An arylinazole cyclic compound, its preparation method, pharmaceutical composition, and uses.

Abstract

This invention relates to an arylinazole cyclic compound, its preparation method, pharmaceutical composition, and uses. The arylinazole cyclic compound includes compounds of formula (I) or pharmaceutically acceptable salts thereof. This invention also relates to pharmaceutical compositions comprising the arylinazole cyclic compound, its preparation method, and the use of these compounds and compositions in the preparation of drugs for the prevention or treatment of rheumatoid arthritis, exhibiting good preventive or therapeutic effects and certain drug-like properties. In in vitro experiments, under hypoxic conditions, phosphorylation of the VEGFR2 tyrosine kinase domain Tyr951 binds to the T cell-specific adapter, triggering activation of downstream PI3K / AKT in VEGFR2 signaling, thereby regulating vascular endothelial cell function. The arylinazole cyclic compound disclosed in this invention has a chemical structure different from existing VEGFR2 inhibitors, representing a novel VEGFR2 inhibitor with good metabolic stability.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmacotherapeutic technology, and particularly relates to an arylinazole cyclic compound, its preparation method, pharmaceutical composition, and uses. Background Technology

[0002] Synovial angiogenesis is crucial for synovial expansion, proliferation, and infiltration, and also contributes to rheumatoid arthritis inflammation and cartilage / bone damage. Statistics show that the incidence of rheumatoid arthritis is 0.5%-1.0%, with a predominantly female population. Due to its long course, high disability rate, and wide affected population, it causes serious social and public health problems. VEGFR2, also known as fetal liver kinase-1 (Flk-1) in mice and kinase insertion domain receptor (KDR) in humans, is a major mediator of angiogenesis, mitosis, and vascular permeability activity. Angiogenesis refers to the process of new blood vessels forming from pre-existing capillaries through budding. This process is involved in many physiological and pathological processes in the human body, including but not limited to embryonic development, the menstrual cycle, wound healing, as well as tumors, rheumatoid arthritis, diabetes, and retinopathy. Therefore, VEGFR2 is of significant importance in the physiological process of angiogenesis and may contribute to future anti-tumor treatments or the treatment of rheumatic diseases such as rheumatoid arthritis and autoimmune diseases.

[0003] Increased KDR expression during hypoxia is a key inducer of VEGF gene transcription. Increased VEGF / KDR signaling not only promotes angiogenesis but also plays a crucial role in atherosclerosis and chronic inflammation. Phosphorylation of Tyr951 by the VEGFR2 tyrosine kinase domain binds to the T cell-specific adapter, triggering activation of downstream PI3K / AKT pathways of VEGFR2 signaling, thereby regulating vascular endothelial cell function. Therefore, targeting the VEGFR2 / PI3K / AKT pathway to inhibit synovial angiogenesis is a rational strategy for treating rheumatoid arthritis.

[0004] The growth and maturation of new blood vessels require stimulation from various growth factors; however, vascular endothelial growth factor (VEGF) signaling is often a key rate-limiting step in both physiological and pathological angiogenesis. VEGFR2 is a major mediator of mitosis, angiogenesis, microvascular permeability, and vascular endothelial cell survival. Therefore, directly inhibiting signal transduction via the VEGF / VEGFR2 system is a promising strategy for inhibiting angiogenesis. Since new blood formation is crucial in RA, directly inhibiting VEGFR2 kinase activity holds promise for reducing angiogenesis, potentially providing a promising strategy for RA treatment. Furthermore, reports of several VEGFR2 inhibitors highlight the interest of medicinal chemists in this class of therapeutics. However, adverse side effects observed in clinical studies, including bleeding complications, indicate a significant need for developing more potent and less toxic VEGFR2 inhibitors in preclinical mechanistic and clinicopathological studies.

[0005] Currently, drug therapy is the primary treatment for rheumatoid arthritis (RA) in clinical practice. While these drugs can alleviate RA symptoms to some extent, most cause serious side effects with long-term use. With ongoing basic and clinical research, numerous RA-related genes and their protein regulatory networks have been identified, playing crucial roles in the occurrence, development, and progression of RA. This research has significantly expanded the targets for new drug development, leading to a series of drugs for treating RA. Although numerous drug treatment options are available clinically, 50%-70% of RA patients still fail to achieve disease remission or reduce disease activity during treatment, ultimately resulting in treatment failure. Therefore, how to safely and effectively treat RA remains a significant clinical challenge. Summary of the Invention

[0006] The technical problem to be solved by this invention is that there is a lack of drugs on the market that target and inhibit angiogenesis with VEGFR2 as the drug target to prevent and treat rheumatoid arthritis. This invention provides aryl indazole cyclic compounds with better in vivo stability, their preparation methods, drug compositions and uses.

[0007] The invention solves the above-mentioned technical problems through the following technical solution: the present invention provides an arylinazole cyclic compound, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008]

[0009] Among them, Ar 1 Selected from the following aromatic rings or aromatic ring systems:

[0010]

[0011] Ar 2Selected from the following aromatic rings or aromatic ring systems:

[0012]

[0013] Ar 3 Selected from the following aromatic rings or aromatic ring systems:

[0014]

[0015] Among them, the alkylinazole cyclic compounds as described above are selected from any of the following compounds:

[0016]

[0017]

[0018]

[0019]

[0020] In one embodiment, a method for preparing an arylinazole cyclic compound as described above includes the following synthetic steps:

[0021] Reactant B1 was added to a dichloromethane solution of reactant A1. The resulting mixture was stirred at room temperature for 8 hours, then diluted with ethyl acetate and washed with water, followed by washing with brine. The organic layer was dried on anhydrous sodium sulfate and concentrated. The residue was diluted with dichloromethane and trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 hours, and the pH was adjusted to 12 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and washed with water, followed by washing with brine. The organic layer was dried on sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with 0-5% methanol in dichloromethane to obtain arylinazole cyclic compounds.

[0022] In one embodiment, a method for preparing an arylinazole cyclic compound as described above includes the following synthetic steps:

[0023] (1) Add catalyst D1 to the mixture of reactant A2 and reactant B2 in solvent C1, stir the mixture at 80°C for 14 h under argon atmosphere, evaporate the solvent and dilute with ethyl acetate, then wash with water and brine, evaporate the organic phase, and elute, precipitate and purify by silica gel column chromatography with ethyl acetate in petroleum ether at a volume fraction of 10%-30% to obtain intermediate E1;

[0024] (2) Add reactant F1 to a dichloromethane solution of intermediate E1; stir the resulting mixture at room temperature for 8 h, then dilute with ethyl acetate and wash with water, then wash with brine; dry the organic layer on anhydrous sodium sulfate and concentrate it, dilute the residue with dichloromethane and trifluoroacetic acid, stir the reaction mixture at room temperature for 4 h, then adjust the pH to 12 with saturated sodium bicarbonate, extract the mixture with ethyl acetate, wash with water, then wash with brine; dry the organic layer with sodium sulfate, then filter, concentrate, elute with 0-5% methanol in dichloromethane through a silica gel column, purify, and obtain arylinazole cyclic compounds.

[0025] In one embodiment, a method for preparing an arylinazole cyclic compound as described above includes the following synthetic steps:

[0026] (1) Add catalyst D2 to the mixture of reactant A3 and reactant B3 in dry solvent C2, stir the mixture at 80°C under argon atmosphere for 14 h, evaporate the solvent and dilute with ethyl acetate, then wash with water and brine, evaporate the organic phase, elute with 10%-30% ethyl acetate in petroleum ether using silica gel column chromatography, and purify to obtain intermediate E2.

[0027] (2) Add reactant F2 to a dichloromethane solution of intermediate E2, stir the resulting mixture at room temperature for 8 h, then dilute with ethyl acetate and wash with water, then wash with brine, dry the organic layer on anhydrous sodium sulfate and concentrate, and dilute the residue with dichloromethane and trifluoroacetic acid; stir the reaction mixture at room temperature for 4 h, then adjust the pH to 12 with saturated sodium bicarbonate, extract the mixture with ethyl acetate, wash with water, then wash with brine, dry the organic layer with sodium sulfate, then filter, concentrate, and elute, precipitate, and purify by silica gel column chromatography with 0-5% methanol in dichloromethane to obtain intermediate E3;

[0028] (3) Sodium hydroxide was added to an anhydrous N,N-dimethylformamide solution of intermediate E3. The mixture was stirred at 0°C. After adding anhydrous N,N-dimethylformamide solution of iodine dropwise, the mixture was stirred at room temperature for 4 hours. The reaction endpoint was detected by LC-MS. After the reaction was completed, the solvent was evaporated, extracted with ethyl acetate, and then washed with water and saturated saline solution respectively. The organic layer was evaporated, mixed, and then eluted with 0-30% ethyl acetate in petroleum ether, purified by silica gel column chromatography to obtain intermediate E4.

[0029] (4) Add catalyst D3 to the dry N,N-dimethylformamide mixture of intermediate E4 and reactant F3, stir the mixture at 80°C under an argon atmosphere for 14 h, evaporate the solvent and dilute with ethyl acetate, then wash with water and brine; evaporate the organic phase, elute with 10%-30% ethyl acetate in petroleum ether by silica gel column chromatography, and purify to obtain aryl indazole cyclic compounds.

[0030] A pharmaceutical composition comprising one or more therapeutically effective amounts of an arylinazole cyclic compound of general formula (I) as described above, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0031] The use of one or more arylinazole cyclic compounds of general formula (I) as described above, or pharmaceutically acceptable salts thereof, in medicaments for diseases caused by upregulation of VEGFR2 kinase activity leading to angiogenesis.

[0032] Furthermore, its application in drugs for diseases caused by VEGFR2 kinase upregulation leading to angiogenesis, wherein the diseases include at least one of the following: anti-tumor therapy or rheumatic diseases such as rheumatoid arthritis, autoimmune diseases, and / or

[0033] The diseases mentioned include at least one of various inflammatory diseases, such as arthritis, asthma, and inflammatory bowel disease.

[0034] Use in a medicament for the prevention or treatment of rheumatoid arthritis, comprising one or more aryl indazole cyclic compounds of general formula (I) as described above or a pharmaceutically acceptable salt thereof, targeting the VEGFR2 / PI3K / AKT pathway to inhibit synovial angiogenesis.

[0035] Furthermore, the application of drugs that target the VEGFR2 / PI3K / AKT pathway to inhibit synovial angiogenesis for the prevention or treatment of rheumatoid arthritis, wherein the rheumatoid arthritis includes at least one of the following: joint involvement, rheumatoid vasculitis, cardiac involvement, respiratory involvement, kidney involvement, and hematologic problems (such as anemia), pleurisy, pleural effusion, pulmonary arteritis, interstitial lung disease, glomerulonephritis, and tubulointerstitial nephritis.

[0036] The positive advancements and beneficial effects of this invention are as follows:

[0037] The present invention provides and demonstrates that the aryl indazole cyclic compounds or pharmaceutically acceptable salts thereof, under hypoxic conditions, phosphorylation of the VEGFR2 tyrosine kinase domain Tyr951 and its binding to the T cell-specific adapter triggers the activation of downstream PI3K / AKT in VEGFR2 signaling, thereby regulating vascular endothelial cell function. The above pharmacological experiments demonstrate that the application of aryl indazole cyclic compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention or treatment of rheumatoid arthritis exhibits good preventive or therapeutic effects and possesses certain drug-like properties.

