BR112018016264B1 - SIX-MEMBERS NITRIC HETEROCYCLIC RING COMPOUND REPLACED BY AMINO AND PREPARATION AND USE THEREOF - Google Patents

Abstract

Provided in the present invention are a compound and a preparation of amino-substituted six-membered nitric heterocyclic ring and use thereof. In particular, there is provided in the present invention a compound as shown by the general formula (I) below, wherein the definition of each group is as described in the description. The compound of the present invention has excellent tyrosine kinase inhibitory activity and can therefore be used to prepare a series of medicines to treat diseases in relation to tyrosine kinase inhibitory activity.

Description

FIELD OF INVENTION

[0001] The present invention relates to a substituted aminopyridine compound that has selective tyrosine kinase inhibitory activity, and a pharmaceutically acceptable salt or solvent, and the process of preparing the same, and the use in the preparation of medicine to prevent or treat diseases associated with fibroblast growth factor receptor, such as abnormal proliferation, morphological changes of cells and hyperkinesia, as well as diseases associated with angiogenesis or cancer metastasis, especially for the preparation of medicine for treating or preventing tumor growth and metastasis .

BACKGROUND OF THE INVENTION

[0002] Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases, members of the family that includes FGFR1, FGFR2, FGFR3 and FGFR4. Its basic structures include extracellular domain, transmembrane region and tyrosine kinase domain. The extracellular domain consists of three immunoglobulin-like domains, including an acidic framework, a membrane domain, and an intracellular tyrosine kinase cleavage domain. Like other tyrosine kinases, when the ligand binds to FGFR, the receptor dimerizes and the ternary complex (FGF-FGFR-HPSG) formed dimerizes to make the FGFR structure change, thereby causing transfer of intramolecular phosphorylation of the tyrosine domain. intracellular kinase and the terminal carboxylic acid chemical moiety, followed by attachment of the FGFR receptor substrate (FRS2α) and phospholipase C (PLCY) to activate a series of downstream signaling pathways, such as the Ras-activated protein kinase pathway/ mitogen (MAPK) and phosphoionositide kinase 3 (PI3K)/Akt pathway, which, in turn, stimulates some physiological processes in the cell, such as cell proliferation, survival, migration and angiogenesis.

[0003] FGFR activation is closely related to the occurrence, development and resistance of various tumors. FGFRs participate in tumorigenesis, mainly through three mechanisms: chromosomal translocation, genetic mutation, amplification or genetic overexpression. Chromosomal translocation of the FGFR1 gene or its fusion gene is mainly present in multiple myeloma; mutation of both FGFR2 and FGFR3 are expressed in lung squamous cell carcinoma and mutation of FGFR4 Y367C in the transmembrane region allows continuous activation of breast cancer cells. FGFR amplification has been reported to occur in a variety of different cancers, FGFR1 amplification occurs in patients with rectal cancer, lung cancer and kidney cancer, in addition, in about 10% of breast cancer, especially patients Positive for estrogen receptor, the FGFR1 8p11-12 site is amplified. Although patients with gastric cancer and rectal cancer have also shown FGFR2 amplification, FGFR3 amplification is more common in patients with bladder cancer. Therefore, studies of inhibitors that target FGFR kinase are of great importance in the treatment of malignant tumors.

[0004] Recently, the development of small molecule tyrosine kinase inhibitors (TKI), whose therapeutic target is FGFRs, has become a hot spot in antitumor drug research. Some FGFR inhibitors have entered the clinical research stage and can be classified as selective FGFR inhibitors or non-selective FGFR inhibitors depending on their range of action. These inhibitors mainly inhibit FGFR activation by targeting the ATP-binding site of FGFR intracellular kinase domain and can be applied to tumor types overexpressing FGFRs, FGFR mutations or expressing FGFR fusion proteins. AZD4547, BGJ398, LY2874455, and AL-3810 are all selective FGFR inhibitors that have entered the clinic and have strong antitumor activity. As reported in the literature, AZD-4547, BGJ-398, and AL-3810 are potent inhibitors of FGFR1-3, while LY2874455 is a pan-FGFR inhibitor (acting on FGFR1-4).

[0005] Due to the highly similar structure of PDGFRs, VEGFRs and FGFRs, most FGFR TKIs have inhibitory activity on PDGFR as well as VEGFR, causing extensive toxic side effects of FGFR inhibitors. The development of FGFR inhibitors still faces major challenges. In terms of structure, the structure of FGFR inhibitors is very limited.

[0006] Briefly, there is a need in the art to develop FGFR inhibitors that have innovative structures.

SUMMARY OF THE INVENTION

[0007] The objective of the present invention is to provide an innovative class of FGFR kinase inhibitors that are structurally innovative and have excellent activity.

[0008] In the first aspect of the present invention, a compound of formula I below, or a pharmaceutically acceptable salt, is provided, where: X is selected from the group consisting of CH and N; Ring A may be selected from the group consisting of a substituted or unsubstituted 6- to 10-membered aryl, substituted and unsubstituted 5- to 12-membered heteroaryl, wherein "substituted" means that one or more hydrogen atoms in a group are substituted by substituents selected from the group consisting of a C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogen, C1-C8 halogenated alkyl; R1 is selected from -CONHR3 or -COOR3; R2 is selected from the group consisting of a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy, a substituted or unsubstituted 4- to 10-membered heterocyclic group, a substituted or unsubstituted amino, substituted or unsubstituted C1-C8 alkylamino group, -NHCOR3; wherein the substituent group is further substituted by one or more substituents selected from the group consisting of a C1-C8 alkyl, a hydroxy, a C1-C8 hydroxy alkyl, -COOR3, a C3-C10 amino-substituted cycloalkyl group, 4 to 10 membered heterocycloalkyl group that is unsubstituted or substituted by one or more halogen, hydroxyl or C1-C8 alkyl atoms; R3 is selected from hydrogen, C1-C8 alkyl, C2-C10 alkenyl.

[0009] In another preferred embodiment, in compound I, ring A is selected from a substituted or unsubstituted 6- to 10-membered aryl, a substituted or unsubstituted 5 to 10-membered heteroaryl.

[0010] In another preferred embodiment, in compound I, ring A is selected from a substituted or unsubstituted 6- to 10-membered aryl, a substituted or unsubstituted 5 to 6-membered heteroaryl.

[0011] In another preferred embodiment, in compound I, ring A is a substituted or unsubstituted group selected from the group consisting of benzene ring, naphthalene ring, pyridine ring, pyrazine ring, thiophene ring, furan ring, imidazole ring, pyrrole ring, oxazole ring, thiazole ring, pyrazole ring, indole ring, pyrimidine ring, benzofuran ring, benzothiazole ring, benzimidazole ring, quinoline ring, isoquinoline.

[0012] In another preferred embodiment, in the compound of formula I, ring A is selected from the group consisting of a substituted or unsubstituted benzene ring, substituted or unsubstituted thiazole ring, substituted or unsubstituted oxazole ring , substituted or unsubstituted pyrimidine ring.

[0013] In another preferred embodiment, in the compound of formula I, R2 is selected from the group consisting of a substituted or unsubstituted C1-C4 alkyl, a substituted or unsubstituted C1-C4 alkoxy, a heterocyclic group of 5 to 6 substituted or unsubstituted members, a substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkylamino, -NHCOR3; wherein “substituent” means that the group is further substituted by one or more substituents selected from the group consisting of a C1-C8 alkyl, a hydroxy, a hydroxy C1-C8 alkyl, -COOR3, a substituted C3-C10 cycloalkyl by amino, 4 to 10 membered heterocycloalkyl that is unsubstituted or substituted by one or more halogen, hydroxyl or C1-C8 alkyl atoms;

[0014] In another preferred embodiment, in the compound of formula I, R3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl.

[0015] In another preferred embodiment, in the compound of formula I, R3 is selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl.

[0016] In another preferred embodiment, in the compound of formula I, R3 is selected from hydrogen, methyl, ethenyl.

[0017] In another preferred embodiment, the compound is selected from the group consisting of: compound S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15 , S16, S17, S18, S19, S20, S21, S22, S23 and S24.

[0018] In the second aspect of the present invention, the method of preparing the compound of the first aspect of the present invention is provided, which comprises the following steps:

[0019] In an inert solvent, the compound of formula A reacts with the compound of formula B to obtain the compound of formula I; where Q is a leaving group, preferably halogen; ring A, X, R1 and R2 are defined as in the first aspect of the invention.

