 g of solid XY2501-2-5, yield: 98.0%, LCMS, M / Z (ESI): 281 [M+H]. + .

[0045] Step 4: Synthesize 4-{3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl}-8-phenylboronic acid pinacol ester (XY2501-2-6) At 25°C, XY2501-2-5 (1.0 g, 3.56 mmol), pinacol diboronate (1.35 g, 5.33 mmol), Pd(dppf)Cl2 (130 mg, 0.178 mmol), and K2CO3 (1.05 g, 10.67 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane solvent (5 mL) was added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 105°C and reacted for 16 h. LC-MS analysis confirmed the reaction was complete. The mixture was concentrated under reduced pressure to obtain crude XY2501-2-6, yield: 100%, LC-MS, M / Z (ESI): 329 [M+H]. + .

[0046] Step 5: Synthesis of 5-{4-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl}-1H-pyrrolo[2,3-b]pyridine (Chem.XY2501-2-8) At 25 °C, XY2501-2-7 (500 mg, 2.54 mmol), XY2501-2-6 (1.0 g, 3.05 mmol), Pd(dppf)Cl2 (93 mg, 0.127 mmol), and K2CO3 (1.05 g, 7.61 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (20 mL) and water (5 mL) were added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 105 °C and reacted for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1, 10 / 1) to obtain 180 mg of solid XY2501-2-8, yield: 22.3%. LCMS, M / Z (ESI): 319 [M+H]. + .

[0047] Step 6: Synthesis of 3-iodo-5-{4-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl}-1 H -Pyrrolo[2,3-b]pyridine (XY2501-2-9) At 25°C, XY2501-2-8 (180 mg, 0.565 mmol) was added sequentially to a 100 mL single-necked flask, followed by DMF (5 mL) and NIS (140 mg, 0.622 mmol). The mixture was stirred for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). A saturated sodium thiosulfate aqueous solution (10 mL) was added, and the aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 200 mg of solid XY2501-2-9, yield: 79.6%. LCMS, M / Z (ESI): 445 [M+H]. + .

[0048] Step 7: Synthesis of 3-iodo-1-[(4-methylphenyl)sulfonyl]-5-[4-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]pyrrolo[2,3-b]pyridine (XY2501-2-10) At 25°C, XY2501-2-9 (200 mg, 0.450 mmol) was added sequentially to a 100 mL single-necked flask, followed by DMF (5 mL). At 0°C, NaH (27 mg, 0.675 mmol) was added, and the mixture was stirred for 30 min. TsCl (103 mg, 0.540 mmol) was then added, and the mixture was stirred at 20°C-30°C for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). A saturated sodium bicarbonate aqueous solution (10 mL) was added, and the aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to obtain 160 mg of solid XY2501-2-10, yield: 59.4%. LCMS, M / Z (ESI): 599 [M+H]. + .

[0049] Step 8: Synthesize 3-(1 H -pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]-5-[4-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]pyrrolo[2,3-b]pyridine (XY2501-2-12) At 25 °C, XY2501-2-10 (160 mg, 0.267 mmol), XY2501-2-11 (63 mg, 0.321 mmol), Pd(dppf)Cl2 (10 mg, 0.013 mmol), and K2CO3 (111 mg, 0.802 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 105 °C and reacted for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to obtain 100 mg of solid XY2501-2-12, yield: 69.4%. LCMS, M / Z (ESI): 539 [M+H]. + .

[0050] Step 9: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-2) At 25°C, XY2501-2-12 (100 mg, 0.186 mmol), methanol (5 mL), and K2CO3 (77 mg, 0.557 mmol) were added sequentially to a 100 mL single-necked flask. The temperature was raised to 80°C, and the reaction was allowed to proceed for 4 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 20 mg of solid XY2501-2. Yield: 28.0%, purity: 94.82%, LCMS, M / Z (ESI): 385 [M+H]. + .

[0051] 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.54 (s, 1H), 8.50 (d, J =2.0 Hz, 1H), 8.87 (d, J =2.4 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 4.31 (s, 2H), 2.68-2.55 (m, 2H), 2.30 (s, 3H), 2.14 (s, 2H), 1.95-1.90 (m, 4H).

[0052] Example 3: Synthesis of compound XY2501-4 The reaction equation for the synthesis of compound XY2501-4 is as follows: .

[0053] The synthetic steps of compound XY2501-4 are as follows: Step 1: Synthesis of 1-(4-bromophenyl)-4-methylpiperazin-2-one (XY2501-4-3) At 25 °C, compounds XY2501-4-1 (1.0 g, 4.38 mmol), XY2501-4-2 (3.0 g, 5.26 mmol), CuI (168.0 mg, 0.44 mmol), K3PO4 (3.72 g, 8.76 mmol), and DMEDA (155 g, 0.88 mmol) were added sequentially to a 100 mL single-necked flask. The solution was then 10 mL of 1,4-dioxane. The mixture was purged three times with nitrogen, and under nitrogen protection, the temperature was raised to 105 °C and stirred for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). A saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1). 1.1 g of solid compound XY2501-4-3 was obtained, yield: 93.9%, LCMS, M / Z (ESI): 269 [M+H] + .

[0054] Step 2: Synthesis of 1-{4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl}-4-methylpiperazin-2-one (compound XY2501-4-5) At 25 °C, compounds XY2501-4-3 (300.0 mg, 1.16 mmol), XY2501-4-4 (408.0 mg, 1.67 mmol), Pd2(dba)3 (109.0 mg, 0.12 mmol), and K2CO3 (481.0 mg, 3.48 mmol) were added sequentially to a 100 mL single-necked flask. 1,4-Dioxane (5 mL) and water (1 mL) were then added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 100 °C and stirred for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1, 10 / 1, 5 / 1) to give 100 mg of solid compound XY2501-4-5, yield: 28.13%, LCMS, M / Z (ESI): 307 [M+H] + .

[0055] Step 3: Synthesis of 1-{4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl}-4-methylpiperazin-2-one (compound XY2501-4-6) At 25°C, compound XY2501-4-5 (100.0 mg, 0.33 mmol) was added sequentially to a 100 mL single-necked flask, followed by DCM (5 mL), methanol (1 mL), and NIS (110.0 mg, 0.49 mmol). The mixture was stirred for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). A saturated sodium thiosulfate aqueous solution (5 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted three times with DCM (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 130 mg of solid compound XY2501-4-6, yield: 91.16%, LCMS, M / Z (ESI): 433 [M+H]. + .

[0056] Step 4: Synthesis of 1-(4-{3-iodo-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)-4-methylpiperazin-2-one (compound XY2501-4-7) Compound XY2501-4-6 (130.0 mg, 0.30 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by tetrahydrofuran (5 mL) and DMF (1 mL). NaH (18.0 mg, 0.45 mmol) was added at 0 °C, and the mixture was stirred for 30 min. TsCl (86.0 mg, 0.45 mmol) was then added, and the mixture was stirred at 20 °C-30 °C for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). A saturated sodium bicarbonate aqueous solution (5 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to obtain 140 mg of solid compound XY2501-4-7, yield: 79.57%. LCMS, M / Z (ESI): 587 [M+H]. + .

[0057] Step 5: Synthesis of 1-{4-[3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}-4-methylpiperazin-2-one (compound XY2501-4-9) At 25 °C, compounds XY2501-4-7 (140.0 mg, 0.24 mmol), XY2501-4-8 (69.0 mg, 0.36 mmol), Pd(dppf)Cl2 (18.0 mg, 0.024 mmol), and K2CO3 (100.0 mg, 0.72 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 105 °C and the reaction was allowed to proceed for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1, 10 / 1) to give 75 mg of solid compound XY2501-4-9, yield: 59.34%. LCMS, M / Z (ESI): 528 [M+H]. + .

[0058] Step 6: Synthesize 1-{4-[3-(1 H -pyrazole-3-yl)-1 H -Pyrrolo[2,3-b]pyridin-5-yl]phenyl}-4-methylpiperazin-2-one (XY2501-4) At 25 °C, compound XY2501-4-9 (75.0 mg, 0.14 mmol), methanol (5 mL), and K2CO3 (59.0 mg, 0.43 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was heated to 80 °C and reacted for 4 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by thin-layer chromatography (DCM / MeOH = 10 / 1) to give 30 mg of solid XY2501-4. Yield: 57.53%, purity: 99.74%, LCMS, M / Z (ESI): 373 [M+H]. + .

[0059] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=2.2 Hz, 1H), 8.58 (d, J=2.2 Hz, 1H), 7.93 (s, 1H), 7.83-7.75 (m, 2H), 7.70 (d, J=2.1 Hz, 1H), 7.51-7.43 (m,2H), 6.71 (d, J = 2.1 Hz, 1H), 3.72 (dd, J=6.3, 4.5 Hz, 2H), 3.15 (s, 2H), 2.76 (t, J=5.4 Hz, 2H), 2.31 (s, 3H).

[0060] Example 4: Synthesis of compound XY2501-5 The reaction equation for the synthesis of compound XY2501-5 is as follows: .

[0061] The synthetic steps of compound XY2501-5 are as follows: Step 1: Synthesis of 2-[4-(4-methylpiperazin-1-yl)phenyl]-5 H -Pyrrolo[2,3-b]pyrazine (compound XY2501-5-3) At 25 °C, compounds XY2501-5-1 (200.0 mg, 1.01 mmol), XY2501-5-2 (458.0 mg, 1.51 mmol), Pd(dppf)Cl2 (73.0 mg, 0.10 mmol), and K2CO3 (419.0 mg, 3.03 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 100 °C and the reaction was allowed to proceed for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 35 / 1) to give 290 mg of solid compound XY2501-5-3, yield: 98.02%. LCMS, M / Z (ESI): 294 [M+H]. + .

[0062] Step 2: Synthesis of 7-iodo-2-[4-(4-methylpiperazin-1-yl)phenyl]-5 H -Pyrrolo[2,3-b]pyrazine (compound XY2501-5-4) At 25°C, compound XY2501-5-3 (290.0 mg, 0.99 mmol) was added sequentially to a 100 mL single-necked flask, followed by dichloromethane (5 mL) and NIS (337.0 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 h. The reaction was determined to be complete by LC-MS. A saturated sodium thiosulfate aqueous solution (5 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 400 mg of solid compound XY2501-5-4, yield: 95.96%, LC-MS, M / Z (ESI): 420 [M+H]. + .

[0063] Step 3: Synthesis of 7-iodo-5-[(4-methylphenyl)sulfonyl]-2-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyrazine (compound XY2501-5-5) Compound XY2501-5-4 (400.0 mg, 0.95 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 5 mL of tetrahydrofuran solvent. NaH (57.0 mg, 1.43 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 30 min. TsCl (273.0 mg, 1.43 mmol) was then added, and the mixture was stirred at 20 °C–30 °C for 2 h. The reaction was determined to be complete by LC-MS. A saturated sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 60 / 1, 50 / 1) to give 300 mg of solid compound XY2501-5-5, yield: 54.74%, LC-MS, M / Z (ESI): 574 [M+H]. + .

[0064] Step 4: Synthesize 7-(1 H -pyrazol-3-yl)-2-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (XY2501-5) At 25°C, compound XY2501-5-5 (300.0 mg, 0.52 mmol), compound 6 (152.0 mg, 0.78 mmol), Pd(dppf)Cl2 (38.0 mg, 0.052 mmol), and K2CO3 (215.6 mg, 1.56 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (4 mL) were added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 100°C and reacted for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure, purified by silica gel column chromatography (DCM / MeOH = 20 / 1, 5 / 1), and further purified by thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain 100 mL of the final product. mg solid XY2501-5, yield: 53.50%, LCMS, M / Z (ESI): 360 [M+H] + .

[0065] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.69 (s, 1H), 7.08 (d, J = 8.8 Hz, 3H), 3.24 (t, J = 4.8 Hz, 4H), 2.48 (t, J =5.2 Hz, 4H), 2.24 (s, 3H).

[0066] Example 5: Synthesis of compound XY2501-6 The reaction equation for the synthesis of compound XY2501-6 is as follows: .

[0067] The synthetic steps of compound XY2501-6 are as follows: Step 1: Synthesis of 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound XY2501-6-2) Compound XY2501-6-1 (500 mg, 2.52 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by DMF (10 mL) and NIS (852 mg, 3.79 mmol). The mixture was stirred at room temperature for 4 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). A saturated sodium thiosulfate aqueous solution (20 mL) was added, and the aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 740 mg of solid compound XY2501-6-2, yield: 90.5%. LCMS, M / Z (ESI): 324 [M+H]. + .

[0068] Step 2: Synthesis of 5-bromo-3-iodo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazolo[3,4-b]pyridine (compound XY2501-6-3) At 25 °C, compound XY2501-6-2 (740 mg, 2.28 mmol) was added sequentially to a 100 mL single-necked flask, followed by the addition of THF solvent (15 mL), 3,4-dihydro-2H-pyran (385 mg, 4.57 mmol), and p-toluenesulfonic acid hydrate (44 mg, 0.228 mmol). The mixture was heated to 65 °C and stirred for 16 h. The reaction was determined to be complete by TLC (PE / EA = 10 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1) to give 960 mg of solid compound XY2501-6-3, yield: 100%, LCMS, M / Z (ESI): 408 [M+H]. + .

[0069] Step 3: Synthesis of 5-bromo-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridine (compound XY2501-6-5) At 25 °C, compound XY2501-6-3 (200 mg, 0.490 mmol), compound XY2501-6-4 (164 mg, 0.588 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), and K2CO3 (203 mg, 1.47 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged three times with nitrogen, and under nitrogen protection, the temperature was raised to 105 °C and reacted for 16 h. The reaction was determined to be complete by TLC (PE / EA = 10 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 10 / 1) to give 160 mg of solid compound XY2501-6-5, yield: 75.5%, LCMS, M / Z (ESI): 432 [M+H]. + .

[0070] Step 4: Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrazolo[3,4-b]pyridine (compound XY2501-6-7) At 25 °C, compound XY2501-6-5 (160 mg, 0.370 mmol), compound XY2501-6-6 (102 mg, 0.336 mmol), Pd(dppf)Cl2 (13 mg, 0.017 mmol), and K2CO3 (140 mg, 1.01 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged three times with nitrogen, and under nitrogen protection, the temperature was raised to 105 °C and reacted for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 120 mg of solid compound XY2501-6-7, yield: 67.6%, LCMS, M / Z (ESI): 528 [M+H]. + .

[0071] Step 5: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine (XY2501-6) Compound XY2501-6-7 (120 mg, 0.227 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 2 N HCl / EA (2 mL). The reaction was carried out at 25 °C for 1 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to obtain 20 mg of solid XY2501-6. Yield: 24.5%, Purity: 95.83%, LCMS, M / Z (ESI): 360 [M+H]. + .

[0072] 1 H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 13.09 (s, 1H), 8.82 (s,1H), 8.70 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4Hz, 2H), 6.80 (s, 1H), 3.22 (t, J = 4.8 Hz, 4H), 3.17 (d, J = 5.2 Hz, 2H), 2.48-2.47 (m, 2H), 2.24 (s, 3H).

[0073] Example 6: Synthesis of compound XY2501-8 The reaction equation for the synthesis of compound XY2501-8 is as follows: .

[0074] The synthetic steps of compound XY2501-8 are as follows: Step 1: Synthesis of 5-bromo-1-[(4-methylphenyl)sulfonyl]-3-(1,2-isothiazolyl-4-yl)pyrrolo[2,3-b]pyridine (compound XY2501-8-3) At 25°C, compound XY2501-8-1 (500 mg, 1.05 mmol), Pd(PPh3)4 (242.7 mg, 0.21 mmol), compound XY2501-8-2 (265 mg, 1.26 mmol), potassium carbonate (435.3 mg, 3.15 mmol), 1,4-dioxane (15 mL), and H2O (1 mL) were added sequentially to a 30 mL sealed tube. The mixture was purged with N2 for 5 minutes and then microwaved at 110°C for 2 hours. The reaction was determined to be complete by TLC (PE / EA = 10 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1). 150 mg of a pale yellow oily liquid, XY2501-8-3, was obtained, yield: 32.7%, LCMS, M / Z (ESI): 437 [M+H]. + .

[0075] Step 2: Synthesis of 1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1,2-isothiazolyl-4-yl)pyrrolo[2,3-b]pyridine (compound XY2501-8-5) At 25°C, compound XY2501-8-3 (43 mg, 0.1 mmol), compound XY2501-8-4 (30 mg, 0.1 mmol), Pd(dppf)Cl2 (14.6 mg, 0.02 mmol), K2CO3 (42 mg, 0.3 mmol), and dioxane / H2O (15 mL, 3 mL) were added sequentially to a 25 mL single-necked flask. The mixture was substituted with N2 three times, and the reaction was carried out at 90°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was filtered, and the filtrate was concentrated under reduced pressure. Preparative TLC (DCM / MeOH = 10 / 1) yielded 15 mg of crude yellow solid XY2501-8-5, yield: 28.8%. LCMS, M / Z (ESI): 530 [M+H]. + .