[0038] The arylinazole cyclic compounds disclosed in this invention have chemical structures that differ from existing VEGFR2 inhibitors, representing a novel class of VEGFR2 inhibitors. Furthermore, the representative compounds disclosed in this invention exhibit good metabolic stability. Detailed Implementation

[0039] the term

[0040] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains.

[0041] Unless otherwise stated, this invention employs conventional methods within the scope of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology. Unless specifically defined, nomenclature and laboratory procedures and techniques related to analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art. Generally, the foregoing techniques and steps can be practiced by conventional methods well-known in the art and described in various general and more specific documents, which are cited and discussed herein.

[0042] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight-chain alkyl group. Depending on the structure, an alkyl group can be a monovalent or divalent group (i.e., an alkylene group). In this invention, the alkyl group is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl group" having 1-6 carbon atoms, and even more preferably an alkyl group having 1-4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that "alkyl" as used herein includes all possible configurations and conformations of the alkyl group; for example, "propyl" as used herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl, and tert-butyl, and "pentyl" includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl, etc.

[0043] The term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

[0044] The term "alkoxyalkyl" refers to an alkyl group as defined herein that has been substituted with an alkoxy group as defined herein.

[0045] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent or bivalent group (e.g., a cycloalkylene group). In this invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0046] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" means that an alkyl group as defined herein is substituted with a cycloalkyl group as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0047] The term "aromatic group" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. An aromatic ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic group" includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0048] As used herein, the term "aryl" refers to an aromatic ring in which every atom constituting the ring is a carbon atom. An aryl ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. Depending on the structure, the aryl group can be a monovalent or divalent group (i.e., an arylene).

[0049] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined herein.

[0050] The term "heteroaryl" refers to an aryl group that includes one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety means that at least one skeletal atom on the ring of the aryl group is a nitrogen atom. Depending on its structure, a heteroaryl can be a monovalent or bivalent group (i.e., a hypoaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoydinolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc.

[0051] The term "alkyl (aryl)" or "aralkyl" means that an alkyl group as defined herein is replaced by an aryl group as defined herein. Non-limiting alkyl (aryl) groups include benzyl, phenethyl, etc.

[0052] The term “alkyl (heteroaryl)” or “heteroarylalkyl” means that an alkyl group as defined herein is replaced by a heteroaryl group as defined herein.

[0053] As used herein, the term "heteroalkyl" means an alkyl group in which one or more skeletal chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatoms (one or more) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.

[0054] As used herein, the term "heterocyclic alkyl" or "heterocyclic group" refers to a non-aromatic ring in which one or more constituent atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl rings can consist of three, four, five, six, seven, eight, nine, or more than nine atoms. Heterocyclic alkyl rings may be optionally substituted. Examples of heterocyclic alkyl groups include, but are not limited to, lactams, lactones, cycloimides, cyclothioimides, cyclocarbamates, tetrahydrothiarans, 4H-pyrans, tetrahydropyrans, piperidine, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxothiacyclohexanes, 1,4-oxothiacyclohexadiene, 1,4-oxothiacyclohexanes, tetrahydro-1,4-thiazines, 2H-1,2-oxazines, maleimides, succinimides, barbiturates, and thiobarbiturates. Acids, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolidone, pyrrolidine, imidazoline, pyrazole, imidazoline, imidazoline, 1,3-dioxacyclopentene, 1,3-dioxacyclopentene, 1,3-dithiocyclopentene, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline ketone, thiazoline, thiazoline, and 1,3-oxothiocyclopentane. Depending on the structure, heterocyclic alkyl groups can be monovalent or bivalent (i.e., heterocyclic alkylene).

[0055] The term "alkyl (heterocyclic alkyl)" or "heterocyclic alkyl alkyl" means that an alkyl group as defined herein is replaced by a heterocyclic alkyl group as defined herein.

[0056] The term "alkoxy (heterocyclic alkyl)" or "heterocyclic alkyl alkoxy" means that the alkoxy group defined herein is substituted with the heterocyclic alkyl group defined herein.

[0057] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0058] The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

[0059] The term "hydroxyl group" refers to the -OH group.

[0060] The term "cyano" refers to the -CN group.

[0061] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (linked by a ring carbon), and heterocyclic (linked by a ring carbon).

[0062] The term "amino" refers to the -NH2 group.

[0063] The term "aminoacyl" refers to the -CO-NH2 group.

[0064] The term "amide group" or "amide group" refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.

[0065] The term "alkylamino" refers to an amino substituent further replaced by one or two alkyl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen or lower alkyl groups, provided that -NRR' is not -NH2. "Alkylamino" includes groups in compounds in which the nitrogen of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, etc. "Dialkylamino" includes groups in which the nitrogen of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, etc.

[0066] The terms “arylamino” and “diarylamino” refer to amino substituents that are further replaced by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, and N is attached to one or two aryl groups respectively.

[0067] The term "cycloalkylamino" refers to an amino substituent that is further replaced by one or two cycloalkyl groups as defined herein.

[0068] The term "heteroalkylamino" refers to an amino substituent that is further replaced by one or two heteroalkyl groups as defined herein.

[0069] The term "arylamino" in this article refers to a group in which R is a lower aryl group and R' is a hydrogen, lower alkyl, aryl, or lower aryl group -NRR'.

[0070] The term “heteroarylamino” refers to an amino substituent that is further replaced by one or two heteroaryl groups as defined herein.

[0071] The term "heterocyclic alkylamino" refers to an amino group as defined herein that has been substituted with a heterocyclic alkyl group as defined herein.

[0072] The term "alkylaminoalkyl" means that an alkyl group as defined herein is replaced by an alkylamino group as defined herein.

[0073] The term "aminoalkyl" refers to an alkyl substituent that is further replaced by one or more amino groups.

[0074] The term "aminoalkoxy" refers to an alkoxy substituent that is further replaced by one or more amino groups.

[0075] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl substituent that is further replaced by one or more hydroxyl groups.

[0076] The term "cyanoalkyl" refers to an alkyl substituent that is further replaced by one or more cyano groups.

[0077] The term "acyl" refers to the monovalent group remaining after removing the hydroxyl group from an organic or inorganic oxyacid, with the general formula RM(O)-, where M is usually C.

[0078] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0079] The term "alkanoyl" or "alkyl carbonyl" refers to a carbonyl group that is further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0080] The term "aryl carbonyl" refers to a carbonyl group as defined herein that has been replaced by an aryl group as defined herein.

[0081] The term "alkoxycarbonyl" refers to a carbonyl group that is further replaced by an alkoxy group.

[0082] The term "heterocyclic alkyl carbonyl" refers to a carbonyl group that is further replaced by a heterocyclic alkyl group.

[0083] The terms “alkylaminocarbonyl”, “cycloalkylaminocarbonyl”, “arylaminocarbonyl”, “arylalkylaminocarbonyl”, and “heteroarylaminocarbonyl” refer to carbonyl groups as defined herein that have been substituted by alkylamino, cycloalkylamino, arylamino, arylalkylamino, or heteroarylamino groups as defined herein.

[0084] The terms “alkylcarbonylalkyl” or “alkanoylalkyl” refer to an alkyl group that is further replaced by an alkylcarbonyl group.

[0085] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group that is further substituted with an alkyl carbonyl group.

[0086] The term "heterocyclic alkyl carbonyl alkyl" refers to an alkyl group that is further replaced by a heterocyclic alkyl carbonyl group.

[0087] The term "thiol" refers to a -SH group. The term "alkathiol" refers to a thiol group as defined herein that has been substituted with an alkyl group as defined herein.

[0088] The term "optional" means that one or more events described below may or may not occur, and includes both the events that occur and the events that do not occur. The terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more additional groups, each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Preferably, the amino protecting group is selected from neopentanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0089] The terms “inhibition,” “inhibitory,” or “inhibitor” used in this article refer to the inhibition of phosphotransferase activity.

[0090] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions, such as oxidation). Thus, enzymes can produce specific structures that are transformed into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while glucuronyl diphosphate transferases catalyze the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from *The Pharmacological Basis of Therapeutics*, 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art. In some embodiments, the metabolites of the compound are formed through an oxidation process and correspond to the corresponding hydroxyl-containing compounds. In some embodiments, the compound is metabolized into a drug-active metabolite. The term "modulation" as used herein refers to an interaction with a target, directly or indirectly, to alter the target's activity, including, by way of example only, enhancing, inhibiting, limiting, or prolonging the target's activity.

[0091] As used herein, the term "target protein" refers to a protein molecule or portion of a protein that can be selectively bound by a binding compound. In some embodiments, the target protein is a tyrosine kinase KIT (wild-type or various mutations or combinations thereof), ABL (wild-type or various mutations or combinations thereof), EGFR (wild-type or various mutations or combinations thereof), FLT3 (wild-type or various mutations or combinations thereof), VEGFR2 (wild-type or various mutations or combinations thereof), RET (wild-type or various mutations or combinations thereof), PDGFRα (wild-type or various mutations or combinations thereof), PDGFRβ (wild-type or various mutations or combinations thereof), BCR / ABL (wild-type or various mutations or combinations thereof), FGFR1 (wild-type or various mutations or combinations thereof), FGFR2 (wild-type or various mutations or combinations thereof), FGFR3 (wild-type or various mutations or combinations thereof), or FGFR4 (wild-type or various mutations or combinations thereof).

[0092] IC used in this article 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum effect in an analysis measuring such an effect.

[0093] EC used in this article 50 A dose-dependent response refers to a dose, concentration, or amount of a measured compound that elicits a specific response induced, stimulated, or enhanced by that compound at a maximum expression of 50%.

[0094] The GI used in this article 50 This refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0095] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0096] Compounds, pharmaceutical compositions and their uses

[0097] An arylinazole cyclic compound comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098]

[0099] Among them, Ar 1 Selected from the following aromatic rings or aromatic ring systems:

[0100]

[0101] Ar 2 Selected from the following aromatic rings or aromatic ring systems:

[0102]

[0103] Ar 3 Selected from the following aromatic rings or aromatic ring systems:

[0104]

[0105] A pharmaceutical composition comprising one or more therapeutically effective amounts of an arylinazole cyclic compound of general formula (I) as described above, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0106] The use of one or more arylinazole cyclic compounds of general formula (I) as described above, or pharmaceutically acceptable salts thereof, in medicaments for diseases caused by upregulation of VEGFR2 kinase activity leading to angiogenesis.

[0107] Furthermore, its application in drugs for diseases caused by VEGFR2 kinase upregulation leading to angiogenesis, wherein the diseases include at least one of the following: anti-tumor therapy or rheumatic diseases such as rheumatoid arthritis, autoimmune diseases, and / or

[0108] The diseases mentioned include at least one of various inflammatory diseases, such as arthritis, asthma, and inflammatory bowel disease.