[0020] In another preferred embodiment, the reaction is conducted in the presence of Pd2(dba)3 [Tris(dibenzylideneacetone)dipalladium], Xantphos[9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthenes] or cesium carbonate .

[0021] In another preferred embodiment, the reaction comprises: dissolving compound A, compound B (1.0 to 1.5 eq), Pd2(dba)3 [Tris(dibenzylideneacetone)dipalladium] (0.05 to 0. 2 eq), nitrogen.

[0022] In another preferred embodiment, the inert solvent is 1,4-dioxane.

[0023] In another preferred embodiment, the reaction is carried out at 100 °C.

[0024] In another preferred embodiment, the process reaction time is 1 to 10h.

[0025] In another preferred embodiment, after the reaction is completed, dichloromethane and water are used for extraction and the organic phase is washed with saturated brine and dried through anhydrous sodium sulfate and then the mixed sample is purified through column to give the compost.

[0026] In the third aspect of the present invention, a pharmaceutical composition is provided which comprises: a therapeutically effective amount of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and, optionally , a pharmaceutically acceptable carrier or excipient.

[0027] In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for treating a tumor or a pharmaceutical composition for treating a disease associated with tyrosine kinase activity (preferably FGFR, more preferably, FGFR1).

[0028] In another preferred embodiment, the pharmaceutical composition is used to treat diseases associated with abnormal expression of the FGF/FGFR signaling pathway.

[0029] In the fourth aspect of the present invention, the use of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, is provided for the preparation of medicine for the prevention and/or treatment of FGFR-related diseases.

[0030] In another preferred embodiment, the tumor-related disease is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma and testicular cancer; preferably breast cancer, non-small cell lung cancer, bladder cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer , renal cell carcinoma, glioblastoma, and testicular cancer; most preferably non-small cell lung cancer, gastric cancer, multiple myeloma.

[0031] In the fifth aspect of the present invention, an inhibitor of protein tyrosine kinase enzyme activity is provided, which comprises an inhibitory effective amount of the compound according to the first aspect of the invention, or a salt, prodrug, hydrate or pharmaceutically acceptable solvent thereof.

[0032] In the sixth aspect of the present invention, a pharmaceutical composition for treating diseases associated with cancer or protein tyrosine kinase activity is provided, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvent thereof as an active ingredient.

[0033] In the seventh aspect of the present invention, a method for treating or preventing cancer or a disease associated with protein tyrosine kinase activity is provided, which comprises: administering a therapeutically or prophylactically effective amount of compound, in accordance with the first aspect of the invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, or a pharmaceutical composition according to the invention, for a subject to be treated or prevented.

[0034] It should be understood that, in the present invention, each of the technical resources specifically described above and below (such as those in the examples) can be combined with each other, thereby constituting new or preferred technical solutions that do not need to be specified again in this document. .

DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 shows the result of inhibition in FGFR2 and phosphorylation of downstream signaling molecules in gastric cancer cell strain SNU16 by S10.

MODALITIES FOR CARRYING OUT THE INVENTION

[0036] After long-term and intensive research, the present inventors unexpectedly discovered that a compound with an innovative structure and aminopyridine nucleus can be obtained by substituting a quinoline in the framework of the FGFR inhibitor AL-3810 reported in the literature with an aminopyridine. Based on the above, a new class of aminopyridine derivatives with better FGFR inhibitory activity and metabolic properties can be obtained by introducing aromatic rings substituted by different water-soluble groups. The present invention is concluded on this basis.

TERMS

[0037] As used herein, the term “heterocyclic group” is a cyclic group that has 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of O, N and S.

[0038] In this document, the alkyl group is preferably an aliphatic alkyl group and may be a linear alkyl group, a branched alkyl group, a spirocycloalkyl group, a bridged cycloalkyl group, an olefin alkyl group, an alkyne group, a cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl, alkoxyalkyl, cycloalkylalkyl, which includes, without limitation: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, allyl, propargyl, cyclobutenyl, cyclohexenyl. An expression of "C1-C8" is intended to include a corresponding group that has 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, "C1-C8 alkyl" means an alkyl group that has 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, "C2-C10 alkenyl" means an alkenyl group that has 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms of carbon.

[0039] In this document, the alkenyl group is preferably vinyl group, propenyl group, butenyl group, styryl group, phenylpropenyl group or the like.

[0040] In this document, the cycloalkyl group can be saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents that include 3 to 20 carbon atoms, which preferably includes 3 to 12 carbon atoms, more preferably, a cycloalkyl group that includes 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl and the like; and polycyclic cycloalkyl groups include spiro, fused or bridged cycloalkyl.

[0041] The heterocyclic group refers to saturated or partially saturated monocyclic or polycyclic substituents that include a 4- to 10-membered heterocyclic group and the heterocyclic group is a saturated or unsaturated monocyclic ring, paracyclic ring, spiro ring, fused ring, ring with bridge comprising one or more heteroatoms (nitrogen, oxygen or sulfur) or the like. The heterocyclic group described herein includes, but is not limited to, a group selected from the group consisting of morpholine ring, piperidine ring, piperazine ring, N-alkyl or acyl substituted piperazine ring, homopiperazine ring, homopiperazine substituted by N-alkyl or acyl, pyrrole, tetrahydropyrrole, 7H-purine and the like.

[0042] The aryl group refers to a 6- to 10-membered carbon-fused monocyclic or polycyclic ring (that is, a ring that shares a pair of adjacent carbon atoms) and the group has a conjugated n-electron system, such as phenyl or naphthyl group. The aryl ring may be fused to a heterocyclic, heteroaryl or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzoindoles, benzodihydrofuran.

[0043] The heteroaryl group refers to a heteroaromatic system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. The heteroaryl group preferably has 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl group can be fused to the aryl group, heterocyclic group or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring.

[0044] Unless otherwise stated, the structural formula described herein is intended to include all tautomeric, optical and stereoisomeric forms (e.g., enantiomers, diastereomers, geometric isomers or conformations), e.g., R configurations, S that contain asymmetric centers, (Z), (E) double bond isomers and conformers of (Z), (E). Therefore, a single stereochemical isomer, tautomer or enantiomer, diastereomer or geometric isomer or conformers or mixture of tautomers of the compounds of the invention are all within the scope of the invention.

[0045] The term "tautomer" means that structural isomers that have different energies can exceed the low energy barrier, thereby transforming between each other. For example, proton tautomers (i.e., proton switches) include interconversions via proton transfer, such as 1H-carbazole and 2H-carbazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversion through some recombination of bonding electrons.

[0046] In this document, a pharmaceutically acceptable salt is not particularly limited, preferably includes: inorganic acid salts, organic acid salts, alkyl sulfonates and arylsulfonates; wherein the inorganic acid salts include hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, etc.; organic acid salts include formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, etc.; alkyl sulfonates include methyl sulfonates, ethyl sulfonates, etc.; aryl sulfonates include benzene sulfonates, p-toluene sulfonates and the like.

[0047] In the present document, a pharmaceutically acceptable solvate of the compound represented by general formula (I) is not particularly limited and preferably includes a solvate of a compound represented by general formula (I) with solvents such as water, ethanol, isopropanol, diethyl ether, acetone.

COMPOUND OF FORMULA (I)

[0048] The inventors designed and synthesized a series of innovative compounds by studying the structure and activity relationship between the crystal structure of FGFR and other tyrosine kinase inhibitors. After screening these compounds using molecular, cellular and animal models, it was found that the compounds can significantly inhibit FGFR kinase activity at the molecular level. Furthermore, they can significantly inhibit FGFR-induced proliferation of various cancer cells at the cellular level, and can significantly inhibit tumor growth in animals.

[0049] In particular, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof:

[0050] In another preferred embodiment, in the compound, any one of X, ring A, R1, R2 and R3 is a corresponding group in the specific compound described in the examples.

[0051] Preferably, the aminopyridine compound of formula (I) of the present invention is selected from the compounds in Table 1 below: TABLE 1

PHARMACEUTICAL COMPOSITION CONTAINING THE COMPOUND OF FORMULA (I)

[0052] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from aminopyridine compounds of formula (I), pharmaceutically acceptable salts, prodrugs, or hydrates or solvates thereof. and, optionally, a pharmaceutically acceptable carrier that can be used to treat an associated disease, such as cancer or the like. The pharmaceutical composition can be prepared in different ways depending on the route of administration.