[0076] Step 3: Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1,2-isothiazo-4-yl)-1 H -Pyrrolo[2,3-b]pyridine (XY2501-8) At 25°C, compound XY2501-8-5 (15 mg, 0.028 mmol), K2CO3 (11.7 mg, 0.085 mmol), and MeOH (10 mL) were added sequentially to a 25 mL single-necked flask. The reaction was carried out at 70°C for 2 h, and TLC (DCM / MeOH = 10 / 1) was used to determine the completeness of the reaction. The reaction solution was concentrated under reduced pressure and prepared by high-pressure reverse phase reaction (H2O / ACN = 40 / 60) to give 5 mg of white solid XY2501-8, yield: 47.2%, purity: 98.31%, LCMS, M / Z (ESI): 376 [M+H]. + .

[0077] 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.38 (s, 1H), 9.12 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.20 (t, J = 5.2 Hz, 4H), 2.48 (m, 4H), 2.24 (s, 3H).

[0078] Example 7: Synthesis of compound XY2501-9 The reaction equation for the synthesis of compound XY2501-9 is as follows: .

[0079] The synthetic steps of compound XY2501-9 are as follows: Step 1: Synthesis of 5-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-1 H -Pyrrolo[2,3-b]pyridine (compound XY2501-9-3) At 25 °C, compound XY2501-9-1 (1.0 g, 3.9 mmol), Pd(dppf)Cl2 (571.4 mg, 0.78 mmol), compound XY2501-9-2 (1.43 g, 5.85 mmol), potassium carbonate (1.62 g, 11.7 mmol), 1,4-dioxane (50 mL), and H2O (10 mL) were added sequentially to a 100 mL single-necked flask. The mixture was substituted with N2 three times, and the reaction was carried out at 90 °C for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1). 280 mg of a pale yellow oily liquid compound XY2501-9-3 was obtained, yield: 24.3%, LCMS, M / Z (ESI): 295 [M+H]. + .

[0080] Step 2: Synthesis of 3-iodo-5-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-1 H -Pyrrolo[2,3-b]pyridine (compound XY2501-9-4) At 25°C, compound XY2501-9-3 (280 mg, 0.95 mmol), DMF (30 mL), and NIS (278 mg, 1.14 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). 60 mL of H2O was added, and the mixture was extracted with EA (60 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 120 mg of crude brown solid XY2501-9-4, yield: 30%. LCMS, M / Z (ESI): 420 [M+H]. + .

[0081] Step 3: Synthesis of 3-iodo-1-[(4-methylphenyl)sulfonyl]-5-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrrolo[2,3-b]pyridine (compound XY2501-9-5) At 25 °C, compound XY2501-9-4 (50 mg, 0.12 mmol), DMF (20 mL), NaH (7.2 mg, 0.18 mmol), and TsCl (28 mg, 0.144 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was reacted under N2 protection at room temperature for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The reaction was quenched with H2O (40 mL), extracted with EA (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 50 mg of reddish-brown solid XY2501-9-5, yield: 72.0%, LCMS, M / Z (ESI): 575 [M+H]. + .

[0082] Step 4: Synthesize 3-(2 H -pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]-5-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrrolo[2,3-b]pyridine (compound XY2501-9-7) At 25°C, compound XY2501-9-5 (50 mg, 0.09 mmol), compound XY2501-9-6 (21 mg, 0.11 mmol), Pd(dppf)Cl2 (13.2 mg, 0.02 mmol), potassium carbonate (37.3 mg, 0.27 mmol), 1,4-dioxane (20 mL), and H2O (4 mL) were added sequentially to a 100 mL single-necked flask. The mixture was then replaced three times with N2. The reaction was carried out at 90°C for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). After filtration with diatomaceous earth and concentration under reduced pressure, 20 mg of yellow solid XY2501-9-7 was obtained by TLC (DCM / MeOH = 10 / 1), yield: 43.0%. LCMS, M / Z (ESI): 515 [M+H]. + .

[0083] Step 5: 3-(2H-pyrazol-3-yl)-5-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-9) Compound XY2501-9-7 (20 mg, 0.04 mmol), potassium carbonate (16.5 mg, 0.12 mmol), and MeOH (15 mL) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 70 °C for 2 h. The reaction was monitored by LCMS until complete. High-pressure reverse-phase preparation (H2O / ACN = 40 / 60) yielded 10 mg of white solid XY2501-9, purity: 96.20%, yield: 70%, LCMS, M / Z (ESI): 361 [M+H]. + .

[0084] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 2.4 Hz, 1H), 8.89 (d, J = 2.4Hz, 1H), 8.43 (d, J = 3.2 Hz, 1H), 8.31 (s, 1H), 7.87 (s,1H), 7.72 (d, J =2.4 Hz, 1H), 7.44 (dd, J = 8.8, 3.2 Hz, 1H), 7.22 (s, 1H), 6.66 (d, J = 2.4Hz, 2H), 3.27 (s, 4H), 3.17 (s, 4H), 2.25 (s, 3H).

[0085] Example 8: Synthesis of compound XY2501-10 The reaction equation for the synthesis of compound XY2501-10 is as follows: .

[0086] The synthetic steps of compound XY2501-10 are as follows: Step 1: Synthesis of 4-(4-bromo-3-fluorophenyl)-1-methylpiperazine (compound XY2501-10-3) At 25°C, compound XY2501-10-1 (500 mg, 1.67 mmol), Pd2(dba)3 (3.53 g, 3.86 mmol), and compound XY2501-10-2 (6.58 g, 23.25 mmol) were added sequentially to a 100 mL single-necked flask. t-BuONa (4.34 g, 38.76 mmol) was added to 1,4-dioxane (50 mL), and the mixture was substituted with N2 three times and reacted at 85 °C for 3 h. The reaction was determined to be complete by TLC (PE / EA = 10 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1). 1.4 g of a yellow oil solid XY2501-10-3 was obtained, yield: 28.0%, LCMS, M / Z (ESI): 259 [M+H]. + .

[0087] Step 2: 4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-methylpiperazine (compound XY2501-10-4) At 25°C, compound XY2501-10-3 (350 mg, 1.35 mmol), pinacol diboronate (525 mg, 2.03 mmol), Pd(dppf)Cl2 (200 mg, 0.27 mmol), potassium acetate (397 mg, 4.05 mmol), and dioxane (40 mL) were added sequentially to a 100 mL single-necked flask. The mixture was substituted three times with N2, and the reaction was carried out at 95°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1) to give 100 mg of a yellow solid XY2501-10-4, yield: 23.0%, 321 [M+H]. + .

[0088] Step 3: Synthesis of 6-[2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[2-(3,4,5,6-tetrahydro-2-yl)-[2-(4,4,5,6-tetrahydro-2-yl)-[2-(4-methylphenyl)sulfonyl]-3-[2-(4,5,6-tetrahydro-2-yl)-[2-(4-methylphenyl)sulfonyl] ... H [-pyran-2-yl]pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-10-5) At 25 °C, compound XY2501-10-4 (100 mg, 0.31 mmol), potassium carbonate (128.5 mg, 0.93 mmol), Pd(dppf)Cl2 (45 mg, 0.063 mmol), dioxane (40 mL), H2O (8 mL), and intermediate I (186 mg, 0.372 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 95 °C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 2 / 1). The mixture was filtered, concentrated under reduced pressure, and prepared by TLC (PE / EA = 2 / 1) to give 70 mg of brown solid XY2501-10-5, yield: 36.7%, LCMS, M / Z (ESI): 615 [M+H].+ .

[0089] Step 4: 3-(2H-pyrazol-3-yl)-6-[2-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (XY2501-10) At 25°C, compound XY2501-10-5 (70 mg, 0.14 mmol) and HCl / EA (20 mL) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at room temperature for 2 h, and the reaction was determined to be complete by LCMS. The mixture was concentrated to dryness, and MeOH (20 mL) and potassium carbonate (117.5 mg, 0.85 mmol) were added. The mixture was reacted at 75°C for 12 h, and the reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and prepared under high pressure (ACN / H2O = 40 / 60) to give 10 mg of white solid XY2501-10, purity: 99.40%, yield: 19.0%, LCMS, M / Z (ESI): 377 [M+H]. + .

[0090] 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 11.83 (s, 1H), 8.52 (s,1H), 8.37 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.69 (s, 1H), 7.45 (t, J = 9.2Hz, 1H), 6.99-6.81 (m, 2H), 6.63 (d, J = 2.0 Hz, 1H), 3.25 (t, J = 5.0 Hz, 4H), 2.57-2.51 (m, 4H), 2.27 (s, 3H).

[0091] Example 9: Synthesis of compound XY2501-11 The reaction equation for the synthesis of compound XY2501-11 is as follows: .

[0092] The synthetic steps of compound XY2501-11 are as follows: Step 1: Synthesis of 5-{1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridin-3-yl}-1H-pyrrolo[2,3-b]pyridine (compound XY2501-11-3) At 25 °C, compounds XY2501-11-1 (150 mg, 0.262 mmol), XY2501-11-2 (96.0 mg, 0.393 mmol), Pd(dppf)Cl2 (38.4 mg, 0.05 mmol), and K2CO3 (108.6 mg, 0.78 mmol) were added sequentially to a 30 mL sealed tube. 1,4-Dioxane (30 mL) and water (5 mL) were added. The mixture was purged three times with nitrogen and reacted at 90 °C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 111 mg of a brown solid compound XY2501-11-3, yield: 75.2%. LCMS, M / Z (ESI): 563 [M+H]. + .

[0093] Step 2: 3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (XY2501-11) At 25°C, compound XY2501-11-3 (60 mg, 0.100 mmol), K2CO3 (44.2 mg, 0.300 mmol), and MeOH (15 mL) were added sequentially to a 25 mL single-necked flask. The reaction was carried out at 70°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and prepared under high pressure (ACN / H2O = 51 / 49) to give 15 mg of off-white solid XY2501-11, purity: 96.68%, yield: 36.5%, LCMS, M / Z (ESI): 410 [M+H]. + .

[0094] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (d, J = 2.4Hz, 1H), 11.64 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.86 (d, J= 2.4 Hz, 1H), 7.71-7.57 (m, 2H), 7.54-7.45 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.51 (dd, J = 3.6, 2.0Hz, 1H), 3.28-3.21 (m, 4H), 3.19 (d, J = 5.2 Hz, 4H), 2.25 (s, 3H).

[0095] Example 10: Synthesis of compound XY2501-13 The reaction equation for the synthesis of compound XY2501-13 is as follows: .

[0096] The synthetic steps of compound XY2501-13 are as follows: Step 1: Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-c]pyridine (compound XY2501-13-3) At 25 °C, compound XY2501-13-1 (700.0 mg, 3.55 mmol), compound XY2501-13-2 (1070.0 mg, 3.55 mmol), Pd(PPh3)4 (416.0 mg, 0.36 mmol), K2CO3 (1470.0 mg, 10.65 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times, and under nitrogen protection, the temperature was raised to 110 °C and stirred for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 5 / 1) to give 310 mg of solid compound XY2501-13-3, yield: 29.81%, LCMS, M / Z (ESI): 293 [M+H] + .

[0097] Step 2: Synthesis of 3-iodo-5-[4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-c]pyridine (compound XY2501-13-4) Compound XY2501-13-3 (310.0 mg, 1.06 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by dichloromethane (15 mL) and NIS (358.0 mg, 1.59 mmol). The mixture was stirred at 25 °C for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). A saturated sodium thiosulfate aqueous solution (15 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with dichloromethane (15 mL). The combined organic phases were washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 300 mg of solid compound XY2501-13-4, yield: 67.66%, LCMS, M / Z (ESI): 419 [M+H]. + .

[0098] Step 3: Synthesis of 3-iodo-1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-c]pyridine (compound XY2501-13-5) At 25°C, compound XY2501-13-4 (300.0 mg, 0.72 mmol) was added sequentially to a 100 mL single-necked flask, followed by tetrahydrofuran (10 mL) and DMF (2 mL). At 0°C, NaH (43.0 mg, 1.08 mmol) was added, and the mixture was stirred for 30 min. TsCl (206.0 mg, 1.08 mmol) was then added, and the mixture was stirred at 20°C–30°C for 4 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). Aqueous solution (25 mL) and ethyl acetate (25 mL) were added, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with ethyl acetate (25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 50 / 1, 40 / 1) to obtain 200 mg of solid compound XY2501-13-5, yield: 48.61%. LCMS, M / Z (ESI): 574. [M+H] + .

[0099] Step 4: Synthesis of 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-c]pyridine (compound XY2501-13-7) At 25 °C, compound XY2501-13-5 (200.0 mg, 0.35 mmol), compound XY2501-13-6 (102.0 mg, 0.53 mmol), Pd(dppf)Cl2 (26.0 mg, 0.035 mmol), K2CO3 (145.0 mg, 1.05 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged three times with nitrogen, and under nitrogen protection, the temperature was raised to 105 °C and reacted for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 50 / 1, 40 / 1) to give 120 mg of solid compound XY2501-13-7, yield: 65.71%, LCMS, M / Z (ESI): 514 [M+H]. + .

[0100] Step 5: Synthesize 3-(1 H -pyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-c]pyridine (XY2501-13) At 25 °C, compound XY2501-13-7 (120.0 mg, 0.23 mmol), methanol (5 mL), and K2CO3 (138.21 mg, 0.70 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was heated to 70 °C and reacted for 4 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by thin-layer chromatography (DCM / MeOH = 10 / 1) to give 60 mg of solid XY2501-13, yield: 72.78%, purity: 97.55%, LCMS, M / Z (ESI): 359 [M+H]. + .

[0101] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.38 (s, 1H), 7.97 (d, J =9.2 Hz, 3H), 7.71 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.69 (d, J =2.0 Hz, 1H), 3.20 (t, J = 5.2 Hz, 4H), 2.48 (t, J= 5.2 Hz, 4H), 2.24 (s, 3H).

[0102] Example 11: Synthesis of compound XY2501-14 The reaction equation for the synthesis of compound XY2501-14 is as follows: .

[0103] The synthetic steps of compound XY2501-14 are as follows: Step 1: Synthesis of 6-methyl-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (compound XY2501-14-3) At 25°C, compound XY2501-14-1 (500 mg, 2.37 mmol), compound XY2501-14-2 (650 mg, 2.15 mmol), Pd(dppf)Cl2 (79 mg, 0.108 mmol), K2CO3 (893 mg, 6.46 mmol), 1,4-dioxane (20 mL), and water (5 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times, and under nitrogen protection, the temperature was raised to 105°C and stirred for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), the reaction was stopped, cooled to room temperature, filtered, the filter cake was washed with EA (20 mL × 2), the filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 560 mg of solid compound XY2501-14-3, yield: 84.9%, LCMS, M / Z (ESI): 307 [M+H] + .

[0104] Step 2: Synthesis of 6-methyl-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (compound XY2501-14-4) At 25 °C, compound XY2501-14-3 (560 mg, 1.83 mmol) was added sequentially to a 100 mL single-necked flask, followed by DMF (13 mL) and NIS (452 ​​mg, 2.01 mmol). The mixture was stirred for 1 h. The reaction was determined to be complete by TLC. A saturated sodium thiosulfate aqueous solution (20 mL) was added, and the aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 440 mg of solid compound XY2501-14-4, yield: 55.7%. LCMS, M / Z (ESI): 433 [M+H].+ .

[0105] Step 3: Synthesis of 3-(1H-pyrazol-3-yl)-6-methyl-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (XY2501-14) Compound XY2501-14-4 (340 mg, 0.786 mmol), compound 5 (230 mg, 1.18 mmol), Pd(dppf)Cl2 (58 mg, 0.079 mmol), and K2CO3 (326 mg, 2.36 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (15 mL) and water (3 mL) were added. The mixture was purged with nitrogen three times. Under nitrogen protection, the temperature was raised to 105 °C and stirred for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), the reaction was stopped, cooled to room temperature, filtered, and the filter cake was washed with EA (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 80 mg of solid compound XY2501-14, yield: 21.1%, purity: 99.08%, LCMS, M / Z (ESI): 373 [M+H]. + .

[0106] 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 11.53 (s, 1H), 8.22 (s,1H), 7.76-7.72 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 3.21-3.17 (m, 4H), 2.50-2.49 (m, 7H), 2.25 (s, 3H).

[0107] Example 12: Synthesis of compound XY2501-15 The reaction equation for the synthesis of compound XY2501-15 is as follows: .

[0108] The synthetic steps of compound XY2501-15 are as follows: Step 1: Synthesis of 5-[4-(1-methylpiperidin-4-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2 ...H [-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-15-2) At 25°C, intermediate I (300 mg, 0.598 mmol), compound XY2501-15-1 (136 mg, 0.778 mmol), Pd(dppf)Cl2 (44 mg, 0.060 mmol), and K2CO3 (248 mg, 1.79 mmol) were added sequentially to a 100 mL single-necked flask. Then, solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times, and under nitrogen protection, the temperature was raised to 105°C and stirred for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), the reaction was stopped, cooled to room temperature, filtered, the filter cake was washed with EA (20 mL × 2), the filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 300 mg of solid compound XY2501-15-2, yield: 84.2%, LCMS, M / Z (ESI): 596 [M+H] + .

[0109] Step 2: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(1-methylpiperidin-4-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-15-3) At 25°C, compound XY2501-15-2 (300 mg, 0.504 mmol) was added sequentially to a 100 mL single-necked flask, followed by DCM (10 mL) and TFA (3 mL). The mixture was stirred for 1 h. The reaction was determined to be complete by LMCS, concentrated under reduced pressure, and purified by reverse-phase C18 column chromatography (ACN / H2O = 5%–95%) to obtain 100 mg of solid compound XY2501-15-3, yield: 38.8%, LCMS, M / Z (ESI): 512 [M+H]. + .

