TW201938538A - Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use therefor for effectively treating and/or preventing FGFR-related diseases such as tumors - Google Patents

Abstract

The present invention relates to an alkynyl-substituted heterocyclic compound serving as an FGFR inhibitor, a preparation method therefor and a medical use therefor. In particular, the present invention relates to a compound represented by the general formula (I) and its pharmaceutically acceptable salt, a pharmaceutical composition including the compound or its pharmaceutically acceptable salt, a method for treating and/or preventing FGFR-related diseases, particularly tumors, by using the compound or its pharmaceutically acceptable salt, and a preparation method of the compound or its pharmaceutically acceptable salt. The present invention also relates to an use of the compound or its pharmaceutically acceptable salt, or an pharmaceutical composition including the compound or its pharmaceutically acceptable salt in the preparation of a drug for treating and/or preventing FGFR-related diseases, particularly tumors, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Alkynylated heterocyclic compound, its preparation method and its application in medicine

The present invention relates to a novel alkynyl heterocyclic compound or a pharmaceutically acceptable salt thereof as an FGFR inhibitor; a pharmaceutical composition containing the alkynyl heterocyclic compound or a pharmaceutically acceptable salt thereof; A method for preparing a compound or a pharmaceutically acceptable salt thereof; the alkyne heterocyclic compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the alkyne heterocyclic compound or a pharmaceutically acceptable salt thereof is used for the preparation Use in a medicament for treating and / or preventing a FGFR-related disorder, particularly a tumor; and a method for treating and / or preventing a FGFR-related disorder, especially a tumor, using the compound or composition.

Fibroblast Growth Factor Receptor (FGFR) is a type of receptor tyrosine kinase (RTK), which is structurally composed of an extramembrane ligand binding domain, a single transmembrane domain, and an intramembrane tyrosine kinase domain It consists of four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. It and its ligand, Fibroblast Growth Factor (FGF), play an important regulatory role in cell signaling. FGF, as an extracellular stimulus signal, binds to the outer membrane region of FGFR, causing its membrane tyrosine kinase to phosphorylate, thereby initiating a series of downstream signaling pathways to regulate cell proliferation, differentiation, and metastasis. Various tumors are closely related to FGF / FGFR expression and activation, such as non-small cell lung cancer, breast cancer, gastric cancer, liver cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, myeloma, and melanoma Et al. (Clin. Cancer Res. 2012, 18, 1855). Studies have shown that FGFR1 amplification accounts for 20% of non-small cell lung cancer, FGFR2 amplification accounts for ~ 5% of gastric cancer, FGFR3 mutation accounts for ~ 70% of non-invasive bladder cancer, and FGFR4 amplification for liver cancer, etc. (PloS One 2012 , 7, e36713). Therefore, the development of FGFR-targeted inhibitors has become a frontier hot spot in anti-tumor drug research (Drug Disc. Today 2014, 19, 51). There are currently some non-FGFR-specific drugs on the market, such as sunitinib from Pfizer, lenvatini from Eisai, and nintedanib from Boehringer Ingelheim, but there are no FGFR-specific inhibitors. FGFR-specific inhibitors entering the clinic include HMPL-453, BGJ-398, LY-2874455, AZ-4547, JNJ-42756493, TAS-120, ARQ-087, and BLU-554. Although the development of FGFR inhibitors has attracted the attention of many biopharmaceutical companies, due to the prospects they have shown in the treatment of a variety of malignancies, new compounds still need to be developed. Through continuous efforts, the present invention has devised a compound having a structure represented by the general formula (I), and found that a compound having such a structure exhibits excellent effects and effects.

The present invention provides a compound represented by the general formula (I) as a FGFR inhibitor, a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof: (I) wherein: A is N or CR ² ; ring B is a benzene ring or a 5- to 6-membered heteroaryl ring, wherein the benzene ring and the heteroaryl ring are optionally substituted with one or more G ¹ ; R ^{1 is} independent Is independently selected from H, halogen, cyano, C _1-6 alkyl or -NHR ³ ; R ^{2 is} independently selected from H, halogen, cyano or C _1-6 alkyl, wherein said alkyl is optionally halogen , Cyano, hydroxy, or -OC _1-6 alkyl; R ^{3 is} independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein Alkyl, cycloalkyl and heterocyclyl are optionally halogen, cyano, -OR ⁴ , -NR ⁵ R ⁶ , C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclyl Substituted; X is absent or is C _1-6 alkylene; Y is absent or is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclo, aryl or heteroaryl, wherein The cycloalkyl, heterocyclo, cycloaryl, and cycloaryl are optionally substituted with one or more G ² ; Z is independently selected from cyano, -NR ⁷ CN, , , or Bond a is a double or triple bond; when bond a is a double bond, each of R ^a , R ^b and R ^{c is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 ring Alkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more G ³ ; R ^a and R ^b or R ^b and R ^{c are} optionally The carbon atoms to which they are attached together form a 3-6 membered ring optionally containing heteroatoms; when bond a is a triple bond, R ^a and R ^c do not exist, and R ^{b is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more G ⁴ ; R ^{4 is} independent Is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl may be optionally substituted by one or more G substituted ^{5; G 1, G 2, G} 3, G 4 and G ⁵ are each independently selected from halogen, cyano, C _{1 - 6} alkyl, C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _{6 - 10} aryl, 5-10 membered ^{heteroaryl, -OR 8, -OC (O)} NR 8 R 9, -C (O) OR ⁸ , -C (O) NR ⁸ R ⁹ , -C (O) R ⁸ , -NR ⁸ R ⁹ , -NR ⁸ C (O) R ⁹ , -NR ⁸ C (O) NR ⁹ R ¹⁰ , -S (O) _m R ⁸ or -NR ⁸ S (O) _m R ⁹ , wherein the alkane Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from one or more of halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl , 3-8 membered heterocyclic group, -OR ¹¹ , -OC (O) NR ¹¹ R ¹² , -C (O) OR ¹¹ , -C (O) NR ¹¹ R ¹² , -C (O) R ¹¹ ,-- NR ¹¹ R ¹² , -NR ¹¹ C (O) R ¹² , -NR ¹¹ C (O) NR ¹² R ¹³ , -S (O) _m R ¹¹ or -NR ¹¹ S (O) _m R ¹² Substitution; R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl; and m is 1 or 2. An embodiment of the present invention relates to a compound represented by the above general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof, wherein A is N or CH, preferably Is N. Another embodiment of the present invention relates to a compound represented by the above-mentioned general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof, wherein ring B is a benzene ring. In one aspect, the present invention provides compounds of the following general formula (II), or prodrugs thereof, stable isotope derivatives, pharmaceutically acceptable salts, isomers, and mixtures thereof: (II) ^{wherein: G