[0053] One or more of the aminopyridine compound of formula (I), pharmaceutically acceptable salts, prodrugs and hydrates or solvates thereof, or the pharmaceutical composition comprising a therapeutically effective amount of one or more of the aminopyridine compound ( I), pharmaceutically acceptable salts, prodrugs and hydrates or solvates thereof, can be used as a protein tyrosine kinase inhibitor, especially as an FGFR inhibitor for the treatment of cancer. FGFR preferably comprises FGFR1.

[0054] The pharmaceutically acceptable salt of the compound of the present invention can be prepared by means of a direct salt formation reaction between the free base of the compound with an inorganic or organic acid. Inorganic or organic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid , trifluoromethanesulfonic acid, ethanesulfonic acid and p-toluenesulfonic acid and the like.

[0055] The compounds of the present invention have notable FGFR kinase inhibition activity, such as FGFR1 and FGFR2. Therefore, the compound of the present invention, and the pharmaceutically acceptable crystalline forms, salts, hydrates or inorganic or organic solvates thereof, and the pharmaceutical composition comprising the compound of the present invention as a main active ingredient can be used to treat, prevent and alleviate diseases related to FGFR activity or expression, for example, prevention and/or treatment of diseases associated with abnormal expression of the FGF/FGFR signaling pathway. According to the prior art, the compound of the present invention can be used to treat the following diseases: tumor-related disease, including breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, AML multiple myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma and testicular cancer. Especially, the tumor is selected from the group consisting of breast cancer, non-small cell lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, multiple myeloma, liver cancer, Melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma and testicular cancer. More particularly, the cancer is non-small cell lung cancer, gastric cancer or multiple myeloma.

[0056] The pharmaceutical composition of the invention comprises the compound of the present invention or pharmaceutically acceptable salts thereof in a safe and effective dosage range and pharmaceutically acceptable excipients or carriers. Where “safe and effective dosage” means that the amount of compound is sufficient to significantly improve the condition without causing significant side effects. In general, the pharmaceutical composition contains from 1 to 2,000 mg of compound of the invention per dose, preferably from 5 to 200 mg of compound of the invention per dose. Preferably, the "dose" is a capsule or tablet.

[0057] “Pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers or gelatinous materials that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. “Compatibility” means that each component in the composition can be mixed by addition with the compounds of the present invention and with each other without significantly reducing the effectiveness of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and derivatives thereof (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), sulfate calcium, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween® ), wetting agent (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0058] There is no special limitation on mode of administration for the compound or pharmaceutical compositions of the present invention, and the representative mode of administration includes (but is not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) administration and topical.

[0059] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compounds are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or CaHPO4, or mixed with any of the following components: (a) fillers or compatibilizers, e.g., starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, such as glycerol; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates and sodium carbonate; (e) dissolution retarding agents such as paraffin; (f) absorption accelerators, e.g. quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, e.g. kaolin; and (i) lubricants such as talc, calcium stearin, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. Capsule, tablet, and pill dosage forms may also contain buffering agents.

[0060] Solid dosage forms, such as tablets, sugar pills, capsules, pills and granules, can be prepared using coating and encapsulating materials, such as enteric coatings and any other materials known in the art. They may contain an opaque agent. The release of the active compounds or compounds in the compositions may be released in a delayed manner in a given part of the digestive tract. Examples of impregnation components include polymers and waxes. If necessary, the active compounds and one or more excipients above can form microcapsules.

[0061] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, liquid dosage forms may contain any conventional inert diluents known in the art such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3- butanediol, dimethylformamide, as well as oil, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a combination thereof.

[0062] In addition to these inert diluents, the composition may also contain additives such as wetting agents, emulsifying and suspending agents, sweetener, flavoring agents and perfume.

[0063] In addition to the active compounds, the suspension may contain suspending agent, for example, ethoxylated iso-octadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar or a combination thereof.

[0064] Compositions for parenteral injection may comprise physiologically acceptable sterile anhydrous or aqueous solutions, dispersions, suspensions or emulsions, and sterile powders that can be redissolved in sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and any suitable mixtures thereof.

[0065] Dosage forms for topical administration of compounds of the invention include ointments, powders, plasters, aerosols and inhalants. The active ingredients are mixed with physiologically acceptable carriers and any preservatives, buffers or propellants, if necessary, under sterile conditions.

[0066] The compounds of the present invention can be administered alone, or in combination with any other pharmaceutically acceptable compounds.

[0067] When pharmaceutical compositions are used, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need thereof, wherein the administration dose is a pharmaceutically effective dose. For a person weighing 60 kg, the daily dose is normally 1 to 2,000 mg, preferably 5 to 500 mg. Obviously, the particular dose must also depend on several factors, such as the route of administration, the healthy situation of the patient, all of which are well covered by the skills of an experienced physician.

[0068] The present invention will be further illustrated below with reference to specific examples. It should be understood that these examples are only to illustrate the invention, but do not limit the scope of the invention. Experimental methods without specific conditions described in the following examples are generally carried out under conventional conditions, or in accordance with the manufacturer's instructions. Unless otherwise noted, parts and percentages are calculated by weight.

I. PREPARATIVE EXAMPLES OF COMPOUND

[0069] 1H NMR was measured using a Varian Mercury AMX300 model; MS was measured using VG model ZAB-HS or VG-7070, EI source (70 ev) (if not otherwise indicated); all solvents were distilled again before use, aqueous free solvents are obtained by drying according to the standard method; Unless otherwise noted, all reactions are performed under nitrogen protection and screened TLC and the entire post-treatment procedure includes washing with saturated aqueous sodium chloride solution and drying with anhydrous sodium sulfate; Product purification, unless otherwise indicated, was conducted with silica gel column chromatography (200 to 300 mesh); in which silica gel (200 to 300 mesh) was produced by Qingdao Ocean Chemical Plant and GF254 thin layer silica gel plate was produced by Yantai Jiangyou Silica Development Co., Ltd. PREPARATION EXAMPLE 1 COMPOUND PREPARATION S1

[0070] The synthesis method for compound 1-1 was conducted with reference to the method disclosed in document WO2011140009.

SYNTHESIS OF COMPOUND 1-3:

[0071] Compound 1-1, Compound 1-2 (1.5 eq.) were weighed in a single-neck flask, dissolved in acetonitrile, then DIPEA was added, and the reaction was carried out at 70 ° C. one day to the next. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted through PE:EA = 5:1 to give compound 1-3.

SYNTHESIS OF COMPOUND 1-4

[0072] Compound 1-3 was dissolved in methanol and an aqueous solution of 2 eq of sodium hydroxide was added, and then the reaction mixture was heated at 60 ° C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and the pH was adjusted to 5 to 6 with 2N HCl. A large amount of solid was precipitated and filtered by suction to yield compound 1-4.

SYNTHESIS OF COMPOUND 1-5

[0073] Compound 1-5 was dissolved in dichloromethane, DMF [N,N-dimethylformamide] (10 eq), sulfoxide (4 eq) were added in an ice bath and the mixture was warmed to room temperature for 2 h. After the reaction was completed, the reaction solution was evaporated to dryness in vacuo, dissolved in DCM and added to an ammonia solution in dichloromethane cooled to 0 °C and reacted at room temperature for 5 h. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was applied to the column and eluted by CH2Cl2:MeOH=50:1 to give compound 1-5.

[0074] Compound 1-6 was synthesized with reference to J. Med. Chem. 2008, 51, 1,649 to 1,667.

SYNTHESIS OF COMPOUND 1-7

[0075] Compound 1-6, methylamine hydrochloride (2.5 eq), EDCI [1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride] (1.5 eq), HOBt [1-Hydroxybenzotriazole] (1 eq ) were weighed in a single-neck flask and dissolved in dichloromethane, then DIPEA [diisopropylethylamine] (2.5 eq) was added and allowed to react overnight at room temperature. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted via PE:EA (v:v) = 1:1 to give compound 1-7.

