Azaindole compound, preparation method therefor, and use thereof

Abstract

The present application relates to the technical field of biological medicines, and particularly discloses an azaindole compound, a preparation method therefor, and a use thereof. The azaindole compound provided by the present application is a compound represented by general formula I or a pharmaceutically acceptable salt, an isomer, a solvate, a hydrate, a prodrug or an isotope derivative thereof; and the structural formula of general formula I is: formula I. The azaindole compound provided by the present application exhibits good inhibitory activity against Ba / F3 cells transfected with BCR-ABL-T315I and BCR-ABL-WT. Therefore, the azaindole compound can be used as a BCR-ABL inhibitor, and is expected to be developed into a drug for treating and / or preventing BCR-ABL related diseases.

Description

A nitrogen-containing indole compound, its preparation method and application Technical Field

[0001] This application relates to the field of biomedical technology, specifically to an azaindole compound and its preparation method and application. Background Technology

[0002] ABL1 is a protein encoded by the ABL1 gene located on chromosome 9 in the human body. It is widely distributed in the cell nucleus and cytoplasm, belonging to the tyrosine kinase family, and is mainly involved in cell differentiation, adhesion, division, and stress responses. The activity of ABL1 protein is self-inhibited by its SH3 domain. The loss of the SH3 domain will cause ABL1 to transform into a proto-oncogene, and the continuous activation of ABL1 protein will lead to cell carcinogenesis. Related studies have shown that the hallmark of chronic myeloid leukemia (CML) is the Philadelphia chromosome, formed by the t(9;22) translocation that causes the expression of the BCR-ABL tyrosine kinase fusion gene. This fusion gene encodes a chimeric BCR-ABL protein, resulting in the loss of the SH3 domain's self-regulation in ABL1 protein. Therefore, the standard treatment for CML patients is the use of a tyrosine kinase inhibitor (TKI) targeting the BCR-ABL protein.

[0003] For the treatment of CML, tyrosine kinase inhibitors, such as imatinib, have been developed. These inhibitors inhibit the tyrosine kinase activity of BCR-ABL through an ATP-competitive mechanism. However, clinical results show that this tyrosine kinase inhibitor has poor resistance, and long-term use is unlikely to achieve ideal results. In recent years, a pharmaceutical company has developed an ABL1 kinase allosteric inhibitor, ABL001, which inactivates ABL1 by targeting the myristoyl pocket of the allosteric site, exhibiting good therapeutic effects. Moreover, when this allosteric inhibitor ABL001 is used in combination with an ATP-competitive BCR-ABL tyrosine kinase inhibitor (nilotinib), it can effectively prevent the development of resistance to ATP-competitive inhibitors and / or allosteric inhibitors, achieving a radical cure for CML.

[0004] Currently, although ABL001, as an allosteric inhibitor of ABL1 kinase, is effective in treating conditions such as CML, discovering compounds with novel structures that can treat CML and other conditions remains a challenging task. Therefore, there is still a need in this field to continue developing compounds with novel structures and inhibitory activity against BCR-ABL kinase.

[0005] Summary of the Invention

[0006] In order to obtain a novel compound with inhibitory activity against BCR-ABL kinase, thereby achieving effective treatment of CML, this application provides an azaindole compound, its preparation method, and its application.

[0007] Firstly, the azaindole compound provided in this application adopts the following technical solution:

[0008] An azaindole compound, which is a compound of general formula I or a pharmaceutically acceptable salt, isomer, solvate, hydrate, prodrug, or isotopic derivative thereof; the structural formula of general formula I is:

[0009] In general formula I, R1 is selected from hydrogen, halogen, amino, hydroxyl, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, C 1-6 Alkyloxy or substituted C 1-6 Alkyloxy;

[0010] R2 is one, two, or three identical or different substituents present on the pyridine ring;

[0011] R2 is independently selected from the following groups: hydrogen, halogen, amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkyloxy group, substituted C 1-6 Alkyloxy, C 1-6 Alkyl mercapto, substituted C 1-6 Alkyl mercapto, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, substituted C 3-10 Heterocyclic alkyl, optionally substituted sulfonyl, optionally substituted phosphoryl, or groups as shown in formula (1):

[0012] In formula (1), L is selected from methylene, substituted methylene, imino, substituted imino, oxygen, or carbonyl; Z is selected from hydrogen, halogen, amino, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl or substituted C 3-10 Heterocyclic alkyl groups.

[0013] Optionally, the structural formula of the azaindole compound is shown in general formula II:

[0014] In general formula II, R3 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, substituted C 3-10 Heterocyclic alkyl groups or groups represented by formula (1);

[0015] The R4 is selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyloxy group, substituted C 1-6 Alkyloxy, C 1-6 Alkyl mercapto, substituted C 1-6 Alkyl mercapto, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, optionally substituted sulfonyl, optionally substituted phosphoryl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl or substituted C 3-10 Heterocyclic alkyl groups.

[0016] Optionally, R1 is selected from hydrogen, amino, C 1-6 Alkyl or C 3-7 Cycloalkyl.

[0017] Optionally, R3 is selected from hydrogen, halogen, C 3-10 Heterocyclic alkyl groups, substituted C 3-10 Heterocyclic alkyl groups, or groups represented by formula (1);

[0018] In formula (1), L is selected from methylene, imino, substituted imino, oxygen, and carbonyl; Z is selected from hydrogen, amino, and C. 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl or substituted C 3-10 Heterocyclic alkyl groups.

[0019] Optionally, R4 is selected from hydrogen, halogens, and C. 1-6 Alkyloxy, C 1-6 Alkyl mercapto, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, optionally substituted sulfonyl, optionally substituted phosphoryl, substituted C 3-10 Heterocyclic alkyl groups.

[0020] Optionally, the azaindole compound is selected from compounds 1 to 74 in Table 1.

[0021] Table 1. Structural formulas of some compounds in this application.

[0022] Secondly, this application provides the use of an azaindole compound in the preparation of a medicament for treating and / or preventing tumor diseases.

[0023] Thirdly, this application provides a medicament for treating and / or preventing tumor diseases, comprising the aforementioned azaindole compound.

[0024] Fourthly, this application provides a BCR-ABL inhibitor comprising the aforementioned azaindole compound.

[0025] Fifthly, this application provides a medicament for treating and / or preventing BCR-ABL-related diseases, comprising the aforementioned azaindole compound and a pharmaceutically acceptable carrier and / or excipient.

[0026] Optionally, the BCR-ABL-related diseases are selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, invasive carcinoma, viral infection, or CNS disorder.

[0027] In this application, for the purpose of more clearly describing the content of this application, the terms used are explained as follows. Those skilled in the art can understand the following terms in conjunction with relevant technologies:

[0028] The term "hydroxyl" refers to -OH. The term "amino" refers to -NH2. The term "cyano" refers to -CN. The term "methylene" refers to -CH2-. The term "imino" refers to -NH-.

[0029] Term "C" 1-6"Alkyl" refers to alkyl groups, either alone or in combination, that contain 1-6, particularly 1-4, saturated straight-chain or branched alkyl groups, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc.

[0030] The term "replaced C" 1-6 "alkyl" refers to a C-shaped compound having at least one substituent. 1-6 Alkyl groups, wherein the substituents include hydroxyl, alkoxy, mercapto, halogen, cyano, nitro, amino, substituted amino, amide, acyl, oxyacyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, etc.

[0031] In this application, the term "heteroaryl" alone or in combination refers to one or more rings having 5 to 20 atoms, wherein at least one atom in one ring is a heteroatom selected from nitrogen, oxygen, and sulfur, and the at least one ring containing the heteroatom is further aromatic. In heteroaryls comprising two or more fused rings, the ring containing the non-heteroatom may be a carbocyclic ring.

[0032] Term "C" 3-7 "Cycloalkyl" refers to a saturated cycloalkyl group containing 3-7, especially 3-6, carbon atoms, either alone or in combination, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0033] Term "C" 1-6 "alkylamino" represents the C group alone or in combination. 1-6 Alkyl-N-, where "C" 1-6 The definition of "alkyl" is as described above. "C" 1-6 Alkylamino compounds include methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino, etc.

[0034] Term "C" 1-6 "alkyloxy" represents the group C alone or in combination. 1-6 alkyl-O-, where "C" 1-6 The definition of "alkyl" is as described above. "C" 1-6 Alkyloxy groups include (but are not limited to): methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), n-pentoxy (-OCH2CH2CH2CH2CH3), neopentoxy (-OCH2C(CH3)3), etc.

[0035] Term "C" 1-6 "alkyl mercapto" represents the group C alone or in combination. 1-6 Alkyl-S-, where "C" 1-6 The definition of "alkyl" is as described above. "C" 1-6 "Alkyl mercapto" includes, but is not limited to: methyl mercapto (-SCH3), ethyl mercapto (-SCH2CH3), n-propanyl mercapto (-SCH2CH2CH3), isopropanyl mercapto (-SCH(CH3)2), n-butyl mercapto (-SCH2CH2CH2CH3), sec-butyl mercapto (-SCH(CH3)CH2CH3), isobutyl mercapto (-SCH2CH(CH3)2), tert-butyl mercapto (-SC(CH3)3), n-pentyl mercapto (-SCH2CH2CH2CH2CH3), neopentyl mercapto (-SCH2C(CH3)3), etc.

[0036] Term "C" 3-10 "Cycloalkyl" refers to a saturated cycloalkyl group containing 3-10 carbon atoms, either alone or in combination. It can exist as a monocyclic, bridged, or spirocyclic ring, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0037] Term "C" 3-10 "Heterocyclic alkyl" refers to a cycloalkyl group containing 3-10 carbon atoms and heteroatoms, either alone or in combination. It can exist as a monocyclic, bridged, or spirocyclic ring, including aziridine, aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazine, aziridine-heptyl, 1,4-diazacycloheptyl, 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, etc.

[0038] The term "substituted methylene" refers to a methylene group having at least one substituent, including halogens, C... 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, C 1-6 Alkyloxy group, substituted C 1-6 Alkyloxy group.

[0039] The term "substituted imino" refers to an imino group having at least one substituent, including halogens, C... 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, C 1-6 Alkyloxy group, substituted C 1-6 Alkyloxy group.

[0040] The term "substituted heteroaryl" refers to a heteroaryl group having at least one substituent; the term "substituted C" refers to a heteroaryl group having at least one substituent. 3-7 "Cycloalkyl" refers to a C-type compound having at least one substituent. 3-7 cycloalkyl; term "substituted C 1-6 "alkylamino" refers to a C-type amino group having at least one substituent. 1-6 Alkylamino; term "substituted C 1-6 "alkyloxy" refers to a C-type compound having at least one substituent. 1-6 Alkyloxy; term "substituted C 1-6 "alkyl mercapto" refers to a C group having at least one substituent. 1-6 Alkyl mercapto; term "substituted C 3-10 "Cycloalkyl" refers to a C-type compound having at least one substituent. 3-10 cycloalkyl; term "substituted C 3-10 "Heterocyclic alkyl" refers to a C-shaped compound having at least one substituent. 3-10 Heterocyclic alkyl; the term "optionally substituted sulfonyl" refers to an unsubstituted sulfonyl group or a sulfonyl group having at least one substituent; the term "optionally substituted phosphoryl" refers to an unsubstituted phosphoryl group or a phosphoryl group having at least one substituent. In the above explanations, the substituents include hydroxyl, alkyl, alkoxy, mercapto, halogen, cyano, nitro, amino, substituted amino, amide, acyl, oxyacyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, etc.

[0041] In this application, the term "pharmaceutically acceptable salt" means that the compounds of this application exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. In this application, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compounds of this application with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, homosine, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. A pharmaceutically acceptable non-toxic base addition salt means a salt formed by the compounds of this application with an organic or inorganic base, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as base salts formed by reacting with an organic base containing an N group or N... + (C 1-6 Alkyl)4 salt; the organic or inorganic base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, tetrabutylammonium hydroxide, etc. "Pharmaceutically acceptable salts" can be synthesized by common chemical methods.

[0042] In this application, the term "pharmaceuticalally acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceuticalally acceptable carrier" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness to the patient. The carriers include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0043] In this application, the term "isomer" encompasses all isomeric forms, including enantiomers, diastereomers, tautomers, and geometric isomers, including cis-trans isomers. Therefore, any single stereochemical isomer of the compound designed in this application, or a mixture of its enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), falls within the scope of this application.

[0044] In this application, the term "solvent" refers to an association formed by one or more solvent molecules and the compound of this application. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0045] In this application, the term "hydrate" refers to a complex formed by water and the compounds described in this application.

[0046] In this application, the term "prodrug" refers to a chemical derivative of the compound of this application, which is converted into the compound represented by general formula I in vivo through a chemical reaction.

[0047] In this application, the term "isotope derivative" refers to isotope derivatives obtained by replacing hydrogen atoms in general formula I with 1-6 deuterium atoms, and isotope derivatives obtained by replacing carbon atoms in general formula I with 1-3 carbon-14 atoms.

[0048] In summary, this application has the following beneficial effects:

[0049] This application provides an azaindole compound that exhibits good inhibitory activity against BCR-ABL-T315I and BCR-ABL-WT transfected Ba / F3 cells. It can be used as a BCR-ABL inhibitor and is expected to be developed into a drug for the treatment and / or prevention of BCR-ABL-related diseases. Detailed Implementation

[0050] All raw materials, reagents, solvents, etc. involved in this application can be obtained commercially. The abbreviations of each raw material are shown in Table 2 below.

[0051] Table 2. Chinese names and abbreviations of the raw materials involved in this application.

[0052] The following describes the general experimental conditions in the embodiments of this application.

[0053] In a specific embodiment of this application, the intermediate and the final product are separated and purified by a chromatographic column, a preparative chromatographic plate and a rapid preparative chromatographic system. The LC-MS instrument is an Agilent 1200 equipped with a G1315C DAD or G1315D DAD Detector, and the mass spectrometry (MS) uses an ESI source.

[0054] In a specific embodiment of this application, the prep-HPLC detection conditions are as follows: flow rate of 1.0 mL / min, detection wavelengths of 220 nm and 254 nm, and a gradient elution method using the mobile phase. The elution conditions are shown in Table 3 below.

[0055] Table 3 Gradient elution conditions

[0056] Furthermore, nuclear magnetic resonance (NMR) spectra were obtained using a 400 MHz NMR spectrometer, typically with CDCl3 or DMSO-d6 as solvents, and chemical shifts (δ) were reported in ppm (parts per million). The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). Coupling constants are expressed in Hz (Hertz).

[0057] The present application will be further described in detail below with reference to the embodiments and performance test results.

[0058] Example 1

[0059] Example 1 provides an N-[4-(chlorodifluoromethoxy)phenyl]-1H-7-azaindole-2-carboxamide (compound 1), with the following structural formula:

[0060] The preparation method of compound 1 is as follows: 1H-7-azaindole-2-carboxylic acid (CAS No. 136818-50-3, 50 mg, 0.31 mmol) was dissolved in 5 mL of DMF, and 4-(chlorodifluoromethoxy)aniline (CAS No. 3965-95-7, 71.60 mg, 0.37 mmol), HATU (175 mg, 0.46 mmol), and DIPEA (0.13 mL, 0.76 mmol) were added. The mixture was heated to 40 °C and stirred for 12 h. After the reaction was completed, 5 mL of water was added to quench the reaction mixture, followed by extraction with EA. The organic phases were combined and washed with NH4Cl and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid compound 1 (76.00 mg, yield: 73.00%).

[0061] The test results are as follows: MS(ESI) m / z = 338.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.31 (s, 1H), 10.45 (s, 1H), 8.39-8.37 (m, 1H), 8 .16-8.13(m, 1H), 7.94-7.91(m, 2H), 7.41-7.37(m, 3H), 7.17-7.14(m, 1H).

[0062] Example 2

[0063] Example 2 provides a 6-chloro-N-[4-(chlorodifluoromethoxy)phenyl]-1H-7-azaindole-2-carboxamide (compound 2), with the following structural formula:

[0064] The preparation method of the above compound 2 is as follows: using 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (CAS No. 800402-07-7, 1g, 5.08mmol) as raw material, it was prepared according to the method of Example 1 to obtain white solid compound 2 (1.4g, yield 73.96%).