a, G b, G} c and G ^d are each independently selected from H, halo, cyano, C _{1 - 6} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , -OR ⁸ , -NR ⁸ R ⁹ or -C (O) NR ⁸ R ⁹ , wherein the alkyl, cycloalkyl and heterocyclic group are optionally selected from one or more selected from halogen, cyano, C _{1 -6} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -OR ¹¹ or -NR ¹¹ R ¹² substituted with substituents; wherein A, R ¹ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , X, Y, Z are as defined above. Another embodiment of the present invention relates to a compound represented by the above general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof, which is represented by the general formula (III) The compounds or their prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof: (III) wherein: G ^a and G ^b is independently selected from H, halo, cyano, C _{1 - 6} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -OR ^8, - NR ⁸ R ⁹ or -C (O) NR ⁸ R ⁹ , wherein the alkyl group, cycloalkyl group and heterocyclic group are optionally one or more selected from halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -OR ¹¹ or -NR ¹¹ R ¹² substituted by substituents; wherein A, R ¹ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , X, The definitions of Y and Z are as described above. Another embodiment of the present invention relates to a compound represented by the above general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof, wherein R ^{1 is} independently selected from H , -NH ₂ or -NHC _1-6 alkyl. In an embodiment of the invention, R ¹ may be H or -NH ₂ . In an embodiment of the present ^{invention, G a, G b, G} c and G ^d can each independently -OC _{1 - 2} alkyl or halogen. In embodiments of the present invention, R ^{1 is} independently selected from H, -NH ₂ or -NHR ₃ ; R ^{3 is} independently selected from C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclic ring Wherein the alkyl, cycloalkyl, and heterocyclyl are optionally halogen, cyano, -OR ⁴ , -NR ⁵ R ⁶ , C _1-6 alkyl, C _3-6 cycloalkyl, or 3- 6-membered heterocyclic group substituted. Another embodiment of the present invention relates to the compounds represented by the above-mentioned general formulae (I), (II) and (III) or their prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof, Where: X is absent or is C _1-6 alkylene; Y is absent or is selected from C _3-8 cycloalkyl or 3-8 membered heterocyclo; Z is independently selected from cyano, -NR ⁷ CN, or Bond a is a double or triple bond; when bond a is a double bond, each of R ^a , R ^b and R ^{c is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 ring Alkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are optionally selected from one or more independently selected from halogen, cyano, C _1-6 alkyl, C _{3- 6} -cycloalkyl, 3-6 membered heterocyclyl, -OR ⁸ or -NR ⁸ R ⁹ are substituted by the substituent; when the bond a is a triple bond, R ^a and R ^{c are} not present, and R ^{b is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally one or more Independently substituted by a substituent selected from halogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR ⁸ or -NR ⁸ R ⁹ ; R ⁴ , R ⁸ and R ⁹ are each independently selected from H or C _1-6 alkyl. One embodiment of the present invention relates to a compound represented by the above general formula (I), wherein the compound is selected from: Or its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof. The compounds of the present invention have a significant inhibitory effect on the activity of FGFR. The compound of the present invention can effectively inhibit the activity of FGFR1, FGFR2, FGFR3 or FGFR4. Preferably, the IC ₅₀ of FGFR1, FGFR2, FGFR3 or FGFR4 is 100 to 1000 nM, more preferably the IC _{50 is} less than 100 nM, and the IC _{50 is} less than 10 nM. In particular, the compound of the present invention has a significant inhibitory effect on the cell proliferation of tumor cells (such as Hep3B, RT4 and SNU-16 tumor cells), preferably its IC ₅₀ is 100 to 1000 nM, more preferably its IC _{50 is} less than 100 nM, most preferably Its IC _{50 is} less than 10 nM. The compounds of the invention are therefore useful in the treatment or prevention of FGFR-related diseases, including but not limited to tumors and inflammatory diseases such as osteoarthritis. The compounds of the present invention can be used to treat or prevent FGFR-related tumors, such as non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, renal cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer , Gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer (such as hepatocellular carcinoma), more specifically liver cancer, gastric cancer, non-small cell lung cancer, and bladder cancer. Therefore, in another aspect, the present invention provides a method for treating or preventing an FGFR-mediated disease (such as the tumor), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a prodrug thereof, a stable isotope Derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof, or pharmaceutical compositions comprising said compounds. Another aspect of the present invention relates to a compound represented by the general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof for use in medicine or medical use, for the treatment or Prevention of FGFR-mediated diseases, such as tumors or inflammatory diseases, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, renal cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrium Cancer, cervical cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer. The present invention further relates to a pharmaceutical composition comprising the compound of the present invention or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer and a mixture thereof, and a pharmaceutically acceptable carrier, Diluents, excipients. Another aspect of the present invention relates to a compound represented by the general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer and a mixture thereof, or a pharmaceutical composition in the preparation of a medicament. Use, wherein the medicament is used to treat or prevent FGFR-mediated diseases, such as tumors and inflammatory diseases. According to the present invention, the medicament may be any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized preparations, injections. The pharmaceutical preparation of the present invention may be administered in the form of a dosage unit containing a predetermined amount of the active ingredient per dosage unit. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 300 mg of a compound of the present invention depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or The pharmaceutical preparation may be administered in the form of a dosage unit containing a predetermined amount of the active ingredient per dosage unit. Preferred dosage unit formulations are those containing the daily or divided dose or active fraction thereof as indicated above. In addition, this type of pharmaceutical preparation can be prepared using methods known in the pharmaceutical art. The pharmaceutical formulations of the present invention may be suitable for administration by any desired suitable method, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all methods known in the pharmaceutical art, for example, by combining the active ingredient with one or more excipients or one or more adjuvants.