THE SYNTHESIS OF COMPOUND S1:

[0076] Compound 1-5, Compound 1-7 (1.2 eq), Pd2(dba)3 [tris(dibenzylideneacetone)dipalladium] (0.1 eq), Xantphos[4,5-bisphenylphosphine-9, 9-dimethyloxanthene (0.2 eq), cesium carbonate (2 eq) were dissolved in 1,4-dioxane under nitrogen and reacted at 100 °C for 5 h. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted by CH2Cl2:MeOH=50:1 to provide compound S1. The analysis data of S1: 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.39 (d, J = 9.1 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.82 (t, J = 8.8 Hz, 3H), 7.56 (s, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 9.9 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 4, 2 Hz, 1H), 6.22 (d, J = 5.0 Hz, 1H), 5.28 - 5.18 (m, 0.5H), 5.09 - 4.97 (m, 0.5H ), 4.03 (t, J = 5.1 Hz, 2H), 3.85 - 3.72 (m, 2H), 3.36 - 3.21 (m, 2H), 3.07 (d, J = 4.8 Hz, 3H), 2.92 (t, J = 5.0 Hz, 2H). PREPARATION EXAMPLE 2 PREPARATION OF COMPOUND S2

[0077] The synthesis of Compound 2-1 was the same as that of compound 1-5.

[0078] The synthesis of Compound S2 was the same as that of S1. The analysis data of S2: 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.98 (s, 1H), 7.79 (t, J = 7.7 Hz, 3H), 7.53 (d, J = 7.1 Hz, 2H), 7 .42 (t, J = 7.6 Hz, 1H), 7.34 - 7.26 (m, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 4.7 Hz, 1H), 6.01 (s, 1H), 4.03 (t, J = 5.0 Hz, 2H), 3.68 (t, J = 12.0 Hz, 4H) , 3.05 (d, J = 4.9 Hz, 3H), 2.94 (t, J = 4.9 Hz, 2H). PREPARATION EXAMPLE 3 PREPARATION OF COMPOUND S3

[0079] The synthesis of Compound 3-1 was the same as that of compound 1-5.

[0080] The synthesis of Compound 3-2 was the same as that of S1.

THE SYNTHESIS OF COMPOUND S3:

[0081] Compound 3-2 was dissolved in methanol and a 2N solution of methanolic hydrochloric acid (30 eq) was added and allowed to react at room temperature overnight. After the reaction was completed, the reaction mixture was evaporated to dryness in vacuo and extracted with saturated sodium bicarbonate solution and DCM, wherein the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted by CH2Cl2:MeOH=30:1 to provide compound S3. The analysis data of S3: 1H NMR (300 MHz,CDCl3) δ 8.58 (s, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.15 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.84 (t, J = 7.7 Hz, 3H), 7.57 (s, 2H), 7.51 - 7.42 ( m, 1H), 7.35 (d, J = 9.7 Hz, 1H), 6.95 (d, J = 8.2 Hz, 2H), 6.67 (d, J = 5.7 Hz, 1H), 6.12 (s, 1H), 3.88 (s, 2H), 3.09 (d, J = 4.0 Hz, 3H), 0.77 (s, 2H), 0.65 ( s, 2H). PREPARATION EXAMPLE 4 PREPARATION OF COMPOUND S4

[0082] The synthesis of Compound 4-1 was the same as that of 1-5.

[0083] The synthesis of Compound S4 was the same as that of S1. The analysis data of S4: 1H NMR (300 MHz,CDCl3) δ 8.87 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.79 (t, J = 7.0 Hz, 3H), 7.55 - 7.46 (m, 2H), 7.40 ( t, J = 7.6 Hz, 1H), 7.33 - 7.26 (m, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 4 .9 Hz, 1H), 6.51 - 6.42 (m, 1H), 4.11 (t, J = 5.8 Hz, 2H), 3.00 (d, J = 4.7 Hz, 3H ), 2.88 (t, J = 5.7 Hz, 2H), 2.59 (s, 4H), 2.35 (s, 1H), 1.78 (s, 4H). PREPARATION EXAMPLE 5 PREPARATION OF COMPOUND S5

SYNTHESIS OF COMPOUND 5-3

[0084] The raw material of 5-1 (1 eq) and 5-2 (2 eq) was weighed in a single-neck flask, dissolved in DMSO [dimethyl sulfoxide] and potassium carbonate (3 eq) was added and reacted at 110 °C overnight. After the reaction was completed, the reaction mixture was cooled, poured into water and extracted with EtOAc three times and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted by DCM [methylene chloride] : MeOH [methanol] (v:v) = 30:1 to give compound 5-3.

SYNTHESIS OF COMPOUND 5-4

[0085] Compound 5-3 was dissolved in methanol and an aqueous solution of 2 eq of sodium hydroxide was added, then the reaction mixture was heated at 60 °C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and the pH was adjusted to 5 to 6 with 2N HCl. A large amount of solid was precipitated and filtered by suction to yield compound 5-4.

SYNTHESIS OF COMPOUND 5-5

[0086] Compound 5-4 was dissolved in dichloromethane, DMF [N,N-dimethylformamide], thionyl chloride (4 eq) were added in an ice bath and the mixture was warmed to room temperature for 2 h. The reaction solution was then evaporated to dryness in vacuo, dissolved in DCM and added to an ammonia solution in dichloromethane cooled to 0°C and reacted at room temperature for 4 h. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The mixture was applied to the column and eluted by CH2Cl2:MeOH=15:1 to give compound 5-5.

[0087] The synthesis of Compound S5 was the same as that of S1. The analysis data of S5: 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.36 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 5.7 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8, 8 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.48 - 7.38 (m, 1H), 7.32 (dd, J = 9.2, 2.3 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.64 (dd, J = 5.7, 2.2 Hz, 1H), 6.34 (s, 1H), 3.33 (d, J = 4.5 Hz, 4H), 3.04 (d, J = 4.8 Hz, 3H), 2.61 - 2.48 (m, 4H), 2.33 (s , 3H). PREPARATION EXAMPLE 6 PREPARATION OF COMPOUND S6

[0088] The synthesis of compound 6-1 was conducted with reference to the method disclosed in document WO2001060846.

[0089] The synthesis of Compound 6-2 was the same as that of S1.

[0090] The synthesis of S6 was the same as that of S3. S6 analysis data: 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 8.31 (d, J = 9.2 Hz, 1H), 8.10 - 7.93 ( m, 2H), 7.73 (dd, J = 13.3, 8.3 Hz, 3H), 7.46 (d, J = 7.7 Hz, 2H), 7.40 - 7.33 (m , 1H), 7.24 (d, J = 9.9 Hz, 2H), 6.57 (d, J = 5.1 Hz, 1H), 6.36 (s, 1H), 3.20 (d , J = 11.8 Hz, 2H), 2.97 (d, J = 4.4 Hz, 3H), 2.69 (dd, J = 25.0, 13.5 Hz, 2H), 1.73 (dd, J = 31.8, 11.6 Hz, 4H). PREPARATION EXAMPLE 7 PREPARATION OF COMPOUND S7

[0091] The synthesis of Compound 7-1 was the same as that of 5-5.

[0092] The synthesis of Compound S7 was the same as that of S1. The analysis data of S7: 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 5.8 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.82 (dd, J = 17.4, 8.4 Hz, 3H), 7.57 (d, J = 5.6 Hz, 2H), 7.51 - 7.43 (m, 1H), 7.35 (dd, J = 9.1, 2.3 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.66 (dd, J = 5.7, 2.1 Hz, 1H), 6.13 (s, 1H), 3.92 - 3.81 (m, 4H) , 3.36 - 3.23 (m, 4H), 3.09 (d, J = 4.9 Hz, 3H). PREPARATION EXAMPLE 8 PREPARATION OF COMPOUND S8

[0093] The synthesis of Compound 8-1 was the same as that of 5-5.

[0094] The synthesis of Compound S8 was the same as that of S1. The analysis data of S8: 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 5.7 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 21.6, 8.4 Hz, 1H), 7.56 (s, 1H), 7.47 ( t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 4.8 Hz, 1H), 6.14 (d, J = 4.4 Hz, 1H), 3.87 - 3.71 (m, 1H), 3, 59 (d, J = 12.0 Hz, 1H), 3.09 (d, J = 4.7 Hz, 1H), 2.51 (t, J = 11.3 Hz, 1H), 1.27 ( d, J = 6.2 Hz, 1H). PREPARATION EXAMPLE 9 PREPARATION OF COMPOUND S9

[0095] The synthesis of Compound 9-1 was the same as that of 5-5.

[0096] The synthesis of Compound 9-2 was the same as that of S1.