[0065] The test results are as follows: MS(ESI) m / z = 371.8 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.60 (s, 1H), 10.51 (s, 1H), 8.23 ​​(d, J=8.0Hz, 1H), 7. 92 (d, J=8.0Hz, 2H), 7.46 (s, 1H), 7.39 (d, J=8.0Hz, 2H), 7.23 (d, J=8.0Hz, 1H).

[0066] Example 3

[0067] Example 3 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(3-hydroxypyrrolidone-1-yl)-1H-7-azaindole-2-carboxamide (compound 3), with the following structural formula:

[0068] The preparation method of compound 3 is as follows: Compound 2 (80.00 mg, 0.22 mmol), 0.25 mL of 3-hydroxypyrrolidine (CAS No. 40499-83-0), and 3 mL of NMP were added to a dry microwave tube, and then the temperature was raised to 220 °C and the reaction was stirred for 0.5 h. After the reaction was completed, 5 mL of water was added to quench the reaction solution, and then it was extracted with EA. The organic phases were combined and washed with NH4Cl and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 3 (49.90 mg, yield 55.01%).

[0069] The test results are as follows: MS(ESI) m / z = 423.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ11.53 (s, 1H), 10.01 (s, 1H), 7.90-7.87 (m, 2H), 7.80 (d, J = 8.8Hz, 1H), 7.34 (d, J = 8.0Hz, 2H), 7.19 (d, J = 2.0Hz, 1H), 6.40 (d, J=8.8Hz, 1H), 4.96 (d, J=3.6Hz, 1H), 4.41 (s, 1H), 3.56-3.50 (m, 3H), 3.38 (d, J=8.0Hz, 1H), 2.06-2.02 (m, 1H), 1.92 (s, 1H).

[0070] Example 4

[0071] Example 4 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-[(2-hydroxyethyl)amino]-1H-7-azaindole-2-carboxamide (compound 4), with the following structural formula:

[0072] The preparation method of compound 4 is as follows: compound 2 (200.00 mg, 0.54 mmol), 0.30 mL of 2-aminoethanol (CAS No. 141-43-5) and 3 mL of NMP were added to a dry microwave tube and prepared according to a method similar to Example 3 to obtain yellow solid compound 4 (19.19 mg, yield 9.00%).

[0073] The test results are as follows: MS(ESI) m / z = 396.9 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ11.49 (s, 1H), 9.99 (s, 1H), 7.88 (d, J = 12.0Hz, 2H), 7.66 (d, J = 8.0Hz, 1H), 7.34 (d, J = 8.0Hz, 2H), 7.15 (s, 1H), 6.75 (t, J=4.0Hz, 1H), 6.41 (d, J=8.0Hz, 1H), 4.72 (t, J=8.0Hz, 1H), 3.60-3.55 (m, 2H), 3.40 (t, J=4.0Hz, 2H).

[0074] Example 5

[0075] Example 5 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methylthio)-1H-7-azaindole-2-carboxamide (compound 5), with the following structural formula:

[0076] The preparation method of compound 5 is as follows: compound 2 (500.00 mg, 0.27 mmol), sodium methanethiol (CAS No. 5188-07-8, 470.80 mg, 6.72 mmol) and 3 mL NMP were added to a dry microwave tube and prepared according to a method similar to Example 3 to obtain white solid compound 5 (50.00 mg, yield 9.70%).

[0077] The test results are as follows: MS(ESI) m / z = 384.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ10.36 (s, 1H), 8.46 (s, 1H), 7.99 (d, J=8.0Hz, 1H), 7.91 (d, J =8.0Hz, 2H), 7.38 (d, J = 12.0Hz, 2H), 7.35 (s, 1H), 7.06 (d, J = 8.0Hz, 1H), 2.59 (s, 3H).

[0078] Example 6

[0079] Example 6 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 6), with the following structural formula:

[0080] The preparation method of compound 6 is as follows: Compound 5 (50 mg, 0.13 mmol) and Oxone (321 mg, 0.52 mmol) were dissolved in a mixed solvent of 8 mL isopropanol and 4 mL water, and reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under vacuum, and then quenched with 5 mL of water. The mixture was extracted with EA, the organic phases were combined and washed with NH4Cl and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 6 (31.81 mg, yield 58.72%).

[0081] The test results are as follows: MS(ESI) m / z = 415.9 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.98 (s, 1H), 10.65 (s, 1H), 8.51 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 2H), 7.83 (d, J=8.0Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 3.31 (s, 3H).

[0082] Example 7

[0083] Example 7 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methylamino)-1H-7-azaindole-2-carboxamide (compound 7), with the following structural formula:

[0084] The preparation method of compound 7 is as follows:

[0085] (1) Preparation of intermediate 7-2: Methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (CAS No. 1140512-58-8, 1.00 g, 4.75 mmol) was dissolved in 20 mL of DCM. IPC-TBA-HS (162 mg, 0.48 mmol) and NaOH (476 mg, 11.87 mmol) were added under ice bath conditions, and the mixture was stirred for 10 min. p-Toluenesulfonyl chloride (CAS No. 98-59-9, 1.36 g, 7.12 mmol) was dissolved in 5 mL of DCM. The above reaction solution was added under ice bath conditions, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, EA was added for extraction and separation. The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 7-2 (1.46 g, yield: 84.29%). The reaction formula is as follows:

[0086] (2) Preparation of intermediate 7-3: Compound 7-2 (1.00 g, 2.74 mmol), tert-butyl carbamate (CAS No. 4248-19-5, 1.61 g, 13.70 mmol), cesium carbonate (2.68 g, 8.22 mmol), palladium acetate (123 mg, 0.55 mmol), and X-PHOS (523.00 mg, 1.10 mmol) were dissolved in 10 mL of dioxane (CAS No. 123-91-1). The mixture was heated to 80 °C under argon protection and refluxed for 1 h. Then, it was cooled to room temperature, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 7-3 (1.20 g, yield: 98.26%). The reaction formula is as follows:

[0087] (3) Preparation of intermediate 7-4: Under nitrogen protection and in an ice bath, compound 7-3 (0.70 g, 1.60 mmol) was added to 2 mL of tetrahydrofuran solution containing sodium hydride (94.00 mg, 2.35 mmol), and the mixture was stirred for 15 min. Then, iodomethane (447.00 mg, 3.15 mmol) was added, and the mixture was slowly heated to room temperature and stirred for 1 h. After the reaction was complete, water and EA were added, the mixture was extracted and separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid 7-4 (150.00 mg, yield: 20.10%). The reaction formula is as follows:

[0088] (4) Preparation of intermediate 7-5: Compound 7-4 (150.00 mg, 0.33 mmol) was dissolved in 10 mL THF and 2 mL water, and lithium hydroxide (39.00 mg, 0.98 mmol) was added. The mixture was heated to 40 °C and stirred for 16 min. After the reaction was complete, 10 mL water and 10 mL EA were added, and the mixture was extracted and separated. The pH of the aqueous layer was adjusted to 8 with citric acid, and EA was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid crude product 7-5 (110 mg). The reaction formula is as follows:

[0089] (5) Preparation of intermediate 7-6: Using compound 7-5 (110.00 mg, 0.38 mmol) and 4-(chlorodifluoromethoxy)aniline (CAS No. 39065-95-7, 48.00 mg, 0.38 mmol) as starting materials, intermediate 7-6 was prepared by a method similar to that in Example 1, yielding a white solid 7-6 (48 mg, yield: 41.70%). The reaction formula is as follows:

[0090] (6) Preparation of compound 7: Compound 7-6 (48 mg, 0.1 mmol) was dissolved in 20 mL of 1,4-dioxane hydrochloric acid solution (CAS No. 7647-01-0) and reacted at 30 °C for 4 h. After the reaction was completed, the reaction solution was concentrated and then purified by high performance liquid chromatography (HPLC) to obtain a white solid compound 7 (23.72 mg, yield: 65%).

[0091] The test results are as follows: MS(ESI) m / z = 366.9 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ11.51 (s, 1H), 9.99 (s, 1H), 7.88 (d, J=4.0Hz, 2H), 7.66 (d, J=8.0Hz, 1H), 7. 34 (d, J=8.0Hz, 2H), 7.16 (s, 1H), 6.73 (d, J=4.0Hz, 1H), 6.36 (d, J=8.0Hz, 1H), 2.83 (d, J=4.0Hz, 3H).

[0092] Example 8

[0093] Example 8 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methoxy)-1H-7-azaindole-2-carboxamide (compound 8), with the following structural formula:

[0094] The preparation method of compound 8 is as follows:

[0095] (1) Preparation of intermediate 8-2: Ethyl 2-azidoethyl acetate (CAS No. 637-81-0, 575.45 mg, 5.00 mmol) and 6-methoxypyridine-3-carboxaldehyde (CAS No. 65873-72-5, 685.68 mg, 5.00 mmol) were added to 8 mL of methanol and stirred at -10 °C for 2 h. After the reaction was completed, the reaction solution was poured into a mixture of ice and NH4Cl solid and stirred until the ice was completely melted. The reaction solution was filtered, washed with ice water and dried. The crude product was then dissolved in DCM, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain a white solid 8-2 (830 mg, yield: 70.88%). The reaction formula is as follows:

[0096] (2) Preparation of intermediate 8-3: Compound 8-2 (468.42 mg, 2.00 mmol) was dissolved in mesitylene (CAS No. 108-67-8), refluxed at 180 °C for 1 h, then cooled to 0 °C, filtered, washed with petroleum ether, and dried to give a white solid 8-3 (280 mg, yield: 67.90%). The reaction formula is as follows:

[0097] (3) Preparation of intermediate 8-4: Compound 8-3 (257.75 mg, 1.25 mmol) and sodium hydroxide (150 mg, 3.75 mmol) were dissolved in 12.5 mL of water and 12.5 mL of ethanol. The mixture was refluxed at 100 °C for 2 h, then cooled to room temperature. The reaction solution was acidified with 1 M HCl, rotary evaporated, washed with water and dichloromethane, and dried to obtain a white solid 8-4 (205 mg, yield: 85.34%). The reaction formula is as follows:

[0098] (4) Preparation of compound 8: Compound 8-4 (168 mg, 0.87 mmol), 4-(chlorodifluoromethoxy)aniline (CAS No. 39065-95-7, 169.23 mg, 0.87 mmol), and DMAP (10.68 mg, 0.09 mmol) were dissolved in DCM under ice bath conditions. EDCl (251.38 mg, 1.31 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was washed with water, extracted with DCM, dried over anhydrous sodium sulfate, and purified to obtain a white solid compound 8 (186 mg, yield: 57.86%).

[0099] The test results are as follows: MS(ESI) m / z = 353.78 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): 11.52 (br, 2H), 10.24 (s, 1H), 7.91-7.88 (m, 3H), 7.37-7.34 (m, 2H), 7.28 (s, 1H), 6.37 (d, J=8.0Hz, 1H).

[0100] Example 9

[0101] Example 9 provides a 4-chloro-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methylthio)-1H-7-azaindole-2-carboxamide (compound 9), with the following structural formula:

[0102] The preparation method of compound 9 is as follows:

[0103] (1) Preparation of intermediate 9-2: Methyl 4-chloro-1H-7-azaindole-2-carboxylate (CAS No. 871583-23-2, 20.0 g, 95 mmol) was dissolved in 200 mL of DCM. 85% M-CPBA (38.6 g, 189.8 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8. The mixture was extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 9-2 (21 g, yield: 98%). The reaction formula is as follows:

[0104] (2) Preparation of intermediate 9-3: Compound 9-2 (42 g, 185.4 mmol) was dissolved in 840 mL of CAN, and PyBrOP (103.8 g, 222.6 mmol) and DIPEA (91.8 mL, 556.2 mmol) were added. 10% methanethiol (210 mL, 463.2 mmol) was added under ice bath conditions, and the mixture was stirred at 20 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under vacuum, and EA and water were added. The mixture was extracted and separated. The aqueous phase was extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with MeCN to obtain a yellow solid 9-3 (31.2 g, yield: 66%). The reaction formula is as follows:

[0105] (3) Preparation of compound 9: Using compound 9-3 (500 mg, 1.85 mmol) as raw material, compound 9 was prepared by a method similar to steps (3)-(4) in Example 8 to obtain a yellow solid compound 9 (278.55 mg, yield: 36%).

[0106] The test results are as follows: MS(ESI) m / z = 417.8 [M+H] + . 1 H NMR (CDCl3, 400MHz): δ9.57 (s, 1H), 7.88 (s, 1H), 7.72-7.69 (m, 2H), 7.29-7.26 (m, 2H), 7.09 (s, 1H), 7.00 (s, 1H), 2.63 (s, 3H).

[0107] Example 10

[0108] Example 10 provides an N-[4-(chlorodifluoromethoxy)phenyl]-3-methyl-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 10), with the following structural formula:

[0109] The preparation method of compound 10 is as follows:

[0110] (1) Preparation of intermediate 10-1: Methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (CAS No. 1140512-58-8; 1.30 g, 6.2 mmol) was dissolved in 20 mL MeCN, and NIS (1.5 g, 6.82 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 40 °C. The crude product was purified by silica gel column chromatography to obtain a yellow solid 10-1 (1.9 g, yield: 91.07%). The reaction formula is as follows:

[0111] (2) Preparation of intermediate 10⁻²: Compound 10⁻¹ (1.9 g, 5.7 mmol) was dissolved in 30 mL of DMF. Sodium hydride (150 mg, 6.27 mmol) was added under ice bath conditions, and the mixture was stirred for 1 h under ice bath conditions. Then, SEMCl (1.05 g, 6.27 mmol) was added, and the mixture was stirred for 5 h at room temperature. After the reaction was complete, water and EA were added, and the mixture was extracted and separated. The organic phases were combined and concentrated under reduced pressure at 40 °C. The crude product was purified by silica gel column chromatography to obtain a yellow oily substance 10⁻² (2.5 g, yield: 93.96%). The reaction formula is as follows:

[0112] (3) Preparation of intermediate 10⁻³: Compound 10⁻² (300 mg, 0.64 mmol) was dissolved in 10 mL of DMF, and MeSNa (CAS No. 5188-07-8; 179 mg, 2.56 mmol) was added at room temperature. The mixture was heated to 90 °C and stirred overnight. After the reaction was complete, water and EA were added, and the mixture was extracted and separated. The organic phases were combined and concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography to obtain a yellow solid 10⁻³ (270 mg, yield: 87.50%). The reaction formula is as follows:

[0113] (4) Preparation of intermediate 10⁻⁴: Compound 10⁻⁃ (270 mg, 0.56 mmol) was dissolved in 10 mL of DMF, and OXONE (CAS No. 37222-66-5; 1.4 g, 2.24 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, water and EA were added, and the mixture was extracted and separated. The organic phases were combined and concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography to obtain a yellow solid 10⁻⁴ (260 mg, yield: 91.07%). The reaction formula is as follows:

[0114] (5) Preparation of intermediate 10-5: Compound 10-4 (260 mg, 0.51 mmol), potassium methyltrifluoroborate (CAS No. 13862-28-7, 93 mg, 0.77 mmol), palladium acetate (11.5 mg, 0.051 mmol), and n-butyldi(1-adamantyl)phosphine (CAS No. 321921-71-5, 6.5 mg, 0.102 mmol) were dissolved in 6 mL of Tol and 2 mL of water. Potassium carbonate (211 mg, 1.53 mmol) was added, and the mixture was heated to 80 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 45 °C. The crude product was purified by silica gel column chromatography to obtain a yellow solid 10-5 (187 mg, yield: 93%). The reaction formula is as follows:

[0115] (6) Preparation of intermediate 10⁻⁶: Compound 10⁻⁵ (187 mg, 0.47 mmol) was dissolved in 6 mL of methanol and 2 mL of water, and sodium hydroxide (94 mg, 2.35 mmol) was added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 45 °C, the pH was adjusted to 6 by adding 0.5 N HCl, EA was added, the mixture was extracted and separated, the organic phases were combined, and the solution was concentrated under reduced pressure at 45 °C to obtain a yellow oily substance 10⁻⁶ (177 mg, yield 98.41%). The reaction formula is as follows:

[0116] (7) Preparation of intermediate 10-7: Using compound 10-6 (177 mg, 0.46 mmol) as a starting material, intermediate 10-7 was prepared according to a method similar to that in Example 1 to obtain a yellow solid 10-7 (160 mg, yield: 63.04%). The reaction formula is as follows:

[0117] (8) Preparation of compound 10: Compound 10-7 (160 mg, 0.29 mmol) was dissolved in 2 mL of DCM, and 5 mL of TFA was added. The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 45 °C and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a white solid compound 10 (52.51 mg, yield: 41.38%).