[0109] Use in a medicament for the prevention or treatment of rheumatoid arthritis, comprising one or more aryl indazole cyclic compounds of general formula (I) as described above or a pharmaceutically acceptable salt thereof, targeting the VEGFR2 / PI3K / AKT pathway to inhibit synovial angiogenesis.

[0110] Furthermore, the application of drugs that target the VEGFR2 / PI3K / AKT pathway to inhibit synovial angiogenesis for the prevention or treatment of rheumatoid arthritis, wherein the rheumatoid arthritis includes at least one of the following: joint involvement, rheumatoid vasculitis, cardiac involvement, respiratory involvement, kidney involvement, and hematologic problems (such as anemia), pleurisy, pleural effusion, pulmonary arteritis, interstitial lung disease, glomerulonephritis, and tubulointerstitial nephritis.

[0111] Preparation of compounds

[0112] Compounds of formula (I) can be synthesized using standard synthetic techniques known to those skilled in the art, or by combining methods known in the art with those described herein. Furthermore, the solvents, temperatures, and other reaction conditions given herein can be varied according to the art. As further guidance, the following synthetic methods may also be used.

[0113] The reactions may be used sequentially to provide the compounds described herein; or they may be used to synthesize fragments subsequently added by the methods described herein and / or methods known in the art.

[0114] In some embodiments, this document provides methods for preparing and using the kinase inhibitor compounds described herein. In some embodiments, the compounds described herein can be synthesized using the following synthetic schemes. The compounds can be synthesized using methods similar to those described below, employing suitable, selectable starting materials.

[0115] The starting materials used to synthesize the compounds described herein can be synthesized or are available from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and these reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties provided herein.

[0116] If necessary, the reaction products can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. These products can be characterized using conventional methods, including physical constants and spectral data.

[0117] Example 1

[0118] The synthesis reaction formula is as follows:

[0119]

[0120] The synthesis steps are as follows:

[0121] (1) 0.27 g (0.23 mmol) of tetra(triphenylphosphine)palladium and 1.28 g (9.28 mmol) of potassium carbonate were added to a mixture of 2 g (4.63 mmol) of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 0.7 g (5.11 mmol) of 2-aminophenylboronic acid in anhydrous N,N-dimethylformamide. The mixture was stirred at 80 °C for 14 h under an argon atmosphere. The solvent was evaporated and diluted with ethyl acetate, then washed with water and brine. The organic phase was evaporated and purified by silica gel column chromatography by elution, chromatography and purification with 10%-30% ethyl acetate in petroleum ether to give 1.4 g of intermediate (E)-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)aniline white solid, with a yield of 76%.

[0122] (2) Add (E)-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)aniline to 5 mL of dichloromethane to form a solution, then add 56 mg (0.36 mmol) of 3-fluorobenzoic acid, 165 mg (0.43 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 86 mg (0.67 mmol) of N,N-diisopropylethylamine. Stir the resulting mixture at room temperature for 8 h; then dilute with 50 mL of ethyl acetate and wash three times with 100 mL of water, then wash with 100 mL of brine. The organic layer is then placed in anhydrous sulfuric acid... The mixture was dried and concentrated on sodium sulfate. The residue was diluted with 5 mL of dichloromethane and 1 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 h, and then the pH was adjusted to 12 with saturated sodium bicarbonate. The mixture was extracted with 50 mL of ethyl acetate, washed twice with 50 mL of water, and then washed with 50 mL of brine. The organic layer was dried with sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with 0-5% methanol in dichloromethane to give 60 mg of (E)-3-fluoro-N-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)phenyl)benzamide, a yellow solid, in a yield of 55%.

[0123] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.32(s,1H),10.04(s,1H),8.62–8.58(m,1H),8.19(d,J=8. 4Hz,1H),7.96(d,J=16.4Hz,1H),7.80(td,J=7.7,1.8Hz,1H),7.68–7.63(m,2H),7.59 (s,2H),7.57(d,J=7.0Hz,1H),7.55–7.52(m,2H),7.51–7.47(m,2H),7.47–7.43(m,1 H),7.40–7.35(m,1H),7.31(dd,J=8.4,1.1Hz,1H),7.26(ddd,J=7.4,4.8,0.9Hz,1H). 13 C NMR (126MHz, DMSO-d6)δ

[0124] 165.02,163.31,161.37,155.48,149.99,142.19,138.79,137.90,137.31,137.28,137.26,135.28,131.10,131.05,13 0.99,129.31,128.83,128.47,127.45,124.55,124.12,123.03,122.84,120.75,118.89,114.85,110.71.HRMS(ESI)m / z calcd forC 27 H 19 FN4O[M+H]+435.1616; found,435.1619.

[0125] Example 2

[0126] The synthesis of (E)-3-fluoro-N-(3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)phenyl)benzamide was carried out using (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 3-aminophenylboronic acid as raw materials, and other implementation methods were the same as in Example 1;

[0127] The prepared compound was a pale yellow solid with a yield of 76.0%.

[0128] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.48(s,1H),10.51(s,1H),8.63(d,J=4.4Hz,1H),8.31(d,J=8.5Hz,1H),8.24(s,1H),8.00(d,J= 16.4Hz,1H),7.91–7.79(m,5H),7.71(d,J=7.8Hz,1H),7.65–7.60(m,2H),7.57–7.45(m,4H),7.29(dd,J=7.2,4.9Hz,1H). 13C NMR (126MHz, DMSO-d6) δ164.72,163.40,161.46,155.49,150.02,141.22,140.04,138.96,137.65,137.33,131.12,131.06,129.84 ,129.44,124.44,123.15,123.03,122.89,121.73,121.26,120.70,120.00,119.62,119.12,118.95,115.12,114.94.HRMS(ESI)m / z calcd for C 27 H 19 FN4O[M+H]+435.1616; found,435.1617.

[0129] Example 3

[0130] (E)-3-fluoro-N-(4-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)phenyl)benzamide was synthesized using (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 4-aminophenylboronic acid as raw materials. Other implementation methods were the same as in Example 1.

[0131] The prepared compound was a pale yellow solid with a yield of 79.3%.

[0132] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.51(s,1H),10.61(s,1H),8.62(d,J=4.1Hz,1H),8.27(d,J=8.5Hz,1H),8.02–7.97(m,3H),7.90(dd,J=16.5,8. 7Hz,2H),7.82(dt,J=19.3,5.0Hz,4H),7.71(d,J=7.8Hz,1H),7.64–7.55(m,3H),7.47(td,J=8.5,2.1Hz,1H),7.29(dd,J=6.9,5.1Hz,1H). 13C NMR (126MHz, DMSO-d6) δ164.65,163.38,161.44,155.52,150.02,142.65,142.17,139.09,138.60,137.62,137.33,136.10 ,131.07,129.32,127.77,124.52,123.03,122.86,121.60,121.35,121.13,120.41,115.19,115.01,108.12.HRMS(ESI)m / z calcd for C 27 H 19 FN4O[M+H] + 435.1616; found, 435.1610.

[0133] Example 4

[0134] The synthesis reaction formula is as follows:

[0135]

[0136] The synthesis steps are as follows:

[0137] (1) To a mixture of 0.63 g (5.09 mmol) of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 0.63 g (5.09 mmol) of dried 1,4-dioxane-2-aminobenzylthiophenol, add 0.2 g (0.23 mmol) of tris(dibenzylideneacetone)dipalladium, 0.5 g (0.87 mmol) of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) and 1.28 g (9.09 mmol) of 2-aminobenzylthiophenol. 28 mmol) of potassium carbonate was added, and the mixture was stirred at 80 °C under an argon atmosphere for 14 h. The solvent was evaporated and diluted with ethyl acetate, then washed with water and brine. The organic phase was evaporated, eluted with 10%-30% ethyl acetate in petroleum ether, purified by silica gel column chromatography, and yielded 1.2 g of intermediate (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)thio)aniline yellow solid, with a yield of 65.2%.

[0138] (2) Add (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline to 5 mL of dichloromethane to form a solution, then add 56 mg (0.36 mmol) of 3-fluorobenzoic acid, 165 mg (0.43 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 86 mg (0.67 mmol) of N,N-diisopropylethylamine. Stir the resulting mixture at room temperature for 8 h, then dilute with 50 mL of ethyl acetate and wash three times with 100 mL of water, then wash with 100 mL of brine; [The remaining text appears to be incomplete and requires further context.] The layer was dried and concentrated on anhydrous sodium sulfate. The residue was diluted with 5 mL of dichloromethane and 1 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 h, and then the pH was adjusted to 12 with saturated sodium bicarbonate. The mixture was extracted with 50 mL of ethyl acetate, washed twice with 50 mL of water, and then washed with 50 mL of brine. The organic layer was dried on sodium sulfate, filtered, concentrated, and purified by chromatography with 0-5% methanol in dichloromethane using a silica gel column to give 68 mg of (E)-N-(3-fluorophenyl)-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)benzamide yellow solid, with a yield of 60.4%.

[0139] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.24(s,1H),10.18(s,1H),8.60(d,J=4.2Hz,1H),8.14(d,J=8.5Hz,1H),7.92(d,J=16.4Hz,1H),7.80(td,J=7.6,1.4Hz ,1H),7.74(d,J=7.7Hz,1H),7.65(d,J=8.1Hz,3H),7.57–7.52(m,2H),7 .47–7.40(m,3H),7.37(s,1H),7.32–7.25(m,2H),7.11(d,J=8.6Hz,1H). 13C NMR (126MHz, DMSO-d6) δ164.66,163.38,161.43,155.34,150.01,142.41,142.27,138.17,137.33,136.89,134.02,133.57,131.27 ,131.18,129.64,129.10,127.66,127.62,124.13,123.74,123.11,122.94,122.08,120.25,119.24,114.88,111.97.HRMS(ESI)m / z calcd for C 27 H 19 FN4OS[M+H]+467.1336; found,467.1310;

[0140] Example 5

[0141] The synthesis of (E)-N-(3-fluorophenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)benzamide was carried out using (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 3-aminobenzylthiophenol as raw materials, and other implementation methods were the same as in Example 4;

[0142] The prepared compound was a pale yellow solid with a yield of 75.5%.

[0143] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.29(s,1H),10.40(s,1H),8.61(d,J=4.7Hz,1H),8.21(d,J=8.5Hz,1H),7.98–7.87(m,2H),7.84–7.77(m,3H),7 .77–7.70(m,1H),7.67(d,J=7.8Hz,1H),7.61–7.54(m,2H),7.50–7.40(m,3H),7.28(dd,J=7.5,4.8Hz,1H),7.19(dd,J=12.2,8.1Hz,2H). 13C NMR (126MHz, DMSO-d6) δ164.81,163.35,161.40,155.36,150.04,142.49,142.35,140.54,137.34,135.39,133.85,131.05,130.38 ,129.72,126.93,124.41,124.39,124.13,123.12,122.99,122.20,120.40,120.05,119.01,115.10,114.92,112.41.HRMS(ESI)m / z calcd for C 27 H 19 FN4OS[M+H]+467.1336; found,467.1343.