[0097] The synthesis of Compound S9 was the same as that of S3. The analysis data of S9: 1H NMR NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 5.7 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.56 (s, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 8 .7 Hz, 2H), 6.66 (d, J = 5.9 Hz, 1H), 6.17 (s, 1H), 3.67 (d, J = 11.9 Hz, 2H), 3, 18 - 3.01 (m, 5H), 2.96 (d, J = 13.2 Hz, 2H), 2.82 (t, J = 11.4 Hz, 1H), 2.46 (t, J = 11.3 Hz, 1H), 1.14 (d, J = 6.2 Hz, 3H). PREPARATION EXAMPLE 10 PREPARATION OF COMPOUND S10

[0098] The synthesis of Compound 10-1 was the same as that of 5-5.

[0099] The synthesis of Compound 10-2 was the same as that of S1.

[0100] The synthesis of Compound S10 was the same as that of S3. S10 analysis data: 1H NMR (300 MHz, CDCl3)δ 8.51 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 5.7 Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7 .57 (d, J = 5.9 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.38 - 7.31 (m, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.70 - 6.62 (m, 1H), 6.13 (d, J = 3.6 Hz, 1H), 3.67 (d, J = 11.1 Hz, 2H), 3.09 (d, J = 4.7 Hz, 3H), 2.99 (td, J = 9.1, 4.4 Hz, 2H), 2.41 (t, J = 11 .2 Hz, 2H), 1.15 (d, J = 6.2 Hz, 6H). PREPARATION EXAMPLE 11 PREPARATION OF COMPOUND S11

[0101] The synthesis of Compound 11-1 was the same as that of 5-5.

[0102] The synthesis of Compound S11 was the same as that of S1. S11 analysis data: 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 5.7 Hz, 1H), 7 .89 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 6, 8 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 5.5 Hz, 2H), 6.84 (d, J = 8.8 Hz , 2H), 6.64 (d, J = 5.7 Hz, 1H), 3.62 (t, J = 5.3 Hz, 2H), 3.28 (s, 6H), 2.61 (s , 5H), 2.54 (t, J = 5.4 Hz, 2H). PREPARATION EXAMPLE 12 PREPARATION OF COMPOUND S12

[0103] The synthesis of compound 12-1 was conducted with reference to the method disclosed in document WO2013170774.

[0104] The synthesis of Compound 12-2 was the same as that of 5-5.

[0105] The synthesis of Compound S12 was the same as that of S1. S12 analysis data: 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 5.8 Hz, 2H), 8.03 (d, J = 6.7 Hz, 1H), 8.00 - 7.92 (m, 2H), 7.86 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 6.7 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 9.1 Hz, 1H) , 6.69 (d, J = 5.3 Hz, 1H), 3.71 (s, 2H), 3.11 (d, J = 4.8 Hz, 3H), 2.54 (s, 8H) , 2.32 (s, 4H). PREPARATION EXAMPLE 13 COMPOUND PREPARATION S13

[0106] The synthesis of Compound 13-1 was the same as that of 5-5.

[0107] The synthesis of Compound 13-2 was the same as that of S1.

[0108] The synthesis of Compound S13 was the same as that of S3. S13 analysis data: 1H NMR (300 MHz, CDCl3) δ 12.38 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.21 - 8.10 ( m, 2H), 8.05 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 6.4 Hz, 2H), 7.45 ( t, J = 7.6 Hz, 1H), 7.34 (d, J = 11.1 Hz, 1H), 6.93 (dd, J = 17.1, 8.9 Hz, 2H), 6, 64 (d, J = 5.5 Hz, 1H), 6.23 (s, 1H), 3.48 (s, 2H), 3.12 - 3.03 (m, 5H), 2.84 (s , 3H), 2.53 (t, J = 10.8 Hz, 2H), 1.14 (d, J = 6.3 Hz, 6H). PREPARATION EXAMPLE 14 PREPARATION OF COMPOUND S14

[0109] The synthesis of Compound 14-1 was the same as that of 5-5.

[0110] The synthesis of Compound 14-2 was the same as that of S1.

[0111] The synthesis of Compound S14 was the same as that of S3. S14 analysis data: 1H NMR (300 MHz, CDCl3) δ 10.28 (s, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 5.7 Hz, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7 .53 (d, J = 6.9 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 9.3 Hz, 1H), 6.63 (d, J = 6.3 Hz, 1H),6.53 (d, J = 8.8 Hz, 1H), 6.36 (s, 1H), 6.27 (d, J = 4.6 Hz , 1H), 4.05 (s, 3H), 3.64 (d, J = 11.9 Hz, 2H), 3.05 (d, J = 4.8 Hz, 3H), 2.98 (d , J = 6.6 Hz, 2H), 2.42 (t, J = 11.2 Hz, 2H), 1.15 (d, J = 6.2 Hz, 6H). PREPARATION EXAMPLE 15 COMPOUND PREPARATION S15

[0112] The synthesis of Compound 15-1 was the same as that of 5-5.

[0113] The synthesis of Compound 15-2 was the same as that of S1.

[0114] The synthesis of Compound S15 was the same as that of S3. S15 analysis data: 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 7 .91 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H), 7.491 - 7 .43 (m, 2H), 7.24 (d, J = 2.3 Hz, 1H), 6.75 (d, J = 7.7 Hz, 2H), 6.41 (d, J = 8, 8 Hz, 1H), 6.27 (s, 1H), 6.13 (s, 1H), 3.67 (d, J=10.9Hz, 2H), 3.12 - 3.03 (m, 5H ), 2.45 (t, J =11.2 Hz, 2H), 2.25 (s, 3H), 1.17 (d, J = 6.8 Hz, 6H). PREPARATION EXAMPLE 16 COMPOUND PREPARATION S16

[0115] The synthesis of Compound 16-1 was the same as that of 5-5.

[0116] The synthesis of Compound 16-2 was the same as that of S1.

[0117] The synthesis of Compound S16 was the same as that of S3. S16 analysis data: 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 2H), 8.49 - 8.36 (m, 2H), 8.15 (d, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.3Hz, 1H), 7.57 (d, J = 6.8 Hz, 2H), 7.51 - 7 .44 (m, 1H), 7.34 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 6.11 (d, J = 5, 7 Hz, 1H), 4.77 (d, J = 12.7 Hz, 2H), 3.10 (d, J = 4.7 Hz, 3H), 2.94 - 2.81 (m, 2H) , 2.54 (t, J = 11.7 Hz, 2H), 1.25 (s, 1H), 1.16 (d, J = 6.2 Hz, 6H). PREPARATION EXAMPLE 17 PREPARATION OF COMPOUND S17

[0118] The synthesis of Compound 17-1 was the same as that of 5-5.

[0119] The synthesis of Compound S17 was the same as that of S1. The analysis data of S17: 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 6, 7 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 9.2 Hz, 1H), 6.71 - 6.64 (m, 1H), 6.08 (d, J = 4.5 Hz, 1H), 3.58 - 3.52 (m, 4H), 3.10 (d, J = 4.9 Hz, 3H), 2.56 - 2.49 (m, 4H), 2.36 (s, 3H). PREPARATION EXAMPLE 18 PREPARATION OF COMPOUND S18

[0120] The synthesis of Compound 18-1 was the same as that of 5-5.

[0121] The synthesis of Compound S18 was the same as that of S1. S18 analysis data: 1H NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J = 7.1 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 9.3 Hz, 1H), 6.67 (d, J = 3, 8 Hz, 1H), 6.05 (d, J = 14.5 Hz, 1H), 3.56 (s, 4H), 3.10 (d, J = 4.8 Hz, 3H), 2.49 (s, 4H), 2.34 (s, 3H). PREPARATION EXAMPLE 19 PREPARATION OF COMPOUND S19

[0122] The synthesis method of compound 19-1 was conducted with reference to the method disclosed in document WO2012040137.

SYNTHESIS OF COMPOUND 19-2:

[0123] 1 eq. of CDI [carbonyldiimidazole] was dissolved in dry THF [tetrahydrofuran] and compound 19-1 was added thereto, and the mixture was reacted at 40 °C for 30 minutes and then an aqueous ammonia solution (20 eq.) in tetrahydrofuran was added thereto and the mixture was reacted at 30°C overnight. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated salt solution, dried through anhydrous sodium sulfate and then directly added in the next step.