[0118] The test results are as follows: MS(ESI) m / z = 430.0 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.59 (s, 1H), 10.35 (s, 1H), 8.45 (d, J=8.0Hz, 1H), 7.88 (d, J=9.2Hz, 2H), 7.80 (d, J=8.0Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 3.31 (s, 3H), 2.58 (s, 3H).

[0119] Example 11

[0120] Example 11 provides an N-[4-(chlorodifluoromethoxy)phenyl]-3-ethyl-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 11), with the following structural formula:

[0121] The preparation method of compound 11 is as follows:

[0122] (1) Preparation of intermediate 11-1: Using compound 10-2 (2.0 g, 4.3 mmol) as a starting material, a yellow oily substance 11-1 (1.7 g, yield: 87.21%) was prepared according to a method similar to step (6) of Example 10. The reaction formula is as follows:

[0123] (2) Preparation of intermediate 11-2: Using compound 11-1 (1.7 g, 3.75 mmol) as a starting material, intermediate 11-2 was prepared according to a method similar to that in Example 1 to obtain a yellow solid 11-2 (1.3 g, yield: 55.46%). The reaction formula is as follows:

[0124] (3) Preparation of intermediate 11-3: Using compound 11-2 (600 mg, 0.96 mmol) and potassium trifluoro(vinyl)borate (CAS No. 13682-77-4, 258 mg, 1.92 mmol) as raw materials, intermediate 11-3 was prepared by a method similar to step (5) of Example 10, yielding a yellow solid 11-3 (400 mg, yield: 79.17%). The reaction formula is as follows:

[0125] (4) Preparation of intermediate 11-4: Compound 11-3 (400 mg, 0.76 mmol) was dissolved in 4 mL of EA, and platinum dioxide (26 mg) was added. The mixture was stirred overnight at room temperature under hydrogen protection. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure at 45 °C to obtain a yellow oily substance 11-4 (350 mg, yield: 86.84%). The reaction formula is as follows:

[0126] (5) Preparation of intermediate 11-5: Using compound 11-4 (350 mg, 0.66 mmol) as a starting material, intermediate 11-5 was prepared according to a method similar to steps (3)-(4) of Example 10, yielding a yellow solid 11-5 (280 mg, yield: 74.24%). The reaction formula is as follows:

[0127] (5) Preparation of compound 11: Using compound 11-5 (280 mg, 0.49 mmol) as raw material, compound 11 was prepared by a method similar to step (8) of Example 10 to obtain white solid compound 11 (77.92 mg, yield: 35.83%).

[0128] The test results are as follows: MS(ESI) m / z = 444.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.60 (s, 1H), 10.40 (s, 1H), 8.49 (d, J=8.0Hz, 1H), 7.88 (d, J=7.2Hz, 2H), 7. 80 (d, J=8.0Hz, 1H), 7.40 (d, J=8.8Hz, 2H), 3.31 (s, 3H), 3.09 (q, J=14.8Hz, 2H), 1.23 (t, J=7.6Hz, 3H).

[0129] Example 12

[0130] Example 12 provides an N-[4-(chlorodifluoromethoxy)phenyl]-3-cyclopropyl-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 12), with the following structural formula:

[0131] The preparation method of compound 12 is as follows:

[0132] (1) Preparation of intermediate 12-1: Using compound 11-2 (600 mg, 0.96 mmol) and potassium cyclopropyltrifluoroborate (CAS No. 1065010-87-8, 284 mg, 1.92 mmol) as raw materials, intermediate 12-1 was prepared by a method similar to step (5) of Example 10, yielding a yellow solid 12-1 (320 mg, 0.59 mmol, yield: 61.46%). The reaction formula is as follows:

[0133] (2) Preparation of intermediate 12-2: Using compound 12-1 (140 mg, 0.26 mmol) as a starting material, intermediate 12-2 was prepared according to a method similar to steps (3)-(4) of Example 10, yielding a yellow solid 12-2 (130 mg, yield: 84.62%). The reaction formula is as follows:

[0134] (3) Preparation of compound 12: Using compound 12-2 (130 mg, 0.22 mmol) as raw material, compound 12 was prepared in a manner similar to step (8) of Example 10 to obtain white solid compound 12 (44.85 mg, yield: 44.72%).

[0135] The test results are as follows: MS(ESI) m / z = 456.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.66 (s, 1H), 10.40 (s, 1H), 8.38 (d, J=8.0Hz, 1H), 7.89 (d, J=9.2Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.41 (d, J=8.8Hz, 2H), 3.29 (s, 3H), 2.50-2.49 (m, 1H), 1.05-1.03 (m, 2H), 0.85-0.84 (m, 2H).

[0136] Example 13

[0137] Example 13 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 13), with the following structural formula:

[0138] The preparation method of compound 13 is as follows:

[0139] (1) Preparation of intermediate 13-2: Ethyl 6-bromo-1H-7-azaindole-2-carboxylate (CAS No. 577711-94-5, 1.7 g, 6.32 mmol) was dissolved in 20 mL of DCM. Under nitrogen protection, (Boc)₂O (1.38 g, 6.32 mmol), DMAP (155 mg, 1.26 mmol), and TEA (1.92 g, 18.95 mmol) were added, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 13-2 (2.10 g, yield: 90.03%). The reaction formula is as follows:

[0140] (2) Preparation of intermediate 13-3: Compound 13-2 (1.30 g, 3.52 mmol) was dissolved in 10 mL of toluene. Under nitrogen protection, palladium acetate (80 mg, 0.35 mmol), XantPhos (408 mg, 0.75 mmol), cesium carbonate (2.29 g, 7.04 mmol), and benzyl mercaptan (875 mg, 7.04 mmol) were added, and the mixture was heated to 100 °C and stirred for 16 h. After the reaction was completed, the reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 13-3 (1.60 g, yield: 72.70%). The reaction formula is as follows:

[0141] (3) Preparation of intermediate 13-4: Compound 13-3 (1.60 g, 5.12 mmol) was dissolved in 20 mL of DCM. Under nitrogen protection, (Boc)₂O (1.12 g, 5.12 mmol), DMAP (126 mg, 1.02 mmol), and TEA (1.55 g, 15.37 mmol) were added, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow solid 13-4 (2.06 g, yield: 97.50%). The reaction formula is as follows:

[0142] (4) Preparation of intermediate 13-5: Compound 13-4 (2.06 g, 4.99 mmol) was dissolved in 15 mL of acetic acid and 5 mL of water, and NCS (2.00 g, 14.98 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under vacuum, and DCM and sodium bicarbonate aqueous solution were added and separated. The aqueous phase was extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 13-5 (725 mg, yield: 37.30%). The reaction formula is as follows:

[0143] (5) Preparation of intermediate 13-6: Compound 13-5 (350 mg, 0.90 mmol) was dissolved in 2 mL of DMA, and methylamine hydrochloride (468 mg, 4.5 mmol) and DIEPA (1.16 g, 9 mmol) were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under vacuum, and EA and sodium bicarbonate aqueous solution were added and separated. The aqueous phase was extracted with EA, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid 13-6 (330 mg, yield: 95.60%). The reaction formula is as follows:

[0144] (6) Preparation of intermediate 13-7: Compound 13-6 (330 mg, 0.86 mmol) was dissolved in 3 mL of methanol and 2 mL of water, and sodium hydroxide (104 mg, 2.58 mmol) was added. The reaction was carried out at room temperature for 1.1 h. After the reaction was completed, the reaction solution was concentrated under vacuum, 2 M HCl was added to adjust the pH to 3, the mixture was filtered, and the filter cake was washed with 5 mL of water and dried under vacuum to obtain a white solid 13-7 (85 mg, yield: 38.7%). The reaction formula is as follows:

[0145] (7) Preparation of compound 13: Compound 13-7 (85 mg, 0.33 mmol) was dissolved in 1 mL of DMF, and TCFH (103 mg, 0.37 mmol) and NMI (69 mg, 0.83 mmol) were added. The reaction was carried out at room temperature for 0.5 h. Then 4-(chlorodifluoromethoxy)aniline (96 mg, 0.50 mmol) was added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was filtered and concentrated, and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a white solid compound 13 (29 mg, yield 20.5%).

[0146] The test results are as follows: MS(ESI) m / z = 431.0 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.85 (s, 1H), 10.61 (s, 1H), 8.42 (d, J=8.4Hz, 1H), 7.93 (d, J=9.2Hz, 2H), 7.71 (d , J=8.0Hz, 1H), 7.61 (d, J=5.2Hz, 1H), 7.58 (d, J=4.8Hz, 1H), 7.40 (d, J=9.2Hz, 2H), 2.59 (d, J=4.4Hz, 3H).

[0147] Example 14

[0148] Example 14 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(aminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 14), with the following structural formula:

[0149] The preparation method of compound 14 is as follows:

[0150] (1) Preparation of intermediate 14-1: Compound 13-5 (200 mg, 0.51 mmol) was added to a 1,4-dioxane solution of 400 mM ammonia (20 mL), and the mixture was stirred for 16 h. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a white solid 14-1 (140 mg, yield: 73.7%). The reaction formula is as follows:

[0151] (2) Preparation of compound 14: Using compound 14-1 (140 mg, 0.38 mmol) as raw material, compound 14 was prepared by a method similar to steps (6)-(7) of Example 13 to obtain white solid compound 14 (5 mg, yield: 15.4%).

[0152] The test results are as follows: MS(ESI) m / z = 417.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.81 (s, 1H), 10.61 (s, 1H), 8.40 (d, J=8.0Hz, 1H), 7.93 (d, J=8.4Hz, 2H), 7.74 (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.49-7.34 (m, 4H).

[0153] Example 15

[0154] Example 15 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(N,N-dimethylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 15), with the following structural formula:

[0155] The preparation method of compound 15 is as follows:

[0156] (1) Preparation of intermediate 15-2: Methyl 7-azaindole-2-carboxylate (CAS No. 94223-02-0, 2.00 g, 11.35 mmol) was dissolved in 30 mL of DCM. 85% M-CPBA (4.61 g, 22.71 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, 5 mL of saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 7–8. 50 mL of DCM and 20 mL of water were added. The aqueous phase was extracted three times with 30 mL of DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 15-2 (2.1 g, yield: 96%). The reaction formula is as follows:

[0157] (2) Preparation of intermediate 15-3: Compound 15-2 (2.00 g, 10.41 mmol), PyBrOP (5.82 g, 12.49 mmol), and DIEPA (5.16 mL, 31.22 mmol) were dissolved in 40 mL MeCN. Benzyl mercaptan (3.88 g, 31.22 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated under vacuum, and 50 mL of EA and 20 mL of water were added. The aqueous phase was extracted three times with 20 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow solid 15-3 (1.5 g, yield: 48%). The reaction formula is as follows:

[0158] (3) Preparation of intermediate 15-4: Compound 15-3 (500 mg, 1.68 mmol) was dissolved in 6 mL AcOH and 2 mL water. NCS (671 mg, 5.03 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under vacuum, and 6 mL DCM and 2 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted three times with 20 mL DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 15-4 (450 mg, yield: 97%). The reaction formula is as follows:

[0159] (4) Preparation of intermediate 15-5: 5 mL of a THF solution of compound 15-4 (450 mg, 1.64 mmol) was added dropwise to a 2M dimethylamine (4.10 mL, 8.19 mmol) solution in an ice-water bath, and the reaction was carried out for 1 h in an ice-water bath. After the reaction was complete, 10 mL of EA and 5 mL of water were added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted three times with 5 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow solid 15-5 (320 mg, yield: 60%). The reaction formula is as follows:

[0160] (5) Preparation of intermediate 15-6: Compound 15-5 (200 mg, 0.71 mmol) was dissolved in 2 mL of 6 M aqueous solution and 2 mL of 1,4-dioxane, and the mixture was heated to 80 °C and reacted for 16 h. After the reaction was completed, the reaction solution was concentrated under vacuum to obtain a light blue solid 15-6 (180 mg, yield: 95%). The reaction formula is as follows:

[0161] (6) Preparation of compound 15: Compound 15-6 (100 mg, 0.37 mmol), DIEPA (184 μL, 1.11 mmol), and HOBT (55 mg, 0.41 mmol) were dissolved in 500 μL of DMF. EDCl hydrochloride (93 mg, 0.48 mmol) was added under ice bath conditions, and the reaction was allowed to proceed for 15 min. Then, 4-(chlorodifluoromethoxy)aniline (79 mg, 0.41 mmol) was added under ice bath conditions, and the reaction was allowed to proceed for 16 h at room temperature. After the reaction was complete, the reaction solution was filtered and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 15 (51.38 mg, yield: 28%).

[0162] The test results are as follows: MS(ESI) m / z = 445.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.91 (s, 1H), 10.63 (s, 1H), 8.46 (d, J=8.0Hz, 1H), 7.93 (d, J =12.0Hz, 2H), 7.79 (d, J = 8.0Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.0Hz, 2H), 2.83 (s, 6H).

[0163] Example 16

[0164] Example 16 provides a 4-(azacyclobutane-1-ylmethyl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 16), with the following structural formula:

[0165] The preparation method of compound 16 is as follows:

[0166] (1) Preparation of intermediate 16-2: Azacyclobutane (CAS No. 503-29-7, 853 mg, 14.94 mmol) was dissolved in 20 mL of THF, and TEA (2.77 mL, 19.92 mmol) and potassium trifluoro(bromomethyl)borate (2.0 g, 9.96 mmol) were added. The reaction was carried out at 20 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and washed with 20 mL of Et2O to obtain a white solid 16-2 (1.5 g, yield: 56.72%). The reaction formula is as follows:

[0167] (2) Preparation of intermediate 16-3: Compound 9-3 (500 mg, 1.85 mmol) was dissolved in 20 mL of 1,4-dioxane and 2 mL of water. Compound 16-2 (328 mg, 1.85 mmol), palladium acetate (83 mg, 0.37 mmol), X-PHOS (353 mg, 0.74 mmol), and cesium carbonate (1.81 g, 5.55 mmol) were added. The mixture was heated to 100 °C and reacted for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow solid 16-3 (400 mg, yield: 74.2%). The reaction formula is as follows:

[0168] (3) Preparation of intermediate 16-4: Compound 16-3 (350 mg, 1.20 mmol) was dissolved in 10 mL of DCM, and 85% M-CPBA (622 mg, 3.60 mmol) was added. The reaction was carried out at 20 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a yellow solid 16-4 (200 mg, yield: 49%). The reaction formula is as follows:

[0169] (4) Preparation of intermediate 16-5: Compound 16-4 (200 mg, 0.59 mmol) was dissolved in 10 mL of CAN, and Pin2B2 (224 mg, 0.88 mmol) was added. The reaction was carried out at 75 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a yellow solid 16-5 (100 mg, yield: 52.47%). The reaction formula is as follows:

[0170] (5) Preparation of intermediate 16-6: Compound 16-5 (100 mg, 0.31 mmol) was dissolved in 1 mL of water and 10 mL of methanol, and lithium hydroxide monohydrate (50 mg, 1.19 mmol) was added. The reaction was carried out at 20 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a white solid 16-6 (20 mg, yield: 20.8%). The reaction formula is as follows:

[0171] (6) Preparation of compound 16: Compound 16-6 (20 mg, 0.065 mmol) was dissolved in 5 mL of DMF, and TCFH (22 mg, 0.078 mmol) and NMI (13 mg, 0.16 mmol) were added. The reaction was allowed to proceed for 15 min. Then, 4-(chlorodifluoromethoxy)aniline (14 mg, 0.071 mmol) was added under nitrogen protection, and the reaction was allowed to proceed for 16 h at room temperature. After the reaction was completed, the reaction solution was filtered and concentrated, and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a white solid compound 16 (4.5 mg, yield: 13.3%).