[0110] Step 3: Synthesize 3-(1 H -pyrazol-3-yl)-5-[4-(1-methylpiperidin-4-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-15) Compound XY2501-15-3 (100 mg, 0.195 mmol), K2CO3 (100 mg, 0.724 mmol), and methanol (5 mL) were added sequentially to a 100 mL single-necked flask. The mixture was heated to 75 °C and stirred for 1 h. The reaction was determined to be complete by LCMS, and the reaction was stopped. The mixture was then purified by reverse-phase C18 column chromatography (ACN / H2O = 5% ~ 95%) to give 20 mg of solid compound XY2501-15. Yield: 28.6%, Purity: 95.22%, LCMS, M / Z (ESI): 358 [M+H]. + .

[0111] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.4Hz, 1H), 7.90 (s, 1H), 7.70-7.66 (m, 3H), 7.37 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 2.0 Hz, 1H), 2.91-2.88 (m, 2H), 2.54-2.51 (m, 1H), 2.21 (s, 3H), 1.99(td, J = 11.6, 2.8 Hz, 2H), 1.80-1.66 (m, 4H).

[0112] Example 13: Synthesis of compound XY2501-16 The reaction equation for the synthesis of compound XY2501-16 is as follows: .

[0113] The synthetic steps of compound XY2501-16 are as follows: Step 1: Synthesis of 1-(4-bromo-3-methylphenyl)-4-methylpiperazine (compound XY2501-16-3) At 25°C, compounds XY2501-16-1 (2.0 g, 6.74 mmol), XY2501-16-2 (448 mg, 4.49 mmol), Pd2(dba)3 (412 mg, 0.449 mmol), and Xantphos (260 mg, 0.449 mmol) were added sequentially to a 100 mL single-necked flask. tBuONa (864 mg, 8.98 mmol) was added to solvent 1,4-dioxane (40 mL), and the mixture was purged with nitrogen three times and reacted at 80 °C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 40 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to give 1.36 g of solid compound XY2501-16-3, yield: 100%, LCMS, M / Z (ESI): 269 [M+H]. + .

[0114] Step 2: Synthesis of 2-methyl-4-(1-methylpiperidin-4-yl)phenylboronic acid pinacol ester (compound XY2501-16-4) At 25°C, compound XY2501-16-3 (300 mg, 1.11 mmol), pinacol diboronic acid ester (566 mg, 2.23 mmol), Pd(dppf)Cl2 (82 mg, 0.111 mmol), and KOAc (328 mg, 3.33 mmol) were added sequentially to a 100 mL single-necked flask. The solution was then added in 10 mL of 1,4-dioxane. The mixture was purged with nitrogen three times and reacted at 105°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 40 / 1). The mixture was concentrated under reduced pressure to give crude compound XY2501-16-4, yield: 100%. LCMS, M / Z (ESI): 317 [M+H]. + .

[0115] Step 3: Synthesis of 5-[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-16-5) At 25°C, intermediate I (200 mg, 0.399 mmol), crude compound XY2501-16-4 (400 mg, 0.632 mmol), Pd(dppf)Cl2 (29 mg, 0.040 mmol), and K2CO3 (166 mg, 1.20 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was purged with nitrogen three times and reacted at 105°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 100 mg of solid compound XY2501-16-5, yield: 41.1%. LCMS, M / Z (ESI): 611 [M+H]. + .

[0116] Step 4: Synthesize 3-(1 H -pyrazol-3-yl)-5-[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-16-6) Compound XY2501-16-5 (100 mg, 0.164 mmol) was dissolved in DCM (3 mL) at 25 °C, and TFA (1 mL) was added. The reaction was carried out at room temperature for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed successively with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by TLC (DCM / MeOH = 20 / 1) to give 50 mg of solid compound XY2501-16-6, yield: 58.0%, LCMS, M / Z (ESI): 527 [M+H]. + .

[0117] Step 5: Synthesize 3-(1 H -pyrazol-3-yl)-5-[2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-16) Compound XY2501-16-6 (50 mg, 0.095 mmol), methanol (3 mL), and K2CO3 (40 mg, 0.285 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 70 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 20 mg of solid XY2501-16. Yield: 56.6%, purity: 98.18%, LCMS, M / Z (ESI): 373 [M+H]. + .

[0118] 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.73 (s, 1H), 8.37 (s,1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.91(d, J= 2.8 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 3.18 (t, J = 4.8 Hz, 4H), 2.48 (t, J = 4.8 Hz, 4H), 2.24 (s, 6H).

[0119] Example 14: Synthesis of compound XY2501-19 The reaction equation for the synthesis of compound XY2501-19 is as follows: .

[0120] The synthetic steps of compound XY2501-19 are as follows: Step 1: 5-Bromo-1-[(4-methylphenyl)sulfonyl]-3-(3,4,5-trimethoxyphenyl)pyrrolo[2,3-b]pyridine (compound XY2501-19-3) At 25 °C, compound XY2501-19-1 (300 mg, 1.41 mmol), compound XY2501-19-2 (613 mg, 1.28 mmol), Pd(dppf)Cl2 (207 mg, 0.282 mmol), and K2CO3 (354 mg, 2.56 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (30 mL) and water (5 mL) were added. The mixture was purged with nitrogen three times and reacted at 90 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give 356 mg of a yellow solid, compound XY2501-19-3, yield: 53.8%, 518 [M+H]. + .

[0121] Step 2: 1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(3,4,5-trimethoxyphenyl)pyrrolo[2,3-b]pyridine (compound XY2501-19-5) At 25 °C, compounds XY2501-19-3 (356 mg, 0.69 mmol), XY2501-19-4 (312.7 mg, 1.04 mmol), Pd(dppf)Cl2 (101 mg, 0.138 mmol), and K2CO3 (190.7 mg, 1.38 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (30 mL) and water (5 mL) were added. The mixture was purged three times with nitrogen, and the reaction was carried out at 90 °C for 16 h under nitrogen protection. The reaction was determined to be complete by TLC. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 2 / 1) to give 150 mg of a yellow solid, XY2501-19-5, yield: 35.4%, 614 [M+H]. + .

[0122] Step 3: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(3,4,5-trimethoxyphenyl)-1 H -Pyrrolo[2,3-b]pyridine (XY2501-19) At 25°C, compound XY2501-19-5 (50 mg, 0.08 mmol), followed by MeOH (5 mL) and potassium carbonate (33.1 mg, 0.24 mmol), was added sequentially to a 100 mL single-necked flask. The reaction was carried out at 70°C for 12 h, and the reaction was determined to be complete by LC-MS. The reaction solution was concentrated and prepared under high pressure (ACN / H2O = 40 / 60) to obtain 20 mg of white solid XY2501-19, purity: 99.20%, yield: 54.3%, 460 [M+H]. + .

[0123] 1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.32(d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 2.0 Hz, 1H), 7.07(d, J = 8.8 Hz, 2H), 6.87 (s, 2H), 3.95 (d, J = 9.2 Hz, 9H), 3.37 (s, 4H), 2.74 (s, 4H), 2.47 (s, 3H).

[0124] Example 15: Synthesis of compound XY2501-20 The reaction equation for the synthesis of compound XY2501-20 is as follows: .

[0125] The synthetic steps of compound XY2501-20 are as follows: Step 1: Synthesis of 1-(4-bromophenyl)piperazine (compound XY2501-20-2) At 25°C, compound XY2501-20-1 (1.0 g, 2.93 mmol), DCM (15 mL), and TFA (5 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), and the reaction was stopped. The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 700 mg of solid compound XY2501-20-2, yield: 99.0%, LCMS, M / Z (ESI): 241 [M+H]. + .

[0126] Step 2: Synthesis of 4-(4-bromophenyl)-1-(trifluoromethyl)piperazine (compound XY2501-20-3) Compound XY2501-20-2 (700 mg, 2.90 mmol) was added to a 60 mL sealed tube at 25 °C, along with solvent EA (29 mL), AgF (1.66 g, 13.06 mmol), DABCO (163 mg, 1.45 mmol), and CS2 (221 mg, 2.90 mmol). The tube was purged three times with nitrogen, sealed, and reacted at 80 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 20 / 1). The mixture was filtered, and the filter cake was washed with EA (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 20 / 1) to give 300 mg of solid compound XY2501-20-3, yield: 33.4%, LCMS, M / Z (ESI): 309 [M+H]. + .

[0127] Step 3: Synthesis of 4-(1-(trifluoromethyl)piperazin-4-yl)phenylpinazone (compound XY2501-20-4) At 25 °C, compound XY2501-20-3 (300 mg, 0.970 mmol), pinacol diboronic acid ester (370 mg, 1.46 mmol), Pd(dppf)Cl2 (36 mg, 0.049 mmol), and KOAc (286 mg, 2.91 mmol) were added sequentially to a 100 mL single-necked flask. 1,4-Dioxane (8 mL) solvent was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 105 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 40 / 1) to give 180 mg of solid compound XY2501-20-4, yield: 52.1%. LCMS, M / Z (ESI): 357 [M+H]. + .

[0128] Step 4: Synthesis of 1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]-5-{4-[4-(trifluoromethyl)piperazin-1-yl]phenyl}pyrrolo[2,3-b]pyridine (compound XY2501-20-5) At 25°C, intermediate I (200 mg, 0.399 mmol), compound XY2501-20-4 (180 mg, 0.505 mmol), Pd(dppf)Cl2 (30 mg, 0.040 mmol), and K2CO3 (166 mg, 1.20 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 105°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5 / 1) to give 180 mg of solid compound XY2501-20-5, yield: 69.4%. LCMS, M / Z (ESI): 651 [M+H]. + .

[0129] Step 5: Synthesize 3-(1 H -pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]-5-{4-[4-(trifluoromethyl)piperazin-1-yl]phenyl}pyrrolo[2,3-b]pyridine (compound XY2501-20-6) At 25 °C, 5 mL of 2 N HCl / EA solution was added to compound XY2501-20-5 (180 mg, 0.277 mmol), and the mixture was stirred for 16 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). The mixture was concentrated under reduced pressure, and 10 mL of saturated sodium bicarbonate aqueous solution was added. The aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed successively with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give 70 mg of solid compound XY2501-20-6, yield: 44.7%. LCMS, M / Z (ESI): 567 [M+H] + .

[0130] Step 6: Synthesize 4-{4-[3-(1 H -pyrazole-3-yl)-1 H methyl pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazine-1-carboxylate (XY2501-20) Compound XY2501-20-6 (70 mg, 0.124 mmol), methanol (30 mL), and K2CO3 (51 mg, 0.372 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 80 °C for 4 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 10 mg of solid XY2501-20, yield: 20.1%, purity: 99.76%, LCMS, M / Z (ESI): 403 [M+H]. + .

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.79 (s, 1H), 8.58 (s,1H), 8.51 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J = 8.0Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 3.64 (s, 3H), 3.55 (t, J = 5.2 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H).

[0132] Example 16: Synthesis of compound XY2501-21 The reaction equation for the synthesis of compound XY2501-21 is as follows: .

[0133] The synthetic steps of compound XY2501-21 are as follows: Step 1: Synthesis of 4-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester (compound XY2501-21-2) At 25 °C, compound XY2501-21-1 (150 mg, 0.3 mmol), intermediate I (175 mg, 0.45 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), and K2CO3 (83 mg, 0.6 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (30 mL) and water (5 mL) were added. The mixture was purged three times with nitrogen and reacted at 90 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 2 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 2 / 1). 120 mg of yellow solid XY2501-21-2 was obtained, yield: 58.4%, LCMS, M / Z (ESI): 684 [M+H]. + .

[0134] Step 2: Synthesize 3-(1 H -pyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-21) Compound XY2501-21-2 (120 mg, 0.175 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 20 mL of 2N HCl / EA. The mixture was stirred at room temperature for 2 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and 20 mL of MeOH and 73 mg of potassium carbonate (0.53 mmol) were added. The reaction was carried out at 70 °C for 12 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and TLC (DCM / MeOH = 10 / 1) was performed to obtain 20 mg of brown solid XY2501-21 with a purity of 94.25% and a yield of 33.0%. LCMS, M / Z (ESI): 346 [M+H]. + .

[0135] 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.43 (m, 2H), 7.88 (s, 1H), 7.80-7.50(m, 3H), 7.12 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 2.0 Hz, 1H), 3.45 (t, J = 5.2Hz, 4H), 3.22 (t, J = 5.2 Hz, 4H).

[0136] Example 17: Synthesis of compound XY2501-23 The reaction equation for the synthesis of compound XY2501-23 is as follows: .

[0137] The synthetic steps of compound XY2501-23 are as follows: Step 1: Synthesis of tert-butyl 4-[4-(pyrazolo[1,5-a]pyrimidin-5-yl)phenyl]piperazine-1-carboxylate (compound XY2501-23-3) At 25°C, compound XY2501-23-1 (300 mg, 1.51 mmol), compound XY2501-23-2 (765 mg, 1.97 mmol), Pd(dppf)Cl2 (88 mg, 0.076 mmol), and K2CO3 (965 mg, 4.54 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was purged with nitrogen three times and stirred at 95°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The reaction was stopped, cooled to room temperature, filtered, and the filter cake was washed with EA (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1, 2 / 1) to give 570 mg of solid compound 3, yield: 99.2%, LCMS, M / Z (ESI): 380 [M+H]. + .

[0138] Step 2: Synthesis of tert-butyl 4-[4-(3-iodopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]piperazine-1-carboxylate (compound XY2501-23-4) At 25°C, compound 3 (570 mg, 1.50 mmol), solvent DMF (10 mL), and NIS (372 mg, 1.65 mmol) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred for 1 h. The reaction was determined to be complete by LCMS. A saturated sodium thiosulfate aqueous solution (20 mL) was added, followed by water (20 mL), and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was washed with water (20 mL × 2). The filter cake was dried to give 740 mg of solid compound XY2501-23-4, yield: 97.5%, LCMS, M / Z (ESI): 506 [M+H]. + .

[0139] Step 3: Synthesis of 4-{4-[3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]phenyl}piperazine-1-carboxylic acid tert-butyl ester (compound XY2501-23-6) At 25 °C, compounds XY2501-23-4 (300 mg, 0.594 mmol), XY2501-23-5 (173 mg, 0.891 mmol), Pd(dppf)Cl2 (44 mg, 0.059 mmol), and K2CO3 (246 mg, 1.78 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (15 mL) and water (3 mL) were added. The mixture was purged with nitrogen three times and reacted at 95 °C for 16 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by reverse-phase C18 chromatography (ACN / H2O = 5% ~ 95%) to give 120 mg of solid compound XY2501-23-6, yield: 45.4%, LCMS, M / Z (ESI): 446 [M+H]. + .

[0140] Step 4: Synthesize 3-(1 H -pyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]pyrazolo[1,5-a]pyrimidine (compound XY2501-23) At 25°C, compound XY2501-23-6 (120 mg, 0.269 mmol) was added sequentially to a 100 mL single-necked flask, followed by DCM (10 mL) and TFA (3 mL). The mixture was stirred for 1 h. The reaction was determined to be complete by LMCS, concentrated under reduced pressure, and purified by reverse-phase C18 column chromatography (ACN / H2O = 5% ~ 95%) to obtain 30 mg of solid compound XY2501-23, purity: 93.70%, yield: 32.3%, LCMS, M / Z (ESI): 346 [M+H]. + .

[0141] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 6.8 Hz, 1H), 8.50 (s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 7.99-7.64 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.09(d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 3.26 (t, J = 5.2 Hz, 4H), 2.88 (t, J = 5.2Hz, 4H).

[0142] Example 18: Synthesis of compound XY2501-24 The reaction equation for the synthesis of compound XY2501-24 is as follows: .

[0143] The synthetic steps of compound XY2501-24 are as follows: Step 1: Synthesis of 4-(4-bromo-2-fluorophenyl)-1-methylpiperazine (compound XY2501-24-3) At 25°C, compounds XY2501-24-1 (2.0 g, 6.65 mmol), XY2501-24-2 (444 mg, 4.43 mmol), Pd2(dba)3 (406 mg, 0.443 mmol), and Xantphos (256 mg, 0.443 mmol) were added sequentially to a 100 mL single-necked flask. t BuONa (1.06 g, 11.08 mmol) was added to solvent 1,4-dioxane (40 mL), and the mixture was purged three times with nitrogen under nitrogen protection at 80 °C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to give 1.4 g of solid compound XY2501-24-3, yield: 100%. LCMS, M / Z (ESI): 273 [M+H]. + .

[0144] Step 2: Synthesis of 3-fluoro-4-[(4-methylpiperazin-1-yl)]phenylboronic acid pinacol ester (compound XY2501-24-4) At 25 °C, compound XY2501-24-3 (1.2 g, 4.43 mmol), pinacol diboronic acid ester (1.7 g, 6.64 mmol), Pd(dppf)Cl2 (324 mg, 0.443 mmol), and KOAc (1.3 g, 13.29 mmol) were added sequentially to a 100 mL single-necked flask. The solution was then added in 10 mL of 1,4-dioxane. The mixture was purged with nitrogen three times and reacted at 95 °C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 40 / 1). The mixture was concentrated under reduced pressure to give crude compound XY2501-24-4, yield: 100%. LCMS, M / Z (ESI): 321[M+H]. + .