[0124] The synthesis of Compound S19 was the same as that of S1. Analysis data of S19: 1H NMR (300 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.63 - 8.51 (m, 1H), 8.43 (s, 1H), 8.33 (d, J = 9.3 Hz, 1H), 8.27 (d, J = 5.7 Hz, 1H), 8.10 (s, 1H), 8.02 (dd, J = 6 .9, 2.0 Hz, 1H), 7.82 (dd, J = 6.8, 1.9 Hz, 2H), 7.59 (d, J = 7.0 Hz, 2H), 7.45 (dd, J = 9.2, 2.5 Hz, 1H), 6.80 (dd, J = 5.8, 2.0 Hz, 1H), 4.94 (t, J = 5.3 Hz, 1H), 4.14 (t, J = 5.2 Hz, 2H), 3.72 (q, J = 5.4 Hz, 2H), 2.86 (d, J = 4.4 Hz, 3H) .EXAMPLE OF PREPARATION 20 PREPARATION OF COMPOUND S20

[0125] The synthesis of Compound 20-1 was the same as that of 1-7.

[0126] The synthesis of Compound 20-2 was the same as that of S1.

[0127] The synthesis of Compound S20 was the same as that of S3. S20 analysis data: 1H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.51 (s, 1H), 7 .41 (dd, J = 11.5, 5.6 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H) , 6.63 (d, J = 8.5 Hz, 2H), 6.41 (d, J = 5.6 Hz, 1H), 3.45 (d, J = 12.3 Hz, 2H), 2 .91 - 2.79 (m, 5H), 2.48 - 2.32 (m, 2H), 1.09 (d, J = 6.2 Hz, 6H). PREPARATION EXAMPLE 21 PREPARATION OF COMPOUND S21

[0128] The synthesis of Compound 21-2 was the same as that of S1.

SYNTHESIS OF COMPOUND 21-3:

[0129] Compound 21-2 was dissolved in ethanol, an aqueous solution of ammonium chloride (10 eq.) was added, then iron powder (5 eq.) was added and the mixture was reacted at 80 ° C for 5 h. After the reaction was completed, the mixture was suction filtered and the filtrate was evaporated to dryness. Then, the mixture was extracted with dichloromethane and water and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted through DCM:MeOH = 30:1 to provide compound 21-3.

THE SYNTHESIS OF COMPOUND S21:

[0130] Compound 21-3 was dissolved in dry dichloromethane under nitrogen, and acryloyl chloride (1.3 eq.) was added under an ice bath, and then DIPEA (2eq) was added and heated to room temperature of one day to day after the addition is complete. After the reaction was completed, it was extracted with dichloromethane and water and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted through DCM:MeOH = 30:1 to provide compound S21. S21 analysis data: 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 5.7 Hz, 2H), 7 .85 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.49 (d, J = 7.4 Hz, 3H), 7 .36 (dt, J = 16.1, 8.1 Hz, 2H), 7.25 (d, J = 2.3 Hz, 1H), 6.64 (d, J = 6.0 Hz, 1H) , 6.37 - 6.15 (m, 2H), 5.65 (d, J = 9.9 Hz, 1H), 2.95 (s, 3H). PREPARATION EXAMPLE 22 PREPARATION OF COMPOUND S22

[0131] The synthesis of Compound 22-1 was the same as that of 21-3.

[0132] The synthesis of Compound S22 was the same as that of S21. Analysis data of S22: 1H NMR (300 MHz, DMSO)δ 10.76 (s, 1H), 10.41 (s, 1H), 8.53 (d, J = 6.5 Hz, 1H) , 8.39 - 8.28 (m, 2H), 8.09 - 8.00 (m, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.88 - 7.80 (m, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 7.0 Hz, 2H), 6.84 (d, J = 5.5 Hz , 1H), 6.46 (dd, J = 17.4, 10.3 Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H), 5.80 (d, J = 12, 6 Hz, 1H), 2.86 (d, J = 4.5 Hz, 3H). PREPARATION EXAMPLE 23 PREPARATION OF COMPOUND S23

[0133] The synthesis method of compound 23-1 was conducted with reference to the method disclosed in document WO2012040137.

THE SYNTHESIS OF COMPOUND S23:

[0134] Compound 21-3 was dissolved in ethanol, compound 23-1 (2 eq) was added and then DIPEA (2 eq) was added, then reacted at 75 ° C for two days. After the reaction was completed, the reaction mixture was evaporated to dryness and extracted with dichloromethane and water and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The mixture was applied to the column and eluted through DCM:MeOH = 20:1 to provide compound S23. The analysis data of S23: 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.11 (d, J = 5.8 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8, 4 Hz, 2H), 7.56 - 7.49 (m, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.31 (dd, J = 9.1, 2.4 Hz, 1H), 6.65 (dd, J = 5.8, 2.3 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 6.43 (d, J = 5 .3 Hz, 1H), 4.54 (t, J = 5.9 Hz, 1H), 3.76 - 3.64 (m, 4H), 3.06 (dd, J = 10.8, 5, 2 Hz, 5H), 1.82 (s, 1H), 1.73 - 1.54 (m, 4H). PREPARATION EXAMPLE 24 COMPOUND PREPARATION S24

SYNTHESIS OF COMPOUND 24-1

[0135] Compound 1-6 was dissolved in methanol and thionyl chloride (1.5 eq) was added under an ice bath and the mixture was heated to 60 °C to react for 5 h. After the reaction was completed, the reaction mixture was evaporated to dryness and extracted with DCM and saturated sodium bicarbonate solution, washed with saturated brine, dried through anhydrous sodium sulfate and directly used in the next step.

[0136] The synthesis of Compound 24-2 was the same as that of S1.

[0137] The synthesis of Compound S24 was the same as that of S3. S24 analysis data: 1H NMR (300 MHz, CDCl3)δ 8.71 (s, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 5.7 Hz, 1H), 8.09 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7 .63(d, J = 5.9 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.47 — 7.40 (m, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.85 - 6.78 (m, 1H), 6.13 (d, J = 3.6 Hz, 1H), 3.91 (s, 3H),3, 65 (d, J = 11.1 Hz, 2H), 2.94 (td, J = 9.1, 4.4 Hz, 2H), 2.39 (t, J = 11.2 Hz, 2H), 1.14 (d, J = 6.2 Hz, 6H).

II. EXPERIMENTAL EXAMPLE 1. PRELIMINARY ASSESSMENT OF COMPOUND TYROSINE KINASE RECEPTOR TYROSINE KINASE INHIBITION IN FGFR1 ACTIVITY EXPERIMENTAL METHOD:

[0138] 1. Enzyme reaction substrate μPoly(Glu,Tyr)4:1 was diluted with PBS without potassium ion (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2 to 7.4 ) to 20μg/mL, an enzyme plate was coated at 125μL/well and incubated at 37°C for 12 to 16 hours. The liquid from the cavity was discarded. The plate was washed three times with T-PBS (0.1% Tween-20 in potassium-free PBS, 200μl/well), 5 minutes each time. The elisa plate was dried in a dryer at 37 °C for 1 to 2 hours.

[0139] 2. 49 μL of ATP solution diluted in reaction buffer (50 mM HEPES, pH 7.4, 50 mM MgCl2, 0.5 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT ) were added into each well and 1 μL of test compound was added to each well and then 50 μL of FGFR1 kinase domain recombinant protein diluted in reaction buffer was added to start the reaction and two control wells without ATP were required for each experiment. The reaction was carried out on a Shaker (100 rpm) at 37 °C for 1 hour. The liquid from the well was discarded and the plate was washed with T-PBS three times.

[0140] 3. The PY99 antibody dilution (antibody diluted 1:500 in T-PBS with 5 mg/mL BSA) was added to 100 μL/well and stirred for 0.5 hours on a shaker at 37°C. The liquid from the well was discarded and the plate was washed with T-PBS three times.

[0141] 4. The second dilution of goat anti-mouse antibody identified with horseradish peroxidase (antibody diluted 1:2,000 in T-PBS with 5 mg/mL BSA) was added to 100 μL/well and stirred for 0 .5 hours on a shaker at 37°C. The liquid from the well was discarded and the plate was washed with T-PBS three times.

[0142] 5. 2 mg/mL of OPD staining solution (diluted with 0.1 M sodium citrate and citric acid buffer containing 0.03% H2O2 (pH = 5.4)) was added to 100 μL/well and reacted for 1 to 10 minutes at 25°C in darkness.