[0172] The test results are as follows: MS(ESI) m / z = 485.4 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.95 (s, 1H), 10.69 (s, 1H), 7.95 (d, J=9.2Hz, 2H), 7.76 (s, 1H), 7.69 (s , 1H), 7.41 (d, J=8.8Hz, 2H), 4.00 (s, 2H), 3.30 (s, 3H), 3.26 (t, J=6.8Hz, 4H), 2.11-2.03 (m, 2H).

[0173] Example 17

[0174] Example 17 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3,3-difluoroazacyclobut-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 17), with the following structural formula:

[0175] The preparation method of compound 17 is as follows:

[0176] (1) Preparation of intermediate 17-2: Using 3,3-difluoroazacyclobutane hydrochloride (CAS No. 288315-03-7, 3.8 g, 29.88 mmol) as the starting material, it was prepared according to a method similar to that in Example 16, yielding a white solid 17-2 (4.2 g, yield: 94%). The reaction formula is as follows:

[0177] (2) Preparation of compound 17: Using compound 17-2 (996 mg, 4.67 mmol) and compound 9-3 (996 mg, 4.67 mmol) as raw materials, compound 17 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 17 (27.3 mg, yield: 16%).

[0178] The test results are as follows: MS(ESI) m / z = 521.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.02 (s, 1H), 10.69 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.78 (s, 1H) ), 7.65 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 4.23 (s, 2H), 3.75 (t, J=16.0Hz, 4H), 3.30 (s, 3H).

[0179] Example 18

[0180] Example 18 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3,3-difluoroazacyclobut-1-yl)methyl]-6-(ethylsulfonyl)-1H-7-azaindole-2-carboxamide (compound 18), with the following structural formula:

[0181] The preparation method of compound 18 is as follows:

[0182] (1) Preparation of intermediate 18-1: Compound 9-2 (1 g, 4.41 mmol), DIPEA (2.21 mL, 13.24 mmol), and PyBrOP (2.7 g, 5.74 mmol) were dissolved in 10 mL MeCN. Ethyl mercaptan (1.01 mL, 13.24 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated under vacuum, and 20 mL of EA and 20 mL of water were added. The mixture was extracted and separated. The aqueous phase was extracted three times with 20 mL of EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with MeCN to obtain a yellow solid 18-1 (530 mg, yield: 44%). The reaction formula is as follows:

[0183] (2) Preparation of compound 18: Compound 18-1 (480 mg, 1.77 mmol) and compound 17-2 (1.13 g, 5.32 mmol) were used as raw materials and prepared according to the method similar to steps (2)-(6) of Example 16 to obtain white solid compound 18 (42.89 mg, yield: 33%).

[0184] The test results are as follows: MS(ESI) m / z = 535.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.02 (s, 1H), 10.70 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.79 (s, 1H), 7.68 (s, 1H), 7 .42 (d, J=12.0Hz, 2H), 4.24 (s, 2H), 3.76 (t, J=12.0Hz, 4H), 3.44 (q, J=8.0Hz, 2H), 1.16 (t, J=8.0Hz, 3H).

[0185] Example 19

[0186] Example 19 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-hydroxy-3-methylazacyclobut-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 19), with the following structural formula:

[0187] The preparation method of compound 19 is as follows:

[0188] (1) Preparation of intermediate 19-2: Using 3-methylazacyclobutane-3-ol (CAS No. 256931-54-1, 2.0 g, 9.96 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 19-2 (2.0 g, yield: 97%). The reaction formula is as follows:

[0189] (2) Preparation of compound 19: Using compound 19-2 (1.21 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 19 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 19 (7.77 mg, yield: 15%).

[0190] The test results are as follows: MS(ESI) m / z = 515.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.97 (s, 1H), 10.67 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.74 (s, 1H), 7.68 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 5.26 (s, 1H), 4.06 (s, 2H), 3.30-3.28 (m, 5H), 3.04 (d, J=8.0Hz, 2H), 1.42 (s, 3H).

[0191] Example 20

[0192] Example 20 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-4-(pyrrolidone-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 20), with the following structural formula:

[0193] The preparation method of compound 20 is as follows:

[0194] (1) Preparation of intermediate 20-2: Using tetrahydropyrrolidine (CAS No. 123-75-1, 1.59 g, 22.41 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white solid 20-2 (2.0 g, yield: 88%). The reaction formula is as follows:

[0195] (2) Preparation of compound 20: Using compound 20-2 (389 mg, 2.04 mmol) and compound 9-3 (475 mg, 1.85 mmol) as raw materials, compound 20 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 20 (16 mg, yield: 3.4%).

[0196] The test results are as follows: MS(ESI) m / z = 499.4 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.97 (s, 1H), 10.65 (s, 1H), 8.13 (s, 1H), 7.94-7.91 (m, 2H), 7.83 (s, 1H), 7.69 (s, 1H), 7.40 (d, J=8.8Hz, 2H), 4.12 (s, 2H), 3.30 (s, 3H), 2.67-2.63 (m, 4H), 1.80-1.77 (m, 4H).

[0197] Example 21

[0198] Example 21 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-hydroxypyrrolidone-1-yl)methyl]-6-(methylsulfonyl)-1H-7-azaindole-2-carboxamide (compound 21), with the following structural formula:

[0199] The preparation method of compound 21 is as follows:

[0200] (1) Preparation of intermediate 21-2: Using 3-hydroxytetrahydropyrrolidine (CAS No. 40499-83-0, 1.30 g, 14.9 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 21-2 (2.0 g, yield: 97%). The reaction formula is as follows:

[0201] (2) Preparation of intermediate 21-3: Using compound 9-3 (500 mg, 1.95 mmol) and compound 21-2 (1.21 g, 5.84 mmol) as raw materials, intermediate 21-3 was prepared by a method similar to steps (2)-(5) of Example 16, yielding a brown solid 21-3 (210 mg, yield: 87%). The reaction formula is as follows:

[0202] (3) Preparation of compound 21: Using compound 21-3 (100 mg, 0.3 mmol) as raw material, compound 21 was prepared by a method similar to step (6) of Example 16 to obtain white solid compound 21 (12.94 mg, yield: 8.0%).

[0203] The test results are as follows: MS(ESI) m / z = 515.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.96 (s, 1H), 10.65 (s, 1H), 7.94 (d, J=8.0Hz, 2H) , 7.81 (s, 1H), 7.69 (s, 1H), 7.41 (d, J = 8.0Hz, 2H), 4.78 (d, J = 4.0Hz, 1H), 4. 26(s, 1H), 4.04(s, 2H), 3.30(s, 3H), 2.84-2.80(m, 1H), 2.72-2.68(m, 1H), 2.57-2.55(m, 1H), 2.44-2.41(m, 1H), 2.10-2.01(m, 1H), 1.65-1.58(m, 1H).

[0204] Example 22

[0205] Example 22 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-chloropyrrolidone-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 22), with the following structural formula:

[0206] The preparation method of compound 22 is as follows:

[0207] (1) Preparation of intermediate 22-1: DMF (3 μL, 0.03 mmol) was added dropwise to 1 mL of a thionyl chloride solution of compound 21-3 (100 mg, 0.3 mmol) in an ice bath, and the reaction was carried out at 80 °C for 2 h. After the reaction was complete, the reaction solution was concentrated under vacuum to obtain a brown solid 22-1 (100 mg, yield: 90%). The reaction formula is as follows:

[0208] (2) Preparation of compound 22: Using compound 22-1 (100 mg, 0.265 mmol) as raw material, compound 22 was prepared by a method similar to step (6) of Example 16 to obtain a white solid compound 22 (6.64 mg, yield: 5.0%).

[0209] The test results are as follows: MS(ESI) m / z = 533.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ13.25 (s, 1H), 10.70 (s, 1H), 8.13 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.72 (s, 1H), 7.42 (d, J=12.0Hz, 2H), 4.95 (s, 2H), 4.68 (s, 2H), 3.76 (s, 3H), 2.84-2.80 (m, 2H), 2.57-2.54 (m, 2H), 2.20-2.19 (m, 1H).

[0210] Example 23

[0211] Example 23 provides a (S)-N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluoropyrrolidone-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 23), with the following structural formula:

[0212] The preparation method of compound 23 is as follows:

[0213] (1) Preparation of intermediate 23-2: Using (S)-3-fluorotetrahydropyrrole hydrochloride (CAS No. 116574-74-4, 2.81 g, 22.4 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 23-2 (4.5 g, yield: 96%). The reaction formula is as follows:

[0214] (2) Preparation of compound 23: Using compound 23-2 (1.43 g, 6.82 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 23 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 23 (19.58 mg, yield: 11.8%).

[0215] The test results are as follows: MS(ESI) m / z = 517.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.99 (s, 1H), 10.66 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.82 (s, 1H), 7.69 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 5.33-5.19 (m, 1H), 4.10 (s, 2H), 3.31 (s, 3H), 2.94-2.71 (m, 3H), 2.47- 2.45 (m, 1H), 2.25-2.16 (m, 1H), 2.01-1.91 (m, 1H).

[0216] Example 24

[0217] Example 24 provides (R)-N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluoropyrrolidone-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 24), with the following structural formula:

[0218] The preparation method of compound 24 is as follows:

[0219] (1) Preparation of intermediate 24-2: Using (S)-3-fluorotetrahydropyrrolidine hydrochloride (CAS No. 136725-53-6, 2.81 g, 22.4 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 24-2 (4.6 g, yield: 97%). The reaction formula is as follows:

[0220] (2) Preparation of compound 24: Using compound 24-2 (1.43 g, 6.82 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 24 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 24 (59.79 mg, yield: 35%).

[0221] The test results are as follows: MS(ESI) m / z = 517.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.25 (s, 1H), 10.71 (s, 1H), 8.13 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.72 (s, 1H), 7.43 (d, J=8.0Hz, 2H), 5.52-5.45 (m, 1H), 4.91 (s, 2H), 3.93-3.59 (m, 5H), 2.89-2.67 (m, 2H), 2.40-2.21 (m, 2H).

[0222] Example 25

[0223] Example 25 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[(3S,4R)-3,4-difluoropyrrolidone-1-yl]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 25), with the following structural formula:

[0224] The preparation method of compound 25 is as follows:

[0225] (1) Preparation of intermediate 25-2: Using (3S,4R)-3,4-difluorotetrahydropyrrolidine (CAS No. 2820191-53-3, 2.4 g, 22.4 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 25-2 (4.9 g, yield: 97%). The reaction formula is as follows:

[0226] (2) Preparation of compound 25: Using compound 25-2 (885 mg, 3.9 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 25 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 25 (58.08 mg, yield: 20.12%).

[0227] The test results are as follows: MS(ESI) m / z = 535.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.01 (s, 1H), 10.66 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.68 ( s, 1H), 7.41 (d, J=12.0Hz, 2H), 5.30-5.14 (m, 2H), 4.15 (s, 2H), 3.31 (s, 3H), 3.04-2.94 (m, 4H).

[0228] Example 26

[0229] Example 26 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[(3S,4S)-3,4-difluoropyrrolidone-1-yl]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 26), with the following structural formula:

[0230] The preparation method of compound 26 is as follows:

[0231] (1) Preparation of intermediate 26-2: Using (3S,4S)-3,4-difluorotetrahydropyrrolidine (CAS No. 863396-80-9, 2.4 g, 22.4 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 26-2 (4.8 g, yield: 96%). The reaction formula is as follows:

[0232] (2) Preparation of compound 26: Using compound 26-2 (584 mg, 2.57 mmol) and compound 9-3 (330 mg, 1.29 mmol) as raw materials, compound 25 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 25 (13.13 mg, yield: 14.47%).

[0233] The test results are as follows: MS(ESI) m / z = 535.3 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.02 (s, 1H), 10.67 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.67 (s, 1H), 7.42 (d, J=12.0Hz, 2H), 5.37-5.20 (m, 2H), 4.14 (q, J=12.0Hz, 2H), 3.31 (s, 3H), 3.20-3.09 (m, 2H), 2.86-2.77 (m, 2H).

[0234] Example 27

[0235] Example 27 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-methylpyrrolidone-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 27), with the following structural formula:

[0236] The preparation method of compound 27 is as follows:

[0237] (1) Preparation of intermediate 27-2: Using 3-methyltetrahydropyrrolidine (CAS No. 34375-89-8, 1.82 g, 14.9 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 27-2 (2.9 g, yield: 95%). The reaction formula is as follows:

[0238] (2) Preparation of compound 27: Using compound 27-2 (1.2 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 27 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 27 (44.57 mg, yield: 28%).

[0239] The test results are as follows: MS(ESI) m / z = 513.1 [M+H] + . 1H NMR (MeOD, 400MHz): δ8.06 (s, 1H), 7.92 (d, J=12.0Hz, 2H), 7.65 (s, 1H), 7.35 (d, J=8.0Hz, 2H), 4.70 (s, 2H), 3.54-3.46 (m, 1H), 3.39-3.35(m, 5H), 2.88-2.85(m, 1H), 2.57-2.48(m, 1H), 2.32-2.24(m, 1H), 1.76-1.68(m, 1H), 1.16(d, J=4.0Hz, 3H).

[0240] Example 28

[0241] Example 28 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-4-(piperidin-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 28), with the following structural formula:

[0242] The preparation method of compound 28 is as follows:

[0243] (1) Preparation of intermediate 28-2: Using piperidine (CAS No. 110-89-4, 2.00 g, 9.96 mmol) as a starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white solid 28-2 (2.0 g, yield: 97%). The reaction formula is as follows:

[0244] (2) Preparation of compound 28: Compound 28-2 (799 mg, 3.9 mmol) and compound 9-3 (500 mg, 1.95 mmol) were used as raw materials and prepared according to the method similar to steps (2)-(6) of Example 16 to obtain white solid compound 28 (51.98 mg, yield: 24%).

[0245] The test results are as follows: MS(ESI) m / z = 513.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.19 (s, 1H), 10.68 (s, 1H), 8.13 (s, 1H), 7.92 (d, J=12.0Hz, 2H), 7.72 (s, 1H), 7 .43 (d, J=8.0Hz, 2H), 4.72 (s, 2H), 3.57-3.50 (m, 2H), 3.13-3.04 (m, 2H), 2.54 (s, 2H), 1.78-1.24 (m, 7H).

[0246] Example 29

[0247] Example 29 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-4-(piperazin-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 29), with the following structural formula:

[0248] The preparation method of compound 29 is as follows:

[0249] (1) Preparation of intermediate 29-2: Using 1-tert-butyloxycarbonylpiperazine (CAS No. 31166-44-6, 2.78 g, 14.9 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 29-2 (3.0 g, yield: 98%). The reaction formula is as follows:

[0250] (2) Preparation of intermediate 29-3: Using compound 29-2 (1.79 mg, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, it was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a white solid 29-3 (240 mg, yield: 55%). The reaction formula is as follows:

[0251] (3) Preparation of compound 29: Compound 29-3 (100 mg, 0.163 mmol) was dissolved in 1 mL of 1,4-dioxane solution in 4 M hydrochloric acid and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum, the filter cake was collected, purified by reversed-phase high performance liquid chromatography (Pre-HPLC), the eluent was concentrated, and freeze-dried to obtain white solid compound 29 (49.94 mg, yield: 54%).

[0252] The test results are as follows: MS(ESI) m / z = 514.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ10.68 (s, 1H), 8.38 (s, 1H), 7.96 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.72 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 3.96 (s, 2H), 3.31 (s, 3H), 2.94 (s, 4H), 2.55 (s, 4H).

[0253] Example 30

[0254] Example 30 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(4-methylpiperazin-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 30), with the following structural formula:

[0255] The preparation method of the above compound 30 is as follows:

[0256] (1) Preparation of intermediate 30-2: Using 1-methylpiperazine (CAS No. 109-01-3, 1.50 g, 14.9 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white solid 30-2 (2.1 g, yield: 95.8%). The reaction formula is as follows:

[0257] (2) Preparation of compound 30: Compound 30-2 (1.29 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) were used as raw materials and prepared according to the method similar to steps (2)-(6) of Example 16 to obtain white solid compound 30 (22.84 mg, yield: 15.3%).