[0145] Step 3: Synthesis of 5-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-24-5) At 25°C, intermediate I (600 mg, 1.20 mmol), crude compound XY2501-24-4 (575 mg, 1.79 mmol), Pd(dppf)Cl2 (88 mg, 0.120 mmol), and K2CO3 (496 mg, 3.59 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was purged with nitrogen three times and reacted at 105°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 500 mg of solid compound XY2501-24-5, yield: 68.0%. LCMS, M / Z (ESI): 615 [M+H]. + .

[0146] Step 4: Synthesize 3-(1 H -pyrazol-3-yl)-5-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-24-6) Compound XY2501-24-5 (500 mg, 0.814 mmol) was dissolved in DCM (25 mL) at 25 °C, and TFA (5 mL) was added. The mixture was stirred for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed successively with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 270 mg of solid compound XY2501-24-6, yield: 62.6%, LCMS, M / Z (ESI): 531 [M+H]. + .

[0147] Step 6: Synthesize 3-(1 H -pyrazol-3-yl)-5-[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-24) Compound XY2501-24-6 (270 mg, 0.509 mmol), methanol (5 mL), and K2CO3 (211 mg, 1.53 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 70 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 40 mg of solid XY2501-24, purity: 98.05%, yield: 20.9%, LCMS, M / Z (ESI): 389 [M+H]. + .

[0148] 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1 H), 11.83 (s, 1 H), 8.64-8.52(m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.60-7.43 (m, 2H), 7.14 (t, J = 8.8 Hz, 1H), 6.71 (s, 1H), 3.40-3.27 (m, 4H), 3.07 (t, J = 4.8 Hz, 4H), 2.24 (s, 3H).

[0149] Example 19: Synthesis of compound XY2501-25 The reaction equation for the synthesis of compound XY2501-25 is as follows: .

[0150] The synthetic steps of compound XY2501-25 are as follows: Step 1: 1-[(4-methylphenyl)dioxane-λ6-thio]-5-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-25-2) At 25°C, intermediate I (200 mg, 0.4 mmol), compound XY2501-25-1 (150 mg, 0.5 mmol), Pd(dppf)Cl2 (58.5 mg, 0.08 mmol), and K2CO3 (110.5 mg, 0.8 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane (30 mL) and water (5 mL) were added. The mixture was purged three times with nitrogen and reacted at 90°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 2 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 2 / 1). 100 mg of brown solid XY2501-25-2 was obtained, yield: 41.7%, LCMS, M / Z (ESI): 599 [M+H]. + .

[0151] Step 2: 3-(1 H -pyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-25) Compound XY2501-25-2 (100 mg, 0.17 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 2N HCl / EA (20 mL). The mixture was stirred at room temperature for 2 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and MeOH (20 mL) and potassium carbonate (70.4 mg, 0.51 mmol) were added. The mixture was reacted at 70 °C for 12 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and TLC (DCM / MeOH = 10 / 1) was used to purify it, yielding 10 mg of a white solid XY2501-25 with a purity of 97.79% and a yield of 16.3%. LCMS, M / Z (ESI): 360 [M+H]. + .

[0152] 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.79 (s, 1H), 8.64-8.38(m, 3H), 7.89 (s, 2H), 7.76 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.71 (s, 1H), 3.55 (t, J = 5.2 Hz, 4H), 2.43 (t, J = 5.2 Hz, 4H), 2.24 (s, 3H).

[0153] Example 20: Synthesis of compound XY2501-26 The reaction equation for the synthesis of compound XY2501-26 is as follows: .

[0154] The synthetic steps of compound XY2501-26 are as follows: Step 1: Synthesis of 1-[(4-methylphenyl)sulfonyl]-5-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)phenyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-26-2) At 25°C, intermediate I (312 mg, 0.63 mmol), compound XY2501-26-1 (150 mg, 0.52 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol), and K2CO3 (215.5 mg, 1.56 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (30 mL) and water (5 mL) were added. The mixture was purged three times with nitrogen and reacted at 90°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 2 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 2 / 1) to give 70 mg of brown solid XY2501-26-2, yield: 23.0%. LCMS, M / Z (ESI): 583 [M+H]. + .

[0155] Step 2: Synthesize 3-(1 H -pyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-26) Compound XY2501-26-2 (70 mg, 0.12 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by stirring at 25 °C for 2 h. The reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and MeOH (20 mL) and potassium carbonate (50 mg, 0.36 mmol) were added. The reaction was continued at 70 °C for 12 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and TLC (DCM / MeOH = 10 / 1) was performed to give 10 mg of a white solid XY2501-26 with a purity of 96.60% and a yield of 24.0%. LCMS, M / Z (ESI): 345 [M+H]. + .

[0156] 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.82 (s, 1H), 8.66 (s,1H), 8.55 (s, 1H), 7.90 (s, 1H), 7.69 (s, 3H), 7.40 (d, J = 8.0 Hz, 2H), 6.70(s, 1H), 3.98 (d, J = 10.4 Hz, 2H), 3.59-3.43 (m, 2H), 2.83 (dt, J = 10.4,5.6 Hz, 1H),1.81-1.75 (m, 4H).

[0157] Example 21: Synthesis of compound XY2501-27 The reaction equation for the synthesis of compound XY2501-27 is as follows: .

[0158] The synthetic steps of compound XY2501-27 are as follows: Step 1: Synthesis of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]-1-thiomorpholine-1,1-dione (compound XY2501-27-2) At 25 °C, compound XY2501-27-1 (1.0 g, 3.45 mmol), pinacol diboronic acid ester (1.3 g, 5.17 mmol), Pd(dppf)Cl2 (252 mg, 0.345 mmol), and KOAc (1.0 g, 10.34 mmol) were added sequentially to a 100 mL single-necked flask. 20 mL of solvent 1,4-dioxane was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 95 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The mixture was concentrated under reduced pressure to give crude compound XY2501-27-2, yield: 100%, LCMS, M / Z (ESI): 338 [M+H]. + .

[0159] Step 2: Synthesis of 4-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)-1-thiomorpholine-1,1-dione (compound XY2501-27-3) At 25°C, intermediate I (200 mg, 0.399 mmol), crude compound XY2501-27-2 (336 mg, 0.598 mmol), Pd(dppf)Cl2 (29 mg, 0.040 mmol), and K2CO3 (165 mg, 1.20 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was purged with nitrogen three times and reacted at 105°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 500 mg of solid compound XY2501-27-3, yield: 100%. LCMS, M / Z (ESI): 632 [M+H]. + .

[0160] Step 3: Synthesis of 4-{4-[3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}-1λ 6 -1,4-Thiazacyclohexane-1,1-dione (compound XY2501-27-4) Compound XY2501-27-3 (500 mg, 0.399 mmol) was dissolved in DCM (1 mL) at 25 °C, and TFA (3 mL) was added. The mixture was stirred for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with EA (20 mL × 2). The organic phases were combined and washed successively with water (20 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 20 / 1) to give 170 mg of solid compound XY2501-27-4, yield: 78.1%, LCMS, M / Z (ESI): 548 [M+H]. + .

[0161] Step 4: Synthesis of 4-{4-[3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}-1-thiomorpholine-1,1-dione (XY2501-27) Compound XY2501-27-4 (170 mg, 0.310 mmol), methanol (5 mL), and K2CO3 (129 mg, 0.931 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 70 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 50 mg of solid XY2501-27, purity: 93.52%, yield: 40.9%, LCMS, M / Z (ESI): 394 [M+H]. + .

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 11.74 (s, 1H), 8.64-8.52(m, 2H), 7.88 (s, 1H), 7.77-7.62 (m, 3H), 7.17 (d, J = 8.8 Hz, 2H), 6.68 (s,1H), 3.85 (t, J = 5.2 Hz, 4H), 3.17 (t, J = 5.2 Hz, 4H).

[0163] Example 22: Synthesis of compound XY2501-28 The reaction equation for the synthesis of compound XY2501-28 is as follows: .

[0164] The synthetic steps of compound XY2501-28 are as follows: Step 1: Synthesis of 1-(4-bromo-2-methylphenyl)-4-methylpiperazine (compound XY2501-28-3) At 25°C, compounds XY2501-28-1 (312 mg, 1.05 mmol), XY2501-28-2 (210 mg, 2.1 mmol), Pd2(dba)3 (91 mg, 0.105 mmol), and Xantphos (61 mg, 0.105 mmol) were added sequentially to a 100 mL single-necked flask. t BuONa (202 mg, 2.1 mmol) was added to solvent 1,4-dioxane (30 mL), and the mixture was purged with nitrogen three times. The reaction was carried out at 85 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give 210 mg of a brown solid compound XY2501-28-3, yield: 74.1%. LCMS, M / Z (ESI): 270 [M+H]. + .

[0165] Step 2: Synthesis of 4-methyl-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]piperazine (compound XY2501-28-4) At 25 °C, compound XY2501-28-3 (210 mg, 0.78 mmol), B2pin2 (525 mg, 2.03 mmol), Pd(dppf)Cl2 (118.3 mg, 0.16 mmol), potassium acetate (397 mg, 2.34 mmol), and dioxane (40 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times, and the reaction was carried out at 100 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give 150 mg of yellow solid compound XY2501-28-4, yield: 60.8%, LCMS, M / Z (ESI): 317 [M+H]. + .

[0166] Step 3: Synthesis of 5-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2 ... H[-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-28-6) At 25 °C, compound XY2501-28-4 (150 mg, 0.47 mmol), potassium carbonate (128.5 mg, 0.93 mmol), Pd(dppf)Cl2 (74 mg, 0.1 mmol), dioxane (40 mL), H2O (8 mL), and compound XY2501-28-5 (282 mg, 0.564 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 90 °C for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was filtered, concentrated under reduced pressure, and prepared by TLC (DCM / MeOH = 20 / 1) to give 50 mg of a yellow solid compound XY2501-28-6, yield: 17.4%, LCMS, M / Z (ESI): 612 [M+H]. + .

[0167] Step 4: Synthesize 3-(1 H -pyrazol-3-yl)-5-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY251-28) Compound XY2501-28-6 (50 mg, 0.08 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 20 mL of EA / HCl. The mixture was stirred at room temperature for 2 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure, and MeOH (20 mL) and potassium carbonate (117.5 mg, 0.85 mmol) were added. The reaction was carried out at 70 °C for 12 h, and the reaction was confirmed to be complete by LCMS. The mixture was then concentrated under reduced pressure and prepared under high pressure (ACN / H2O = 40 / 60) to give 10 mg of white solid XY2501-28, purity: 95.8%, yield: 33.5%, LCMS, M / Z (ESI): 373 [M+H]. + .

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 11.84 (s, 1H), 8.57 (s,1H), 8.51 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.75-7.67 (m, 1H), 7.58-7.48 (m, 2H), 7.14 (dd, J= 8.4, 4.4 Hz, 1H), 6.69 (t, J = 2.4 Hz, 1H), 3.20 (m, 5H), 3.03-2.82 (m, 4H), 2.35 (s, 3H), 2.27 (d, J = 2.4 Hz, 3H).

[0169] Example 23: Synthesis of compound XY2501-29 The reaction equation for the synthesis of compound XY2501-29 is as follows: .

[0170] The synthetic steps of compound XY2501-29 are as follows: Step 1: Synthesis of 3-(1H-pyrazol-3-yl)-5-{4-[4-(methanesulfonyl)piperazin-1-yl]phenyl}-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-29-2) At 25°C, compound XY2501-29-1 (200 mg, 0.29 mmol) was added sequentially to a 100 mL single-necked flask, followed by 2N HCl / EA (20 mL). The mixture was stirred at room temperature for 2 h, and the reaction was determined to be complete by LCMS. The solution was concentrated to dryness. Triethylamine was added to adjust the pH to 7-8, followed by DCM (20 mL). The mixture was stirred in an ice bath for 15 min, then MsCl (36.7 mg, 0.32 mmol) was added, and the mixture was stirred for 1 h. The reaction was determined to be complete by LCMS. 20 mL of water was added, and the mixture was extracted with DCM (20 mL). The organic phase was concentrated under reduced pressure, and TLC (DCM / MeOH = 20 / 1) was used to prepare 100 mg of a white solid compound XY2501-29-2, yield: 59.7%, LCMS, M / Z (ESI): 578 [M+H]. + .

[0171] Step 2: 3-(1H-pyrazol-3-yl)-5-{4-[4-(methanesulfonyl)piperazin-1-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine (XY2501-29) Compound XY2501-29-2 (100 mg, 0.17 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 20 mL of MeOH and 117.5 mg, 0.85 mmol of potassium carbonate. The reaction was carried out at 70 °C for 12 h, and LCMS determined the reaction to be complete. The mixture was concentrated under reduced pressure and prepared under high pressure (ACN / H₂O = 40 / 60) to give 25 mg of a white solid XY2501-29, with a purity of 98.96% and a yield of 13.9%. LCMS, M / Z (ESI): 324 [M+H]. + .

[0172] 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 11.82 (s, 1H), 8.98-8.39(m, 2H), 7.89 (d, J = 2.4 Hz, 1H), 7.79-7.54 (m, 3H), 7.17-7.01 (m, 2H), 6.68(d, J = 2.0 Hz, 1H), 3.35-3.25 (m, 8H), 2.94 (s, 3H).

[0173] Example 24: Synthesis of compound XY2501-31 The reaction equation for the synthesis of compound XY2501-31 is as follows: .

[0174] The synthetic steps of compound XY2501-31 are as follows: Step 1: Synthesis of 4-(4-bromophenyl)-N-methylpiperazine-1-carboxamide (compound XY2501-31-2) At 25°C, compound XY2501-31-1 (1.0 g, 4.15 mmol), followed by toluene (20 mL) and pyridine (492 mg, 6.22 mmol) in a 100 mL single-necked flask, was added sequentially. The mixture was cooled to 0°C, and a toluene solution of triphosgene (615 mg, 2.07 mmol) (5 mL) was added. The mixture was then heated to 25°C and reacted for 16 h. The reaction was determined to be complete by TLC, concentrated under reduced pressure, and DCM (20 mL), triethylamine (2.1 g, 20.74 mmol), and methylamine hydrochloride (840 mg, 12.44 mmol) were added. The reaction was then allowed to proceed at room temperature for 3 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 600 mg of solid compound XY2501-31-2, yield: 48.5%, LCMS, M / Z (ESI): 298 [M+H] + .

[0175] Step 2: Synthesis of N-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]piperazine-1-carboxamide (compound XY2501-31-3) At 25 °C, compound XY2501-31-2 (600 mg, 2.01 mmol), pinacol diboronic acid ester (766 mg, 3.02 mmol), Pd(dppf)Cl2 (147 mg, 0.201 mmol), and KOAc (592 mg, 6.04 mmol) were added sequentially to a 100 mL single-necked flask. The solvent 1,4-dioxane (10 mL) was added, and the mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 95 °C and reacted for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure to give crude compound XY2501-31-3, yield: 100%, LCMS, M / Z (ESI): 346 [M+H]. + .

[0176] Step 3: Synthesis of N-methyl-4-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazine-1-carboxamide (compound XY2501-31-4) At 25°C, intermediate I (600 mg, 1.20 mmol), crude compound XY2501-31-3 (620 mg, 1.79 mmol), Pd(dppf)Cl2 (88 mg, 0.120 mmol), and K2CO3 (496 mg, 3.59 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was purged with nitrogen three times and reacted at 95°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to give 720 mg of solid compound XY2501-31-4, yield: 94.1%. LCMS, M / Z (ESI): 640 [M+H]. + .

[0177] Step 4: Synthesize 4-{4-[3-(1 H ⁻pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}-N-methylpiperazin-1-carboxamide (compound XY2501-31-5) Compound XY2501-31-4 (720 mg, 1.13 mmol) was dissolved in DCM (21 mL) at 25 °C, and TFA (7 mL) was added. The mixture was stirred for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with EA (50 mL × 2). The organic phases were combined and washed successively with water (50 mL × 2) and saturated NaCl solution (50 mL). The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to give 300 mg of solid compound XY2501-31-5, yield: 48.0%, LCMS, M / Z (ESI): 556 [M+H]. + .

[0178] Step 5: Synthesize 4-{4-[3-(1 H -pyrazole-3-yl)-1 H ⁻Pyrrolo[2,3-b]pyridin-5-yl]phenyl}-N-methylpiperazin-1-carboxamide (XY2501-31) At 25 °C, compound XY2501-31-5 (300 mg, 0.540 mmol), methanol (5 mL), and K2CO3 (224 mg, 1.62 mmol) were added sequentially to a 100 mL single-necked flask. The temperature was raised to 80 °C, and the reaction was allowed to proceed for 2 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 20 / 1, 10 / 1) to obtain 50 mg of solid XY2501-24 with a purity of 94.45% and a yield of 23.1%. LCMS, M / Z (ESI): 402 [M+H]. + .

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 11.80 (s, 1H), 8.56 (s,1H), 8.51 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.70 (s, 1H), 7.61(d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.0 Hz, 1H), 6.55(q, J = 4.3 Hz, 1H), 3.41-3.87 (m, 4H), 3.16 - 3.14 (m, 4H), 2.60 (d, J = 4.0Hz, 3H).

[0180] Example 25: Synthesis of compound XY2501-32 The reaction equation for the synthesis of compound XY2501-32 is as follows: .