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.的 Notation used in this article "C_xy "Means a range of carbon atoms, where x and y are integers, such as C_3-8 Cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, that is, a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms. It should also be understood that "C3-8" also includes any sub-range thereof, such as C3-7, C3-6, C4-7, C4-6, C5-6, and the like. "Alkyl" means a saturation of 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms Straight or branched chain hydrocarbyl group. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, second butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl Radical, 1,3-dimethylbutyl and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted. "Alkenyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond and usually 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Group. Non-limiting examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1 , 4-pentadienyl and 1,4-butadienyl. The alkenyl may be substituted or unsubstituted. "Alkynyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond and usually 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Group. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl may be substituted or unsubstituted. "Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent having 3 to 14 carbon ring atoms. A cycloalkyl group may be a single carbocyclic ring and typically contains 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl can optionally be bi or tricyclic fused together, such as decahydronaphthyl. The cycloalkyl group may be substituted or unsubstituted. "Heterocycle or heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group, which includes 3 to 20 ring atoms, and may be 3 to 16, 3 to 14, 3 to 12, for example Three to ten, three to eight, three to six, or five to six ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O)_m (Where m is an integer from 0 to 2), excluding the ring portion of -O-O-, -O-S-, or -S-S-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, and most preferably 1 ~ 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, pyridinyl, fluorazinyl, morpholinyl, thiomorpholinyl, homoperazinyl, oxetanyl, and azetidine base. Polycyclic heterocyclyls include fused, bridged or spiro polycyclic heterocyclyls. The heterocyclic ring or heterocyclic group may be substituted or unsubstituted. "Aryl" means an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include: withThe aryl group may be substituted or unsubstituted. "Heteroaryl or heteroaryl ring" refers to a heteroaromatic system containing 5 to 14 ring atoms, where 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members. More preferred heteroaryl groups are 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include: withThe heteroaryl group may be substituted or unsubstituted. "Halogen" means fluorine, chlorine, bromine or iodine. "Cyano" refers to -CN. "Optional" or "optionally" means that the event or environment described later can, but need not, occur, and the description includes situations where the event or environment occurs or does not occur. For example, "an optionally substituted heterocyclic group" means that an alkyl group may but need not exist, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group . "Substituted" refers to one or more hydrogen atoms in a group, preferably five, more preferably one to three hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond. The substituent includes, but is not limited to, hydroxyl, amine, halogen, cyano, C_{1 - 6} Alkyl, C_{1 - 6} Alkoxy, C_{2 - 6} Alkenyl, C_{2 - 6} Alkynyl, C_3-8 Cycloalkyl and the like. (2) "Pharmaceutical composition" means a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity. "Isomers" refer to compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space, and are called "isomers." Isomers whose atomic arrangement is different are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers, and conformers.的 The compounds of the present invention can exist as optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.几何 The compounds of the present invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. The substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated as the Z or E configuration, and the substituents around the cycloalkyl or heterocyclic ring are designated as the cis or trans configuration.化合物 The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism. It should be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one of the tautomeric or stereoisomeric forms used in the nomenclature of a compound or the chemical structural formula. "Isotopes" are all isotopes of the atoms present in the compounds of the invention. Isotopes include those atoms that have the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, respectively² H,³ H,¹³ C,¹⁴ C,¹⁵ N,¹⁸ O,¹⁷ O,³¹ P,³² P,³⁵ S,¹⁸ F and³⁶ Cl. The isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples using appropriate isotopically-labeled reagents instead of non-isotopically-labeled reagents. Such compounds have a variety of potential uses, such as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to beneficially alter biological, pharmacological or pharmacokinetic properties. "Prodrug" means that a compound of the invention can be administered in the form of a prodrug. A prodrug refers to a derivative of a biologically active compound of the present invention that is transformed under physiological conditions in the living body, such as by oxidation, reduction, hydrolysis, etc. (they each use an enzyme or without the participation of an enzyme). An example of a prodrug is a compound in which the amine group in the compound of the present invention is tritiated, alkylated, or phosphorylated, such as eicosylamidoamino, propylaminoamido, neopentyloxymethyl Amino groups, or where hydroxyl groups are tritiated, alkylated, phosphorylated, or converted to borates, such as ethoxy, palmito, neopentyl, succinyl, fumarate, Alaninoxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and / or to the cytosol of the cell. These compounds can be prepared from a compound of the present invention according to a known method. "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt made from a pharmaceutically acceptable base or acid, including an inorganic base or acid and an organic base or acid. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups can exist in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium, potassium, calcium, magnesium, or salts with amines or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. The compounds of the invention containing basic groups may exist in the form of salts and may be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene Acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid , Adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, internal salts or internal ammonium salts. Each salt can be obtained by conventional methods known to those skilled in the art, such as by contacting these with organic or inorganic acids or bases in a solvent or dispersant or by anion exchange or cation exchange with other salts. Therefore, when referring to "compounds", "compounds of the invention" or "compounds of the invention" in this application, all such compound forms are included, such as their prodrugs, stable isotope derivatives, pharmaceutically acceptable salts , Isomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof.术语 As used herein, the term "tumor" includes both benign and malignant tumors (eg, cancer). As used herein, the term "cancer" includes various malignancies in which FGFR is involved, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, renal cell carcinoma, multiple myeloma, breast cancer, ovarian cancer , Endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer (such as hepatocellular carcinoma), more specifically liver cancer, gastric cancer, non-small cell lung cancer, and bladder cancer .术语 As used herein, the term "inflammatory disease" refers to any inflammatory disease in which FGFR is involved in its inflammation, such as osteoarthritis. As used herein, the term "therapeutically effective amount" means an amount that includes a compound of the invention that is effective to inhibit the function of FGFR and / or treat or prevent the disease. Synthetic method The present invention also provides a method for preparing the compound. The preparation of the compound of the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods of the present invention can be used in combination. The products obtained in each step are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (available from SciFinder). The pyrazole compounds of the general formula (I) of the present invention can be synthesized according to the route described in Method A: 1) The starting material A1 can be obtained by Sandmeyer reaction A2, or can be brominated to obtain A3 R₁ Can be -CN or ester (-COOR, where R is alkyl); 2) A2 or A3 and precursor XL ~ NP (where X is a leaving group, L ~ NP is a functional group containing a protected amine group, P is an amine-protecting group) A4 undergoes a substitution reaction under base catalysis to form A4, and A4 can also be obtained by a Mitsunobu reaction with a precursor with a hydroxyl group (HO-L ~ NP); 3) When R of A4₁ Yes -CN, in NaOH / H₂ O₂ Hydrolyzed to amidine A5 under the conditions; when R of A4₁ It is an ester (-COOR, where R is an alkyl group), which is firstly hydrolyzed to a carboxylic acid under basic conditions (such as LiOH), and then amidated to obtain A5; 4) A5 is coupled with alkyne to obtain A6 by Sonogashira; 5) A6 Deprotection of the amine group in the middle to obtain A7; 6) The amine group in A7 is derivatized with a chemical reagent (such as BrCN, allyl chloride, etc.) containing a functional group that reacts with a cysteine residue in the kinase ligand binding domain The target compound A8 was obtained. Method A:In addition, it can also be synthesized according to the route described in Method B. The pyrazole NH protecting group Q is introduced in the second step, and the common intermediate B7 is deprotected in the fifth step. The pyrazole NH of B7 is different from the one containing the protected amine group. The precursor reaction replaces the reaction, and after deprotection and derivatization, the target product A8 is obtained. Method B:The pyrazole compounds of the general formula (I) of the present invention can also be synthesized according to the route described in Method C: 1) A4 is firstly coupled with alkyne via Sonogashira to obtain C1; 2) -NH in C1² Substitution reaction occurs under base catalysis or C2 is generated by reductive amination; 3) CN of C2 is in NaOH / H₂ O₂ It is hydrolyzed to ammonium amine C3 under certain conditions. In some cases, it is necessary to first protect -NH- with Boc, and then hydrolyze. Finally, it is deprotected and derivatized to obtain the target product C5. C5 can also be obtained by directly replacing A8 . Method C:Example The structure of a europium compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic analyzer, and the solvent was DMSO-DMSO-d ₆ ), Deuterated chloroform (CDC1₃ ), Deuterated methanol (CD₃ OD), internal standard is tetramethylsilane (TMS), chemical shift is 10^-6 (Ppm) is given as a unit. MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120). HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatography (Sunfirc C18, 150 × 4.6mm, 5 μm column) and a Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 × 4.6mm, 5 μm column). The thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silicone plate. The thin-layer chromatography (TLC) silicon plate uses a size of 0.15mm ~ 0.2mm, and the thin-layer chromatography separation and purification product uses a size of 0.4mm ~ 0.5mm Silicone board. Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier. The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Coupling companies such as chemicals.如 Unless otherwise specified in the examples, the reaction is performed under an argon atmosphere or a nitrogen atmosphere. Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L. The tritium atmosphere refers to a hydrogen gas balloon with a volume of about 1L connected to the reaction flask. For the pressurized hydrogenation reaction, Beijing Jiawei Kechuang Technology Co., Ltd. GCD-500G high-purity hydrogen generator and BLT-2000 medium-pressure hydrogenation instrument were used. The tritium hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times. Microwave reaction uses CEM Discover-SP type microwave reactor.如 Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20 ° C-30 ° C. The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC). The developing systems used in the reaction are A: dichloromethane and methanol; B: petroleum ether and ethyl acetate. The volume ratio of the solvent is based on The polarity of the compounds is adjusted. The eluent system for column chromatography and the eluent system for thin-layer chromatography for purifying compounds include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate systems. It can be adjusted by different polarities. It can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents. Example 1 (S) -1- (1-propenylpyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-methyl Amidine (R) -3- (Toluenesulfonyloxo) pyrrolidine-1-carboxylic acid third butyl ester (R) -3-hydroxypyrrolidine-1-carboxylic acid third butyl ester 1a (3.5 g, 18.7 mmol), triethylamine (5.25 mL, 37.9 mmol), 4-dimethylaminopyridine (0.35 g, 2.87 mmol) were dissolved in dichloromethane (50 mL), and p-toluenesulfonyl chloride (5.4 g, 28.1 mmol), and the reaction mixture was stirred at room temperature for 12 hours. Dilute with water (50 mL) and extract with ethyl acetate (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product (R)- 3- (Toluenesulfonyloxo) pyrrolidine-1-carboxylic acid third butyl ester 1b (6.0 g, yellow oil), yield: 94%. MS m / z (ESI): 364 [M + 23] The second step ((3,5-dimethoxyphenyl) ethynyl) trimethylsilane is a mixture of 1-bromo-3,5-dimethyl Oxybenzene 1c (6.51g, 30mmol), trimethylsilylacetylene (8.8g, 90mmol), bis (triphenylphosphine) palladium chloride (1.05g, 1.5mmol), cuprous iodide (0.56g , 3.0 mmol), triethylamine (80 mL), and N, N-dimethylformamide (150 mL) were heated to 80 ° C. and stirred under nitrogen protection for 12 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain the target product ((3,5-dimethoxyphenyl) ethynyl) trimethylsilane 1d (6.2 g, brown solid), yield: 88%. MS m / z (ESI): 235 [M + 1] Step 1 1-Ethynyl-3,5-dimethoxybenzene will be ((3,5-dimethoxyphenyl) ethynyl) trimethyl Monosilane 1d (3.0 g, 12.8 mmol) was dissolved in methanol (100 mL), potassium carbonate (3.5 g, 25.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain the target product 1-ethynyl-3,5-dimethoxybenzene 1e (2 g, yellow solid), yield: 96% . Step 4 3-Iodine-1H-pyrazole-4-carboxylic acid ethyl ester Dissolve 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester 1f (4.7g, 30.3mmol) in concentrated hydrochloric acid (12M, 40mL) , And cooled to 0 ° C, added a solution of sodium nitrite (4.25g, 60mmol) (7.5mL), and stirred for 5 minutes, and then slowly added a solution of potassium iodide (12.5g, 75mmol) (17.5mL), and continued stirring for 30 minutes. The reaction mixture was poured into a saturated sodium thiosulfate solution (200 mL), and extracted with ethyl acetate (400 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product 3-iodine- 1 g of 1H-pyrazole-4-carboxylic acid ethyl ester (6.4 g, pale yellow solid), yield: 80%. MS m / z (ESI): 267 [M + 1] Step 5 (S) -1- (1- (Third-butoxycarbonyl) pyrrolidin-3-yl) -3-iodo-1H-pyrazole Ethyl-4-carboxylate 1 g (4.5 g, 17 mmol) of 3-iodo-1H-pyrazole-4-carboxylic acid ethyl ester, (R) -3- (tosylhydrazone oxo) pyrrolidine-1-carboxylic acid third A mixture of butyl ester 1b (6.1 g, 17.8 mmol), cesium carbonate (7.5 g, 20.4 mmol) and N, N-dimethylformamide (50 mL) was heated to 80 ° C and stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into a saturated sodium bicarbonate solution (200 mL), and extracted with ethyl acetate (300 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1 to 2/1) to obtain the target product. (S) -1- (1- (Third-butoxycarbonyl) pyrrolidin-3-yl) -3-iodo-1H-pyrazole-4-carboxylic acid ethyl ester 1h (3.1 g, pale yellow solid), produced Rate: 42%. MS m / z (ESI): 458 [M + 23] Step 6 (S) -1- (1- (Third butoxycarbonyl) pyrrolidin-3-yl) -3-((3,5- Dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid ethyl ester (S) -1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl) -3-iodine -1H-pyrazole-4-carboxylic acid ethyl ester 1h (1g, 2.25mmol), 1-ethynyl-3,5-dimethoxybenzene 1e (0.75g, 4.5mmol), bis (triphenylphosphine) chloride A mixture of palladium (175mg, 0.25mmol), cuprous iodide (95mg, 0.5mmol), triethylamine (12.5ml) and N, N-dimethylformamide (12.5mL) was heated to 80 ° C, Stir for 12 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product (S) -1- (1- ( Tributoxycarbonyl) pyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid ethyl ester 1i (0.95 g, yellow oil Material), yield: 90%. MS m / z (ESI): 414 [M + 1-56] Step 7 (S) -1- (1- (third butoxycarbonyl) pyrrolidin-3-yl) -3-((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid (S) -1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl) -3- ( (3,5-Dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid ethyl ester 1i (0.30 g, 0.64 mmol) was dissolved in tetrahydrofuran (3 mL), and a sodium hydroxide solution (4 M, 2 mL) was added. ), Stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was acidified with hydrochloric acid (6M, 1 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure to obtain the target product (S) -1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl)- 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid 1j (200 mg, pale yellow oil), yield: 71%. MS m / z (ESI): 386 [M + 1-56] Step 8 (S) -3- (4-aminomethylmethyl-3-((3,5-dimethoxyphenyl) ethynyl ) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl) -3- ((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid 1j (220 mg, 0.5 mmol), ammonium chloride (270 mg, 5 mmol), O- (7-azabenzene Benzotriazol-1-yl) -N, N, N ', N'-tetramethylurenium hexafluorophosphate (HATU) (228 mg, 0.6 mmol), N, N-diisopropylethylamine (129 mg , 1 mmol) and N, N-dimethylformamide (5 mL) were stirred at room temperature overnight. Dilute with water and extract with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure. The residue was purified by thin-layer silica gel preparative chromatography (dichloromethane / methanol = 20/1) to obtain the target product (S)- 3- (4-Aminomethylamino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 1k (140 mg, white solid), yield: 64%. MS m / z (ESI): 385 [M + 1-56] Step 9 (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidine-3- (Syl) -1H-pyrazole-4-carboxamide, (S) -3- (4-Aminomethoxo-3-((3,5-dimethoxyphenyl) ethynyl) -1H-py The reaction mixture of azole-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 1k (50mg, 0.11mmol), hydrochloric acid (6M, 5mL) and dioxane (5mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the target product (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4 -Formamidine 1 1 (42 mg, hydrochloride, crude), yield: 100%. MS m / z (ESI): 341 [M + 1] Step 10 (S) -1- (1-propenylpyrrolidin-3-yl) -3-((3,5-dimethoxybenzene (Yl) ethynyl) -1H-pyrazol-4-methylamidine (S) -3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) To a mixture of -1H-pyrazole-4-carboxamide hydrochloride 1 l (30 mg, 0.08 mmol), N, N-diisopropylethylamine (31 mg, 0.24 mmol) and tetrahydrofuran (15 mL) was added dropwise propylene arsine A solution of chlorine (11 mg, 0.12 mmol) in tetrahydrofuran (5 mL), and the reaction mixture was stirred at room temperature for 30 minutes. Add water (30 mL) to quench and extract with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure. The residue was purified by thin-layer silica gel preparative chromatography (dichloromethane / methanol = 20/1) to obtain the target product (S)- 1- (1-propenylpyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 1 (15mg, white (Solid), yield: 50%. MS m / z (ESI): 395 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.10 (d,J = 9.8 Hz, 1H), 6.96 (brs, 1H), 6.71 (d,J = 2.3 Hz, 2H), 6.54-6.52 (m, 1H), 6.46-6.39 (m, 2H), 5.80 (brs, 1H), 5.76-5.72 (m, 1H), 5.01-4.92 (m, 1H), 4.13-4.00 (m, 2H), 3.90-3.75 (m, 8H), 2.62-2.44 (m, 2H). Example 2 1- (1-propenylpyridin-4-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide First step 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxylic acid ethyl ester Compound 3-iodo-1H-pyrazole- 1 g (2.01 g, 7.5 mmol) of ethyl 4-formate was dissolved in tetrahydrofuran (80 mL) and cooled to 0 ° C. Sodium hydride (60% mineral oil dispersion, 0.42 g, 10.5 mmol) was added and stirred at room temperature for 1 hour. . To the reaction mixture was added 2- (trimethylsilyl) ethoxymethyl chloride (1.76 g, 10.5 mmol), and stirring was continued for 15 hours. To the reaction mixture was added saturated saline (100 mL), and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined and washed with saturated brine (100 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1 to 1/2) to obtain the target product 3- Iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxylic acid ethyl ester 2a (2.6 g, colorless oil), yield: 87% . MS m / z (ESI): 397 [M + 1] Second step 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4- Formic acid Dissolve the compound 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxylic acid ethyl ester 2a (2.6 g, 6.5 mmol) in tetrahydrofuran (40 mL), an aqueous lithium hydroxide solution (1M, 13 mL) was added and stirred at room temperature for 15 hours. Dilute with water (20 mL), acidify with hydrochloric acid (1M) to pH = 4-5, and extract with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), the solvent was removed under reduced pressure, and the target product 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) was obtained after drying. -1H-pyrazole-4-carboxylic acid 2b (2.03 g, white solid), yield: 85%. MS m / z (ESI): 391 [M + 23] Step 3 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4- Methylamine is a compound 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxylic acid 2b (2.03 g, 5.5 mmol), diiso Propylethylamine (2.13g, 16.5mmol) and N, N-dimethylformamide (20mL) were mixed, and O- (7-azabenzotriazol-1-yl) -N, N , N ', N'-tetramethylurenium hexafluorophosphate (HATU) (2.5 g, 6.6 mmol) and 1-hydroxybenzotriazole (890 mg, 6.6 mmol), stirred at room temperature for 1 hour and added solid Ammonium chloride (1.47 g, 27.5 mmol), stirring was continued for 15 hours. To the reaction mixture was added saturated brine (30 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (100 mL). After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to obtain the target product 3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxamide 2c (2.3 g, yellow oil), yield: 100%. MS m / z (ESI): 368 [M + 1] Step 4 3-((3,5-dimethoxyphenyl) ethynyl) -1-((2- (trimethylsilyl) Ethoxy) methyl) -1H-pyrazole-4-carboxamide. Compound 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole -4-formamidine 2c (2.7 g, 7.3 mmol), 1-ethynyl-3,5-dimethoxybenzene (1.78 g, 11 mmol), triethylamine (2.2 g, 21.9 mmol), di (tri Phenyl phosphorus) palladium chloride (512 mg, 0.73 mmol) and anhydrous tetrahydrofuran (70 mL) were mixed, deoxidized, and stirred at room temperature under an argon atmosphere for 15 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10/1 to 2/1) to give the target product 3-((3,5-dimethoxyphenyl) acetylene Yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxamide 2d (1.5 g, yellow solid), yield: 51%. MS m / z (ESI): 402 [M + 1] Step 5 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide will be 3- ( (3,5-dimethoxyphenyl) ethynyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxamide 2d ( 1.4g, 3.5mmol), ethylenediamine (525mg, 8.75mmol) and tetrahydrofuran (30mL) were