[0144] Example 6

[0145] The synthesis of (E)-N-(3-fluorophenyl)-4-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)benzamide was carried out using (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 4-aminobenzylthiophenol as raw materials, and other implementation methods were the same as in Example 4;

[0146] The prepared compound was a pale yellow solid with a yield of 68.5%.

[0147] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.19(s,1H),10.50(s,1H),8.61(d,J=4.1Hz,1H),8.17(d,J=8.5Hz,1H),7.93–7.88(m,3H),7.84–7.78(m,3H),7.6 6(d,J=7.8Hz,1H),7.61(td,J=8.0,6.1Hz,1H),7.55–7.51(m,3H),7.47(td,J=8.4,2.1Hz,1H),7.28(d,J=4.3Hz,2H),7.13(d,J=8.5Hz,1H). 13C NMR (126MHz, DMSO-d6) δ164.84,163.37,161.43,155.36,150.01,142.42,139.77,137.32,136.06,134.07,131.15,131.08 ,129.62,127.85,124.45,124.19,123.08,122.93,122.66,121.94,119.90,119.20,119.03,115.13,110.18.HRMS(ESI)m / z calcd for C 27 H 19 FN4OS[M+H]+467.1336; found,467.1335.

[0148] Example 7

[0149] The synthesis reaction formula is as follows:

[0150]

[0151] The synthesis steps are as follows:

[0152] (1) To a mixture of 2 g (4.63 mmol) of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 0.63 g (3.89 mmol) of dried 1,4-dioxane-3-mercaptobenzoic acid, add 0.2 g (0.23 mmol) of tris(dibenzylacetone)dipalladium, 0.5 g (0.87 mmol) of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), and 1.28 g (9.2 mmol) of [unclear text - possibly a typo, should be removed]. 8 mmol) of potassium carbonate was added, and the mixture was stirred at 80 °C under an argon atmosphere for 14 h. The solvent was evaporated and diluted with ethyl acetate, then washed with water and brine. The organic phase was evaporated, eluted with 10%-30% ethyl acetate in petroleum ether, purified by silica gel column chromatography, and gave 1.2 g of intermediate (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline yellow solid in a yield of 65.2%.

[0153] (2) Add 100 mg (0.22 mmol) (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline to 5 mL of dichloromethane to form a solution, then add 24 mg (0.22 mmol) of 3-fluoroaniline, 165 mg (0.43 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 86 mg (0.67 mmol) of N,N-diisopropylethylamine, and stir the resulting mixture at room temperature for 8 h; then dilute with 50 mL of ethyl acetate and wash three times with 100 mL of water, then rinse with 10 mL of ethyl acetate. The organic layer was washed with 0 mL of brine, dried on anhydrous sodium sulfate and concentrated. The residue was diluted with 5 mL of dichloromethane and 1 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 h, and then the pH was adjusted to 12 with saturated sodium bicarbonate. The mixture was extracted with 50 mL of ethyl acetate, washed twice with 50 mL of water, and then washed with 50 mL of brine. The organic layer was dried with sodium sulfate and then purified by silica gel column chromatography with 0-5% methanol in dichloromethane to give 60 mg of (E)-N-(3-fluorophenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)benzamide yellow solid, with a yield of 59.2%.

[0154] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.25(s,1H),10.44(s,1H),8.54(d,J=4.3Hz,1H),8.16(d,J=8. 5Hz,1H),7.94–7.83(m,3H),7.74(td,J=7.7,1.5Hz,1H),7.66(d,J=11.7Hz,1H),7.59(d, J=7.8Hz,1H),7.51(d,J=5.4Hz,2H),7.46(dd,J=15.4,10.0Hz,3H),7.31(dd,J=15.2,8. 0Hz, 1H), 7.21 (dd, J=7.0, 5.1Hz, 1H), 7.15 (d, J=8.6Hz, 1H), 6.87 (td, J=8.4, 2.1Hz, 1H). 13C NMR (126MHz, DMSO-d6) δ165.35,163.45,161.53,155.32,150.03,142.51,141.21,137.35,136.29,136.03,134.41,133.05,130.76 ,130.32,130.19,129.79,127.38,124.39,124.03,123.13,122.98,122.39,120.57,116.56,113.05,110.86,107.66.HRMS(ESI)m / z calcd for C 27 H 19 FN4OS[M+H]+467.1336; found,467.1368.

[0155] Example 8

[0156] The synthesis of (E)-2-(3-fluorophenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and m-fluorophenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0157] The prepared compound was a pale yellow solid with a yield of 66.5%.

[0158] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.28 (s, 1H), 10.29 (s, 1H), 8.61 (d, J = 4.1Hz, 1H), 8.20 (d,J=8.5Hz,1H),7.94(d,J=16.4Hz,1H),7.81(td,J=7.7,1.6Hz,1H),7.67(d,J =6.7Hz,2H),7.58(t,J=14.2Hz,2H),7.46(s,1H),7.38–7.33(m,2H),7.28(dd,J =7.0,5.1Hz,1H),7.16(dd,J=15.3,8.8Hz,3H),7.11–7.05(m,2H),3.66(s,2H). 13C NMR (126MHz, DMSO-d6) δ169.26,163.46,155.33,150.02,142.46,140.68,138.90,137.34,135.62,133.62,130.63,130.46,130.12,12 9.71,126.14,125.82,124.25,124.09,123.12,122.97,122.21,121.50,120.39,118.71,116.55,113.95,112.59,43.19.HRMS(ESI)m / z calcd for C 26 H 23 N3O3S[M+H]+458.1533; found,458.1598.

[0159] Example 9

[0160] The synthesis reaction formula is as follows:

[0161]

[0162] The synthesis steps are as follows:

[0163] Add 50 mg (0.12 mmol) of (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline to 20 mL of dichloromethane to form a solution, then add 16 mg (0.12 mmol) of 3-fluorophenyl isocyanate. Stir the resulting mixture at room temperature for 8 h, then concentrate to dryness. Dilute the residue with 2 mL of dichloromethane and 1 mL of trifluoroacetic acid. Stir the reaction mixture at room temperature for 4 h, then use a saturated... The pH was adjusted to 12 with sodium bicarbonate, and the mixture was extracted with 50 mL of ethyl acetate and washed twice with 50 mL of water, then washed with 50 mL of brine. The organic layer was dried on sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with 0-5% methanol in dichloromethane to give 30 mg of (E)-1-(3-fluorophenyl)-3-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)phenyl)urea white solid, with a yield of 54.8%.

[0164] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.29(s,1H),9.34–9.25(m,2H),8.61(d,J=4.2Hz,1H),8.20(d,J= 8.5Hz,1H),7.94(d,J=16.4Hz,1H),7.81(td,J=7.7,1.4Hz,1H),7.66(d,J=7.8Hz,1H),7.59 –7.54(m,2H),7.48–7.42(m,3H),7.34(t,J=7.9Hz,1H),7.28(dd,J=14.4,7.7Hz,2H),7.18 (d,J=8.6Hz,1H),7.10(d,J=9.0Hz,1H),7.02(d,J=7.7Hz,1H),6.77(td,J=8.5,2.3Hz,1H). 13 CNMR(126MHz,DMSO-d6)δ163.80,161.88,155.35,152.85,150.02,142.45,142.01,141.22,137.33,135.30,134.00,130.80,130.51 ,130.11,129.68,125.04,124.14,123.12,122.95,122.15,120.77,120.30,117.95,114.35,112.18,108.71,105.15.HRMS(ESI)m / z calcd for C 27 H 20 FN5OS[M+H]+482.1445; found,482.1440.

[0165] Example 10

[0166] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)propionamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and propionic acid as raw materials, and other implementation methods were the same as in Example 4;

[0167] The prepared compound was a pale yellow solid with a yield of 56.5%.

[0168] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.32(s,1H),10.02(s,1H),8.61(d,J=4.4Hz,1H),8.20(d,J=8 .5Hz,1H),7.93(dd,J=16.4,6.3Hz,1H),7.84–7.79(m,1H),7.70–7.65(m,2H),7.58(dt, J=16.3,7.9Hz,2H),7.45(s,1H),7.34(t,J=8.0Hz,1H),7.28(dd,J=6.9,5.2Hz,1H),7. 17(d,J=9.3Hz,1H),7.07(d,J=7.7Hz,1H),2.29(q,J=7.5Hz,2H),1.05(t,J=7.6Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ172.70,155.34,150.02,140.99,137.35,135.34,133.82,130.36,129.68,125.83,125.58,1 24.14,123.12,122.97,122.18,121.49,120.33,119.17,118.72,118.63,112.42,29.95,10.00.HRMS(ESI)m / zcalcd for C 23 H 20 N4OS[M+H]+401.1431; found,401.1439.

[0169] Example 11

[0170] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)butyramide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and n-butyric acid as raw materials, and other implementation methods were the same as in Example 4;

[0171] The prepared compound was a pale yellow solid with a yield of 62.8%.

[0172] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.31(s,1H),10.00(s,1H),8.65(d,J=4.4Hz,1H),8.25(d,J=8.5Hz,1 H),7.98(dd,J=16.4,6.4Hz,1H),7.85(dd,J=10.8,4.5Hz,1H),7.71(d,J=8.3Hz,2H),7.67–7.5 8(m,2H),7.50(s,1H),7.39(dd,J=16.7,8.7Hz,1H),7.32(dd,J=6.8,5.3Hz,1H),7.24–7.21(m, 1H), 7.12 (d, J = 7.7Hz, 1H), 2.30 (t, J = 7.3Hz, 2H), 1.62 (h, J = 7.4Hz, 2H), 0.93 (t, J = 7.4Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δ171.84,155.34,150.02,142.37,140.92,137.34,135.39,133.79,130.37,129.69,125.87,1 24.18,123.12,122.96,122.18,121.47,120.35,119.20,118.64,116.96,114.04,38.77,18.90,14.07.HRMS(ESI)m / z calcd for C 24 H 22 N4OS[M+H]+415.1587; found,415.1586.

[0173] Example 12

[0174] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)isobutyramide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and isobutyric acid as raw materials, and other implementation methods were the same as in Example 4;

[0175] The prepared compound was a pale yellow solid with a yield of 68.5%.

[0176] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.28(s,1H),9.94(s,1H),8.61(d,J=4.1Hz,1H),8.20(d,J=8.5Hz,1 H),7.94(d,J=16.4Hz,1H),7.82(td,J=7.7,1.7Hz,1H),7.67(d,J=7.5Hz,2H),7.59(dd,J=18 .1,12.3Hz,2H),7.45(s,1H),7.34(t,J=8.0Hz,1H),7.28(dd,J=6.8,5.0Hz,1H),7.19–7.16( m,1H),7.07(d,J=7.9Hz,1H),2.15(d,J=7.1Hz,2H),2.06–2.02(m,1H),0.91(d,J=6.6Hz,6H). 13 C NMR(126MHz,DMSO-d6)δ171.36,155.33,150.02,142.32,140.86,137.35,135.39,133.76,130.38,130.12,129.69,1 25.90,124.19,124.09,123.12,122.97,122.18,121.49,120.34,118.67,112.45,46.05,25.96,22.73.HRMS(ESI)m / z calcd for C 25 H 24 N4OS[M+H]+429.1744; found,429.1740.