[0181] The synthetic steps of compound XY2501-32 are as follows: Step 1: Synthesis of 1-[4-(4-bromophenyl)piperazin-1-yl]ethyl-1-one (compound XY2501-32-2) At 25°C, compound XY2501-32-1 (1.0 g, 4.15 mmol), triethylamine (629.0 mg, 6.22 mmol), and DCM solvent (10 mL) were added sequentially to a 100 mL single-necked flask. Acetyl chloride (488.0 mg, 6.22 mmol) was added at 0°C, and the mixture was heated to room temperature and stirred for 4 h. The reaction was determined to be complete by TLC (PE / EA = 2 / 1). Sodium bicarbonate aqueous solution (10 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted once with DCM (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.03 g solid compound XY2501-32-2, yield: 87.71%, LCMS, M / Z (ESI): 284 [M+H]. + .

[0182] Step 2: Synthesis of 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]piperazin-1-yl}acet-1-one (compound XY2501-32-3) At 25 °C, compound XY2501-32-2 (1.03 g, 3.64 mmol), pinacol diboronic acid ester (1.39 g, 5.46 mmol), potassium acetate (1.07 g, 10.92 mmol), and Pd(dppf)Cl2 (263.0 mg, 0.36 mmol) were added sequentially to a 100 mL single-necked flask. Then, 1,4-dioxane solvent (10 mL) was added. The reaction was allowed to proceed for 16 h. TLC (PE / EA = 2 / 1) confirmed the reaction was complete. The mixture was filtered, concentrated under reduced pressure, and yielded 1.2 g of solid compound XY2501-32-3, yield: 99.73%. LCMS, M / Z (ESI): 331 [M+H]. + .

[0183] Step 3: Synthesis of 1-[4-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazin-1-yl]aceto-1-one (compound XY2501-32-4) At 25°C, intermediate I (500.0 mg, 1.0 mmol), compound XY2501-32-3 (495.0 mg, 1.5 mmol), Pd(dppf)Cl2 (73.0 mg, 0.1 mmol), and K2CO3 (415.0 mg, 3.0 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 100°C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5 / 1, 2 / 1, EA) to give 330 mg of solid compound XY2501-32-4, yield: 52.82%. LCMS, M / Z (ESI): 626 [M+H]. + .

[0184] Step 4: Synthesis of 1-(4-{4-[3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazin-1-yl)ethyl-1-onepyridine (compound XY2501-32-5) Compound XY2501-32-4 (330.0 mg, 0.53 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by 10 mL of dichloromethane and 2 mL of trifluoroacetic acid. The reaction was carried out at 25 °C for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and 10 mL of dichloromethane and 10 mL of sodium bicarbonate aqueous solution were added. The mixture was allowed to stand and separate into layers, yielding an organic phase. The aqueous phase was extracted twice with 15 mL of dichloromethane. The mixture was then purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to obtain 270 mg of solid compound XY2501-32-5, yield: 94.34%. LCMS, M / Z (ESI): 542 [M+H] + .

[0185] Step 5: Synthesis of 1-(4-{4-[3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazin-1-yl)ethyl-1-one (XY2501-32) Compound XY2501-32-5 (270.0 mg, 0.50 mmol), methanol (5 mL), and K2CO3 (207 mg, 1.50 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 80 °C for 4 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was dried, and dichloromethane (3 mL) and methanol (3 mL) were added. The mixture was stirred for 1 h, filtered, and the filter cake was dried to give 100 mg of solid XY2501-32. Yield: 51.76%, purity: 94.21%, LCMS, M / Z (ESI): 387 [M+H]. + .

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 8.63-8.40 (m, 2H), 7.87 (s, 1H), 7.76-7.60(m, 3H), 7.09 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 3.60 (m, 4H), 3.18 (m, 4H), 2.06 (s, 3H).

[0187] Example 26: Synthesis of compound XY2501-33 The reaction equation for the synthesis of compound XY2501-33 is as follows: .

[0188] The synthetic steps of compound XY2501-33 are as follows: Step 1: Synthesis of tert-butyl {[1-(4-bromophenyl)hexahydropyridin-4-yl]amino}carbamate (XY2501-33-3) At 25 °C, XY2501-33-1 (5.0 g, 24.96 mmol), Pd2(dba)3 (3.53 g, 3.86 mmol), XY2501-33-2 (9.18 g, 32.45 mmol), and sodium tert-butoxide (3.19 g, 32.50 mmol) were added sequentially to a 250 mL single-necked flask. 1,4-Dioxane (150 mL) was then added, and the mixture was substituted with N2 three times. The reaction was carried out at 95 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 10 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1). 4.2 g of a yellow solid, XY2501-33-3, was obtained, yield: 47.28%. LCMS, M / Z (ESI): 356 [M+H]. + .

[0189] Step 2: Synthesis of tert-butyl ({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]hexahydropyridin-4-yl}amino)carboxylate (XY2501-33-4) At 25 °C, XY2501-33-3 (4.2 g, 11.82 mmol), B2pin2 (4.50 g, 17.73 mmol), Pd(dppf)Cl2 (865 mg, 1.18 mmol), potassium acetate (3.48 g, 35.46 mmol), and dioxane (200 mL) were added sequentially to a 500 mL single-necked flask. The mixture was substituted with N2 three times, and the reaction was carried out at 95 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1) to give 2.7 g of a yellow solid compound XY2501-33-4, yield: 56.82%, LCMS, M / Z (ESI): 403 [M+H]. + .

[0190] Step 3: Synthesize tert-butyl carbamate {[1-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)hexahydropyridin-4-yl]amino}carbamate (XY2501-33-5) At 25 °C, XY2501-33-4 (500 mg, 1.24 mmol), potassium carbonate (514.6 mg, 3.72 mmol), Pd(dppf)Cl2 (90 mg, 0.124 mmol), dioxane (50 mL), H2O (10 mL), and intermediate I (744 mg, 1.49 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was substituted with N2 three times, and the reaction was carried out at 95 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 1 / 1) to give 500 mg of a yellow solid compound XY2501-33-5, yield: 57.8%, LCMS, M / Z (ESI): 698 [M+H]. + .

[0191] Step 4: Synthesize 1-{4-[3-(1 H -pyrazole-3-yl)-1 H -pyrrolo[2,3- b [Pyridin-5-yl]phenyl}hexahydropyridine-4-amine (XY2501-33) XY2501-33-5 (300 mg, 0.43 mmol) and 2 NHCl / EA (20 mL) were added sequentially to a 100 mL single-necked flask at 25 °C. The mixture was stirred at 25 °C for 2 h. LCMS determined the reaction was complete. The mixture was concentrated under reduced pressure, and MeOH (10 mL) and K2CO3 (178 mg, 1.29 mmol) were added. The mixture was reacted at 75 °C for 12 h. LCMS determined the reaction was complete. The mixture was concentrated under reduced pressure and prepared under high pressure (ACN / H2O = 35 / 65) to give 35 mg of white compound XY2501-33, purity: 97.85%, yield: 22.7%, LCMS, M / Z (ESI): 359 [M+H]. + . 1 HNMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.55 (s, 1H), 8.51 (d, J = 2.0 Hz,1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.08(d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.0Hz, 1H), 3.79 (d, J = 12.8 Hz, 2H), 3.06(s, 2H), 2.82 (t, J = 12.0Hz, 2H), 1.91 (d, J = 12.4 Hz, 2H), 1.53 (q, J =12.8, 12.4 Hz, 3H). Example 27: Synthesis of compound XY2501-34 The reaction equation for the synthesis of compound XY2501-34 is as follows: .

[0192] The synthetic steps of compound XY2501-34 are as follows: Step 1: Synthesis of 4-(4-bromophenyl)-1-(2-methoxyethyl)piperazine (compound XY2501-34-3) At 25°C, compounds XY2501-34-1 (300.0 mg, 2.07 mmol), XY2501-34-2 (882.0 mg, 3.11 mmol), Pd2(dba)3 (192.0 mg, 0.21 mmol), Xantphos (123.0 mg, 0.21 mmol), and sodium tert-butoxide (597.0 mg, 6.21 mmol) were added sequentially to a 100 mL single-necked flask. The solution was 1,4-dioxane (10 mL), and the mixture was purged with nitrogen three times. The mixture was stirred at 95°C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 1 / 1) to give 700 mg of solid compound XY2501-34-3, yield: 113%. LCMS, M / Z (ESI): 300 [M+H]. + .

[0193] Step 2: Synthesis of 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]piperazine (compound XY2501-34-4) At 25 °C, compound XY2501-34-3 (700.0 mg, 2.34 mmol), pinacol diboronic acid ester (891.0 mg, 3.51 mmol), potassium acetate (689.0 mg, 7.02 mmol), and Pd(dppf)Cl2 (168.0 mg, 0.23 mmol) were added sequentially to a 100 mL single-necked flask. The solvent 1,4-dioxane (10 mL) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). The mixture was filtered, concentrated under reduced pressure, and 700 mg of solid compound XY2501-34-4 was obtained, yield: 86.40%. LCMS, M / Z (ESI): 347 [M+H]. + .

[0194] Step 3: Synthesis of 5-{4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2-yl]pyrrolidone] H [-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-34-5) At 25 °C, intermediate I (500.0 mg, 1.0 mmol), compound XY2501-34-4 (519.0 mg, 1.5 mmol), Pd(dppf)Cl2 (73.0 mg, 0.1 mmol), and K2CO3 (415.0 mg, 3.0 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 100 °C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 1 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 1 / 1, EA) to give 190 mg of solid compound XY2501-34-5, yield: 29.65%. LCMS, M / Z (ESI): 642 [M+H]. + .

[0195] Step 4: Synthesize 3-(1 H -pyrazol-3-yl)-5-[4-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-34-6) Compound XY2501-34-5 (190.0 mg, 0.30 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by dichloromethane (5 mL) and trifluoroacetic acid (1 mL). The reaction was carried out at 25 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 40 / 1). The mixture was concentrated under reduced pressure, and dichloromethane (10 mL) and sodium bicarbonate aqueous solution (10 mL) were added. The mixture was allowed to stand for phase separation, yielding an organic phase. The aqueous phase was extracted twice with dichloromethane (15 mL), mixed, and purified by silica gel column chromatography (DCM / MeOH = 80 / 1, 40 / 1) to obtain 140 mg of solid compound XY2501-34-6, yield: 84.68%, LCMS, M / Z (ESI): 558 [M+H]. + .

[0196] Step 5: Synthesize 3-(1 H -pyrazol-3-yl)-5-{4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-1 H -Pyrrolo[2,3-b]pyridine (XY2501-34) Compound XY2501-34-6 (140.0 mg, 0.25 mmol), methanol (5 mL), and K2CO3 (104.0 mg, 0.75 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The mixture was reacted at 80 °C for 4 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by thin-layer silica gel chromatography (DCM / MeOH = 20 / 1) and high-performance liquid chromatography to prepare 15 mg of solid XY2501-34 with a purity of 92.92% and a yield of 14.85%. LCMS, M / Z (ESI): 403 [M+H] + .

[0197] 1 H NMR (400 MHz, DMSO-d6) δ 8.70-8.48 (m, 2H), 7.87 (d, J = 2.8 Hz,1H), 7.80-7.52 (m, 3H), 7.12-7.01 (m, 2H), 6.69 (d, J = 6.4 Hz, 1H), 3.49 (t, J = 5.6 Hz, 2H), 3.26 (s, 3H), 3.19 (t, J = 5.2 Hz, 4H), 2.64-2.52 (m, 6H).

[0198] Example 28: Synthesis of compound XY2501-35 The reaction equation for the synthesis of compound XY2501-35 is as follows: .

[0199] The synthetic steps of compound XY2501-35 are as follows: Step 1: Synthesis of methyl methane [(1-{4-[3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}hexahydropyridin-4-yl)amino]methane (XY2501-35-3) At 25 °C, XY2501-35-1 (100.0 mg, 0.194 mmol) and DMF (20 mL) were added sequentially to a 100 mL single-necked flask. The mixture was stirred in an ice bath for 15 minutes, and then XY2501-35-2 (20.2 mg, 0.213 mmol) was added dropwise. The reaction was carried out at 0 °C for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). Preparative TLC (DCM / MeOH = 10 / 1) yielded 70 mg of a yellow solid compound XY2501-35-3, yield: 63.19%, LCMS, M / Z (ESI): 572 [M+H]. + .

[0200] Step 2: Synthesize methyl methane [(1-{4-[3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}hexahydropyridin-4-yl)amino]methane (XY2510-35) At 25 °C, XY2501-35-3 (70 mg, 0.122 mmol), MeOH (20 mL), and potassium carbonate (50.5 mg, 0.366 mmol) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at 75 °C for 12 h, and the reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure, and TLC (DCM / MeOH = 10 / 1) was performed to give 15 mg of white solid compound XY2501-35, yield: 29.48%, purity: 97.86%, LCMS, M / Z (ESI): 417 [M+H]. + .

[0201] 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.75 (s, 1H), 8.61 (s,1H), 8.50 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 2H), 7.22(d, J = 8.0 Hz, 1H), 7.12 – 7.02 (m, 2H), 6.68 (s, 1H), 3.73 (d, J = 12.8 Hz, 2H), 3.53 (s, 3H), 3.40-3.31 (m, 1H), 2.83 (t, J = 12.0 Hz, 2H), 1.83 (d, J =12.4 Hz, 2H), 1.50 (q, J= 12.0, 11.2 Hz, 2H).

[0202] Example 29: Synthesis of compound XY2501-36 The reaction equation for the synthesis of compound XY2501-36 is as follows: .

[0203] The synthetic steps of compound XY2501-36 are as follows: Step 1: Synthesis of 4-(4-bromophenyl)-1,4-thiazacyclohexane (compound XY2501-36-2) At 25°C, compounds XY2501-36-1 (1.0 g, 3.53 mmol), thiomorpholine (281 mg, 2.72 mmol), Pd2(dba)3 (125 mg, 0.136 mmol), and Xantphos (158 mg, 0.272 mmol) were added sequentially to a 100 mL single-necked flask. t BuONa (653 mg, 6.80 mmol) was added to solvent 1,4-dioxane (20 mL), the mixture was purged with nitrogen three times, and stirred at 90 °C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 20 / 1), the reaction was stopped, cooled to room temperature, filtered, and the filter cake was washed with EA (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 20 / 1) to give 800 mg of solid compound XY2501-36-2, yield: 88.8%, LCMS, M / Z (ESI): 258 [M+H]. + .

[0204] Step 2: Synthesis of 4-(4-bromophenyl)-1λ 4 -1,4-Thiazazacyclohexane-1-one (compound XY2501-36-3) At 25°C, compound XY2501-36-2 (800 mg, 3.10 mmol) was added sequentially to a 100 mL single-necked flask, followed by the addition of DCM (15 mL). The mixture was cooled to 0–5°C, and m-CPBA (629 mg, 3.10 mmol) was slowly added. The temperature was raised to 25°C, and the mixture was stirred for 16 h. The reaction was determined to be complete by LCMS, and the reaction was quenched by adding 20 mL of saturated Na2S2O3 solution. The mixture was extracted with DCM (20 mL × 2), and the organic phases were combined. The mixture was washed sequentially with water (20 mL × 2) and saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 660 mg of solid compound XY2501-36-3, yield: 77.7%, LCMS, M / Z (ESI): 274 [M+H]. + .

[0205] Step 3: Synthesis of 4-(4-bromophenyl)-1-[(trifluoroacetyl)azapyridyl]-1λ6-1,4-thiazacyclohexane-1-one (compound XY2501-36-4) At 25°C, compound XY2501-36-3 (630 mg, 2.30 mmol) was added sequentially to a 100 mL single-necked flask, followed by DCM (20 mL), trifluoroacetamide (650 mg, 5.74 mmol), rhodium dimer acetate (102 mg, 0.230 mmol), iodobenzene acetate (1.15 g, 3.56 mmol), and magnesium oxide (371 mg, 9.19 mmol). The mixture was purged with nitrogen three times and stirred at 40°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1). The mixture was filtered, and the filter cake was washed with DCM (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1) to give 880 mg of solid compound XY2501-36-4, yield: 94.9%, LCMS, M / Z (ESI): 385 [M+H]. + .

[0206] Step 4: Synthesis of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl]-1-[(trifluoroacetyl)aza-ylidene]-1λ 6 -1,4-Thiazazacyclohex-1-one (compound XY2501-36-5) At 25°C, compound XY2501-36-4 (880 mg, 2.28 mmol), pinacol diboronic acid ester (870 mg, 3.43 mmol), Pd(dppf)Cl2 (167 mg, 0.228 mmol), and K2CO3 (673 mg, 6.85 mmol) were added sequentially to a 100 mL single-necked flask. 1,4-Dioxane (20 mL) solvent was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 95°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1). The mixture was filtered, and the filter cake was washed with DCM (20 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1). The purified filtrate was then concentrated under reduced pressure to give 800 mg of solid compound XY2501-36-5, yield: 81.0%. LCMS, M / Z (ESI): 433 [M+H]. + .

[0207] Step 5: Synthesis of 1-aza-4-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)-1λ 6 -1,4-Thiazazacyclohexane-1-one (compound XY2501-36-6) At 25°C, intermediate I (600 mg, 1.20 mmol), compound XY2501-36-5 (776 mg, 1.79 mmol), Pd(dppf)Cl2 (88 mg, 0.120 mmol), and K2CO3 (352 mg, 3.59 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (2 mL) were added. The mixture was purged with nitrogen three times and reacted at 95°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 50 / 1) to give 300 mg of solid compound XY2501-36-6, yield: 39.7%. LCMS, M / Z (ESI): 631 [M+H]. + .