[0143] 6. The reaction was quenched with 50 μL/well of 2M H2SO4 and the plate was read using a VERSAmax tunable microplate reader at 490 nm.

[0144] 7. Analysis of results

[0145] The IC50 values were obtained by four-parameter regression analysis using the software supplied with the microplate reader.

[0146] The level of inhibition in tyrosine kinase receptor FGFR1 activity of a compound is shown in the following table:

[0147] Test results at the molecular level show that these compounds have strong inhibitory activities on FGFR and half of the compounds have an IC50 of less than 10 nM.

2. ASSESSMENT OF COMPOUND TYROSINE KINASE RECEPTOR ACTIVITY IN FGFR CELLS EXPERIMENTAL METHOD:

[0148] The inhibitory effect on SNU16 cell proliferation of a compound was examined using CCK-8 Cell Counting Kit (Dojindo). The steps are as follows: SNU16 cells in logarithmic growth phase were inoculated into a 96-well culture plate at appropriate density, 90 μL for each well. After being cultured overnight, different concentrations of drugs were added and treated for 72h, while the solvent control well was defined (negative control). After 72h, the influence of the compound on cell proliferation was observed using the CCK-8 cell counting kit (Dojindo). 10 μl of CCK-8 reagent was added to each well. After incubated for 2 to 4 hours in an incubator at 37 °C, the plate was read with a SpectraMax 190 microplate reader at a wavelength of 450 nm.

[0149] The inhibition rate (%) of the compound on tumor cell growth was calculated using the following formula:

[0150] inhibition rate (%) = (control cavity OD - drug cavity OD) / control cavity OD x 100%.

[0151] The IC50 values were obtained by four-parameter regression analysis using the software supplied with the microplate reader.

[0152] The inhibitory rates for SNU16 cell proliferation of the compounds are as follows:

[0153] Inhibitory test results on SNU16 cell proliferation show that these compounds have strong inhibitory activities on FGFR and some of the compounds have an IC50 of less than 10 nM.

3. FGFR2 INHIBITION EXPERIMENT AND PHOSPHORYLATION OF SIGNALING MOLECULES DOWNSTREAM OF THE COMPOUND

[0154] The results were shown in Figure 1. The results show that the compound has the ability to target FGFR at the cellular level and inhibit signal transduction of the corresponding downstream signaling pathway. 4. IN VITRO SCREENING TEST ON INHIBITION OF TYROSINE KINASE ACTIVITY Screening method: Enzyme-linked immunosorbent assay (ELISA) Tyrosine kinase: Enzymatic spectrum Time of action: 1h TABLE 1. TYROSINE KINASE INHIBITION RATIO OF THE COMPOUND (% ) TABLE 2. TYROSINE KINASE INHIBITION RATIO OF THE COMPOUND (%)

5. EXPERIMENTAL STUDY ON PHARMACOKINETICS OF SOME COMPOUNDS IN RATS 1) DOSAGE REGIME

[0155] Seven male SD rats, weighing 200 to 220 g, were randomly divided into two groups, 4 or 3 in each group. Compound S10 was administered by intragastric or intravenous administration. The specific arrangement is shown in the following table:

[0156] Rats were fasted for 12 h before testing and had access to water ad libitum. Rats were uniformly fed 2 h after administration.

[0157] Blood sampling and sample preparation time point: intragastric administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration; administration intravenous: 5Min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration; 0.3 mL of venous blood was collected at the above time points through the rat eye venous plexus, placed in a heparinized test tube and centrifuged at 11,000 rpm for 5 min and plasma was separated and frozen in a refrigerator at -20 °C.

2) SAMPLE TESTING AND DATA ANALYSIS

[0158] S10 in rat plasma was determined by LC/MS/MS.

[0159] Pharmacokinetic parameters after administration were calculated by a non-behavioral model of WinNonlin 6.3 software (Pharsight, USA).

[0160] The peak concentration Cmax and the peak time Tmax are measured values;

[0161] The area under the drug-time AUC0-t value curve: calculated by the trapezoidal method; AUCo-/ = AUCo-t + Ct/ke, Ct is the drug blood concentration at the last measurable time point; ke is the elimination rate constant; Elimination half-life t1/2 = 0.693 / ke; Release rate CL = D/AUCo-»; Steady state volume of distribution Vss = CL x MRT; Absolute bioavailability F = (Intragastric AUC X Dintravenous) / (AUCintravenous x Dintragastric) x 100%. 3) TEST RESULTS

6. INHIBITORY EFFECTS OF COMPOUND ON THE GROWTH OF SUBCUTANEOUSLY TRANSPLANTED TUMOR IN NCI-H1581 NAKED MICE WITH HUMAN LUNG CANCER 1) CELLULAR STRAIN

[0162] The lung cancer cell strain NCI-H1581 was preserved in the laboratory. The cell strain was inoculated into the right axilla of nude mice and the amount of inoculated cells was 5*106/mouse to form the transplanted tumor, which was directly inoculated and used.

2) EXPERIMENTAL METHOD

[0163] Tumor tissue in the period of successful growth was cut into 1.5 mm3 and inoculated subcutaneously into the right axilla of nude mice under aseptic conditions. The diameter of the transplanted tumor in the nude mice was measured with a vernier caliper and the animals were randomly grouped when the average volume of tumors was about 150 to 160 mm3. S10 groups (10 mg/kg, 5 mg/kg, and 2.5 mg/kg) were orally administered once daily for two weeks. The solvent control group was given an equal amount of water for injection. The diameter of the transplanted tumor was measured twice in one week throughout the experiment and the body weight of the mice was also measured. The tumor volume (TV) calculation formula is: TV=1/2xaxb2, where a and b represent, respectively, the length and width of the tumor. The relative tumor volume (RTV) was calculated based on the measured results and the formula was: RTV = Vt/V0, where V0 is the tumor volume measured in grouping and dosing (d0) and Vt is the tumor volume in each measurement. The antitumor activity evaluation index is relative tumor proliferation rate T/C (%) and the formula is as follows: T/C (%) = (TRTV / CRTV) x 100%, TRTV: RTV treatment group; CRTV: RTV negative control group;

3) RESULTS

[0164] The experimental results are shown in the following Table. The S10 groups (10 mg/kg, 5 mg/kg and 2.5 mg/kg) were orally administered once a day for two weeks, which significantly inhibited the growth of subcutaneously transplanted tumors in NCI-H1581 nude mice with cancer of human lung. On the 14th day, the T/C percentages of tumor inhibition rate obtained were 10.03%, 17.18% and 40.19%, respectively. During the experiment, the animals in each group were in good condition and no mice died.

[0165] Therapeutic effects of compound S10 on tumor transplanted into NCI-H1581 nude mice with human lung cancer.

7. INHIBITORY EFFECTS OF S10 COMPOUND ON THE GROWTH OF SUBCUTANEOUSLY TRANSPLANTED TUMOR IN SNU-16 NUS MICE WITH HUMAN GASTRIC CANCER 1) CELLULAR STRAIN

[0166] The human gastric cancer cell strain SNU-16 was preserved in the laboratory. The cell strain was inoculated into the right axilla of nude mice and the amount of inoculated cells was 5xl06/mouse to form the transplanted tumor, which was passed in vivo in nude mice for 2 generations and then used.

2) EXPERIMENTAL METHOD

[0167] Tumor tissue in the period of successful growth was cut into 1.5 mm3 and inoculated subcutaneously into the right axilla of nude mice under aseptic conditions. The diameter of the transplanted tumor in the nude mice was measured by a vernier caliper and the animals were randomly grouped when the average volume of tumors was about 100 mm3. The S10 groups (30 mg/kg and 10 mg/kg) were orally administered once daily for 21 days; the AZD4547 group (10 mg/kg) was administered orally once a day for 21 days; the solvent control group was given the same amount of water per injection. The diameter of the transplanted tumor was measured twice in one week throughout the experiment and the body weight of the mice was also measured. The tumor volume (TV) calculation formula is: TV=1/2xaxb2, where a and b represent, respectively, the length and width of the tumor. The relative tumor volume (RTV) was calculated based on the measured results and the formula was: RTV = Vt/V0, where V0 is the tumor volume measured in grouping and dosing (d0) and Vt is the tumor volume in each measurement. The antitumor activity evaluation index is relative tumor proliferation rate T/C (%) and the formula is as follows: T/C (%) = (TRTV / CRTV) x 100%, TRTV: RTV treatment group; CRTV: RTV negative control group.