[0258] The test results are as follows: MS(ESI) m / z = 528.2 [M+H] + . 1 H NMR (MeOD, 400MHz): δ 7.90 (d, J=8.0Hz, 2H), 7.87 (s, 1H), 7.64 (s, 1H), 7.32 (d, J=8.0Hz, 2H), 4.03 (s, 2H), 2.58 (s, 4H), 2.70 (s, 4H), 2.53 (s, 3H).

[0259] Example 31

[0260] Example 31 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-4-(morpholinylmethyl)-1H-7-azaindole-2-carboxamide (compound 31), with the following structural formula:

[0261] The preparation method of compound 31 is as follows:

[0262] (1) Preparation of intermediate 31-2: Using morpholine (CAS No. 110-91-8, 1.31 mL, 14.9 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white solid 31-2 (2.01 g, yield: 97%). The reaction formula is as follows:

[0263] (2) Preparation of compound 31: Using compound 31-2 (1.21 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 31 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a white solid compound 31 (27.3 mg, yield: 16%).

[0264] The test results are as follows: MS(ESI) m / z = 515.2 [M+H] + . 1 H NMR (MeOD, 400MHz): δ 8.10 (s, 1H), 7.90 (d, J=12.0Hz, 2H), 7.66 (s, 1H), 7.33 (d, J=8.0Hz, 2H), 4.83 (s, 2H), 3.94 (s, 4H), 3.45 (s, 4H), 3.33 (s, 3H).

[0265] Example 32

[0266] Example 32 provides a 4-[(1,4-diazacycloheptane-1-yl)methyl]-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 32), with the following structural formula:

[0267] The preparation method of compound 32 is as follows:

[0268] (1) Preparation of intermediate 32-2: Using 1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester (CAS No. 112275-50-0; 3g, 14.9mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white oily substance 32-2 (4.5g, yield: 94.6%). The reaction formula is as follows:

[0269] (2) Preparation of intermediate 32-3: Using compound 32-2 (1.87 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, intermediate 32-3 was prepared by a method similar to steps (2)-(6) of Example 16, yielding a yellow oily substance 32-3 (130 mg, yield: 78%). The reaction formula is as follows:

[0270] (3) Preparation of compound 32: Using compound 32-3 (130 mg, 0.21 mmol) as raw material, compound 32 was prepared by a method similar to step (3) of Example 29 to obtain white solid compound 32 (41.04 mg, yield: 33.9%).

[0271] The test results are as follows: MS(ESI) m / z = 528.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ11.18 (s, 1H), 8.48 (s, 1H), 7.97 (d, J=8.0Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7. 40(d, J=12.0Hz, 2H), 4.14(s, 2H), 3.31(s, 3H), 3.14(s, 4H), 2.86(s, 2H), 2.73(s, 2H), 1.90(s, 2H).

[0272] Example 33

[0273] Example 33 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 33), with the following structural formula:

[0274] The preparation method of the above compound 33 is as follows:

[0275] (1) Preparation of intermediate 33-2: Using 6,6-difluoro-2-azaspiro[3.3]heptane (CAS No. 1427367-47-2, 1.1 g, 6.52 mmol) as the starting material, a white oily substance 33-2 (1.5 g, yield: 89.6%) was prepared according to a method similar to step (1) of Example 16. The reaction formula is as follows:

[0276] (2) Preparation of compound 33: Using compound 33-2 (1.5 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 33 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a white solid compound 33 (23.67 mg, yield: 33%).

[0277] The test results are as follows: MS(ESI) m / z = 561.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.00 (s, 1H), 10.68 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.77 (s, 1H), 7.68 (s , 1H), 7.42 (d, J=8.0Hz, 2H), 4.11 (s, 2H), 3.47-3.31 (m, 4H), 3.31 (s, 3H), 2.78 (t, J=12.0Hz, 4H).

[0278] Example 34

[0279] Example 34 provides a 4-[(2-oxa-6-azaspiro[3,4]octane-6-yl)methyl]-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 34), with the following structural formula:

[0280] The preparation method of the above compound 34 is as follows:

[0281] (1) Preparation of intermediate 34-2: Using 2-oxa-6-azaspiro[3.4]octane (CAS No. 220290-68-6, 1.5 g, 7.46 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a yellow solid 34-2 (1.5 g, yield: 86.33%). The reaction formula is as follows:

[0282] (2) Preparation of compound 34: Using compound 34-2 (1.36 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 34 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a white solid compound 34 (2.84 mg, yield: 25%).

[0283] The test results are as follows: MS(ESI) m / z = 541.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.03 (s, 1H), 10.68 (s, 1H), 8.29 (s, 1H), 7.95 (d, J=12.0Hz, 2H), 7.79 (s, 1H), 7.67 (s, 1H), 7.41 ( d, J=8.0Hz, 2H), 4.51 (q, J=8.0Hz, 4H), 4.03 (s, 2H), 3.31 (s, 3H), 2.85 (s, 2H), 2.59 (t, J=8.0Hz, 2H), 2.11 (t, J=8.0Hz, 2H).

[0284] Example 35

[0285] Example 35 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[methyl(propyl)amino]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 35), with the following structural formula:

[0286] The preparation method of the above compound 35 is as follows:

[0287] (1) Preparation of intermediate 35-2: Using N-methyl-1-propylamine (CAS No. 627-35-0, 1.09 g, 14.2 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white oily substance 35-2 (1.9 g, yield: 98%). The reaction formula is as follows:

[0288] (2) Preparation of compound 35: Compound 35-2 (1.02 g, 5.26 mmol) and compound 9-3 (450 mg, 1.75 mmol) were used as raw materials and prepared according to the method similar to steps (2)-(6) of Example 16 to obtain white solid compound 35 (57.34 mg, yield: 28%).

[0289] The test results are as follows: MS(ESI) m / z = 501.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.96 (s, 1H), 10.65 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.84 (s, 1H), 7.68 (s, 1H), 7.41 (d, J=8. 0Hz, 2H), 3.92 (s, 2H), 3.30 (s, 3H), 2.41 (t, J=8.0Hz, 2H), 2.22 (s, 3H), 1.54 (q, J=8.0Hz, 2H), 0.89 (t, J=8.0Hz, 3H).

[0290] Example 36

[0291] Example 36 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[ethyl(propyl)amino]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 36), with the following structural formula:

[0292] The preparation method of compound 36 is as follows:

[0293] (1) Preparation of intermediate 36-2: Using N-ethyl-1-propylamine (CAS No. 20193-20-8; 1.24 g, 14.9 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white oily substance 36-2 (2.3 g, yield: 74.5%). The reaction formula is as follows:

[0294] (2) Preparation of compound 36: Using compound 36-2 (1.09 g, 5.26 mmol) and compound 9-3 (450 mg, 1.75 mmol) as raw materials, compound 36 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a white solid compound 36 (20.27 mg, yield: 15%).

[0295] The test results are as follows: MS(ESI) m / z = 515.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.95 (s, 1H), 10.65 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.89 (s, 1H), 7.67 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 4.00 (s , 2H), 3.30 (s, 3H), 2.58 (q, J=8.0Hz, 2H), 2.46 (t, J=8.0Hz, 2H), 1.48 (q, J=8.0Hz, 2H), 1.04 (t, J=8.0Hz, 3H), 0.85 (t, J=8.0Hz, 3H).

[0296] Example 37

[0297] Example 37 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 37), with the following structural formula:

[0298] The preparation method of compound 37 is as follows:

[0299] (1) Preparation of intermediate 37-2: Using 2-(tert-butyldimethylsiloxy)-N-methylethylamine (CAS No. 204580-28-9, 2.26 g, 11.95 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white oily substance 37-2 (3.33 g, yield: 90%). The reaction formula is as follows:

[0300] (2) Preparation of compound 37: Using compound 37-2 (1.81 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 37 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 37 (8.64 mg, yield: 4.5%).

[0301] The test results are as follows: MS(ESI) m / z = 503.1 [M+H] + .1 H NMR (DMSO-d6, 400MHz): δ10.67 (s, 1H), 8.25 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.84 (s, 1H), 7.69 (s, 1H), 7.41 (d, J =8.0Hz, 2H), 4.54 (s, 1H), 3.99 (s, 2H), 3.60 (t, J = 8.0Hz, 2H), 3.30 (s, 3H), 2.57 (t, J = 8.0Hz, 2H), 2.27 (s, 3H).

[0302] Example 38

[0303] Example 38 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[ethyl(2-hydroxyethyl)amino]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 38), with the following structural formula:

[0304] The preparation method of compound 38 is as follows:

[0305] (1) Preparation of intermediate 38-2: Using 2-(ethylamino)-1-ethanol (CAS No. 100-37-8, 2 g, 9.96 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 38-2 (1.98 g, yield: 95%). The reaction formula is as follows:

[0306] (2) Preparation of compound 38: Using compound 38-2 (1.22 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 38 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 38 (24.43 mg, yield: 10.83%).

[0307] The test results are as follows: MS(ESI) m / z = 517.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.96 (s, 1H), 10.66 (s, 1H), 8.16 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.89 (s, 1H), 7.68 (s, 1H), 7.42 (d, J=8.0Hz, 2H), 4.49 (s, 1H), 4.08 (s, 2H), 3.54 (t, J=4.0Hz, 2H), 3.31 (s, 3H), 2.64-2.59 (m, 4H), 1.05 (t, J=8.0Hz, 3H).

[0308] Example 39

[0309] Example 39 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[(2-hydroxyethyl)(isopropyl)amino]methyl}-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 39), with the following structural formula:

[0310] The preparation method of compound 39 is as follows:

[0311] (1) Preparation of intermediate 39-2: Using 2-(isopropylamino)-1-ethanol (CAS No. 109-56-8, 1.56 g, 14.9 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a white oily substance 39-2 (2.5 g, yield: 75.37%). The reaction formula is as follows:

[0312] (2) Preparation of compound 39: Using compound 39-2 (1.3 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 39 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 39 (45.02 mg, yield: 20%).

[0313] The test results are as follows: MS(ESI) m / z = 531.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.25 (s, 1H), 10.76 (s, 1H), 9.68 (s, 1H), 8.26 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.43 (d, J=8.0Hz, 2H), 5.33 (s, 1H), 4.76 (s, 2H), 3.76-3.67 (m, 2H), 3.34 (s, 3H), 3.07 (s, 2H), 1.38 (s, 6H).

[0314] Example 40

[0315] Example 40 provides a 4-(aminomethyl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 40), with the following structural formula:

[0316] The preparation method of the above compound 40 is as follows:

[0317] (1) Preparation of intermediate 40-2: Using potassium [(tert-butyloxycarbonylamino)methyl]trifluoroborate (CAS No. 1314538-55-0, 502 mg, 2.01 mmol) and compound 9-3 (430 mg, 1.68 mmol) as raw materials, it was prepared by a method similar to steps (2)-(6) of Example 16 to obtain white solid 40-2 (20 mg, yield: 68%). The reaction formula is as follows:

[0318] (2) Preparation of compound 40: Using compound 40-2 (40 mg, 0.037 mmol) as raw material, compound 40 was prepared by a method similar to step (3) of Example 29 to obtain white solid compound 40 (2.52 mg, yield: 14%).

[0319] The test results are as follows: MS(ESI) m / z = 445.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ 10.66 (s, 1H), 8.26 (s, 1H), 7.95 (d, J=12.0Hz, 2H), 7.66 (s, 1H), 7.41 (d, J=8.0Hz, 2H), 4.22 (s, 2H), 3.29 (s, 3H).

[0320] Example 41

[0321] Example 41 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3,3-difluorocyclobutyl)amino]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 41), with the following structural formula:

[0322] The preparation method of compound 41 is as follows:

[0323] (1) Preparation of intermediate 41-1: 3,3-difluorocyclobutane-1-amine (CAS No. 791061-00-2, 329 mg, 2.92 mg), compound 9-3 (500 mg), and cesium carbonate (1.94 g, 5.84 mmol) were dissolved in 10 mL of 1,4-dioxane, and RuPhos Pd G3 (332 mg, 0.39 mmol) was added. The reaction was carried out at 30 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 41-1 (220 mg, yield: 35%). The reaction formula is as follows:

[0324] (2) Preparation of compound 41: Using compound 41-1 (190 mg, 0.58 mmol) as raw material, compound 41 was prepared by a method similar to steps (3)-(6) of Example 16 to obtain a yellow solid compound 41 (6.79 mg, yield: 8%).

[0325] The test results are as follows: MS(ESI) m / z = 521.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.49 (s, 1H), 10.53 (s, 1H), 7.98 (d, J = 4.0Hz, 1H), 7.92 (d, J = 4.0Hz, 2H), 7.55 (s , 1H), 7.40 (d, J=12.0Hz, 2H), 6.77 (s, 1H), 4.22 (s, 1H), 3.24 (s, 3H), 3.19-3.12 (m, 2H), 2.81-2.68 (m, 2H).

[0326] Example 42

[0327] Example 42 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(2-hydroxyethyl)amino]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 42), with the following structural formula:

[0328] The preparation method of compound 42 is as follows:

[0329] (1) Preparation of intermediate 42-1: Using 2-(tert-butyldimethylsiloxy)ethyl-1-amine (CAS No. 101711-55-1, 540 mg, 2.92 mg) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, the intermediate 42-1 was prepared by a method similar to step (1) of Example 41, yielding a yellow solid 42-1 (370 mg, yield: 48%). The reaction formula is as follows:

[0330] (2) Preparation of compound 42: Using compound 42-1 (280 mg, 0.71 mmol) as raw material, compound 42 was prepared by a method similar to steps (3)-(6) of Example 16 to obtain a yellow solid compound 42 (5.37 mg, yield: 6.94%).

[0331] The test results are as follows: MS(ESI) m / z = 475.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.37 (s, 1H), 10.47 (s, 1H), 7.92 (d, J=8.0Hz, 2H), 7.56 (t, J=8.0Hz, 2H) , 7.38 (d, J=8.0Hz, 2H), 6.84 (s, 1H), 4.92 (s, 1H), 3.65 (s, 2H), 3.43 (t, J=4.0Hz, 2H), 3.21 (s, 3H).

[0332] Example 43

[0333] Example 43 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-4-(2-oxa-6-azaspiro[3.4]octane-6-yl)-1H-7-azaindole-2-carboxamide (compound 43), with the following structural formula:

[0334] The preparation method of compound 43 is as follows:

[0335] (1) Preparation of intermediate 43-1: 2-oxa-6-azaspiro[3.4]octane (712 mg, 3.51 mmol), compound 9-3 (600 mg, 2.34 mmol), and cesium carbonate were dissolved in 14 mL of 1,4-dioxane. XantPhos (541 mg, 0.93 mmol) and Pd2dba3 (428 mg, 0.47 mmol) were added. The reaction was carried out at 130 °C for 36 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated, and purified by silica gel column chromatography to obtain a yellow solid 43-1 (540 mg, yield: 69%). The reaction formula is as follows:

[0336] (2) Preparation of compound 43: Using compound 43-1 (150 mg, 0.45 mmol) as raw material, compound 43 was prepared by a method similar to steps (3)-(6) of Example 16 to obtain a yellow solid compound 43 (7.68 mg, yield: 3.23%).

[0337] The test results are as follows: MS(ESI) m / z = 527.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ 12.47 (s, 1H), 10.35 (s, 1H), 7.90 (d, J=8.0Hz, 2H), 7.80 (s, 1H), 7.40 (d, J=8.0Hz, 2H), 6.67 (s, 1H), 4.6 8 (d, J=4.0Hz, 2H), 4.59 (d, J=8.0Hz, 2H), 4.02 (s, 2H), 3.77 (s, 2H), 3.21 (s, 3H), 2.38 (t, J=8.0Hz, 2H).