[0208] Step 6: Synthesize 4-{4-[3-(1 H -pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}-1-aza-1λ 6 -1,4-Thiazazacyclohex-1-one (compound XY2501-36-7) Compound XY2501-36-6 (300 mg, 0.476 mmol) was dissolved in DCM (10 mL) at 25 °C, and TFA (3 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The aqueous phase was extracted with EA (50 mL × 2). The organic phases were combined and washed successively with water (50 mL × 2) and saturated NaCl solution (50 mL). The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 50 / 1, 20 / 1) to give 140 mg of solid compound XY2501-36-7, yield: 53.9%, LCMS, M / Z (ESI): 547 [M+H]. + .

[0209] Step 7: Synthesize 4-{4-[3-(1 H -pyrazole-3-yl)-1 H -pyrrolo[2,3-b]pyridin-5-yl]phenyl}-1-aza-1λ 6 -1,4-Thiazazacyclohexane-1-one (compound XY2501-36) Compound XY2501-36-7 (140 mg, 0.256 mmol), methanol (5 mL), and K2CO3 (106 mg, 0.768 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 80 °C for 2 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1, 10 / 1) to give 30 mg of solid XY2501-36. Yield: 30.0%, purity: 95.60%, LCMS, M / Z (ESI): 393 [M+H]. + .

[0210] 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.80 (s, 1H), 8.64-8.50(m, 2H), 7.89 (s, 1H), 7.74-7.60 (m, 3H), 7.14 (d, J = 9.2 Hz, 2H), 6.69 (s,1H), 3.92 (dt, J = 14.4, 4.4 Hz, 2H), 3.83 (s, 1H), 3.73-3.66 (m, 2H), 3.04(t, J = 4.0 Hz, 4H).

[0211] Example 30: Synthesis of compound XY2501-39 The reaction equation for the synthesis of compound XY2501-39 is as follows: .

[0212] The synthetic steps of compound XY2501-39 are as follows: Step 1: 4-(4-bromophenyl)-1,4-thiazacyclohexane (compound XY2501-39-2) At 25°C, compounds XY2501-39-1 (2.0 g, 19.38 mmol), Pd2(dba)3 (3.53 g, 3.86 mmol), Xantphos (1.12 g, 1.94 mmol), p-bromoiodobenzene (6.58 g, 23.25 mmol), and potassium tert-butoxide (4.34 g, 38.76 mmol) were added sequentially to a 100 mL single-necked flask. 1,4-Dioxane (50 mL) was then added, and the mixture was purged three times with nitrogen. The reaction was carried out at 85°C for 3 h. The reaction was determined to be complete by TLC (PE / EA = 10 / 1). The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1). 1.4 g of a yellow oil solid, compound XY2501-39-2, was obtained, yield: 28.1%, LCMS, M / Z (ESI): 259 [M+H]. + .

[0213] Step 2: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1,4-thiazazacyclohexane (compound XY2501-39-3) At 25°C, compound XY2501-39-2 (356 mg, 1.38 mmol), B2pin2 (525 mg, 2.07 mmol), Pd(dppf)Cl2 (202 mg, 0.276 mmol), potassium acetate (406.3 mg, 4.14 mmol), and dioxane (40 mL) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 95°C for 16 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1) to give 250 mg of a yellow solid compound XY2501-39-3, yield: 59.1%, LCMS, M / Z (ESI): 306 [M+H]. + .

[0214] Step 3: 1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]-5-[4-(1,4-thiazacyclohex-4-yl)phenyl]pyrrolo[2,3-b]pyridine (compound XY2501-39-4) At 25 °C, compound XY2501-39-3 (250 mg, 0.82 mmol), potassium carbonate (315.6 mg, 2.46 mmol), Pd(dppf)Cl2 (90 mg, 0.123 mmol), dioxane (40 mL), H2O (8 mL), and intermediate I (450 mg, 0.9 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 95 °C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The mixture was filtered, concentrated under reduced pressure, and prepared by TLC (PE / EA = 3 / 1) to give 170 mg of a brown solid compound XY2501-39-4, yield: 34.5%, LCMS, M / Z (ESI): 601 [M+H]. + .

[0215] Step 4: 3-(1 H -pyrazol-3-yl)-5-[4-(1,4-thiazacyclohex-4-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (compound XY2501-39-5) At 25°C, compound XY2501-39-4 (170 mg, 0.283 mmol) and EA / HCl (20 mL) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at 25°C for 2 h, and the reaction was determined to be complete by LCMS. The mixture was concentrated to dryness, and MeOH (20 mL) and potassium carbonate (117.5 mg, 0.85 mmol) were added. The mixture was purged with nitrogen three times, and the reaction was carried out at 75°C for 12 h. The reaction was determined to be complete by LCMS. The reaction solution was concentrated, and TLC (DCM / MeOH = 10 / 1) was used to obtain 40 mg of brown solid compound XY2501-39-5, yield: 39.3%, LCMS, M / Z (ESI): 361 [M+H]. + .

[0216] Step 5: 4-{4-[3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}-1λ 4 -1,4-Thiazazacyclohexane-1-one (XY2501-39) At 25°C, compound XY2501-39-5 (40 mg, 0.11 mmol), DCM (20 mL), and m-CPBA (23 mg, 0.133 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at 25°C for 12 h. The reaction was determined to be complete by LCMS. The mixture was concentrated to dryness and prepared under high pressure (ACN / H2O = 35 / 65) to give 10 mg of brown solid XY2501-39, purity: 96.81%, yield: 24%, LCMS, M / Z (ESI): 378 [M+H]. + .

[0217] 1 H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 11.76 (s, 1H), 8.92-8.27(m, 2H), 7.88 (s, 1H), 7.84- 7.77 (m, 1H), 7.64 (s, 2H), 7.16 (d, J = 8.8 Hz,2H), 6.68 (s, 1H), 3.98-3.79 (m, 2H), 3.70 (d, J = 14.8 Hz, 2H), 3.10-2.90(m, 2H), 2.79-2.59 (m, 2H).

[0218] Example 31: Synthesis of compound XY2501-43 The reaction equation for the synthesis of compound XY2501-43 is as follows: .

[0219] The synthetic steps of compound XY2501-43 are as follows: Step 1: Synthesis of 3-chloro-5-iodo-7H-pyrrolo[2,3-c][1,2]diazine (compound XY2501-43-2) At 25°C, compound XY2501-43-1 (100.0 mg, 0.65 mmol) was added sequentially to a 100 mL single-necked flask, followed by dichloromethane (10 mL) and NIS (176.0 mg, 0.78 mmol). The mixture was stirred at 20-30°C for 2 h. The reaction was determined to be complete by LC-MS. A saturated sodium thiosulfate aqueous solution (10 mL) was added, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with dichloromethane (10 mL). The combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 180 mg of solid compound XY2501-43-2, yield: 99.06%, LC-MS, M / Z (ESI): 281 [M+H].+ .

[0220] Step 2: Synthesis of 3-chloro-5-iodo-7-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-c][1,2]diazine (compound XY2501-43-3) Compound XY2501-43-2 (180.0 mg, 0.64 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by DMF (5 mL). NaH (31.0 mg, 0.77 mmol) was added at 0 °C, and the mixture was stirred for 30 min. TsCl (159.0 mg, 0.83 mmol) was then added, and the mixture was stirred at 20-30 °C for 4 h. The reaction was determined to be complete by LC-MS. Aqueous solution (20 mL) and ethyl acetate (20 mL) were added, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 200 mg of solid compound XY2501-43-3, yield: 72.06%, LC-MS, M / Z (ESI): 434 [M+H]. + .

[0221] Step 3: Synthesis of 3-chloro-7-[(4-methylphenyl)sulfonyl]-5-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-c][1,2]diazine (compound XY2501-43-5) At 25 °C, compound XY2501-43-3 (200.0 mg, 0.46 mmol), compound XY2501-43-4 (192.0 mg, 0.69 mmol), Pd(dppf)Cl2 (34.0 mg, 0.046 mmol), and K2CO3 (191.0 mg, 1.38 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged three times with nitrogen. Under nitrogen protection, the temperature was raised to 90 °C and the reaction was carried out for 12 h. The reaction was determined to be complete by TLC (PE / EA = 2 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, 2 / 1) to give 205 mg of solid compound XY2501-43-5, yield: 97.32%. LCMS, M / Z (ESI): 459 [M+H]. + .

[0222] Step 4: Synthesis of 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-c]pyridine (compound XY2501-43-7) At 25 °C, compounds XY2501-43-5 (205.0 mg, 0.45 mmol), XY2501-43-6 (163.0 mg, 0.54 mmol), Pd(dppf)Cl2 (33.0 mg, 0.045 mmol), and K3PO4 (287.0 mg, 1.35 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (5 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 110 °C for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 100 mg of solid compound XY2501-43-7, yield: 50.10%. LCMS, M / Z (ESI): 445 [M+H]. + .

[0223] Step 5: Synthesis of 5-(1H-pyrazol-3-yl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-7H-pyrrolo[2,3-c][1,2]diazine (XY2501-43) Compound XY2501-43-7 (60.0 mg, 0.14 mmol), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) were added sequentially to a 100 mL single-necked flask at 25 °C. The mixture was reacted at 20–30 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by preparative TLC (DCM / MeOH = 10 / 1) to give 20 mg of solid XY2501-43. Yield: 41.22%, Purity: 97.32%, LCMS, M / Z (ESI): 360 [M+H]. + .

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 11.2 Hz, 1H), 8.26 (s, 1H), 8.03 (dd, J = 8.8, 6.0 Hz, 2H), 7.76 (s, 1H), 7.16-7.03 (m, 2H), 6.78 (d, J =2.4 Hz, 1H), 3.24 (m, 4H), 2.48 (d, J = 4.8 Hz, 4H), 2.25 (s, 3H).

[0225] Example 32: Synthesis of compound XY2501-45 The reaction equation for the synthesis of compound XY2501-45 is as follows: .

[0226] The synthetic steps of compound XY2501-45 are as follows: Step 1: Synthesis of 1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1,3-thiazolyl-5-yl)pyrrolo[2,3-b]pyridine (compound XY2501-45-3) At 25°C, compounds XY2501-45-1 (300 mg, 0.524 mmol), XY2501-45-2 (166 mg, 0.786 mmol), Pd(dppf)Cl2 (38 mg, 0.052 mmol), and K2CO3 (217 mg, 1.572 mmol) were added sequentially to a 100 mL single-necked flask. The solvent 1,4-dioxane (5 mL) and water (1 mL) were added, and the mixture was purged with nitrogen three times. The mixture was stirred at 100°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1), the reaction was stopped, cooled to room temperature, filtered, the filter cake was washed with EA (10 mL × 2), the filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (EA / MeOH = 40 / 1, 10 / 1) to give 120 mg of white solid compound XY2501-45-3, yield: 43.2%, LCMS, M / Z (ESI): 531 [M+H] + .

[0227] Step 2: Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1,3-thiazolyl-5-yl)-1 H -Pyrrolo[2,3-b]pyridine (XY2501-45) Compound XY2501-45-3 (120 mg, 0.009 mmol), methanol (10 mL), and K2CO3 (313 mg, 0.094 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 25 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure, and preparative TLC (DCM / MeOH = 10 / 1) yielded 20 mg of solid XY2501-45, yield: 23.5%, purity: 99.37%, LCMS, M / Z (ESI): 376 [M+H]. + .

[0228] 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 9.02 (s, 1H), 8.56 (d, J =2.0 Hz, 1H), 8.34 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 2.8 Hz,1H), 7.66-7.64 (m, 2H), 7.07-7.05 (m, 2H), 3.22-3.20 (m, 4H), 2.53-2.51 (m,4H), 2.26 (s, 3H).

[0229] Example 33: Synthesis of compound XY2501-46 The reaction equation for the synthesis of compound XY2501-46 is as follows: .

[0230] The synthetic steps of compound XY2501-46 are as follows: Step 1: Synthesis of 1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[1-(triphenylmethyl)imidazol-4-yl]pyrrolo[2,3-b]pyridine (compound XY2501-46-3) At 25°C, compound XY2501-46-1 (172 mg, 0.301 mmol), compound XY2501-46-2 (160 mg, 0.452 mmol), Pd(dppf)Cl2 (22 mg, 0.030 mmol), and K2CO3 (125 mg, 0.901 mmol) were added sequentially to a 50 mL single-necked flask. Solvent 1,4-dioxane (6 mL) and water (1.5 mL) were added. The mixture was purged with nitrogen three times and stirred at 105°C for 16 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The reaction was stopped, cooled to room temperature, filtered, and the filter cake was washed with EA (10 mL × 2). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (EA / MeOH = 20 / 1) to give 130 mg of brown solid compound 2, yield: 57.3%, LCMS, M / Z (ESI): 756 [M+H]. + .

[0231] Step 2: Synthesis of 3-(1H-imidazol-4-yl)-1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (compound XY2501-46-4) At 25°C, compound XY2501-46-3 (130 mg, 0.172 mmol) was added sequentially to a 50 mL single-necked flask, followed by DCM (4 mL) and TFA (1 mL). The mixture was stirred at 25°C for 1 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with EA (10 mL × 2). The organic phases were combined and washed sequentially with water (10 mL × 2) and saturated NaCl solution (20 mL). The mixture was dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 7 / 1) to give 70 mg of solid compound XY2501-46-4, yield: 79.7%, LCMS, M / Z (ESI): 514 [M+H]. + .

[0232] Step 3: Synthesize 3-(1 H -imidazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-46) At 25°C, compound XY2501-46-4 (70 mg, 0.137 mmol), methanol (4 mL), and K2CO3 (57 mg, 0.410 mmol) were added sequentially to a 50 mL single-necked flask. The mixture was stirred for 16 h, and the reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by high-pressure reverse-phase chromatography to obtain 11 mg of solid XY2501-46, yield: 15.3%, purity: 96.95%, LCMS, M / Z (ESI): 359 [M+H]. + .

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.66 (s, 1H), 8.48 (d, J =2.0 Hz, 2H), 7.72 (d, J = 5.2 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.52 (s,1H), 7.10-7.00 (m, 2H), 3.19 (t, J = 5.2 Hz, 4H), 2.48 (t, J = 5.2 Hz, 4H), 2.24 (s, 3H).

[0234] Example 34: Synthesis of compound XY2501-48 The reaction equation for the synthesis of compound XY2501-48 is as follows: .

[0235] The synthetic steps of compound XY2501-48 are as follows: Step 1: Synthesis of 6-[4-(4-methylpiperazin-1-yl)phenyl]imidazo[3,2-a]pyrimidine (compound XY2501-48-3) At 25°C, compound XY2501-48-1 (2.0 g, 6.62 mmol), potassium carbonate (2.74 g, 19.86 mmol), Pd(dppf)Cl2 (970 mg, 1.33 mmol), dioxane (60 mL), H2O (12 mL), and compound XY2501-48-2 (1.31 g, 6.62 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 90°C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 3 / 1). The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give 1.5 g of brown solid compound XY2501-48-3, yield: 77.2%, LCMS, M / Z (ESI): 294 [M+H]. + .

[0236] Step 2: Synthesis of 3-iodo-6-[4-(4-methylpiperazin-1-yl)phenyl]imidazo[3,2-a]pyrimidine (compound XY2501-48-4) At 25°C, compound XY2501-48-3 (500 mg, 1.7 mmol), NIS (460 mg, 2.04 mmol), and DMF (30 mL) were added sequentially to a 100 mL single-necked flask, and the reaction was carried out at 25°C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). H₂O (30 mL) was added, and the mixture was extracted with EA (30 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give 120 mg of crude brown solid compound XY2501-48-4, yield: 16.8%, LCMS, M / Z (ESI): 420 [M+H]. + .

[0237] Step 3: Synthesis of 3-(1H-pyrazol-3-yl)-6-[4-(4-methylpiperazin-1-yl)phenyl]imidazo[3,2-a]pyrimidine (XY2501-48) At 25°C, compound XY2501-48-4 (120 mg, 0.29 mmol), potassium carbonate (120.5 mg, 0.87 mmol), Pd(dppf)Cl2 (42.4 mg, 0.06 mmol), dioxane (40 mL), H2O (8 mL), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (73 mg, 0.377 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was purged with nitrogen three times and reacted at 95°C for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). Filtration, concentration under reduced pressure, and preparative TLC (DCM / MeOH = 10 / 1) yielded 20 mg of brown solid XY2501-48, purity: 93.72%, yield: 19.1%, LCMS, M / Z (ESI): 360 [M+H]. + .

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.82 (d, J = 13.2 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.23 ​​(d, J = 5.6 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H),7.69-7.50 (m, 2H), 7.22-7.06 (m, 2H), 6.89 (d, J = 2.4 Hz, 1H), 3.23 (t, J =5.2 Hz, 4H), 2.48 (t, J = 5.2 Hz, 4H), 2.24 (s, 3H).

[0239] Example 35: Synthesis of compound XY2501-50 The reaction equation for the synthesis of compound XY2501-50 is as follows: .