3) RESULTS

[0168] The experimental results are listed in the following Table. The S10 groups (30 mg/kg and 10 mg/kg) were orally administered once a day for 21 days, which significantly inhibited the growth of subcutaneously transplanted tumors in SNU-16 nude mice with human gastric cancer. On the 21st day, the T/C percentages obtained were 8.67% and 25.35%, respectively. The positive control group AZD4547 (10 mg/kg) was orally administered once a day for 21 days, in which the growth of subcutaneously transplanted tumors in SNU-16 nude mice with human gastric cancer was partially inhibited. On the 21st day, the T/C percentages obtained in the group were 59.80%. During the experiment, only the average weight of mice in the S10 group (30 mg/kg) was decreased, but the mice were still in good condition and no mice died. The inhibitory effect of compound S10 on the growth of subcutaneously transplanted tumor in SNU-16 nude mice with human gastric cancer was significantly improved by compound AZD4547.

[0169] The therapeutic effect of S10 on tumor transplanted into SNU-16 nude mice with human gastric cancer. 8. When compared to E7090 (FGFR Inhibitor, Clinical Phase I), which also has a nucleus of aminopyridine while the side chain is indol, inhibitory effect of S10 compound on transplanted tumor growth in naked mice NCI-H1581 with cancer of cancer HUMAN LUNG WAS MORE OBVIOUS, AND THE COMPARISON RESULTS ARE SHOWN IN THE TABLE BELOW.

[0170] T/C is the relative tumor proliferation rate and the lower the value, the greater the antitumor activity. When the dose of Compound S10 was 2.5 mg/Kg, the T/C value was 40% and when the dose of compound E7090 was 6.25 mg/Kg, the T/C value was 46%, which indicated that compound E7090 needs to be administered at a dose 2 to 3 times that of S10 to achieve the same antitumor inhibition effect. In comparison with other results, it is shown that the inhibitory effect of compound S10 on the growth of transplanted tumor in NCI-H1581 nude mice with human lung cancer was significantly greater than that of compound E7090.9. COMPARED WITH E7090, THE INHIBITORY EFFECT OF COMPOUND S10 ON TRANSPLANT TUMOR GROWTH IN SNU-16 NUS MICE WITH HUMAN GASTRIC CANCER WAS MORE SIGNIFICANT AND THE COMPARISON RESULTS ARE SHOWN IN THE FOLLOWING TABLE

[0171] When the dose of compound S10 was 30 mg/Kg, the T/C relative tumor proliferation rate value was 9%, while the T/C relative tumor proliferation rate value was 18% when the compound dose E7090 was 50 mg/kg. The comparison results demonstrated that in the human gastric cancer SNU-16 nude mouse xenograft model, the dose of compound S10 was significantly lower than that of E7090 to achieve the same antitumor activity in vivo.

[0172] Thus, the newly designed compounds have excellent enzymatic inhibitory activity against FGFR and significant inhibitory activity against FGFR-dependent cell proliferation, which has the ability to target FGFR at the cellular level and inhibit signal transduction of the corresponding downstream signaling pathway . Representative compound S10 also has good pharmacokinetic properties and is highly sensitive to FGFR-dependent gastric cancer and lung cancer, which exhibits significantly greater inhibitory effects on the growth of xenografts from NCI-H1581 nude mice with human lung cancer and the growth of xenografts. of SNU-16 nude mice with human gastric cancer compared to compound E7090. Therefore, such compounds have good prospects for research and development as innovative FGFR inhibitors.

[0173] All literature mentioned in the present application is incorporated into this document by reference, as if each were individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents are also within the scope defined by the appended claims.

Claims (13)

1. Compound of the following formula I, or pharmaceutically acceptable salts thereof: CHARACTERIZED by the fact that: X is selected from the group consisting of CH and N; ring A may be selected from the group consisting of a substituted or unsubstituted 6- to 10-membered aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, wherein "substituted" means that one or more hydrogen atoms in a group are replaced by a substituent selected from the group consisting of a C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylamino, halogen, C1-C8 halogenated alkyl; R1 is selected from -CONHR3, -COOR3; R2 is selected from the group consisting of a substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted 4- to 10-membered heterocyclic group, substituted or unsubstituted amino, C1-C8 substituted or unsubstituted alkylamino, -NHCOR3; wherein the substituent is further substituted by one or more substituents selected from the group consisting of a C1-C8 alkyl, hydroxy, hydroxy C1-C8 alkyl, -COOR3, amino-substituted C3-C10 cycloalkyl group, heterocycloalkyl of 4 to 10 member that is unsubstituted or substituted by one or more halogen, hydroxyl or C1-C8 alkyl atoms; R3 is hydrogen, or C1-C8 alkyl. 2. Compound according to claim 1, CHARACTERIZED by the fact that, in the compound of formula I, R2 is selected from the group consisting of a substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy substituted, substituted or unsubstituted 5- to 6-membered heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkylamino, -NHCOR3; wherein the substituent group is further substituted by one or more substituents selected from the group consisting of a C1-C8 alkyl, hydroxy, C1-C8 hydroxy alkyl, -COOR3, amino-substituted C3-C10 cycloalkyl, heterocycloalkyl to 10 members that is unsubstituted or substituted by one or more halogen, hydroxyl or C1-C8 alkyl atoms. 3. Compound according to claim 1, CHARACTERIZED by the fact that, in the compound of formula I, ring A is selected from a substituted or unsubstituted 6- to 10-membered aryl or 5 to 6-membered heteroaryl replaced or not replaced. 4. Compound according to claim 1, CHARACTERIZED by the fact that, in the compound of formula I, ring A is a substituted or unsubstituted group selected from the group consisting of benzene ring, naphthalene ring, ring pyridine ring, pyrazine ring, thiophene ring, furan ring, imidazole ring, pyrrole ring, oxazole ring, thiazole ring, pyrazole ring, indole ring, pyrimidine ring, benzofuran ring, benzothiazole ring , benzimidazole ring, quinoline ring, isoquinoline ring. 5. Compound according to claim 1, CHARACTERIZED by the fact that R3 is selected from hydrogen or C1-C4 alkyl. 6. Compound according to claim 1, CHARACTERIZED by the fact that, in the compound of formula I, ring A is selected from the group consisting of a substituted or unsubstituted benzene ring, substituted or unsubstituted thiazole ring substituted, substituted or unsubstituted oxazole ring, substituted or unsubstituted pyrimidine ring. 7. Compound according to claim 1, CHARACTERIZED by the fact that, in the compound of formula I, R3 is selected from the group consisting of hydrogen or methyl. 8. Compound, according to claim 1, CHARACTERIZED by the fact that the compound is selected from the following group: 9. Method of preparation for the compound, as defined in claim 1, CHARACTERIZED by the fact that it comprises the following step: in an inert solvent, react the compound of formula A with the compound of formula B to obtain the compound of formula I; wherein Q is a leaving group; ring A, X, R1 and R2 are defined as defined in claim 1. 10. Pharmaceutical composition, CHARACTERIZED by the fact that it comprises: a therapeutically effective amount of the compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and, optionally, a pharmaceutically acceptable carrier or excipient. 11. Compound, or pharmaceutically acceptable salt thereof, according to claim 1, CHARACTERIZED by the fact that it is for use in the prevention and/or treatment of disease that is selected from the group consisting of breast cancer, breast cancer lung, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, myeloma, liver cancer, melanoma, head and neck cancer, thyroid cancer, renal cell carcinoma, glioblastoma and testicular cancer. 12. Protein tyrosine kinase enzyme activity inhibitor, CHARACTERIZED by the fact that it comprises an inhibitory effective amount of the compound, as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. 13. Pharmaceutical composition for treating diseases associated with protein tyrosine kinase activity, CHARACTERIZED by the fact that the pharmaceutical composition comprises a therapeutically effective amount of a compound, as defined in any one of claims 1 to 8, or of a pharmaceutically acceptable salt of the even as an active ingredient; wherein the disease is selected from the group consisting of breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, myeloma, liver cancer, melanoma, head cancer and neck, thyroid cancer, renal cell carcinoma, glioblastoma and testicular cancer.