[0338] Example 44

[0339] Example 44 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(methylamino)-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 44), with the following structural formula:

[0340] The preparation method of compound 44 is as follows:

[0341] (1) Preparation of intermediate 44-1: Compound 9-3 (2.20 g, 7.72 mmol) was dissolved in 20 mL of EA, and M-CPBA (7.82 g, 38.56 mmol) was added. The reaction was carried out at room temperature for 17 h. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8, and sodium sulfite was added to quench the reaction. The reaction solution was extracted twice with 20 mL of EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under pressure, and purified by silica gel column chromatography to obtain a white solid 44-1 (1.8 g, yield: 80.8%). The reaction formula is as follows:

[0342] (2) Preparation of compound 44-2: Compound 44-1 (1 g, 3.46 mmol) was dissolved in 10 mL of NMP, and methylamine hydrochloride (702 mg, 10.39 mmol) and DIPEA (2.69 g, 20.78 mmol) were added. The mixture was reacted at 130 °C for 4 h. After the reaction was completed, 70 mL of water and 70 mL of EA were added to the reaction solution for extraction twice. The mixture was then filtered and concentrated to obtain a yellow solid 44-2 (500 mg, yield: 50.87%). The reaction formula is as follows:

[0343] (3) Preparation of compound 44: Using compound 44-2 (500 mg, 1.76 mmol) as raw material, compound 44 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 44 (20.50 mg, yield: 15.5%).

[0344] The test results are as follows: MS(ESI) m / z = 445.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.37 (s, 1H), 10.45 (s, 1H), 7.93-7.86 (m, 2H), 7.66 (d, J=5.6Hz, 1H), 7.49 (s, 1H), 7.38 (d, J=8.8Hz, 2H), 6.75 (s, 1H), 3.21 (s, 3H), 2.98 (d, J=4.8Hz, 3H).

[0345] Example 45

[0346] Example 45 provides a 3-amino-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-4-(pyrrolidone-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 45), with the following structural formula:

[0347] The preparation method of the above compound 45 is as follows:

[0348] (1) Preparation of intermediate 45-1: Compound 9-3 (1.2 g, 4.68 mmol) was dissolved in 12 mL of sulfuric acid, and potassium nitrate (520 mg, 5.14 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the reaction solution was slowly poured into an aqueous sodium carbonate solution to adjust the pH to 8. The solution was extracted with EA, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain a yellow solid 45-1 (700 mg, yield: 50%). The reaction formula is as follows:

[0349] (2) Preparation of intermediate 45-2: Compound 45-1 (630 mg, 2.09 mmol) was dissolved in 3.2 mL of methanol and 3.2 mL of THF. An aqueous solution of ammonium chloride (558 mg, 10.4 mmol) was added, and zinc (683 mg, 10.4 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was filtered and concentrated. The pH was adjusted to 9 by adding an aqueous solution of sodium carbonate. 30 mL of EA and 20 mL of water were added, and the mixture was extracted and separated. The aqueous phase was extracted three times with 30 mL of EA. The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain a yellow solid 45-2 (270 mg, yield: 48%). The reaction formula is as follows:

[0350] (3) Preparation of compound 45: Using compound 45-2 (270 mg, 0.99 mmol) and compound 20-2 (570 mg, 2.98 mmol) as raw materials, compound 45 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 45 (14.4 mg, yield: 2.8%).

[0351] The test results are as follows: MS(ESI) m / z = 514.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ11.71 (s, 1H), 9.81 (s, 1H), 7.84 (d, J=8.0Hz, 2H), 7.53 (s, 1H), 7.37 (d, J=8.0Hz, 2H), 6.69 (s, 2H), 4.03 (s, 2H), 3.31 (s, 3H), 2.60 (s, 4H), 1.77 (s, 4H).

[0352] Example 46

[0353] Example 46 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3,3-difluoroazacyclobut-1-yl)methyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 46), with the following structural formula:

[0354] The preparation method of compound 46 is as follows:

[0355] (1) Preparation of intermediate 46-2: Using methyl 4-chloro-1H-7-azaindole-2-carboxylate (CAS No. 871583-23-2, 225 g, 10.7 mol) as the raw material, it was prepared according to steps (1)-(3) of Example 15 to obtain a yellow oily substance 46-2 (45 g, yield: 93%). The reaction formula is as follows:

[0356] (2) Preparation of intermediate 46-3: Using a THF solution of compound 46-2 (40 g, 129.4 mmol) and 3.1 M methylamine (208 mL, 648 mmol) as raw materials, intermediate 46-3 was prepared by a method similar to step (4) in Example 15, yielding a yellow solid 46-3 (24 g, yield: 61%). The reaction formula is as follows:

[0357] (3) Preparation of compound 46: Using compound 46-3 (300 mg, 0.988 mmol) and compound 17-2 (631 mg, 2.96 mmol) as raw materials, compound 46 was prepared by a method similar to steps (2), (5)-(6) of Example 16, to obtain white solid compound 46 (12.56 mg, yield: 22%).

[0358] The test results are as follows: MS(ESI) m / z = 536.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.90 (s, 1H), 10.68 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.68 (s, 1H), 7. 62 (s, 2H), 7.41 (d, J=8.0Hz, 2H), 4.21 (s, 2H), 3.75 (t, J=12.0Hz, 4H), 2.58 (d, J=8.0Hz, 3H).

[0359] Example 47

[0360] Example 47 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-4-(pyrrolidone-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 47), with the following structural formula:

[0361] The preparation method of the above compound 47 is as follows: using compound 46-3 (500 mg, 1.65 mmol) and compound 20-2 (943 mg, 4.94 mmol) as raw materials, the compound 47 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a white solid compound 47 (31.04 mg, yield: 15%).

[0362] The test results are as follows: MS(ESI) m / z = 514.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.83 (s, 1H), 10.61 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.71 (s, 1H), 7.65 (s, 1H), 7. 58 (q, J=4.0Hz, 1H), 7.41 (d, J=12.0Hz, 2H), 4.02 (s, 2H), 2.58 (d, J=4.0Hz, 3H), 2.56 (s, 4H), 1.77 (s, 4H).

[0363] Example 48

[0364] Example 48 provides a (S)-N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluoropyrrolidone-1-yl)methyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 48), with the following structural formula:

[0365] The preparation method of the above compound 48 is as follows: using compound 46-3 (200 mg, 0.658 mmol) and compound 23-2 (413 mg, 1.98 mmol) as raw materials, the compound 48 was prepared in a manner similar to steps (2), (5)-(6) of Example 16 to obtain a yellow solid compound 48 (65.0 mg, yield: 26%).

[0366] The test results are as follows: MS(ESI) m / z = 532.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.85 (s, 1H), 10.60 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.73 (s, 1H), 7.63 (s, 1H), 7.58 (q, J=4.0Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 5.34-5.17 (m, 1H), 4.07 (s, 2H), 2.94-2.73 (m, 3H), 2.59 (d, J=4.0Hz, 3H), 2.27-2.14 (m, 1H), 2.02-1.89 (m, 1H).

[0367] Example 49

[0368] Example 49 provides (R)-N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluoropyrrolidone-1-yl)methyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 49), with the following structural formula:

[0369] The preparation method of the above compound 49 is as follows: using compound 46-3 (200 mg, 0.659 mmol) and compound 24-2 (482 mg, 2.30 mmol) as raw materials, the compound 49 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a yellow solid compound 49 (58.33 mg, yield: 23.7%).

[0370] The test results are as follows: MS(ESI) m / z = 532.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.87 (s, 1H), 10.63 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.73 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=8.0Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 5.33-5.19 (m, 1H), 4.07 (s, 2H), 2.94-2.70 (m, 3H), 2.59 (d, J=4.0Hz, 3H), 2.48-2.44 (m, 1H), 2.25-2.16 (m, 1H), 2.01-1.91 (m, 1H).

[0371] Example 50

[0372] Example 50 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[(3S,4R)-3,4-difluoropyrrolidone-1-yl]methyl}-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 50), with the following structural formula:

[0373] The preparation method of the above compound 50 is as follows: using compound 46-3 (180 mg, 0.592 mmol) and compound 25-2 (269 mg, 1.19 mmol) as raw materials, the compound 50 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a yellow solid compound 50 (21.34 mg, yield: 16%).

[0374] The test results are as follows: MS(ESI) m / z = 550.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.88 (s, 1H), 10.62 (s, 1H), 7.94 (d, J=12.0Hz, 2H), 7.71 (s, 1H), 7.63-7.60 ( m, 2H), 7.41 (d, J=8.0Hz, 2H), 5.28-5.15 (m, 2H), 4.13 (s, 2H), 3.05-2.94 (m, 4H), 2.59 (d, J=4.0Hz, 3H).

[0375] Example 51

[0376] Example 51 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-{[(3S,4S)-3,4-difluoropyrrolidone-1-yl]methyl}-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 51), with the following structural formula:

[0377] The preparation method of the above compound 51 is as follows: using compound 46-3 (180 mg, 0.592 mmol) and compound 26-2 (269 mg, 1.19 mmol) as raw materials, it was prepared according to the method similar to steps (2), (5)-(6) of Example 16 to obtain yellow solid compound 51 (11.4 mg, yield: 9%).

[0378] The test results are as follows: MS(ESI) m / z = 550.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.88 (s, 1H), 10.63 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.71 (s, 1H), 7.63-7.60 (m, 2H), 7.41 (d, J=4.0Hz, 2H), 5.37-5.18 (m, 2H), 4.12 (q, J=12.0Hz, 2H), 3.20-3.09 (m, 2H), 2.87-2.77 (m, 2H), 2.59 (d, J=4.0Hz, 3H).

[0379] Example 52

[0380] Example 52 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3,3-difluoropyrrolidone-1-yl)methyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 52), with the following structural formula:

[0381] The preparation method of compound 52 is as follows:

[0382] (1) Preparation of intermediate 52-2: Using 3,3-difluoropyrrolidine (CAS No. 163457-23-6, 2.14 g, 14.9 mmol) as the starting material, it was prepared according to a method similar to step (1) of Example 16, yielding a yellow oily substance 52-2 (2.2 g, yield: 48.65%). The reaction formula is as follows:

[0383] (2) Preparation of compound 52: Using compound 46-3 (449 mg, 1.98 mmol) and compound 52-2 (200 mg, 0.659 mmol) as raw materials, compound 52 was prepared by a method similar to steps (2), (5)-(6) of Example 16, to obtain white solid compound 52 (63.57 mg, yield: 26.78%).

[0384] The test results are as follows: MS(ESI) m / z = 550.1 [M+H] + . 1H NMR (MeOD, 400MHz): δ7.90 (t, J=4.0Hz, 3H), 7.63 (s, 1H), 7.34 (d, J=4.0Hz, 2H), 4.4 9 (s, 2H), 3.48 (t, J=12.0Hz, 2H), 3.31-3.27 (m, 2H), 2.74 (s, 3H), 2.57-2.46 (m, 2H).

[0385] Example 53

[0386] Example 53 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-4-(piperidin-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 53), with the following structural formula:

[0387] The preparation method of the above compound 53 is as follows: using compound 46-3 (200 mg, 0.659 mmol) and compound 28-2 (405 mg, 1.98 mmol) as raw materials, it was prepared according to the method similar to steps (2), (5)-(6) of Example 16 to obtain yellow solid compound 53 (36.5 mg, yield: 18%).

[0388] The test results are as follows: MS(ESI) m / z = 528.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.82 (s, 1H), 10.60 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.71 (s, 1H), 7.66 (s, 1H), 7.59 (q, J=4. 0Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 3.87 (s, 2H), 2.59 (d, J=4.0Hz, 3H), 2.43 (s, 4H), 1.56 (t, J=4.0Hz, 4H), 1.43 (s, 2H).

[0389] Example 54

[0390] Example 54 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(4-methylpiperazin-1-yl)methyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 54), with the following structural formula:

[0391] The preparation method of the above compound 54 is as follows: using compound 46-3 (150 mg, 0.47 mmol) and compound 30-2 (326 mg, 1.48 mmol) as raw materials, the compound 54 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a white solid compound 54 (47.65 mg, yield: 31%).

[0392] The test results are as follows: MS(ESI) m / z = 543.1 [M+H] + . 1 H NMR (MeOD, 400MHz): δ7.88 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.61 (s, 1H), 7.31 (d, J=4 .0Hz, 2H), 4.03(s, 2H), 3.31(s, 3H), 3.01(s, 4H), 2.74-2.69(m, 7H), 2.64(s, 3H).

[0393] Example 55

[0394] Example 55 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-4-(morpholinylmethyl)-1H-7-azaindole-2-carboxamide (compound 55), with the following structural formula:

[0395] The preparation method of the above compound 55 is as follows: using compound 46-3 (150 mg, 0.47 mmol) and compound 31-2 (291 mg, 1.41 mmol) as raw materials, the compound 55 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a yellow solid compound 55 (68.47 mg, yield: 40%).

[0396] The test results are as follows: MS(ESI) m / z = 530.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.85 (s, 1H), 10.61 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.73 (s, 1H), 7.68 (s, 1H), 7.60 (q , J=4.0Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 3.92 (s, 2H), 3.64 (t, J=4.0Hz, 4H), 2.59 (d, J=4.0Hz, 3H), 2.48 (s, 4H).

[0397] Example 56

[0398] Example 56 provides a 4-(azaphen-1-ylmethyl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 56), with the following structural formula:

[0399] The preparation method of compound 56 is as follows:

[0400] (1) Preparation of intermediate 56-2: Tert-butyl aziridine-1-carboxylate (CAS No. 87661-17-4; 1 g, 4.76 mmol) was dissolved in 10 mL of 4 M hydrochloric acid in a 1,4-dioxane solution and reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated to obtain a white solid 56-2 (640 mg, yield: 98%). The reaction formula is as follows:

[0401] (2) Preparation of intermediate 56-3: Using compound 56-2 (636 mg, 4.68 mmol) as a starting material, intermediate 56-3 was prepared according to a method similar to step (1) of Example 16, yielding a white solid 56-3 (820 mg, yield: 80%). The reaction formula is as follows:

[0402] (3) Preparation of compound 56: Using compound 46-3 (250 mg, 0.823 mmol) and compound 56-3 (541 mg, 2.47 mmol) as raw materials, compound 56 was prepared by a method similar to steps (2), (5)-(6) of Example 16 to obtain a yellow solid compound 56 (18.66 mg, yield: 10%).

[0403] The test results are as follows: MS(ESI) m / z = 542.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.80 (s, 1H), 10.59 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.78 (s, 1H), 7.65 (s, 1H), 7.58 (d , J=4.0Hz, 1H), 7.41 (d, J=8.0Hz, 2H), 4.06 (s, 2H), 2.68 (t, J=4.0Hz, 4H), 2.59 (d, J=4.0Hz, 3H), 1.62 (s, 8H).

[0404] Example 57

[0405] Example 57 provides a (S)-N-[4-(chlorodifluoromethoxy)phenyl]-4-(3-fluoropyrrolidine-1-formyl)-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 57), with the following structural formula:

[0406] The preparation method of compound 57 is as follows:

[0407] (1) Preparation of intermediate 57-1: Compound 46-3 (500 mg, 1.65 mmol), XantPhos (191 mg, 0.329 mmol), palladium acetate (36 mg, 0.164 mmol), oxalic acid (296 mg, 3.29 mmol), Ac2O (309 μL, 3.29 mmol), and DIPEA (544 μL, 3.29 mmol) were dissolved in 10 mL of DMF and reacted at 100 °C for 8 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered, 10 mL of EA and 5 mL of water were added, and the mixture was extracted and separated. The aqueous phase was extracted three times with 5 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid 57-1 (320 mg, yield: 62%). The reaction formula is as follows:

[0408] (2) Preparation of intermediate 57-2: Compound 57-1 (160 mg, 0.51 mmol), HOBT (76 mg, 0.562 mmol), and DIPEA (295 μL, 1.79 mmol) were dissolved in 3 mL of DMF. EDCI (129 mg, 0.664 mmol) was added under ice bath conditions, and the reaction was allowed to proceed for 15 min. Then, (S)-3-fluoropyrrolidine hydrochloride (77 mg, 0.612 mmol) was added under ice bath conditions, and the reaction was allowed to proceed for 16 h at room temperature. After the reaction was complete, 10 mL of EA and 5 mL of water were added to the reaction solution, and the mixture was extracted and separated. The aqueous phase was extracted three times with 5 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid 57-2 (100 mg, yield: 51%). The reaction formula is as follows:

[0409] (3) Preparation of compound 57: Using compound 57-2 (70 mg, 0.182 mmol) as the raw material, compound 57 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain white solid compound 57 (9.85 mg, yield: 31%).