[0240] The synthetic steps of compound XY2501-50 are as follows: Step 1: Synthesis of 1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)-1,2,3-triazol-4-yl]pyrrolo[2,3-b]pyridine (compound XY2501-50-3) At 25 °C, compound XY2501-50-1 (200.0 mg, 0.35 mmol), compound XY2501-50-2 (117.0 mg, 0.42 mmol), Pd(dppf)Cl2 (26.0 mg, 0.035 mmol), and K2CO3 (145.0 mg, 1.05 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 90 °C for 12 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1) to give 170 mg of solid compound XY2501-50-3, yield: 81.25%. LCMS, M / Z (ESI): 599 [M+H]. + .

[0241] Step 2: Synthesis of 3-(2H-1,2,3-triazol-4-yl)-1-[(4-methylphenyl)sulfonyl]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (compound XY2501-50-4) Compound XY2501-50-3 (170.0 mg, 0.28 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by dichloromethane (5 mL) and trifluoroacetic acid (1 mL). The reaction was carried out at 25 °C for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and dichloromethane (10 mL) and sodium bicarbonate aqueous solution (10 mL) were added. The mixture was allowed to stand for separation, yielding an organic phase. The aqueous phase was extracted twice with dichloromethane (15 mL). The organic phases were combined, mixed, and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 10 / 1) to obtain 60 mg of solid compound XY2501-50-4, yield: 41.72%. LCMS, M / Z (ESI): 515 [M+H]. + .

[0242] Step 3: Synthesize 3-(2 H -1,2,3-triazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-50) At 25 °C, compound XY2501-50-4 (60.0 mg, 0.12 mmol), methanol (5 mL), and K2CO3 (50.0 mg, 0.36 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was heated to 50 °C and reacted for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 10 / 1). The mixture was concentrated under reduced pressure and purified by thin-layer silica gel chromatography (DCM / MeOH = 10 / 1) to obtain 25 mg of solid XY2501-50. Yield: 47.56%, Purity: 95.23%, LCMS, M / Z (ESI): 360 [M+H]. + .

[0243] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.10-7.04 (m, 2H), 3.20 (t, J = 5.2 Hz, 4H), 2.48(d, J = 5.2 Hz, 4H), 2.24 (s, 3H).

[0244] Example 36: Synthesis of compound XY2501-51 The reaction equation for the synthesis of compound XY2501-51 is as follows: .

[0245] The synthetic steps of compound XY2501-51 are as follows: Step 1: Synthesis of 5-(4-bromophenyl)-3,3a,4,5,6,6a-hexahydro-1H-furano[4,3-c]pyrrole (compound XY2501-51-3) At 25°C, compounds XY2501-51-1 (396.0 mg, 2.65 mmol), XY2501-51-2 (1.13 g, 3.98 mmol), Pd2(dba)3 (121.0 mg, 0.13 mmol), Xantphos (75.0 mg, 0.13 mmol), and sodium tert-butoxide (764.0 mg, 7.95 mmol) were added sequentially to a 100 mL single-necked flask. The solution was 1,4-dioxane (10 mL), and the mixture was purged with nitrogen three times. The mixture was stirred at 100°C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1), concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1) to give 620 mg of solid compound XY2501-51-3, yield: 87.17%, LCMS, M / Z (ESI): 269 [M+H]. + .

[0246] Step 2: Synthesis of 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-3,3a,4,5,6,6a-hexahydro-1 H -furano[4,3-c]pyrrole (compound XY2501-51-4) At 25 °C, compound XY2501-51-3 (620.0 mg, 2.31 mmol), B2pin2 (881.0 mg, 3.47 mmol), potassium acetate (680.0 mg, 6.93 mmol), and Pd(dppf)Cl2 (168.0 mg, 0.23 mmol) were added sequentially to a 100 mL single-necked flask. The solvent 1,4-dioxane (10 mL) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 12 h. The reaction was determined to be complete by TLC (PE / EA = 5 / 1). The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 10 / 1) to give 490 mg of solid compound XY2501-51-4, yield: 67.10%. LCMS, M / Z (ESI): 316 [M+H]. + .

[0247] Step 3: Synthesis of 5-[4-(3,3a,4,5,6,6a-hexahydro-1- H -furano[4,3-c]pyrrolo-5-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-51-5) At 25 °C, intermediate I (707.0 mg, 1.41 mmol), compound XY2501-51-4 (490.0 mg, 1.55 mmol), Pd(dppf)Cl2 (52.0 mg, 0.07 mmol), and K2CO3 (585.0 mg, 4.23 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 100 °C for 12 h. The reaction was determined to be complete by TLC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 10 / 1, 5 / 1) to give 700 mg of solid compound XY2501-51-5, yield: 81.56%. LCMS, M / Z (ESI): 611 [M+H]. + .

[0248] Step 4: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(3,3a,4,5,6,6a-hexahydro-1-yl) H -furano[4,3-c]pyrrolo-5-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-51-6) Compound XY2501-51-5 (700.0 mg, 1.15 mmol) was added sequentially to a 100 mL single-necked flask at 25 °C, followed by dichloromethane (10 mL) and trifluoroacetic acid (2 mL). The reaction was allowed to proceed at room temperature for 2 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure, and dichloromethane (15 mL) and sodium bicarbonate aqueous solution (15 mL) were added. The mixture was allowed to stand and separate into layers, yielding an organic phase. The aqueous phase was extracted twice with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure preparative treatment to obtain 180 mg of solid compound XY2501-51-6, yield: 29.57%, LCMS, M / Z (ESI): 527 [M+H]. + .

[0249] Step 5: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(3,3a,4,5,6,6a-hexahydro-1-yl) H -furano[4,3-c]pyrrolo-5-yl)phenyl]-1 H -Pyrrolo[2,3-b]pyridine (XY2501-51) Compound XY2501-51-6 (180.0 mg, 0.34 mmol), methanol (10 mL), and K2CO3 (142.0 mg, 1.03 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 40 °C for 4 h. The reaction was determined to be complete by TLC (DCM / MeOH = 20 / 1). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to give 56 mg of solid XY2501-51. Yield: 44.34%, Purity: 94.84%, LCMS, M / Z (ESI): 372 [M+H]. + .

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 41.2 Hz, 2H), 7.87 (d, J =2.4 Hz, 1H), 7.65 (d, J = 69.8 Hz, 3H), 6.79-6.72 (m, 2H), 6.71-6.61 (m, 1H), 3.86 (dd, J = 8.8, 6.4 Hz, 2H), 3.56 (dd, J = 8.8, 3.2 Hz, 2H), 3.36 (s, 2H), 3.23-3.15 (m, 2H), 3.00 (m, 2H).

[0251] Example 37: Synthesis of compound XY2501-62 The reaction equation for the synthesis of compound XY2501-62 is as follows: .

[0252] The synthetic steps of compound XY2501-62 are as follows: Step 1: Synthesis of [4-(4-bromophenyl)piperazin-1-yl](cyclopropyl)methyl ketone (compound XY2501-62-3) At 25°C, compound XY2501-62-1 (500 mg, 2.07 mmol), DCM (5 mL), TEA (628 mg, 6.21 mmol), and XY2501-62-2 (217 mg, 2.07 mmol) were added sequentially to a 100 mL single-necked flask. The mixture was stirred at 25°C for 12 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure, mixed with silica gel, and purified by silica gel column chromatography (PE / EA = 3 / 1, 2 / 1) to obtain 620 mg of solid compound XY2501-62-3, yield: 96.62%, LCMS, M / Z (ESI): 310 [M+H]. + .

[0253] Step 2: Synthesis of cyclopropyl{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]piperazin-1-yl} methyl ketone (compound XY2501-62-4) At 25 °C, compound XY2501-62-3 (620 mg, 2.00 mmol), pinacol diboronic acid ester (764 mg, 3.00 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol), and KOAc (589 mg, 6.00 mmol) were added sequentially to a 100 mL single-necked flask. 1,4-Dioxane solvent (10 mL) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 16 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5 / 1, 2 / 1) to give 700 mg of compound XY2501-62-4, yield: 98.50%, LCMS, M / Z (ESI): 357 [M+H]. + .

[0254] Step 3: Synthesis of cyclopropyl[4-(4-{1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazin-1-yl] methyl ketone (compound XY2501-62-5) At 25 °C, intermediate I (821 mg, 1.64 mmol), compound XY2501-62-4 (700 mg, 1.97 mmol), Pd(dppf)Cl2 (72 mg, 0.10 mmol), and K2CO3 (829 mg, 6.0 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 95 °C for 16 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, 1 / 2) to give 800 mg of solid compound XY2501-62-5, yield: 75.0%. LCMS, M / Z (ESI): 652 [M+H]. + .

[0255] Step 4: Synthesis of (4-{4-[3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazin-1-yl)(cyclopropyl) methyl ketone (compound XY2501-62-6) Compound XY2501-62-5 (800 mg, 1.23 mmol) was dissolved in DCM (5 mL) at 25 °C, and TFA (2.5 mL) was added. The mixture was stirred at 25 °C for 2 h. The reaction was determined to be complete by LCMS. The solution was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (15 mL) was added. The aqueous phase was extracted with DCM (15 mL × 2). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 690 mg of solid compound XY2501-62-6, yield: 100%, LCMS, M / Z (ESI): 567 [M+H]. + .

[0256] Step 5: Synthesis of (4-{4-[3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazin-1-yl)(cyclopropyl) methyl ketone (compound XY2501-62) Compound XY2501-62-6 (690 mg, 1.22 mmol), methanol (15 mL), and K2CO3 (506 mg, 3.66 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 50 °C for 1 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 30 / 1, 25 / 1) to give 220 mg of solid XY2501-62. Yield: 43.71%, purity: 98.35%, LCMS, M / Z (ESI): 413 [M+H]. + .

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 46.4 Hz, 2H), 7.89 (s, 1H),7.84-7.51 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 3.86 (s, 2H), 3.65(s, 2H), 3.30-3.15 (m, 4H), 2.04 (td, J = 7.8, 4.2 Hz, 1H), 0.83-0.69 (m,4H). Example 38: Synthesis of compound XY2501-63 The reaction equation for the synthesis of compound XY2501-63 is as follows: .

[0258] The synthetic steps of compound XY2501-63 are as follows: Step 1: Synthesis of 1-(4-bromophenyl)-4-methoxy-4-methylhexahydropyridine (compound XY2501-63-3) At 25 °C, compound XY2501-63-1 (500 mg, 3.02 mmol), Pd2(dba)3 (138 mg, 0.15 mmol), t-BuONa (871 mg, 9.06 mmol), XY2501-63-2 (1.02 g, 3.62 mmol), and Xantphos (87 mg, 0.15 mmol) were added sequentially to a 100 mL single-necked flask. The solvent 1,4-dioxane (15 mL) was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 16 h. The reaction was determined to be complete by LC-MS. The mixture was concentrated under reduced pressure, mixed with silica gel, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 800 mg of solid compound XY2501-63-3, yield: 93.05%, LC-MS, M / Z (ESI): 285 [M+H]. + .

[0259] Step 2: Synthesis of 4-methoxy-4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]hexahydropyridine (compound XY2501-63-4) At 25 °C, compound XY2501-63-3 (800 mg, 2.81 mmol), pinacol diboronic acid ester (1.07 g, 4.22 mmol), Pd(dppf)Cl2 (103 mg, 0.14 mmol), and KOAc (827 mg, 8.43 mmol) were added sequentially to a 100 mL single-necked flask. 1,4-Dioxane (15 mL) solvent was added, and the mixture was purged with nitrogen three times. The reaction was carried out at 100 °C for 16 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 20 / 1, 10 / 1) to give 900 mg of compound XY2501-63-4, yield: 96.69%, LCMS, M / Z (ESI): 332 [M+H]. + .

[0260] Step 3: Synthesis of 5-[4-(4-methoxy-4-methylhexahydropyridin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]-3-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (compound XY2501-63-5) At 25 °C, intermediate I (900 mg, 1.79 mmol), compound XY2501-63-4 (714 mg, 2.15 mmol), Pd(dppf)Cl2 (65 mg, 0.09 mmol), and K2CO3 (742 mg, 5.37 mmol) were added sequentially to a 100 mL single-necked flask. Solvent 1,4-dioxane (10 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times and reacted at 95 °C for 16 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 4 / 1, 3 / 1, 1 / 1) to give 600 mg of solid compound XY2501-63-5, yield: 53.56%. LCMS, M / Z (ESI): 652 [M+H]. + .

[0261] Step 4: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(4-methoxy-4-methylhexahydropyridin-1-yl)phenyl]-1-[(4-methylphenyl)sulfonyl]pyrrolo[2,3-b]pyridine (compound XY2501-63-6) Compound XY2501-63-5 (600 mg, 0.96 mmol) was dissolved in DCM (5 mL) at 25 °C, and TFA (2.5 mL) was added. The mixture was stirred at 25 °C for 2 h. The reaction was determined to be complete by LCMS. The solution was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (15 mL) was added. The aqueous phase was extracted with DCM (15 mL × 2). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 500 mg of solid compound XY2501-63-6, yield: 95.83%, LCMS, M / Z (ESI): 542 [M+H]. + .

[0262] Step 5: Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(4-methoxy-4-methylhexahydropyridin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (compound XY2501-63) Compound XY2501-63-6 (500 mg, 0.92 mmol), methanol (15 mL), and K2CO3 (381 mg, 2.76 mmol) were added sequentially to a 100 mL single-necked flask at 25 °C. The reaction was carried out at 30 °C for 12 h. The reaction was determined to be complete by LCMS. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH = 40 / 1, 30 / 1) to give 160 mg of solid XY2501-63. Yield: 44.88%, purity: 97.54%, LCMS, M / Z (ESI): 388 [M+H]. + .

[0263] 1 H NMR (400 MHz, DMSO-d6) 8.57 (d, J = 53.6 Hz, 2H), 7.88 (s, 1H),7.82-7.49 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 6.75-6.61 (m, 1H), 3.39 (s, 2H), 3.14 (s, 3H), 3.06 (m, 2H), 1.78 (d, J = 13.4 Hz, 2H), 1.59 (m, 2H), 1.15 (s, 3H).

[0264] Performance testing I. Evaluation of in vitro bioactivity 1. Experimental Objective The effect of the compound on the activity of activin receptor 2B (ActRIIB) enzyme was determined by homogeneous time-resolved fluorescence (HTRF).

[0265] 2. Experimental instruments and reagents / consumables 2.1 Experimental Apparatus High-throughput acoustic liquid handling system (LABCYTE, 655); centrifuge (CENCE, TDZ5-WS); microplate reader (BMG, PHERAstar FSX).

[0266] 2.2 Experimental reagents and consumables HEPES buffer (Gibco, 15630080); Brij35 (Millipore, 1018940100); EGTA (Sigma, E3889); MgCl2 (Sigma, M1028); DTT (Sigma, 43816-50ML); DMSO (HiPure Chem, D6889-4L); ATP (Promega, V915B); LANCE assay buffer (LANCE, CR97-100C); 96-well conical bottom polypropylene plate (CHUANGLIANYI TCEH, CLY96001); 384-well conical bottom polypropylene plate (Greiner, 784075); Echo® system certified 384-well polypropylene microplate (ABCYTE, PP-0200).

[0267] 3. Experimental Methods 1) Prepare a 2×ATP / ULight-DNA topoisomerase 2α (Thr1342) peptide solution and a 2× kinase solution using kinase reaction buffer.

[0268] 2) Transfer 100 nL of compound dilution or positive control dilution to a 384-well detection plate; after centrifugation, add 5 μL of 2× kinase solution to the detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0269] 3) Add 5 μL of a mixture of 2×ULight-DNA topoisomerase 2α (Thr1342) peptide and ATP to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 120 minutes.

[0270] 4) Add 10 μL of Eu-antiphosphorylation-Topo2α (Thr1342) and 1×LANCE detection buffer (containing detection buffer) to the detection plate, incubate at 25°C, centrifuge at 1000 rpm for 1 minute, and continue incubating at 25°C for 1 hour.

[0271] 5) Read the fluorescence signals at 620nm and 665nm on a multifunctional enzyme-linked immunosorbent assay (ELISA) instrument.

[0272] 4. Data Analysis The inhibition rate (%inh) of the compound was calculated using the following formula: .

[0273] The half-maximal inhibitory concentration (IC50) of the compound 50 The dose-response-variable slope fitting model in GraphPad Prism 8.0 was used to calculate the dose-response relationship using the gradient concentration logarithm (X) and the corresponding inhibition rate (Y). The formula is as follows: .

[0274] 5. Experimental Results and Conclusions The compound of this application has a half-maximal inhibitory concentration (IC50) determined in an in vitro ActRIIB enzyme activity assay. 50 The data is shown in Table 1.

[0275] Table 1

[0276] Experimental results show that the above-mentioned compounds synthesized in this application exhibit good inhibitory effects in in vitro ActRIIB enzyme activity assays.

[0277] II. Target Selectivity Test 1. Experimental objective: The effects of the compounds on the activities of ALK4 and ALK5 enzymes were determined using the ADP-Glo ​​method; the effects of the compounds on the activities of ALK7 enzymes were determined using homogeneous time-resolved fluorescence (HTRF).

[0278] 2. Experimental instruments and reagents / consumables: 2.1 Experimental Apparatus ECHO® 655 system (LABCYTE, 655); centrifuge (CENCE, TDZ5-WS); microplate reader (BMG, PHERAstarFSX).