[0177] Example 13

[0178] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)pentanamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and trimethylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0179] The prepared compound was a pale yellow solid with a yield of 54.5%.

[0180] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.36 (s, 1H), 9.98 (s, 1H), 8.65 (d, J = 3.8Hz, 1H), 8.24 (d,J=8.5Hz,1H),7.98(d,J=16.4Hz,1H),7.85(t,J=6.9Hz,1H),7.74–7.69(m,3 H),7.68–7.58(m,3H),7.49(s,1H),7.37(t,J=8.0Hz,1H),7.32(dd,J=6.4,5.0 Hz,2H),7.21(d,J=8.5Hz,1H),7.10(d,J=7.6Hz,1H),2.21(s,2H),1.04(s,6H). 13 C NMR(126MHz,DMSO-d6)δ170.73,155.34,150.02,142.38,140.85,137.34,135.26,133.84,130.35,129.68,128.52,1 25.99,124.11,123.12,122.96,122.17,121.68,120.32,118.83,116.94,112.39,49.99,31.29,30.04.HRMS(ESI)m / z calcd for C 26 H 26 N4OS[M+H]+443.1900; found,443.1906.

[0181] Example 14

[0182] The synthesis of (E)-2-cyclopropyl-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and cyclopropionic acid as raw materials, and other implementation methods were the same as in Example 4;

[0183] The prepared compound was a pale yellow solid with a yield of 57.2%.

[0184] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.11(s,1H),9.74(s,1H),8.44(d,J=4.0Hz,1H),8.03(d,J=8.5Hz,1H),7. 77(d,J=16.4Hz,1H),7.65(td,J=7.7,1.7Hz,1H),7.53–7.48(m,2H),7.42(dd,J=18.1,12.3Hz,2H), 7.29(s,1H),7.18(t,J=8.0Hz,1H),7.11(dd,J=6.7,4.9Hz,1H),7.01(dd,J=8.5,1.3Hz,1H),6.91(d ,J=7.9Hz,1H),2.01(d,J=7.0Hz,2H),0.91–0.84(m,1H),0.32–0.27(m,2H),-0.00(q,J=4.9Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ171.47,155.35,150.02,142.39,140.92,137.32,135.39,133.81,130.36,129.71,125.95, 124.17,124.10,124.06,123.09,122.95,122.16,121.56,120.35,118.69,112.45,41.86,8.09,4.54.HRMS(ESI)m / z calcd for C 25 H 22 N4OS[M+H]+427.1587; found,427.1587.

[0185] Example 15

[0186] The synthesis of (E)-2-cyclobutyl-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)thio)aniline and cyclobutylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0187] The prepared compound was a pale yellow solid with a yield of 66.8%.

[0188] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.28(s,1H),9.93(s,1H),8.61(d,J=4.1Hz,1H),8.20(d,J=8.5Hz,1H),7.94( d,J=16.4Hz,1H),7.81(td,J=7.7,1.4Hz,1H),7.67(d,J=7.5Hz,2H),7.60–7.55(m,2H),7.45(s,1H),7 .33(t,J=8.0Hz,1H),7.28(dd,J=7.0,5.1Hz,1H),7.17(d,J=8.4Hz,1H),7.07(d,J=7.7Hz,1H),2.64(d t,J=15.6,7.8Hz,1H),2.39(d,J=7.5Hz,2H),2.06–1.99(m,2H),1.86–1.78(m,2H),1.73–1.65(m,2H). 13 C NMR (126MHz, DMSO-d6) δ170.92,155.34,150.02,142.46,142.32,140.88,137.35,135.35,133.82,130.37,129.70,125. 91,124.15,124.11,123.12,122.97,122.17,121.48,120.35,118.63,112.41,43.81,32.79,28.09,18.59.HRMS(ESI)m / z calcd forC 26 H 24 N4OS[M+H]+441.1744; found,441.1746.

[0189] Example 16

[0190] The synthesis of (E)-2-cyclopentyl-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and cyclopentylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0191] The prepared compound was a pale yellow solid with a yield of 64.7%.

[0192] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.28(s,1H),9.95(s,1H),8.61(d,J=4.0Hz,1H),8.20(d,J=8.5Hz,1H),7.94(d,J=16.4Hz ,1H),7.82(td,J=7.7,1.7Hz,1H),7.67(d,J=7.2Hz,2H),7.58(t,J=13.8Hz,2H),7.45(s,1H),7.33(t,J=8.0Hz,1H) ,7.28(dd,J=7.0,5.1Hz,1H),7.17(dd,J=8.5,1.2Hz,1H),7.07(d,J=7.7Hz,1H),2.27(d,J=7.4Hz,2H),2.20(dd,J= 14.9,7.5Hz,1H),1.72(dt,J=11.6,5.9Hz,2H),1.62–1.54(m,2H),1.52–1.47(m,2H),1.15(td,J=15.3,7.7Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ171.59,155.33,150.02,142.46,142.32,140.92,137.35,135.36,133.79,130.37,129.69,125. 89,124.16,123.62,123.12,122.97,122.18,121.50,120.34,118.66,112.42,43.00,36.99,32.33,24.95.HRMS(ESI)m / z calcd for C 27 H 26 N4OS[M+H]+455.1900; found,455.1982.

[0193] Example 17

[0194] The synthesis of (E)-2-cyclohexyl-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)thio)aniline and cyclohexylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0195] The prepared compound was a pale yellow solid with a yield of 58.5%.

[0196] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.27(s,1H),9.94(s,1H),8.61(d,J=4.3Hz,1H),8.20(d,J=8.5Hz,1H),7.94 (d,J=16.4Hz,1H),7.81(td,J=7.7,1.5Hz,1H),7.67(d,J=7.5Hz,2H),7.58(t,J=13.6Hz,2H),7.45(s, 1H),7.33(t,J=8.0Hz,1H),7.28(dd,J=7.0,5.1Hz,1H),7.17(d,J=8.5Hz,1H),7.07(d,J=7.8Hz,1H), 2.15(d,J=7.1Hz,2H),1.78–1.70(m,1H),1.66(d,J=6.9Hz,4H),1.26–1.05(m,4H),0.99–0.89(m,2H). 13 C NMR(126MHz,DMSO-d6)δ171.22,155.34,150.02,142.47,142.45,140.87,137.34,135.38,133.77,130.36,129.69,125.89, 124.18,124.10,123.12,122.96,122.18,121.48,120.35,118.65,112.47,44.72,35.16,32.96,26.27,26.03.HRMS(ESI)m / z calcdfor C 28 H 28 N4OS[M+H]+469.2057; found,469.1947.

[0197] Example 18

[0198] The synthesis of (E)-2-phenyl-N-(4-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and phenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0199] The prepared compound was a pale yellow solid with a yield of 62.5%.

[0200] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.28(s,1H),10.26(s,1H),8.61(d,J=4.2Hz,1H),8.20(d,J=8.5Hz,1 H),7.95(d,J=16.4Hz,1H),7.81(td,J=7.7,1.3Hz,1H),7.67(d,J=8.1Hz,2H),7.59(dd,J=18. 0,12.4Hz,2H),7.46(s,1H),7.35(t,J=8.0Hz,1H),7.31(d,J=4.3Hz,4H),7.28(dd,J=7.1,5.2 Hz,1H),7.23(dt,J=8.7,4.2Hz,1H),7.17(d,J=8.4Hz,1H),7.09(d,J=7.7Hz,1H),3.61(s,2H). 13 C NMR(126MHz,DMSO-d6)δ169.80,155.34,150.02,142.48,142.32,140.80,137.34,136.21,135.56,133.70,130.44,12 9.72,129.58,128.78,127.04,126.11,124.21,123.12,122.20,121.51,120.40,118.70,112.53,43.75.HRMS(ESI)m / z calcd for C 28 H 22 N4OS[M+H]+463.1587; found,463.1583.

[0201] Example 19

[0202] The synthesis of (E)-2-(2-methoxyphenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 2-methoxyphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0203] The prepared compound was a pale yellow solid with a yield of 65.5%.

[0204] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.28(s,1H),10.15(s,1H),8.63–8.58(m,1H),8.20(d,J=8.5Hz,1H),7.94(d ,J=16.4Hz,1H),7.82(td,J=7.7,1.8Hz,1H),7.67(d,J=7.9Hz,2H),7.60(dd,J=11.1,3.4Hz,2H),7.45 (s,1H),7.34(t,J=8.0Hz,1H),7.28(dd,J=7.3,4.9Hz,1H),7.23(s,1H),7.18(dd,J=7.7,5.6Hz,2H),7 .08(d,J=7.7Hz,1H),6.96(d,J=8.1Hz,1H),6.89(t,J=7.5Hz,1H),3.73(d,J=7.5Hz,3H),3.60(s,2H). 13 C NMR (126MHz, DMSO-d6)δ

[0205] 160.24,158.79,158.20,155.37,150.03,142.55,140.03,137.34,136.35,133.01,132.79,132.71,132.63,130.66,129.65,126.6 6,124.56,124.07,123.13,122.95,122.29,121.28,120.56,118.78,115.66,115.48,113.36,112.67,112.48.HRMS(ESI)m / zcalcd for C 29 H 24 N4O2S[M+H]+493.1696; found,493.1696.

[0206] Example 20

[0207] The synthesis of (E)-2-(3-methoxyphenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 3-methoxyphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0208] The prepared compound was a pale yellow solid with a yield of 68.5%.

[0209] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.27(s,1H),10.21(s,1H),8.63–8.59(m,1H),8.20(d,J=8.5Hz,1H), 7.94(d,J=16.3Hz,1H),7.81(td,J=7.7,1.8Hz,1H),7.71–7.65(m,2H),7.63–7.57(m,2H),7.4 5(s,1H),7.34(t,J=8.0Hz,1H),7.28(ddd,J=7.5,4.7,1.1Hz,1H),7.25–7.20(m,2H),7.17(dd ,J=8.5,1.5Hz,1H),7.08(dt,J=8.1,1.1Hz,1H),6.90–6.85(m,2H),3.72(s,3H),3.53(s,2H). 13 C NMR (126MHz, DMSO-d6) δ170.19,158.53,155.35,150.04,142.48,142.32,140.87,137.36,135.50,133.75,130.58,130.44,129.7 2,128.11,126.09,124.19,124.12,123.14,122.98,122.21,121.53,120.39,118.70,114.22,112.48,55.49,42.87.HRMS(ESI)m / z calcd for C 29 H 24 N4O2S[M+H]+493.1696; found,493.1692.

[0210] Example 21

[0211] The synthesis of (E)-2-(4-methoxyphenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 4-methoxyphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0212] The prepared compound was a pale yellow solid with a yield of 56.5%.