[0410] The test results are as follows: MS(ESI) m / z = 546.1 [M+H] + . 1H NMR (MeOD, 400MHz): δ7.88-7.82 (m, 3H), 7.45 (s, 1H), 7.30 (d, J=8.0Hz, 2H), 5.49-5.19 (m, 1 H), 4.08-3.93(m, 1H), 3.88-3.75(m, 1H), 3.70-3.49(m, 2H), 2.73(s, 3H), 2.43-2.11(m, 2H).

[0411] Example 58

[0412] Example 58 provides a 4-amino-N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 58), with the following structural formula:

[0413] The preparation method of compound 58 is as follows:

[0414] (1) Preparation of intermediate 58-1: Compound 46-3 (180 mg, 0.592 mmol) and (4-methoxyphenyl)methylamine (313 μL, 2.37 mmol) were dissolved in 1,4-dioxane and reacted at 120 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under vacuum to obtain a yellow oily substance 58-1 (230 mg, yield: 96%). The reaction formula is as follows:

[0415] (2) Preparation of intermediate 58-2: Compound 58-1 (230 mg, 0.568 mmol) was dissolved in 2.5 mL of TFA and reacted at 60 °C for 1 h. After the reaction was completed, the reaction solution was concentrated, and sodium bicarbonate aqueous solution was added to adjust the pH to 8-9. 3 mL of EA and 1 mL of water were added, and the mixture was extracted and separated. The aqueous phase was extracted three times with 20 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a white solid 58-2 (35 mg, yield 22%). The reaction formula is as follows:

[0416] (3) Preparation of compound 58: Using compound 58-2 (30 mg, 0.105 mmol) as raw material, compound 58 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 58 (3.86 mg, yield: 11%).

[0417] The test results are as follows: MS(ESI) m / z = 446.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.15 (s, 1H), 10.46 (s, 1H), 7.90 (d, J=8.0Hz, 2H), 7.42 (s, 1H), 7. 38 (d, J=8.0Hz, 2H), 7.30 (q, J=4.0Hz, 1H), 7.03 (s, 2H), 6.84 (s, 1H), 2.56 (d, J=4.0Hz, 3H).

[0418] Example 59

[0419] Example 59 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(methylamino)-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 59), with the following structural formula:

[0420] The preparation method of compound 59 is as follows:

[0421] (1) Preparation of intermediate 59-1: Compound 46-3 (200 mg, 0.658 mmol), methylamine hydrochloride (133 mg, 1.98 mmol), and DIPEA (653 μL, 3.95 mmol) were dissolved in 4 mL MeCN and reacted at 90 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 59-1 (130 mg, yield: 66%). The reaction formula is as follows:

[0422] (2) Preparation of compound 59: Using compound 59-1 (120 mg, 0.402 mmol) as the raw material, compound 59 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 59 (57.29 mg, yield: 32%).

[0423] The test results are as follows: MS(ESI) m / z = 460.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.23 (s, 1H), 10.42 (s, 1H), 7.99 (d, J = 12.0Hz, 2H), 7.51 (d, J = 4.0Hz, 1H), 7.46 (s, 1H), 7.38 (d, J=8.0Hz, 2H), 7.34 (t, J=4.0Hz, 1H), 6.68 (s, 1H), 2.95 (d, J=4.0Hz, 3H), 2.57 (d, J=4.0Hz, 3H).

[0424] Example 60

[0425] Example 60 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(dimethylamino)-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 60), with the following structural formula:

[0426] The preparation method of the above compound 60 is as follows:

[0427] (1) Preparation of intermediate 60-1: Using compound 46-3 (200 mg, 0.658 mmol) and dimethylamine hydrochloride (161 mg, 1.98 mmol) as raw materials, intermediate 60-1 was prepared by a method similar to step (1) of Example 59, yielding a yellow solid 60-1 (170 mg, yield: 83%). The reaction formula is as follows:

[0428] (2) Preparation of compound 60: Using compound 60-1 (120 mg, 0.384 mmol) as raw material, compound 60 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 60 (77.36 mg, yield: 40%).

[0429] The test results are as follows: MS(ESI) m / z = 474.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.34 (s, 1H), 10.31 (s, 1H), 7.99 (d, J=8.0Hz, 2H), 7.78 (s, 1H), 7. 39 (d, J=8.0Hz, 2H), 7.34 (q, J=4.0Hz, 1H), 6.71 (s, 1H), 3.36 (s, 6H), 2.56 (d, J=4.0Hz, 3H).

[0430] Example 61

[0431] Example 61 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(cyclopentylamino)-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 61), with the following structural formula:

[0432] The preparation method of compound 61 is as follows:

[0433] (1) Preparation of intermediate 61-1: Using compound 46-3 (200 mg, 0.658 mmol) and cyclopentylamine (196 μL, 1.98 mmol) as raw materials, intermediate 61-1 was prepared by a method similar to step (1) of Example 59, yielding a yellow solid 61-1 (110 mg, yield: 47%). The reaction formula is as follows:

[0434] (2) Preparation of compound 61: Using compound 61-1 (90 mg, 0.255 mmol) as raw material, compound 61 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain white solid compound 61 (2.54 mg, yield: 2.2%).

[0435] The test results are as follows: MS(ESI) m / z = 514.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.20 (s, 1H), 10.40 (s, 1H), 7.90 (d, J=8.0Hz, 2H), 7.58 (s, 1H), 7.39 -7.32 (m, 4H), 6.75 (s, 1H), 4.02 (s, 1H), 2.56 (d, J=4.0Hz, 3H), 2.02 (s, 2H), 1.77-1.61 (m, 6H).

[0436] Example 62

[0437] Example 62 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(3-fluoropyrrolidone-1-yl)-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 62), with the following structural formula:

[0438] The preparation method of compound 62 is as follows:

[0439] (1) Preparation of intermediate 62-1: Using compound 46-3 (180 mg, 0.592 mmol) and 3-fluoropyrrolidine hydrochloride (228 mg, 1.78 mmol) as raw materials, intermediate 62-1 was prepared by a method similar to step (1) of Example 59, yielding a yellow solid 62-1 (200 mg, yield: 94%). The reaction formula is as follows:

[0440] (2) Preparation of compound 62: Using compound 62-1 (180 mg, 0.505 mmol) as raw material, compound 62 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 62 (97.68 mg, yield: 36%).

[0441] The test results are as follows: MS(ESI) m / z = 518.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.38 (s, 1H), 10.31 (s, 1H), 7.89 (d, J=8.0Hz, 2H), 7.78 (s, 1H), 7.39-7 .35 (m, 3H), 6.64 (s, 1H), 5.58 (d, J = 52.0Hz, 1H), 4.06-3.82 (m, 4H), 2.56 (d, J = 4.0Hz, 3H), 2.40- 2.28(m,2H).

[0442] Example 63

[0443] Example 63 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(3-hydroxypyrrolidone-1-yl)-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 63), with the following structural formula:

[0444] The preparation method of the above compound 63 is as follows:

[0445] (1) Preparation of intermediate 63-1: Using compound 46-3 (200 mg, 0.658 mmol) and 3-hydroxypyrrolidine (172 mg, 1.98 mmol) as starting materials, intermediate 63-1 was prepared by a method similar to step (1) of Example 59, yielding a yellow solid 63-1 (120 mg, yield: 51%). The reaction formula is as follows:

[0446] (2) Preparation of compound 63: Using compound 63-1 (100 mg, 0.28 mmol) as raw material, compound 63 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 63 (35.91 mg, yield: 24%).

[0447] The test results are as follows: MS(ESI) m / z = 516.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.31 (s, 1H), 10.34 (s, 1H), 7.89 (d, J=12.0Hz, 2H), 7.78 (s, 1H), 7.40-7 .32 (m, 3H), 6.59 (s, 1H), 4.52 (s, 1H), 3.83-3.58 (m, 4H), 2.56 (d, J=8.0Hz, 3H), 2.16-2.02 (m, 2H).

[0448] Example 64

[0449] Example 64 provides a 4-(3-aminopiperidin-1-yl)-N-[4-(chlorodifluoromethoxy)phenyl]-6-(N-methylaminosulfonyl)-1H-7-azaindole-2-carboxamide (compound 64), with the following structural formula:

[0450] The preparation method of compound 64 is as follows:

[0451] (1) Preparation of intermediate 64-1: Using compound 46-3 (200 mg, 0.658 mmol) and piperidine-3-carbamate tert-butyl ester (CAS No. 172603-05-3, 403 mg, 1.98 mmol) as raw materials, intermediate 64-1 was prepared by a method similar to step (1) of Example 59, yielding a yellow solid 64-1 (170 mg, yield: 55%). The reaction formula is as follows:

[0452] (2) Preparation of intermediate 64-2: Using compound 63-1 (145 mg, 0.31 mmol) as a starting material, intermediate 64-2 was prepared by a method similar to steps (5)-(6) of Example 16 to obtain a yellow solid compound 63-2 (65 mg, yield: 67%). The reaction formula is as follows:

[0453] (3) Preparation of compound 64: Using compound 64-2 (35 mg, 0.056 mmol) as raw material, compound 64 was prepared by a method similar to step (2) of Example 29 to obtain white solid compound 64 (4.34 mg, yield: 14%).

[0454] The test results are as follows: MS(ESI) m / z = 529.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ10.73 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.72 (s, 1H), 7.40-7.38 (m, 3H), 6.99 (s, 1H), 4.12 (d, J =12.0Hz, 1H), 3.92 (d, J = 12.0Hz, 1H), 3.20-3.03 (m, 6H), 2.57 (d, J = 4.0Hz, 3H), 2.02-1.88 (m, 2H), 1.69-1.45 (m, 2H).

[0455] Example 65

[0456] Example 65 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3,3-difluoroazacyclobut-1-yl)methyl]-6-aminosulfonyl-1H-7-azaindole-2-carboxamide (compound 65), with the following structural formula:

[0457] The preparation method of the above compound 65 is as follows:

[0458] (1) Preparation of intermediate 65-1: 2-Methyl-2-propylamine (CAS No. 75-64-9, 779 μL, 7.28 mmol) was added dropwise to 5 mL of a THF solution of compound 46-2 (450 mg, 1.46 mmol) under ice bath conditions, and the reaction was carried out for 30 min under ice bath conditions. After the reaction was completed, 5 mL of EA and 1 mL of water were added to the reaction solution. The aqueous phase was extracted three times with 1 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid 65-1 (190 mg, yield: 38%). The reaction formula is as follows:

[0459] (2) Preparation of intermediate 65-2: Using compound 65-1 (170 mg, 0.492 mmol) and compound 17-2 (314 mg, 1.47 mmol) as raw materials, the intermediate 65-2 was prepared according to steps (2), (5)-(6) of Example 16, yielding a brown oily substance 65-2 (60 mg, yield: 84%). The reaction formula is as follows:

[0460] (3) Preparation of compound 65: Compound 65-2 (50 mg, 0.0865 mmol) was dissolved in 600 μL of DCM, and 600 μL of TFA was added under ice bath conditions. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered and purified by reversed-phase high-performance liquid chromatography (Pre-HPLC) to obtain a white solid compound 65 (11 mg, yield: 22%).

[0461] The test results are as follows: MS(ESI) m / z = 522.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.87 (s, 1H), 10.70 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7. 72 (s, 1H), 7.61 (s, 1H), 7.45-7.39 (m, 4H), 4.20 (s, 2H), 3.75 (t, J=12.0Hz, 1H).

[0462] Example 66

[0463] Example 66 provides a (S)-N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluoropyrrolidone-1-yl)methyl]-6-(pyrrolidone-1-ylsulfonyl)-1H-7-azaindole-2-carboxamide (compound 66), with the following structural formula:

[0464] The preparation method of compound 66 is as follows:

[0465] (1) Preparation of intermediate 66-1: Tetrahydropyrrolidine (CAS No. 123-75-1, 368 μL, 4.46 mmol) and DIPEA (1.48 mL, 8.92 mmol) were added to 6 mL of THF under ice bath conditions. Then, 10 mL of a THF solution of compound 46-2 (920 mg, 2.98 mmol) was added dropwise. The reaction was carried out under ice bath conditions for 1 h. After the reaction was completed, 10 mL of EA and 5 mL of water were added to the reaction solution. The mixture was extracted and separated. The aqueous phase was extracted three times with 5 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid 66-1 (680 mg, yield: 66%). The reaction formula is as follows:

[0466] (2) Preparation of compound 66: Using compound 66-1 (280 mg, 0.814 mmol) and compound 23-2 (511 mg, 2.44 mmol) as raw materials, compound 66 was prepared by a method similar to steps (2), (5)-(6) of Example 16 to obtain a yellow solid compound 66 (28.4 mg, yield: 14%).

[0467] The test results are as follows: MS(ESI) m / z = 572.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.12 (s, 1H), 10.70 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.72 (s, 1H), 7.4 3 (d, J=8.0Hz, 2H), 5.47 (d, J=52.0Hz, 1H), 4.84 (s, 2H), 3.80-3.45 (m, 4H), 2.20 (s, 2H), 1.78-1.75 (m, 4H).

[0468] Example 67

[0469] Example 67 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-(pyrrolidine-1-ylmethyl)-6-(pyrrolidine-1-ylsulfonyl)-1H-7-azaindole-2-carboxamide (compound 67), with the following structural formula:

[0470] The preparation method of the above compound 67 is as follows: using compound 66-1 (280 mg, 0.814 mmol) and compound 20-2 (465 mg, 2.44 mmol) as raw materials, the compound 67 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a yellow solid compound 67 (24.6 mg, yield: 14%).

[0471] The test results are as follows: MS(ESI) m / z = 554.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.84 (s, 1H), 10.60 (s, 1H), 7.94 (d, J=9.2Hz, 2H), 7.66 (d, J=15.6Hz, 2 H), 7.40 (d, J=9.2Hz, 2H), 4.02 (s, 2H), 3.37-3.29 (m, 4H), 2.55-2.49 (m, 4H), 1.76-1.74 (m, 8H).

[0472] Example 68

[0473] Example 68 provides a 6-(azacyclobutane-1-ylsulfonyl)-N-[4-(chlorodifluoromethoxy)phenyl]-4-(pyrrolidone-1-ylmethyl)-1H-7-azaindole-2-carboxamide (compound 68), with the following structural formula:

[0474] The preparation method of compound 68 is as follows:

[0475] (1) Preparation of intermediate 68-1: Using aziridine (CAS No. 503-29-7, 114.19 mg, 2.23 mmol) as a starting material, intermediate 68-1 was prepared according to a method similar to step (1) of Example 66, yielding a yellow solid 68-1 (412 mg, yield: 56%). The reaction formula is as follows:

[0476] (2) Preparation of compound 68: Using compound 68-1 (268.42 mg, 0.814 mmol) and compound 16-2 (432.61 mg, 2.44 mmol) as raw materials, compound 68 was prepared by a method similar to steps (2), (5)-(6) of Example 16 to obtain a yellow solid compound 68 (23.6 mg, yield: 13%).

[0477] The test results are as follows: MS(ESI) m / z = 540.2 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ13.24 (s, 1H), 10.72 (s, 1H), 10.14 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=9.2Hz, 2H), 7.76 (s, 1H), 7.43 (d, J=9.2Hz, 2H), 4.87 (d, J=4.8Hz, 2H), 4.00 (t, J=7.6Hz, 4H), 3.51 (s, 2H), 3.22 (s, 2H), 2.13-2.09 (m, 4H), 1.93 (s, 2H).