[0279] 2.2 Experimental Reagents and Consumables HEPES buffer (Gibco, 15630080); Brij35 (Millipore, 1018940100); EGTA (Sigma, E3889); MgCl2 (Sigma, M1028); DTT (Merck, 646563); DMSO (Sigma, D4540); ATP (Promega, V915B); LANCE buffer (Revvity, CR97-100C); MnCl2 (Sigma, M1787); ADP-Glo ​​kinase assay kit (Promega, V9103); casein peptide (Sigma, C5890-500G); TGFBR peptide (Genscript, PE0407); 96-well plate (CHUANGLIANYI TCEH, CLY96001); 384-well plate (Greiner, 784075).

[0280] 3. Experimental methods: 3.1 Detection of ALK4 and ALK5 enzyme activities using the ADP-Glo ​​method 1) Prepare a 2× ATP / substrate solution according to the instructions of the kinase assay kit, and prepare a 2× kinase solution using kinase reaction buffer.

[0281] 2) Use an Echo 655 to transfer 100 nL of compound dilution to a 384-well plate; after centrifugation, add 5 μL of 2× kinase solution to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0282] 3) Add 5 μL of 2× substrate and ATP mixture to the 384-well plate and centrifuge at 1000 rpm for 1 minute. Incubate ALK4 protein at 25°C for 120 minutes and ALK5 protein at 25°C for 180 minutes.

[0283] 4) Transfer 5 μL of ADP-Glo ​​reagent to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0284] 5) Transfer 10 μL of kinase assay reagent to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0285] 6) Use a multi-functional microplate reader to read the luminescent signal.

[0286] 3.2 Detection of ALK7 enzyme activity using HTRF method 1) Prepare a 2× ATP / ULight-DNA topoisomerase 2-α (Thr1342) peptide solution and prepare a 2× kinase solution using kinase reaction buffer.

[0287] 2) Transfer 50 nL of compound dilution to a 384-well detection plate; after centrifugation, add 2.5 μL of 2× kinase solution to the detection plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0288] 3) Add 2.5 μL of 2× ULight-DNA topoisomerase 2-α (Thr1342) peptide and ATP mixture to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 180 minutes.

[0289] 4) Add 5 μL of Eu-labeled antiphosphorylated-Topo2a (Thr1342) antibody and 1×LANCE detection buffer to the detection plate and incubate at 25°C. Centrifuge at 1000 rpm for 1 minute, then continue incubation at 25°C for 1 hour.

[0290] 5) Use a multi-functional microplate reader to read the fluorescence signals at 620 nm and 665 nm.

[0291] 4. Data Analysis The inhibition rate (%inh) of the compound was calculated using the following formula: .

[0292] The half-maximal inhibitory concentration (IC50) of the compound 50 The formula is calculated using the gradient concentration logarithm (X) and the corresponding inhibition rate (Y) through the GraphPad Prism 8.0 "dose-effect-variable slope fitting model". .

[0293] 5. Experimental Results and Analysis The compounds of this application exhibit in vitro half-maximal inhibitory concentrations (IC50) of ALK4, ALK5, and ALK7. 50 The data is shown in Table 2.

[0294] Table 2

[0295] Experimental results show that the above-mentioned compounds synthesized in this application have good inhibitory activity against ActRIIB enzymes in vitro, while having no effect on ALK4, ALK5, and ALK7, exhibiting good selectivity.

[0296] III. Study on the metabolic stability of liver microsomes 1. Experimental objective: The stability of the compound was tested in mouse, rat, and human liver microsomes.

[0297] 2. Experimental reagents Human liver microsomes (BIOIVT, IVX-25); mouse liver microsomes (BIOIVT, RNX); rat liver microsomes (XenoTech, 2210274).

[0298] 3. Experimental Methods 1) Prepare liver microsomal working solution and compound working solution, and prepare 8 96-well sample plates, named T0, T5, T15, T30, T60, T120, NCFT0, NCF120, NCF0 and Blank, respectively.

[0299] 2) Add 100 μL of the corresponding liver microsome working solution to the wells of the sample plate. For Blank and T0 sample plates, first add 600 μL of stop solution to the corresponding wells; then add 2.00 μL of the solvent and working solution used for the compound; finally, add 98.0 μL of coenzyme factor and mix the sample plate. For NCFTO sample plates, first add 600 μL of stop solution to the corresponding wells; then add 2.00 μL of the working solution; finally, add 98.0 μL of LPB and mix the sample plate. For the T5, T15, T30, T60, T120, and NCF120 sample plates, first add 2.00 μL of the compound working solution to the corresponding well of the sample plate; then, pre-incubate in a 37°C water bath for about 10 min; finally, for the T5, T15, T30, T60, and T120 sample plates, add 98.0 μL of coenzyme factor to the corresponding well of the sample plate to start the reaction; for the NCF120 sample plate, add 98.0 μL of PB to the corresponding well of the sample plate to start the reaction.

[0300] 3) After reacting for 5, 15, 30, 60 and 120 minutes, add 600 μL of stop solution to the corresponding well of the sample plate to terminate the reaction.

[0301] 4) Mix all sample plates, centrifuge at 3200×g for 20 minutes, add 100 μL of supernatant to 100 μL of ultrapure water, shake well, and then perform LC-MS / MS analysis.

[0302] 4. Data Analysis The remaining percentage (%Remaining) is calculated using the following formula: .

[0303] T1 / 2 The half-life is calculated using the following equation: The k value was obtained by fitting the residual percentage and the slope of the time curve at each time point using EXCEL; CL in vitro （ The in vitro clearance rate is calculated using the following formula: .

[0304] 5. Experimental Results and Conclusions The metabolic stability data of the compounds in human liver microsomes are shown in Table 3.

[0305] Table 3

[0306] The above data show that the compounds described in the embodiments of this application exhibit good metabolic stability in human liver microsomes.

[0307] IV. Tests on the effect of compounds on hERG potassium ions 1. Experimental objective: The inhibitory effect of the compound on the hERG potassium ion channel was tested.

[0308] 2. Experimental cell lines The HEK-293 cell line, which stably expresses the hERG potassium channel, was used.

[0309] 3. Experimental instruments and reagents / consumables 3.1 Test Instruments Qpatch (Sophion, QPatch 48X); Temperature control module (JULABO, FPE50-HE); Data acquisition and analysis software (Sophion & GraphPad, Sophion Analyzer 6.5 & GraphPad Prism).

[0310] 3.2 Test Reagents DMEM (Gibco), Fetal Bovine Serum (avantor), G418 (GPC), TrypLE™ Express (Gibco), Cisapride (Sigma), Potassium Aspartate (K-aspartic) (Sigma), Sodium Chloride (NaCl) (Sigma), Potassium Chloride (KCl) (Sigma), Ethylene Glycol Di(2-aminoethyl ether)tetraacetic Acid (EGTA) (Sigma), 4-Hydroxyethylpiperazine Ethylsulfonic Acid (HEPES) (SantaCruz), Magnesium Chloride (MgCl2•6H2O) (Sigma), Glucose (D-Glucose) (Sigma), Calcium Chloride (CaCl2•2H2O) (Sigma), Sodium Dihydrogen Phosphate (NaH2PO4•2H2O) (GENERAL-REAGENT), Sodium Adenosine Triphosphate (Na2-ATP) (Sigma).

[0311] 4. Test methods: 4.1 Cell Culture: The HEK293 cell line, stably expressing potassium channels, was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL LG418 at 37°C and 5% carbon dioxide. To maintain cell electrophysiological activity, the cell density must not exceed 80%. Before patch-clamp assays, cells were separated using TrypLE™ Express, digestion was stopped by adding culture medium, and the cells were centrifuged, resuspended, counted, and adjusted to a density of 2–3 × 10⁶ cells / year. 6 Cells / mL were collected, and then the cells were gently mixed on a balanced shaker for 15-20 min at room temperature before being analyzed.

[0312] 4.2 Patch-clamp testing: This study used the fully automated patch-clamp QPatch 48X (Sophion) device for electrophysiological testing.

[0313] First, the prepared cells are placed on a centrifuge in the Qpatch workbench and washed using multiple centrifugation / resuspension methods to replace the cell culture medium with extracellular fluid. An MTP-96 plate is removed and placed in the MTP source position. The QPlate chip is removed and placed in the QPlate source position. The robotic arm scans the barcodes on the MTP-96 plate and the QPlate chip and picks them up to the measurement station. Intracellular fluid and extracellular fluid are aspirated from the liquid pools and added to the intracellular fluid pool and cell and compound pool of the QPlate chip, respectively. At the measurement station, all measurement sites on the QPlate undergo initial quality control. The quality control process includes aspirating the cell suspension from the centrifuge's cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal, forming a whole-cell recording mode. Once a stable control current baseline is obtained, the test substances are sequentially aspirated from the MTP-96 plate according to their concentration and applied to the cells.

[0314] The voltage stimulation protocol for whole-cell patch-clamp recording of potassium channel currents is as follows: After whole-cell occlusion, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV and maintained for 0.5 s (as a leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to observe the tail current. Data is collected every 10 s to observe the effect of the drug on the potassium channel tail current. Experimental data are collected by a QPatch screening workstation and stored in a database server.

[0315] Each drug concentration was administered twice, with a time interval of at least 5 minutes. The current detected in each cell in an external solution free of the compound served as its own control group, and two cells were independently measured repeatedly. All electrophysiological experiments were performed at room temperature.

[0316] 5. Experimental data processing methods: The second dose in a two-dose regimen was used for data analysis. For each drug concentration, the average of the last three data points before the next dose concentration was taken to represent the current value after that concentration. The current values ​​after each drug concentration were normalized to the blank control current. Then calculate the inhibition rate (1-) for each drug concentration. For each concentration inhibition rate, the mean (Mean), standard deviation (SD), and standard error (SE) are calculated.

[0317] Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X) *HillSlope)) Calculate the IC for each compound using the above equations. 50The values ​​were calculated, and a nonlinear fit was performed on the dose-dependent effect, where IC 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software.

[0318] 6. Experimental Results and Conclusions: The inhibitory effects of the compounds in this application on hERG potassium ion channels are shown in Table 4.

[0319] Table 4

[0320] Based on the above data, it can be concluded that the compounds described in the embodiments of this application have no inhibitory effect on hERG potassium ion channels and have a low risk of cardiotoxicity.

[0321] V. Pharmacokinetic Study of Single Oral Administration in Rats Experimental Methods: Male SD rats (6-8 weeks old; 200g-300g) were randomly divided into groups (n=3). After fasting overnight before administration, each rat was administered the compound at 10 mg / kg via gavage (solvent: 5% DMSO + 10% Solutol HS-15 + 85% physiological saline). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-administration. Approximately 150 µL of blood was collected via the jugular vein into EDTA-K2 anticoagulant tubes and placed on moist ice. The plasma was separated by centrifugation (2000g, 10min, 4℃) over 30 min. 50.0 µL of plasma was transferred to a separate test tube and immediately frozen (at -70℃) until analysis. The concentration of free molecules of the compound in the plasma was determined by LC-MS / MS.

[0322] Experimental results: The compounds described in the embodiments of this application have good pharmacokinetic properties.

[0323] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0324] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A heterocyclic compound, characterized in that, The heterocyclic compound is a compound of Formula I or a racemic mixture, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug. ， In the formula, ring A is a 4-8 member aliphatic ring or aliphatic heterocycle, and the number of R1 substituents on ring A is 1-4; Ring B is a 5- to 10-membered aromatic or aromatic heterocyclic ring or a fused ring, and the number of R2 substituents on ring B is 1 to 4; X1, X2, X3, and X4 are each independently selected from N or CR3; Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are each independently selected from N, NH, or CR4; R1 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, cyano, carboxyl, sulfonyl, aminoacyl, carbonyl, and -OR. 11 -OC(=O)N(R) 11 )2、(=O) q 、(=NR 11 ) q 、(=O)(=NR 11 -C(=O)R 11 -C(=O)OR 11 -C(=O)N(R) 11 )2、-C(=O)C(R 11 3. -C(=O)CH=C(R) 11 )2、-C(=O)CH=CH-CH2N(R 11 )2、-C(=O)C(=O)R 11 -C(=O)C(=O)N(R) 11 )2、-C(=S)R 11 -C(=NR) 11 )R 11 -C(=NR) 11 )N(R 11 )2、-N(R 11 )2、-NR 11 C(=O)R 11 -NR 11 C(=NR 11 )N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 C(O)OR 11 -NR 11 S(=O) q R 11 -NR 11 S(=O) q OR 11 -NR 11 S(=O) q SR 11 -NR 11 S(=O) q N(R 11 )2、-N=S(=O)(R 11 2. -S (=O) q R 11 -S(=O) q OR 11 -S(=O) q SR 11 -S(=O) q N(R 11 )2、-S(=O)(=NR 11 )R 11 -S(=O)(=NR) 11 )N(R 11 2. C 1~6 Alkyl, C 1~6 alkenyl, C 1~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 alkenyl C 1~6 Alkyl, C 1~6 alkynyl C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, S, and O, and 4-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, S, and O, wherein the above alkyl, alkenyl, alkynyl, amino, hydroxyl, carbonyl, acyl, sulfonyl, alkoxy, alkanoyl, cycloalkyl, heterocyclic alkyl, and heterocyclic aryl groups have 1-3 R groups. 11 Substituents; R 11 Independently selected from hydrogen, deuterium, halogen, amino, imino, hydroxyl, mercapto, cyano, carbonyl, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl, benzyl, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, S, and O, -NHC(O)C 1~6 Alkyl group, -NHC(O)C 3~6 cycloalkyl, -NHC(O)C 4~6 Heterocyclic alkyl groups, -NHC(O)NHC 1~6 Alkyl or -NHC(O)OC 1~6 alkyl; q is independently selected from 0, 1, or 2; R2 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, sulfonyl pentafluoride, cyano, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl or containing 1 to 3 4-6 membered heterocycloalkyl groups selected from N, S, and O heteroatoms, or containing 1 to 3 4-6 membered heterocyclic aryl groups selected from N, S, and O heteroatoms; R3 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, sulfonyl pentafluoride, cyano, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl groups or 4- to 6-membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from N, S, and O; R4 is independently selected from H, deuterium, halogen, amino, hydroxyl, mercapto, sulfonyl pentafluoride, cyano, carboxyl, sulfonyl, aminoacyl, C 1~6 Alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 1~6 Alkoxy, C 1~6 Alkyl mercapto, C 1~6 Alkyl group, C 1~6 Alkyl sulfone group, C 1~6 Alkyl sulfoxide group, C 3~6 Cycloalkyl groups, and 4- to 6-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, S, and O.

2. The heterocyclic compound according to claim 1, characterized in that, The heterocyclic compound is a compound of Formula II or its racemate, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug. ， In the formula, W is selected from N, O, SR1 or CR1.

3. The heterocyclic compound according to claim 2, characterized in that, The heterocyclic compound is a compound of Formula III or its racemate, stereoisomer, geometric isomer, tautomer, nitride, hydrate, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or pharmaceutically acceptable prodrug. ， In the formula, Z1, Z2, Z3, and Z4 are each independently selected from N, O, S, or CR2.

4. The heterocyclic compound according to any one of claims 1 to 3, characterized in that, The two R1s on ring A form a 4-7 quintile aliphatic ring or aliphatic heterocyclic ring, and together with ring A, they form a fused ring, a spiral ring, or a bridged ring.

5. The heterocyclic compound according to claim 4, characterized in that, The 4-7 membered aliphatic ring or aliphatic heterocycle has 1-3 R1 substituents.

6. The heterocyclic compound according to any one of claims 1 to 3, characterized in that, Meet at least one of the following: (1) The hydroxyl, amino, alkyl, alkenyl, alkoxy, alkanoyl, cycloalkyl, heterocyclic alkyl, and heterocyclic aryl groups in R2 have 1 to 3 deuterium, halogen, hydroxyl, amino, C 1~6 Alkyl or C 3~6 Cycloalkyl substituents; (2) The hydroxyl, amino, alkyl, alkenyl, alkoxy, alkanoyl, cycloalkyl, and heterocyclic alkyl groups in R3 have 1 to 3 deuterium, halogen, hydroxyl, amino, or C groups. 1~6 Alkyl or C 3~6 Cycloalkyl substituents; (3) The hydroxyl, amino, alkyl, alkenyl, alkoxy, alkanoyl, cycloalkyl, and heterocyclic alkyl groups in R4 have 1 to 3 deuterium, halogen, hydroxyl, amino, or C groups. 1~6 Alkyl or C 3~6 Cycloalkyl substituents; (4) R 11 The hydroxyl, amino, alkyl, alkenyl, alkoxy, alkanoyl, cycloalkyl, and heterocyclic alkyl groups contain 1 to 3 deuterium, halogen, hydroxyl, amino, and C groups. 1~6 Alkyl, C 3~6 cycloalkyl, C 3~6 Heterocyclic alkyl, heterophenyl, or heteroaryl substituents.

7. The heterocyclic compound according to any one of claims 1 to 3, characterized in that, The heterocyclic compound is any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. A pharmaceutical composition, characterized in that, Includes the heterocyclic compounds according to any one of claims 1 to 7.

9. An activin type II receptor inhibitor, characterized in that, The heterocyclic compound includes any one of claims 1 to 7; optionally, the activin type II receptor is activin receptor 2B.

10. The use of any heterocyclic compound of claims 1 to 7, the pharmaceutical composition of claim 8, or the activin type II receptor inhibitor of claim 9 in the preparation of anti-cachexia drugs, anti-muscle dystrophic drugs, or anti-metabolic disease drugs.

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