[0213] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.16(s,1H),8.53(dd,J=4.8,1.8Hz,1H),8.13(d,J=8.5Hz,1H) ,7.87(d,J=16.4Hz,1H),7.74(td,J=7.6,1.9Hz,1H),7.59(dd,J=4.6,2.8Hz,2H),7.55–7.48(m,2H),7. 38(d,J=1.5Hz,1H),7.27(t,J=8.0Hz,1H),7.23–7.19(m,1H),7.15(t,J=7.8Hz,1H),7.10(dd,J=8.5,1 .5Hz,1H),7.01(dt,J=7.8,1.3Hz,1H),6.82–6.78(m,2H),6.76–6.72(m,1H),3.65(s,3H),3.50(s,2H). 13 C NMR (126MHz, DMSO-d6) δ169.68,159.68,155.36,150.04,142.49,142.33,140.80,137.64,137.35,135.57,133.70,130.46,129.81,12 9.73,126.12,124.22,124.13,123.13,122.97,122.21,121.80,121.52,120.41,118.72,115.38,112.44,55.43,43.81.HRMS(ESI)m / z calcd for C 29 H 24 N4O2S[M+H]+493.1696; found,493.1697.

[0214] Example 22

[0215] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)-2-(o-tolyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 2-methylphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0216] The prepared compound was a pale yellow solid with a yield of 61.5%.

[0217] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),10.26(s,1H),8.60(d,J=4.2Hz,1H),8.20(d,J=8.5Hz,1H), 7.93(d,J=16.3Hz,1H),7.81(td,J=7.7,1.5Hz,1H),7.66(d,J=7.5Hz,2H),7.61(d,J=8.3Hz,1H),7 .56(d,J=16.4Hz,1H),7.45(s,1H),7.34(t,J=8.0Hz,1H),7.28(dd,J=7.0,5.1Hz,1H),7.22–7.19 (m,1H),7.17(d,J=8.7Hz,1H),7.15–7.11(m,3H),7.08(d,J=7.8Hz,1H),3.65(s,2H),2.26(s,3H). 13 C NMR (126MHz, DMSO-d6) δ169.75,155.34,150.02,142.46,142.31,140.82,137.35,137.11,135.51,134.89,133.71,130.44,130.34,129.7 0,127.27,127.18,126.22,126.08,124.19,124.11,123.12,122.97,122.20,121.55,120.38,118.72,112.50,41.36,19.84.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H]+477.1744; found,477.1740.

[0218] Example 23

[0219] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)-2-(m-tolyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 3-methylphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0220] The prepared compound was a pale yellow solid with a yield of 57.2%.

[0221] The product's 1H NMR spectrum is as follows: 1H NMR(600MHz,DMSO-d6)δ13.24(s,1H),10.22(s,1H),8.58(s,1H),8.17(d,J=8.3Hz,1H) ,7.91(d,J=16.6Hz,1H),7.78(t,J=7.3Hz,1H),7.64(d,J=11.4Hz,2H),7.56(dd,J=22.9 ,12.1Hz,2H),7.43(s,1H),7.32(t,J=7.9Hz,1H),7.26(d,J=6.3Hz,1H),7.15(dd,J=17 .1,8.6Hz,2H),7.07(d,J=13.7Hz,3H),7.02(d,J=7.1Hz,1H),3.54(s,2H),2.25(s,3H). 13 C NMR(151MHz,DMSO-d6)δ169.81,155.30,150.02,142.42,142.26,140.77,137.77,137.39,136.04,135.48,133.67,130.40,130.21,130.0 8,129.75,129.58,128.64,124.15,123.14,122.96,122.20,122.08,121.61,121.39,120.35,118.78,118.57,43.68,29.46.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H] + 477.1744; found, 477.1742.

[0222] Example 24

[0223] The synthesis of (E)-2-(4-methylphenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 4-methylphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0224] The prepared compound was a pale yellow solid with a yield of 58.4%.

[0225] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.34(s,1H),10.37(s,1H),8.61(d,J=4.4Hz,1H),8.19(d,J=8.5Hz,1H),7.93( dd,J=16.4,4.6Hz,1H),7.81(t,J=7.6Hz,1H),7.66(d,J=7.8Hz,1H),7.61(d,J=8.3Hz,1H),7.56(dd,J= 16.4,5.4Hz,1H),7.45(s,1H),7.34(t,J=8.0Hz,1H),7.28(dd,J=6.8,5.4Hz,1H),7.19(d,J=7.9Hz,2H) ,7.17–7.14(m,1H),7.11(d,J=7.8Hz,2H),7.07(d,J=9.0Hz,1H),5.29(s,1H),3.57(s,2H),2.26(s,3H). 13 C NMR (126MHz, DMSO-d6) δ170.03,155.34,150.02,140.88,137.35,136.03,135.43,133.70,133.20,130.40,129.66,129.44,12 9.31,126.08,124.15,123.12,122.96,122.19,121.56,120.33,119.15,118.72,116.92,114.03,43.33,21.10.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H]+477.1744; found,477.1745.

[0226] Example 25

[0227] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)-2-(p-tolyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 2-trifluoromethylphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0228] The prepared compound was a pale yellow solid with a yield of 62.5%.

[0229] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),10.32(s,1H),8.61(d,J=4.0Hz,1H),8.2 0(d,J=8.5Hz,1H),7.94(d,J=16.4Hz,1H),7.82(td,J=7.7,1.7Hz,1H),7.71–7. 62(m,4H),7.58(s,2H),7.49(dd,J=13.7,7.3Hz,3H),7.35(t,J=8.0Hz,1H),7.2 8(dd,J=7.1,5.0Hz,1H),7.19–7.16(m,1H),7.09(d,J=7.8Hz,1H),3.90(s,2H). 13 C NMR (126MHz, DMSO-d6) δ168.72,150.03,140.72,137.35,135.62,134.63,133.93,133.62,132.71,131.86,130.48,129.70,128.48,127.88 ,127.81,126.14,126.10,126.06,125.36,124.25,124.09,123.13,122.98,122.22,121.44,120.92,118.65,113.25,39.48.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H]+531.1461; found,531.1460.

[0230] Example 26

[0231] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 3-trifluoromethylphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0232] The prepared compound was a pale yellow solid with a yield of 59.5%.

[0233] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),10.32(s,1H),8.61(d,J=4.2Hz,1H),8 .20(d,J=8.5Hz,1H),7.96(s,1H),7.81(td,J=7.7,1.6Hz,1H),7.68–7.64(m ,3H),7.63–7.54(m,5H),7.47(s,1H),7.35(t,J=8.0Hz,1H),7.28(dd,J=7.3 ,4.9Hz,1H),7.17(dd,J=8.5,1.2Hz,1H),7.10(d,J=7.9Hz,1H),3.76(s,2H). 13 CNMR(126MHz,DMSO-d6)δ169.22,155.33,150.02,142.46,140.63,137.51,137.34,135.69,133.96,133.56,130.47,129.77,129.70,129.5 3,129.28,126.34,126.14,125.81,124.29,123.86,123.65,123.12,122.97,122.22,121.47,120.40,118.71,112.66,43.00.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H]+531.1461; found,531.1469.

[0234] Example 27

[0235] The synthesis of (E)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 4-trifluoromethylphenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0236] The prepared compound was a pale yellow solid with a yield of 63.5%.

[0237] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.29(s,1H),10.36(s,1H),8.61(d,J=4.0Hz,1H),8.21(d,J= 8.5Hz,1H),7.95(d,J=16.4Hz,1H),7.81(td,J=7.7,1.7Hz,1H),7.68(d,J=8.2Hz,3H) ,7.60(d,J=10.1Hz,2H),7.56–7.52(m,3H),7.47(s,1H),7.35(t,J=8.0Hz,1H),7.28( dd,J=7.2,4.9Hz,1H),7.17(dd,J=8.5,1.1Hz,1H),7.10(d,J=7.9Hz,1H),3.75(s,2H). 13 C NMR (126MHz, DMSO-d6)δ

[0238] 155.33,150.02,142.47,142.31,141.00,140.64,137.34,135.69,133.59,132.52,131.99,131.92,130.55,130.46,12 9.72,129.28,126.15,125.59,124.29,123.12,122.97,122.22,121.47,120.42,118.70,112.66,43.28.HRMS(ESI)m / z calcd forC 29 H 24 N4OS[M+H]+531.1461; found,531.1460.

[0239] Example 28

[0240] The synthesis of (E)-2-(2-fluorophenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and o-fluorophenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0241] The prepared compound was a pale yellow solid with a yield of 66.5%.

[0242] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.27(s,1H),10.31(s,1H),8.60(d,J=4.3Hz,1H),8.20( d,J=8.5Hz,1H),7.93(d,J=16.4Hz,1H),7.81(t,J=7.5Hz,1H),7.66(d,J=7.1Hz, 2H),7.58(dd,J=16.5,12.5Hz,2H),7.46(s,1H),7.35(dd,J=9.4,6.5Hz,2H),7.2 9(dd,J=13.6,8.4Hz,2H),7.19–7.13(m,3H),7.09(d,J=7.7Hz,1H),3.70(s,2H). 13 C NMR (126MHz, DMSO-d6) δ168.75,162.08,160.14,155.34,150.02,142.47,142.31,140.72,137.35,135.60,133.65,132.49,130.47,12 9.71,129.33,126.10,124.71,124.23,123.24,123.12,122.97,122.21,121.47,120.39,118.67,115.56,112.56,36.75.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H]+481.1493; found,481.1496.

[0243] Example 29

[0244] The synthesis of (E)-2-(4-fluorophenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and p-fluorophenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0245] The prepared compound was a pale yellow solid with a yield of 61.2%.

[0246] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),10.27(s,1H),8.61(d,J=3.9Hz,1H), 8.20(d,J=8.5Hz,1H),7.94(d,J=16.3Hz,1H),7.81(t,J=7.0Hz,1H),7.68–7 .65(m,2H),7.60(d,J=10.5Hz,2H),7.46(s,1H),7.35–7.32(m,3H),7.30–7. 26(m,1H),7.14(dd,J=15.5,6.6Hz,3H),7.09(d,J=7.7Hz,1H),3.61(s,2H). 13 C NMR (126MHz, DMSO-d6) δ169.71,162.56,160.63,155.34,150.02,142.31,140.75,137.34,135.59,133.65,132.35,131.51,13 0.44,129.71,126.10,124.23,124.11,123.12,122.96,122.20,121.49,120.40,118.69,115.55,112.57,42.69.HRMS(ESI)m / z calcd for C 29 H 24 N4OS[M+H]+481.1493; found,481.1495.

[0247] Example 30

[0248] The synthesis of (E)-2-(2-chlorophenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 2-chlorophenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0249] The prepared compound was a pale yellow solid with a yield of 65.8%.

[0250] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),10.32(s,1H),8.61(d,J=4.0Hz,1H),8.20(d, J=8.5Hz,1H),7.94(d,J=16.4Hz,1H),7.81(td,J=7.7,1.6Hz,1H),7.67(d,J=4.1Hz ,2H),7.62–7.56(m,2H),7.46(s,1H),7.44–7.38(m,2H),7.35(t,J=8.0Hz,1H),7.2 9(dd,J=5.9,3.4Hz,3H),7.18(d,J=8.4Hz,1H),7.09(d,J=7.7Hz,1H),3.81(s,2H). 13 C NMR (126MHz, DMSO-d6)δ

[0251] 168.61,155.36,150.02,142.47,142.32,140.77,137.32,135.60,134.19,134.13,133.65,132.66,130.44,129.72,129.4 5,129.08,127.51,126.06,124.24,124.11,123.09,122.95,122.18,121.50,120.41,118.67,112.58,41.22.HRMS(ESI)m / z calcd forC 28 H 21 ClN4OS[M+H]+497.1197; found,497.1198.