[0478] Example 69

[0479] Example 69 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluorozacricyclobut-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 69), with the following structural formula:

[0480] The preparation method of compound 69 is as follows:

[0481] (1) Preparation of intermediate 69-1: Compound 9-3 (450 mg, 1.75 mmol), oxalic acid (332 mg, 3.51 mmol), acetic anhydride (358 mg, 3.51 mmol), DIPEA (585 μL, 3.51 mmol), palladium acetate (40 mg, 0.175 mmol), and XantPhos (207 mg, 0.35 mmol) were dissolved in 10 mL of DMF and reacted at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under vacuum and purified by silica gel column chromatography to obtain a yellow solid 69-1 (459.26 mg, yield: 98.56%). The reaction formula is as follows:

[0482] (2) Preparation of intermediate 69-2: Under ice bath conditions, TCFH (457 mg, 1.60 mmol) and NMI (454 μL, 5.59 mmol) were dissolved in 6 mL of DMFZ. Compound 69-1 (425 mg, 1.60 mmol) was added, and the mixture was stirred for 15 min. Then, under ice bath conditions, 3-fluorozacriane hydrochloride (CAS No. 617718-46-4, 202 mg, 1.76 mmol) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was complete, 3 mL of EA and 1 mL of water were added to the reaction solution, and the mixture was extracted. The aqueous phase was extracted three times with 2 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid 69-2 (380 mg, yield: 74%). The reaction formula is as follows:

[0483] (3) Preparation of intermediate 69-3: Compound 69-2 (330 mg, 1.02 mmol) was dissolved in 4 mL of THF, and a 10 M BMS (255 μL, 2.55 mmol) THF solution was added under ice bath conditions. The reaction was carried out at 50 °C for 5 h. After the reaction was completed, methanol was added to the reaction solution and the mixture was concentrated. The solution was purified by silica gel column chromatography to obtain a yellow solid 69-3 (260 mg, yield: 82%). The reaction formula is as follows:

[0484] (4) Preparation of compound 69: Using compound 69-3 (220 mg, 0.71 mmol) as raw material, compound 69 was prepared by a method similar to steps (3)-(6) of Example 16 to obtain white solid compound 69 (25.31 mg, yield: 29%).

[0485] The test results are as follows: MS(ESI) m / z = 503.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.99 (s, 1H), 10.69 (s, 1H), 7.96 (d, J=8.0Hz, 2H), 7.77 (s, 1H), 7.69 (s, 1H) , 7.42 (d, J=12.0Hz, 2H), 5.26 (dt, J=56.0Hz, 1H), 4.13 (s, 2H), 4.13-3.65 (m, 2H), 3.35-3.26 (m, 5H).

[0486] Example 70

[0487] Example 70 provides an N-[4-(chlorodifluoromethoxy)phenyl]-4-[(3-fluoro-3-methylazacyclobut-1-yl)methyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 70), with the following structural formula:

[0488] The preparation method of the above compound 70 is as follows:

[0489] (1) Preparation of intermediate 70-2: Using 3-fluoro-3-methylazacyclobutane (CAS No. 1427379-42-7, 1.88 g, 14.94 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16, yielding a white solid 70-2 (3 g, yield: 96.06%). The reaction formula is as follows:

[0490] (2) Preparation of compound 70: Using compound 70-2 (1.22 g, 5.84 mmol) and compound 9-3 (500 mg, 1.95 mmol) as raw materials, compound 70 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 70 (29.70 mg, yield: 29%).

[0491] The test results are as follows: MS(ESI) m / z = 517.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ12.98 (s, 1H), 10.67 (s, 1H), 7.95 (d, J=8.0Hz, 2H), 7.77 (s, 1H), 7.70 (s, 1H), 4.42 (d, J=12.0Hz, 2H), 4.15 (s, 2H), 3.47-3.37 (m, 4H), 3.31 (s, 3H), 1.58 (d, J=20.0Hz, 3H).

[0492] Example 71

[0493] Example 71 provides a 4-[(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)methyl]-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 71), with the following structural formula:

[0494] The preparation method of the above compound 71 is as follows:

[0495] (1) Preparation of intermediate 71-2: Using 6-oxa-3-azabicyclo[3.1.1]heptane (CAS No. 112461-31-1, 476 mg, 3.41 mmol) as the starting material, a white oily substance 71-2 (700 mg, yield: 93.71%) was prepared according to a method similar to step (1) of Example 16. The reaction formula is as follows:

[0496] (2) Preparation of compound 71: Compound 70-2 (683 mg, 3.12 mmol) and compound 9-3 (400 mg, 1.56 mmol) were used as raw materials and prepared according to the method similar to steps (2)-(6) of Example 16 to obtain white solid compound 71 (56 mg, yield: 26%).

[0497] The test results are as follows: MS(ESI) m / z = 527.2 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ12.97 (s, 1H), 10.63 (s, 1H), 7.94 (d, J=8.0Hz, 2H), 7.84 (s, 1H), 7.75 (s, 1H), 7.42 (d, J=8Hz, 2H), 4. 46 (d, J=4Hz, 2H), 4.20 (s, 2H), 3.10 (s, 3H), 3.07 (d, J=4Hz, 2H), 2.93-2.88 (m, 1H), 2.80 (d, J=8.0Hz, 2H), 3.36-3.34 (m, 1H).

[0498] Example 72

[0499] Example 72 provides a 4-[(2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl]-N-[4-(chlorodifluoromethoxy)phenyl]-6-(methanesulfonyl)-1H-7-azaindole-2-carboxamide (compound 72), with the following structural formula:

[0500] The preparation method of the above compound 72 is as follows:

[0501] (1) Preparation of intermediate 72-2: Using 2-oxa-5-azabicyclo[2.2.1]heptane (CAS No. 279-33-4, 1 g, 7.47 mmol) as the starting material, it was prepared by a method similar to step (1) of Example 16 to obtain a yellow solid 72-2 (1.2 g, yield: 73.33%). The reaction formula is as follows:

[0502] (2) Preparation of compound 72: Using compound 72-2 (896 mg, 4.09 mmol) and compound 9-3 (350 mg, 1.36 mmol) as raw materials, compound 72 was prepared by a method similar to steps (2)-(6) of Example 16 to obtain a yellow solid compound 72 (26.53 mg, yield: 13.61%).

[0503] The detection results are as follows: MS(ESI) m / z = 527.21 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.05 (s, 1H), 10.70 (s, 1H), 8.14 (s, 1H), 7.96 (d, J=4.0Hz, 2H), 7.76 (s, 1H), 7.42 (d, J= 8.0Hz, 2H), 4.50-4.32(m, 4H), 4.07-4.0(m, 1H), 3.76-3.66(m, 2H), 3.20(s, 3H), 2.90-2.74(m, 1H), 2.04(s, 2H).

[0504] Example 73

[0505] Example 73 provides a (S)-N-[4-(chlorodifluoromethoxy)phenyl]-6-(dimethylphosphoryl)-4-[(3-fluoropyrrolidone-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (compound 73), with the following structural formula:

[0506] The preparation method of the above compound 73 is as follows:

[0507] (1) Preparation of intermediate 73-1: Ethyl 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (CAS No. 577711-94-5, 1.10 g, 4.09 mmol), Pd2(dba)3 (374 mg, 0.409 mmol), XantPhos (473 mg, 0.817 mmol), and potassium phosphate (1.30 g, 6.13 mmol) were dissolved in 20 mL of 1,4-dioxane. Dimethylphosphine oxide (638 mg, 8.18 mmol) was added, and the reaction was carried out at 110 °C for 3 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography to obtain a white solid 73-1 (550 mg, yield: 50%). The reaction formula is as follows:

[0508] (2) Preparation of intermediate 73-2: Compound 73-1 (500 mg, 1.88 mmol) was dissolved in 10 mL of DCM, and 85% M-CPBA (1.03 g, 5.07 mmol) was added. The reaction was carried out at 20 °C for 16 h. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a yellow liquid 73-2 (480 mg, yield: 90.46%). The reaction formula is as follows:

[0509] (3) Preparation of intermediate 73-3: Compound 73-2 (477 mg, 1.69 mmol) was dissolved in 10 mL of DCM, and phosphorus oxychloride (315 μL, 3.38 mmol) was added under ice bath conditions. The reaction was carried out at 20 °C for 2 h. Then, 10 mL of saturated sodium bicarbonate was added to the reaction solution, and the mixture was stirred for 5 min. After the reaction was completed, the aqueous phase was extracted twice with 10 mL of DCM. The organic phases were combined and washed twice with 5 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a yellow solid 73-3 (535 mg, yield: 98%). The reaction formula is as follows:

[0510] (4) Preparation of intermediate 73-4: Compound 73-3 (535 mg, 1.68 mmol) was dissolved in 10 mL MeCN, and Pin2B2 (644 mg, 2.53 mmol) was added. The reaction was carried out at 75 °C for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated, and purified by silica gel column chromatography to obtain a white solid 73-4 (400 mg, yield: 78%). The reaction formula is as follows:

[0511] (5) Preparation of compound 73: Using compound 73-4 (150 mg, 0.50 mmol) and compound 23-2 (312.85 mg, 1.50 mmol) as raw materials, compound 73 was prepared by a method similar to steps (2), (5)-(6) of Example 16, to obtain white solid compound 73 (23.11 mg, yield: 13.8%).

[0512] The test results are as follows: MS(ESI) m / z = 515.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ13.02 (s, 1H), 10.56 (s, 1H), 8.63 (s, 1H), 7.91-7.89 (m, 3H), 7.45 (d, J=8.0Hz , 2H), 5.57-5.28(m, 1H), 4.92(s, 2H), 4.13-3.44(m, 4H), 2.37-2.08(m, 2H), 1.76(s, 3H), 1.72(s, 3H).

[0513] Example 74

[0514] Example 74 provides an N-[4-(chlorodifluoromethoxy)phenyl]-6-(dimethylphosphoryl)-4-(pyrrolidine-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (compound 74), with the following structural formula:

[0515] The preparation method of the above compound 74 is as follows: using compound 74-4 (150 mg, 0.50 mmol) and compound 20-2 (286 mg, 1.5 mmol) as raw materials, the compound 74 was prepared in a manner similar to steps (2), (5)-(6) of Example 16, to obtain a white solid compound 74 (25.82 mg, yield: 12%).

[0516] The test results are as follows: MS(ESI) m / z = 497.1 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ13.00 (s, 1H), 10.57 (s, 1H), 8.63 (d, J=8.0Hz, 1H), 7.92-7.87 (m, 3H), 7.45 (d, J=8.0Hz, 2H) , 4.86 (s, 2H), 4.86 (s, 2H), 3.46 (t, J=4.0Hz, 2H), 3.27 (t, J=4.0Hz, 2H), 2.09-2.08 (m, 2H), 1.76 (s, 3H), 1.72 (s, 3H).

[0517] Inhibition activity test

[0518] The inhibitory activity of some of the azaindole compounds provided in the embodiments of this application was tested. The results are shown in Table 4 below.

[0519] The following experiments investigated the inhibitory effects of the test compounds (compounds 1, 2, 5, 6, 8, 13, 17, 22, 23, 24, 26, 28, 31, 34, 41, 46, 48, 49, 51, 53, 66, and the existing ABL001) on the proliferation of Ba / F3 cells transfected with BCR-ABL-T315I and BCR-ABL-WT. The specific procedures are as follows:

[0520] (1) First, prepare complete culture medium (RPMI-1640 + 10% FBS + 1% P / S) to revive Ba / F3-BCR-ABL-WT and Ba / F3-BCR-ABL-T315I cells (purchased from Hefei Presun). After passage for about two generations, centrifuge to collect cells in the logarithmic growth phase and count them. Resuspend the cells to an appropriate concentration and seed the cell suspension into 96-well plates. Add 95 μL of cell suspension to each well, and the seeding density is 2000 cells / well.

[0521] (2) The test compound was prepared into a stock solution using DMSO, and serially diluted with DMSO. The test compound was diluted 50-fold with culture medium, and 5 μL of each solution was added to a 96-well cell plate containing 95 μL of cells. Cell-free culture medium was added to the Min control wells, and 5 μL of DMSO-cell culture medium mixture was added to the Max control wells. The mixture was incubated at 37°C and 5% CO2 for 72 h. 50 μL / well CellTiter Glo was added to stop the reaction, and the mixture was incubated at room temperature in the dark for 30 min. After gentle shaking, the fluorescence value (RLU) was measured in SpectraMax Paradigm.

[0522] (3) Calculate the cell proliferation inhibition rate (Inh%) according to the following formula: Cell proliferation inhibition rate = 100 - (RLUDrug - RLUMin) / (RLUMax - RLUMin) × 100%. Calculate the inhibition rate corresponding to different concentrations of the compound in EXCEL, and use GraphPad Prism software to plot the inhibition rate curve to obtain the half-maximum inhibitory concentration (IC50). 50 value.

[0523] Note: IC 50 A value <5000 nM is considered to indicate that the compound has an inhibitory effect on the proliferation of BCR-ABL-WT transfected Ba / F3 cells, and the IC50 value is <5000 nM. 50 The smaller the value, the stronger the inhibitory effect of the compound.

[0524] Table 4. Results of the inhibitory effects of the compounds on the proliferation of BCR-ABL-T315I and BCR-ABL-WT transfected Ba / F3 cells.

[0525] According to the activity test results in Table 4, the compounds provided in this application showed good inhibitory activity against Ba / F3 cells transfected with BCR-ABL-T315I and BCR-ABL-WT, indicating that the azaindole compounds provided in this application can be used as BCR-ABL inhibitors and are expected to be developed into drugs for the treatment and / or prevention of BCR-ABL-related diseases.

[0526] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A azidoindole compound, characterized in that, The azaindole compound is a compound represented by general formula I or a pharmaceutically acceptable salt, isomer, solvate, hydrate, prodrug, or isotope derivative thereof; the structural formula of general formula I is: In general formula I, R1 is selected from hydrogen, halogen, amino, hydroxyl, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, C 1-6 Alkyloxy or substituted C 1-6 Alkyloxy; R2 is one, two, or three identical or different substituents present on the pyridine ring; R2 is independently selected from the following groups: hydrogen, halogen, amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkyloxy group, substituted C 1-6 Alkyloxy, C 1-6 Alkyl mercapto, substituted C 1-6 Alkyl mercapto, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, substituted C 3-10 Heterocyclic alkyl, optionally substituted sulfonyl, optionally substituted phosphoryl, or groups as shown in formula (1): In formula (1), L is selected from methylene, substituted methylene, imino, substituted imino, oxygen, or carbonyl; Z is selected from hydrogen, halogen, amino, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl or substituted C 3-10 Heterocyclic alkyl groups.

2. The azaindole compound according to claim 1, characterized in that, The structural formula of the azaindole compound is shown in general formula II: In general formula II, R3 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, substituted C 3-10 Heterocyclic alkyl groups or groups represented by formula (1); R4 is selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyloxy group, substituted C 1-6 Alkyloxy, C 1-6 Alkyl mercapto, substituted C 1-6 Alkyl mercapto, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, optionally substituted sulfonyl, optionally substituted phosphoryl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl or substituted C 3-10 Heterocyclic alkyl groups.

3. The azaindole compound according to claim 1, characterized in that, R1 is selected from hydrogen, amino, C 1-6 Alkyl or C 3-7 Cycloalkyl.

4. The azaindole compound according to claim 2, characterized in that, R3 is selected from hydrogen, halogens, and C. 3-10 Heterocyclic alkyl groups, substituted C 3-10 Heterocyclic alkyl groups, or groups represented by formula (1); In formula (1), L is selected from methylene, imino, substituted imino, oxygen, and carbonyl; Z is selected from hydrogen, amino, and C. 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl or substituted C 3-10 Heterocyclic alkyl groups; R4 is selected from hydrogen, halogens, and C. 1-6 Alkyloxy, C 1-6 Alkyl mercapto, C 1-6 Alkylamino, substituted C 1-6 Alkylamino, optionally substituted sulfonyl, optionally substituted phosphoryl, substituted C 3-10 Heterocyclic alkyl groups.

5. The azaindole compound according to claim 1, characterized in that, The azaindole compounds are selected from:

6. The use of the azaindole compound as described in any one of claims 1-5 in the preparation of medicaments for treating and / or preventing tumor diseases.

7. A medicament for treating and / or preventing tumor diseases, characterized in that, The compound comprising any one of claims 1-5.

8. A BCR-ABL inhibitor, characterized in that, The compound comprising any one of claims 1-5.

9. A medicament for treating and / or preventing BCR-ABL-related diseases, characterized in that, It comprises any one of the azaindole compounds according to claims 1-5, as well as pharmaceutically acceptable carriers and / or excipients.

10. The medicine according to claim 9, characterized in that, The BCR-ABL-related diseases are selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, invasive carcinoma, viral infection, or CNS disorder.

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