[0252] Example 31

[0253] The synthesis of (E)-2-(3-chlorophenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 3-chlorophenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0254] The prepared compound was a pale yellow solid with a yield of 66.5%.

[0255] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.28(s,1H),10.30(s,1H),8.61(d,J=4.7Hz,1H),8.20(d,J= 8.5Hz,1H),7.94(d,J=16.4Hz,1H),7.81(td,J=7.7,1.8Hz,1H),7.68–7.65(m,2H),7.6 2–7.54(m,2H),7.46(s,1H),7.38(s,1H),7.35(dd,J=7.9,2.1Hz,1H),7.34–7.31(m,1 H),7.30–7.25(m,2H),7.17(dd,J=8.5,1.4Hz,1H),7.09(d,J=7.9Hz,1H),3.65(s,2H). 13 C NMR (126MHz, DMSO-d6) δ169.23,155.36,150.02,142.48,142.32,140.66,138.59,137.32,135.64,133.63,133.28,130.57,130.44,12 9.73,129.55,128.42,127.04,126.16,124.25,124.11,123.09,122.95,122.19,121.54,120.42,118.73,112.61,43.06.HRMS(ESI)m / z calcd for C 28 H 21 ClN4OS[M+H]+497.1197; found,497.1198.

[0256] Example 32

[0257] The synthesis of (E)-2-(4-chlorophenyl)-N-(3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)phenyl)acetamide was carried out using (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline and 4-chlorophenylacetic acid as raw materials, and other implementation methods were the same as in Example 4;

[0258] The prepared compound was a pale yellow solid with a yield of 58.5%.

[0259] The product's 1H NMR spectrum is as follows: 1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),10.28(s,1H),8.61(d,J=4.1Hz,1H),8.20(d, J=8.5Hz,1H),7.94(d,J=16.3Hz,1H),7.81(td,J=7.7,1.7Hz,1H),7.66(d,J=9.2Hz, 2H),7.60–7.55(m,2H),7.46(s,1H),7.37(d,J=8.4Hz,2H),7.33(t,J=8.5Hz,3H),7. 28(dd,J=7.1,5.0Hz,1H),7.17(d,J=8.4Hz,1H),7.09(d,J=7.8Hz,1H),3.62(s,2H). 13 C NMR (126MHz, DMSO-d6) δ169.44,155.34,150.02,142.47,142.31,140.70,137.34,135.63,135.17,133.62,131.79,131.52,13 0.45,129.72,128.69,126.12,124.26,124.10,123.12,122.97,122.21,121.47,120.41,118.69,112.61,42.84.HRMS(ESI)m / z calcd for C 28 H 21 ClN4OS[M+H]+497.1197; found,497.1204.

[0260] Example 33

[0261] The synthesis reaction formula is as follows:

[0262]

[0263] The synthesis steps are as follows:

[0264] (1) To a mixture of 2 g (8.97 mmol) of 6-iodo-1H-indazole and 0.63 g (5.09 mmol) of 3-aminobenzylthiophenol in a dry 1,4-dioxane, 0.2 g (0.23 mmol) of tris(dibenzylacetone)dipalladium, 0.5 g (0.87 mmol) of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) and 1.28 g (9.28 mmol) of potassium carbonate were added. The mixture was stirred at 80 °C under an argon atmosphere for 14 h. The solvent was evaporated and diluted with ethyl acetate, and then washed with water and brine. The organic phase was evaporated, eluted with 10%-30% ethyl acetate in petroleum ether, purified by silica gel column chromatography, and 1.6 g of intermediate 3-((1H-indazole-6-yl)thio)aniline yellow solid was obtained, with a yield of 71%.

[0265] (2) Add 1.22 g (7.91 mmol) of 3-((1H-indazol-6-yl)thio)aniline solution to 20 mL of dichloromethane, then add 3-fluorophenylacetic acid, 3.78 g (10 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and 1.71 g (13.27 mmol) of N,N-diisopropylethylamine. Stir the resulting mixture at room temperature for 8 h; then dilute with 50 mL of ethyl acetate and wash three times with 100 mL of water. The organic layer was washed with 100 mL of brine, dried on anhydrous sodium sulfate, and concentrated. The residue was diluted with 20 mL of dichloromethane and 4 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 h, and then the pH was adjusted to 12 with saturated sodium bicarbonate. The mixture was extracted with 50 mL of ethyl acetate, washed twice with 50 mL of water, and then washed with 50 mL of brine. The organic layer was dried with sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with 0-5% methanol in dichloromethane to give 1.8 g of N-(3-((1H-indazol-6-yl)thio)phenyl)-2-(2-fluorophenyl)acetamide, a yellow solid, in a yield of 72%.

[0266] (3) Add 1.8 g (4.7 mmol) of N-(3-((1H-indazol-6-yl)thio)phenyl)-2-(2-fluorophenyl)acetamide to 10 mL of anhydrous N,N-dimethylformamide (10 mL) solution, then add 0.51 g (12.74 mmol) of sodium hydroxide. Stir the mixture at 0 °C. Add 12.08 g (47.74 mmol) of iodine to 5 mL of anhydrous N,N-dimethylformamide to form a solution. Mix this solution with the previous solution and stir at room temperature for 4 h. Detect the reaction endpoint by LC-MS. After the reaction is complete, evaporate the solvent, extract with 100 mL of ethyl acetate, wash twice with 100 mL of water, and then wash with 100 mL of saturated saline. Elute the organic layer with 0-30% ethyl acetate in petroleum ether, elute, and purify to obtain 1.8 g of N-dimethylformamide. 2-(2-fluorophenyl)-N-(3-((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide, yellow crystals, yield 75%;

[0267] (4) To a dry N,N-dimethylformamide mixture of 100 mg (0.21 mmol) 2-(2-fluorophenyl)-N-(3-(((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and 30 mg (0.24 mmol) phenylboronic acid, add 11.5 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium and 27.5 mg (0.2 mmol) potassium carbonate. Stir the mixture at 80 °C under an argon atmosphere for 14 h. Evaporate the solvent and dilute with ethyl acetate, then wash with water and brine. Evaporate the organic phase and elute with 10%-30% ethyl acetate in petroleum ether, purify by silica gel column chromatography, and obtain 2-(2-fluorophenyl)-N-(3-((3-phenyl-1H-indazol-6-yl)thio)phenyl)acetamide.

[0268] The compound was prepared as a pale yellow solid with a yield of 66% (60 mg).

[0269] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.30(s,1H),10.46(s,1H),8.06(d,J=8.5Hz,1H),7.97(d,J=7.7Hz,2H),7.70(s,1H),7.62(d,J=8.1Hz,1H),7.52(t,J=7.6 Hz,2H),7.48(s,1H),7.42(d,J=7.4Hz,1H),7.38–7.34(m,2H),7.31–7.27 (m,1H),7.15(dd,J=11.3,6.6Hz,3H),7.09(d,J=7.8Hz,1H),3.72(s,2H). 13CNMR(126MHz,DMSO-d6)δ168.78,162.09,160.15,143.86,142.57,140.78,135.52,133.45,132.47,130.42,129.38,129.2 9,128.33,127.22,126.15,124.68,124.12,123.31,122.18,121.62,119.65,118.73,115.55,112.56,36.74.HRMS(ESI)m / z calcd for C 27 H 20 FN3OS[M+H] + 454.1384; found, 454.1386.

[0270] Example 34

[0271] 2-(2-fluorophenyl)-N-(3-((3-(p-tolyl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-(((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and p-methylphenylboronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0272] The prepared compound was a pale yellow solid with a yield of 53.5%.

[0273] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.17(s,1H),10.29(s,1H),8.04(d,J=8.6Hz,1H),7.86(d,J=8.0Hz,2H),7.66(s,1H),7.60( d,J=8.3Hz,1H),7.47(s,1H),7.39–7.30(m,5H),7.18–7.12(m,3H),7.09(d,J=7.8Hz,1H),3.71(s,2H),2.37(s,3H). 13 C NMR(126MHz,DMSO-d6)δ168.73,162.09,143.97,142.53,140.70,137.67,135.72,133.27,132.47,131.03,130.43,129.95,12 9.32,127.13,126.05,124.69,124.08,123.25,122.25,121.46,119.69,118.64,115.55,112.64,36.75,21.33.HRMS(ESI)m / z calcd forC28 H 22 FN3OS[M+H] + 468.1540; found, 468.1545.

[0274] Example 35

[0275] 2-(2-fluorophenyl)-N-(3-((3-(4-(trifluoromethyl)phenyl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and 4-trifluoromethylphenylboronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0276] The prepared compound was a pale yellow solid with a yield of 62.5%.

[0277] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.46(s,1H),10.30(s,1H),8.21(d,J=8.1Hz,2H),8.12(d,J=8.6Hz,1H),7.86(d,J=8.2Hz,2H),7.69(s,1H),7.60(d,J=8 .6Hz,1H),7.50(s,1H),7.36(t,J=7.9Hz,2H),7.30(d,J=7.2Hz,1H),7.1 9(d,J=8.6Hz,1H),7.16–7.13(m,2H),7.11(d,J=7.9Hz,1H),3.70(s,2H). 13 C NMR (126MHz, DMSO-d6) δ168.75,162.08,160.14,142.66,142.39,140.74,137.77,135.32,133.99,132.47,130.50,129.33,12 7.67,126.33,126.30,126.27,124.70,124.52,123.23,122.00,121.73,119.62,118.82,115.55,112.54,36.76.HRMS(ESI)m / z calcd for C 25 H 18 FN5OS[M+H] + 552.1258; found, 552.1259.

[0278] Example 37

[0279] 2-(2-fluorophenyl)-N-(3-((3-(pyridin-3-yl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-(((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and pyridin-3-ylboronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0280] The prepared compound was a pale yellow solid with a yield of 62.5%.

[0281] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.42(s,1H),10.32(s,1H),9.18(s,1H),8.62(d,J=3.3Hz,1H),8.35(d,J=7.5Hz,1H),8.11(d,J=8.4Hz,1H ),7.70(s,1H),7.61(d,J=7.6Hz,1H),7.53(dd,J=17.7,10.7Hz,2H),7.39–7.27(m,3H),7.14(dd,J=27.6,7.9Hz,4H),3.71(s,2H). 13 C NMR (126MHz, DMSO-d6) δ168.76,162.09,149.28,147.90,142.53,141.25,140.74,135.34,134.42,134.00,132.47,130.49,129.7 1,129.32,126.36,124.69,124.52,124.36,123.24,122.04,121.77,119.66,118.82,115.55,112.44,36.76.HRMS(ESI)m / zcalcd for C 26 H 19 FN4OS[M+H] + 455.1336; found, 455.1338.

[0282] Example 37

[0283] 2-(2-fluorophenyl)-N-(3-((3-(pyridin-4-yl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-(((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and pyridin-4-ylboronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0284] The prepared compound was a pale yellow solid with a yield of 68.5%.

[0285] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.56(s,1H),10.32(s,1H),8.69(d,J=5.9Hz,2H),8.18(d,J=8.6Hz,1H),7.98(d,J=5.9Hz,2H),7.70(s,1H),7.61(d, J=8.3Hz,1H),7.50(s,1H),7.36(t,J=8.0Hz,2H),7.33–7.28(m,2H),7. 20(d,J=8.6Hz,1H),7.16–7.15(m,1H),7.14–7.12(m,1H),3.71(s,2H). 13 C NMR (126MHz, DMSO-d6) δ168.76,162.09,160.79,160.15,151.14,150.76,142.70,140.76,135.19,134.18,132.47,130.52,12 9.33,128.29,127.82,126.43,124.67,122.00,121.28,119.71,118.87,115.92,115.63,115.38,112.50,36.76.HRMS(ESI)m / z calcd for C 26 H 19 FN4OS[M+H] + 455.1336; found, 455.1352.

[0286] Example 38

[0287] 2-(2-fluorophenyl)-N-(3-((3-(pyrimidin-2-yl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-(((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and pyrimidin-2-ylboronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0288] The prepared compound was a pale yellow solid with a yield of 54.5%.

[0289] The product's 1H NMR spectrum is as follows: 1H NMR (500MHz, DMSO-d6) δ13.59(s,1H),10.31(s,1H),9.38(s,2H),9.23(s,1H),8.18(d,J=8.5Hz,1H),7.71(d,J=2.0Hz,1H),7 .63(d,J=1.4Hz,2H),7.57(d,J=2.7Hz,2H),7.51(s,1H),7.37(s,2H),7.31–7.28(m,1H),7.16(d,J=1.3Hz,1H),3.71(s,2H). 13 C NMR (126MHz, DMSO) δ168.78,162.10,157.92,154.76,142.50,140.77,138.44,135.13,134.53,133.63,132.82,132. 53,132.01,130.54,129.28,128.00,126.57,124.53,122.05,119.62,118.94,115.40,112.30,36.76.HRMS(ESI)m / z calcd forC 25 H 18 FN5OS[M+H] + 456.1245; found, 456.1245.

[0290] Example 39

[0291] 2-(2-fluorophenyl)-N-(3-((3-(2-fluoropyridin-3-yl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and (2-fluoropyridin-3-yl)boronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0292] The prepared compound was a pale yellow solid with a yield of 63.5%.

[0293] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.54(s,1H),10.30(s,1H),8.35(dd,J=14.8,5.7Hz,2H),7.82(dd,J=8.6,2.6Hz,1H),7.68(s, 1H),7.61(d,J=8.3Hz,1H),7.55–7.49(m,2H),7.38–7.28(m,3H),7.18–7.14(m,3H),7.10(d,J=7.8Hz,1H),3.71(s,2H). 13C NMR (126MHz, DMSO-d6) δ168.75,162.09,161.10,160.15,159.20,147.70,142.15,141.97,140.74,135.37,134.04,132.48,130.4 9,129.33,126.31,124.70,124.26,123.24,123.04,122.16,121.71,120.41,118.80,115.55,112.39,36.75.HRMS(ESI)m / zcalcd for C 26 H 18 F2N4OS[M+H] + 473.1242; found, 473.1242.

[0294] Example 40

[0295] N-(3-((3-(1H-pyrazole-4-yl)-1H-indazole-6-yl)thio)phenyl)-2-(2-fluorophenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-(((3-iodo-1H-indazole-6-yl)thio)phenyl)acetamide and (1H-pyrazole-4-yl)boronic acid as raw materials. Other implementation methods were the same as in Example 32.

[0296] The prepared compound was a pale yellow solid with a yield of 49.5%.

[0297] The product's 1H NMR spectrum is as follows: 1 H NMR (500MHz, DMSO-d6) δ13.28(s,1H),10.30(s,1H),8.61(d,J=4.7Hz,1H),8.20(d,J= 8.5Hz,1H),7.94(d,J=16.4Hz,1H),7.81(td,J=7.7,1.8Hz,1H),7.68–7.65(m,2H),7.6 2–7.54(m,2H),7.46(s,1H),7.38(s,1H),7.35(dd,J=7.9,2.1Hz,1H),7.34–7.31(m,1 H),7.30–7.25(m,2H),7.17(dd,J=8.5,1.4Hz,1H),7.09(d,J=7.9Hz,1H),3.65(s,2H). 13C NMR (126MHz, DMSO-d6) δ169.23,155.36,150.02,142.48,142.32,140.66,138.59,137.32,135.64,133.63,133.28,130.57,130.44,12 9.73,129.55,128.42,127.04,126.16,124.25,124.11,123.09,122.95,122.19,121.54,120.42,118.73,112.61,43.06.HRMS(ESI)m / z calcd for C 28 H 21 ClN4OS[M+H] + 497.1197; found, 497.1198.

[0298] Example 41

[0299] 2-(2-fluorophenyl)-N-(3-((3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazol-6-yl)thio)phenyl)acetamide was synthesized using 2-(2-fluorophenyl)-N-(3-((3-iodo-1H-indazol-6-yl)thio)phenyl)acetamide and 2-(4-methylpiperazin-1-yl)pyridin-5-boronic acid pinacol ester as raw materials. Other implementation methods were the same as in Example 32.

[0300] The prepared compound was a pale yellow solid with a yield of 55.5%.

[0301] The product's 1H NMR spectrum is as follows: 1 H NMR(500MHz,DMSO-d6)δ13.00(s,1H),10.27(s,1H),8.12(d,J=2.0Hz,1H),8.05(s ,1H),7.72(dd,J=8.3,4.5Hz,2H),7.58(dd,J=8.8,2.1Hz,1H),7.53(s,1H),7.33( dd,J=8.0,4.1Hz,2H),7.29(s,2H),7.17–7.11(m,2H),6.95(d,J=8.4Hz,1H),6.82 (d,J=8.8Hz,1H),3.68(s,2H),3.51–3.46(m,4H),2.39–2.36(m,4H),2.21(s,3H). 13C NMR (126MHz, DMSO-d6) δ168.65,162.07,160.13,158.43,147.84,140.86,139.62,138.74,135.61,134.11,133.63,132.44,131.42,129. 30,125.01,124.68,123.26,123.13,122.90,122.31,122.01,119.21,115.55,111.69,106.38,54.86,46.28,44.96,36.70.HRMS(ESI)m / z calcd for C 31 H 29 FN6OS[M+H] + 531.2337; found, 553.2187.

[0302] Table 1. Aromatic indazole cyclic compounds prepared in Examples 1-41

[0303]

[0304]

[0305]

[0306]

[0307]

[0308] The properties of the compounds prepared in Examples 1-41 were tested below:

[0309] Inhibitory effects of the compounds prepared in Examples 1-41 on BaF3-TEL-VEGFR2 cells and parental BaF3 cells.

[0310] Parental BaF3 cells were grown in RPMI 1640 medium (Corning, USA) supplemented with 100 ng / mL IL-3, while Tel-VEGFR2-BaF3 cells were cultured in the same medium without IL-3. All cell lines were incubated in 96-well plates at 37°C and 5% CO2, with 1500–3000 cells per well. Serially diluted compounds were added to the wells, and cell proliferation was assessed after 72 hours. Cell viability was determined using a cell counting kit-8 (MedChemExpress, China) according to the manufacturer's instructions, and absorbance was measured at 450 nm using a microplate reader (iMARK, Bio-Rad). Data were normalized to a control group treated with DMSO and are expressed as the mean of three independent measurements. Dose-response curves were generated using Prism 7.0 (GraphPad Software, San Diego, USA).

[0311] Table 2. Inhibitory activity of arylinazole compounds prepared in Examples 1-40 against BaF3-TEL-VEGFR2 cells and parental BaF3 cells. 50 Level 1: 0-1 nm, Level 2: 1-10 nm, Level 3: 10-100 nm

[0312] Level 4: 100-1000 nm, Level 5: 1000-10000 nm, Level 6: >10000 nm

[0313]

[0314]

[0315] Industrial application

[0316] This invention provides a novel kinase inhibitor compound that can be used to reduce or inhibit VEGFR2 kinase activity in cells or subjects, and / or to prevent or treat VEGFR2 activity-related conditions in subjects. Therefore, it can be formulated into a corresponding drug suitable for industrial application.

[0317] Although the present invention has been described in detail herein, the present invention is not limited thereto. Those skilled in the art can make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood as falling within the protection scope of the present invention.

Claims

1. An arylinazole cyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound has structural formula (I).

2. A method for preparing an arylinazole cyclic compound as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The synthesis steps are as follows: (1) Tris(dibenzylacetone)dipalladium, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) and potassium carbonate were added to a mixture of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole and 3-aminobenzylthiophenol in a dry 1,4-dioxane. The mixture was stirred at 80 °C under an argon atmosphere for 14 h. The solvent was evaporated and diluted with ethyl acetate, and then washed with water and brine. The organic phase was evaporated, eluted with 10%-30% ethyl acetate in petroleum ether, purified by silica gel column chromatography, and the intermediate (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)thio)aniline yellow solid was obtained. (2) A solution of (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline was formed by adding (E)-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thio)aniline was then added to dichloromethane. 3-fluorobenzoic acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine were then added. The resulting mixture was stirred at room temperature for 8 hours, diluted with ethyl acetate, washed three times with water, and then washed with brine. The organic layer was dried on anhydrous sodium sulfate and concentrated. The residue was diluted with dichloromethane and trifluoroacetic acid. The reaction mixture was stirred at room temperature for 4 h, and then the pH was adjusted to 12 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, washed twice with water, and then washed with brine. The organic layer was dried with sodium sulfate, then filtered, concentrated, and purified by silica gel column chromatography with 0-5% methanol in dichloromethane to give (E)-N-(3-fluorophenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6-yl)thio)benzamide yellow solid.

3. A pharmaceutical composition comprising an arylinazole cyclic compound of the compound structural formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. The use of an arylinazole ring compound of the compound structure (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for diseases caused by upregulation of VEGFR2 kinase activity leading to angiogenesis.

5. The application as described in claim 4, wherein, The disease is selected from at least one of tumors or rheumatoid arthritis, and / or at least one of arthritis, asthma, or inflammatory bowel disease.

6. The application as described in claim 4, wherein, The disease in question is an autoimmune disease.

7. The use of an arylinazole ring compound of the compound structure (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of rheumatoid arthritis by inhibiting synovial angiogenesis through the VEGFR2 / PI3K / AKT pathway.

8. The application as described in claim 7, wherein, The rheumatoid arthritis disease mentioned is selected from at least one of the following: joint involvement, rheumatoid vasculitis, cardiac involvement, respiratory involvement, kidney involvement, and diseases such as anemia, pleurisy, pleural effusion, pulmonary arteritis, interstitial lung disease, glomerulonephritis, and tubulointerstitial nephritis.

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