mixed, and a tetrahydrofuran solution (1M, 17.5mL, 17.5mmol) of tetrabutylammonium fluoride was added. After heating under reflux for 15 hours, it was cooled to room temperature, saturated brine (20 mL) was added, and extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to obtain the target product 3-((3 , 5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-methylamidine 2e (600 mg, white solid), yield: 63%. MS m / z (ESI): 272 [M + 1] Step 6 4- (4-Aminomethylamido-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole 1-yl) piperidine-1-carboxylic acid third butyl ester compound 3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 2e (180mg , 0.66 mmol), 4-bromopyridine-1-carboxylic acid third butyl ester (264 mg, 0.99 mmol), potassium carbonate (182 mg, 1.32 mmol) and N, N-dimethylformamide (10 mL) , Heat to 75 ° C, and stir for 15 hours. Water (30 mL) was added, and extraction was performed with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to obtain the target product 4- (4-aminomethylamido-3-((3 , 5-Dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid third butyl ester 2f (120 mg, yellow solid, containing regioisomers), yield : 40%. MS m / z (ESI): 477 [M + 23] Step 7 3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyridin-4-yl) -1H-pyridine Azol-4-methylamidine is a compound 4- (4-aminomethylamido-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyridine- 1-formic acid third butyl ester 2f (120 mg, 0.26 mmol, mixture) was dissolved in ethanol (20 mL), hydrogen chloride in ethanol solution (4M, 1 mL, 4 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (20 mL), and then adjusted to pH = 8-9 with a saturated sodium bicarbonate solution. After the solvent was removed again under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1) to obtain the target product 3-((3,5-dimethoxyphenyl) ethynyl) 1- (pyridin-4-yl) -1H-pyrazole-4-carboxamide 2 g (25 mg, white solid), yield: 27%. MS m / z (ESI): 355 [M + 1] Step 8 1- (1-propenylpyridin-4-yl) -3-((3,5-dimethoxyphenyl) ethynyl ) -1H-pyrazole-4-carboxamide will compound 3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyridin-4-yl) -1H-pyrazole-4 -Formamidine 2g (25mg, 0.07mmol), allyl chloride (10mg, 0.11mmol), solid sodium bicarbonate (18mg, 0.21mmol), water (2mL) and tetrahydrofuran (10mL) at 0 ° C and mixed at Stir at this temperature for 10 hours. Extract with ethyl acetate (20mL × 3), combine the organic phases and dry over anhydrous sodium sulfate, filter to remove the desiccant, remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1), the target product 1- (1-propenylpyridin-4-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-methylpyrene is obtained Amine 2 (17 mg, white solid), yield: 60%. MS m / z (ESI): 409 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.10 (s, 1H), 7.01 (brs, 1H), 6.72 (d,J = 2.2 Hz, 2H), 6.62 (dd,J = 16.8, 10.6 Hz, 1H), 6.55 (t,J = 2.2 Hz, 1H), 6.33 (dd,J = 16.8, 1.5 Hz, 1H), 5.80 (brs, 1H), 5.76 (dd,J = 10.6, 1.6 Hz, 1H), 4.81 (brs, 1H), 4.40 (t,J = 11.4 Hz, 1H), 4.18 (brs, 1H), 3.82 (s, 6H), 3.26 (brs, 1H), 2.89 (brs, 1H), 2.42-2.25 (m, 2H), 2.08-2.00 (m, 2H). Example 3-6 was synthesized with reference to the operation steps of Example 2: Example 3 1- (1-propenylazetidin-3-yl) -3-((3,5-dimethoxyphenyl ) Ethynyl) -1H-pyrazole-4-carboxamideMS m / z (ESI): 381 [M + 1]¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 7.30 (s, 2H), 6.73 (d,J = 2.2 Hz, 2H), 6.60 (t,J = 2.2 Hz, 1H), 6.38 (dd,J = 17.0, 10.3 Hz, 1H), 6.16 (dd,J = 17.0, 2.1 Hz, 1H), 5.73 (dd,J = 10.3, 2.1 Hz, 1H), 5.41-5.28 (m, 1H), 4.71 (t,J = 8.6 Hz, 1H), 4.50 (dd,J = 9.2, 4.9 Hz, 1H), 4.46-4.36 (m, 1H), 4.20 (dd,J = 10.7, 4.8 Hz, 1H), 3.78 (s, 6H). Example 4 1-((1-propenylpyridin-4-yl) methyl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-methyl AmidineMS m / z (ESI): 423 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.00 (s, 1H), 6.98 (brs, 1H), 6.72 (s, 2H), 6.61-6.54 (m, 2H), 6.28 (d,J = 16.8 Hz, 1H), 5.87 (brs, 1H), 5.70 (d,J = 10.5 Hz, 1H), 4.72 (brs, 1H), 4.04 (brs, 3H), 3.82 (s, 6H), 3.05 (brs, 1H), 2.64 (brs, 1H), 2.27 (brs, 1H), 1.69 (brs, 2H), 1.24 (brs, 2H). 5 Example 5 1- (4-propenylaminoaminocyclohexyl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamideMS m / z (ESI): 423 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 8.25 (s, 1H), 6.77 (d,J = 2.3 Hz, 2H), 6.58 (t,J = 2.3 Hz, 1H), 6.38 (dd,J = 17.1, 10.0 Hz, 1H), 6.26 (dd,J = 17.1, 2.0 Hz, 1H), 5.68 (dd,J = 10.1, 2.0 Hz, 1H), 4.38-4.33 (m, 1H), 4.13-4.11 (m, 1H), 3.82 (s, 6H), 2.28-2.18 (m, 2H), 2.07-2.02 (m, 2H ), 1.96-1.80 (m, 4H). Example 6 3-((3,5-dimethoxyphenyl) ethynyl) -1- (2- (N-methacrylfluorenylamino) ethyl) -1H-pyrazole-4-methyl AmidineMS m / z (ESI): 383 [M + 1]¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 7.10-6.90 (m, 2H), 6.76 (s, 2H), 6.69-6.54 (m, 2H), 6.07 (d,J = 16.5 Hz, 1H), 5.64 (d,J = 9.8 Hz, 1H), 4.37 (t,J = 5.7 Hz, 2H), 3.89-3.80 (m, 8H), 2.94 (s, 3H). Example 7 (S) -1- (1-propenylpyrrolidin-3-yl) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyridine Azole-4-methylamidine First step 5-Amino-3-bromo-1H-pyrazole-4-carbonitrile Dissolve the compound 5-amino-1H-pyrazole-4-carbonitrile 7a (20 g, 185 mmol) in N, N-di Methylformamide (200 mL) was cooled to 0 ° C, and N-bromosuccinimide (34 g, 190 mmol) was added in portions, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was poured into a sodium sulfite solution, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloro Methane / methanol = 20/1) to give the target product 5-amino-3-bromo-1H-pyrazole-4-carbonitrile 7b (32 g, yellow solid), yield: 93%. MS m / z (ESI): 187/189 [M + 1] Step (S) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrole Alkane-1-carboxylic acid third butyl ester 5-amino-3-bromo-1H-pyrazole-4-carbonitrile 7b (10 g, 53.8 mmol), 3- (toluenesulfonyloxo) pyrrolidine-1 -A mixture of third butyl formate (22 g, 64.5 mmol), cesium carbonate (58 g, 107.6 mmol) and acetonitrile (250 mL) was heated to 90 ° C. and reacted for 4 hours. Cool to room temperature, filter, and wash the filter cake with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain the target product (S)- 3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7c (5g, yellow oil), yield: 26%. MS m / z (ESI): 300/302 [M + 1-56] The third step (S) -3- (5-amino-4-cyano-3-((3,5-dimethoxy) Phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester (S) -3- (5-amino-3-bromo-4-cyano-1H -Pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7c (5g, 14.1mmol), cuprous iodide (0.6g, 2.8mmol), triethylamine (9mL), [1,1 A mixture of '-bis (diphenylphosphino) ferrocene] palladium dichloride (2g, 2.8mmol) and N, N-dimethylformamide (150mL) was heated to 80 ° C under argon Then, 1-ethynyl-3,5-dimethoxybenzene (14 g, 84.5 mmol) was added in portions and stirred for 2 hours. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain the target product (S) -3- ( 5-amino-4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (5 g, brown oil), yield: 81%. MS m / z (ESI): 382 [M + 1-56] Step 4 (S) -3- (5-Amino-4-aminomethylamido-3-((3,5-dimethoxy) Phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester (S) -3- (5-amino-4-cyano-3-((3 , 5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (5g, 11.4mmol), sodium hydroxide (1.5g, 37.5 mmol, dissolved in 2 mL of water), ethanol (50 mL) and dimethyl sulfene (10 mL) was cooled to 0 ° C, hydrogen peroxide (20 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a sodium sulfite solution, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether). / Ethyl acetate = 1/1) to give the target product (S) -3- (5-amino-4-aminomethylmethyl-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7e (5 g, brown oil), yield: 96%. MS m / z (ESI): 400 [M + 1-56] Step 5 (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- ( Pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide. Compound (S) -3- (5-amino-4-aminoformamyl-3-((3,5-dimethoxy) Phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7e (5 g, 11 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (15 mL) was added ), Stirred at room temperature for 2 hours. Concentrated under reduced pressure to give the target product (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazole 4-methylamidine 7f (7.1 g, brown oil, trifluoroacetate, crude), yield:> 100%, the product was used in the next reaction without purification. MS m / z (ESI): 356 [M + 1] Step 6 (S) -1- (1-propenylpyrrolidin-3-yl) -5-amino-3-((3,5- Dimethoxyphenyl) ethynyl) -1H-pyrazole-4-methylamidine. Compound (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) 1- (Pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 7f (7.1 g, 11 mmol, trifluoroacetate, crude) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 ° C. A saturated sodium bicarbonate solution (20 mL) and propylene chloride (900 mg, 10 mmol) were added successively, and stirred for 30 minutes. The reaction solution was poured into water (100 mL), and extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/2) to obtain the target product (S) -1- ( 1-propenylpyrrolidin-3-yl) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 7 (1.9 g, white solid), yield: 42%. MS m / z (ESI): 410 [M + 1]¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.18 (brs, 1H), 6.75 (d,J = 2.3 Hz, 2H), 6.69-6.55 (m, 3H), 6.20-6.14 (m, 1H), 5.72-5.67 (m, 1H), 5.03-4.91 (m, 1H), 4.01-3.96 (m, 1H ), 3.84-3.70 (m, 7H), 3.66-3.60 (m, 1H), 3.55-3.48 (m, 1H), 2.36-2.21 (m, 2H). Example 8 (S, E) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (1- (4- (dimethylamino) butane-2 -Alkenyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide First step (S, E) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (1- (4- (dimethylamino) butane-2 -Alkenyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (E) -4- (dimethylamino) but-2-enoic acid (23 mg, 0.14 mmol), O -(7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurenium hexafluorophosphate (HATU) (64 mg, 0.17 mmol), (S) -5 -Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 7f (50mg, 0.14mmol ), A reaction mixture of N, N-diisopropylethylamine (2 mL) and dichloromethane (3 mL) was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the target product (S, E) -5-amino-3-((3,5 -Dimethoxyphenyl) ethynyl) -1- (1- (4- (dimethylamino) but-2-enylfluorenyl) pyrrolidin-3-yl) -1H-pyrazole-4-methyl Amidine 8 (2.4 mg, white solid, formate), yield: 4%. MS m / z (ESI): 467 [M + 1]¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (brs, 1H), 7.20 (brs, 1H), 6.75 (d,J = 2.3 Hz, 2H), 6.70-6.61 (m, 3H), 6.44-6.35 (m, 1H), 5.01-4.93 (m, 1H), 4.01-3.93 (m, 1H), 3.77 (s, 6H), 3.74-3.64 (m, 3H), 3.06-3.03 (m, 2H), 2.38-2.24 (m, 2H), 2.17-2.15 (m, 6H). Example 9 (S) -5-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (1- (2-fluoropropenyl) pyrrolidin-3-yl ) -1H-pyrazole-4-carboxamide First step (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (1- (2-fluoropropenyl) pyrrolidin-3-yl ) -1H-pyrazole-4-carboxamide. Compound (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidine-3- Group) -1H-pyrazole-4-carboxamide 7f (50 mg, 0.14 mmol) and 2-fluoroacrylic acid (15 mg, 0.17 mmol) were dissolved in dichloromethane, and N, N-diisopropylethylamine (54 mg , 0.42 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurenium hexafluorophosphate (HATU) (69 mg, 0.18 mmol) And stirred at room temperature for 2 hours. Water (10 mL) was added to dilute the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by thin-layer silica gel preparative chromatography (dichloromethane / methanol = 20/1) to give the target product (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl ) -1- (1- (2-fluoropropenyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 9 (3.6 mg, white solid), yield: 6%. MS m / z (ESI): 428 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 6.62 (t,J = 2.5 Hz, 2H), 6.47 (t,J = 2.3 Hz, 1H), 5.39 (dd,J = 47.2, 3.5 Hz, 1H), 5.16 (ddd,J = 16.6, 5.7, 3.5 Hz, 1H), 4.86-4.81 (m, 1H), 4.02-3.91 (m, 2H), 3.87-3.72 (m, 2H), 3.71 (s, 6H), 2.34-2.23 (m , 2H). Example 10 (S) -5-Amino-1- (1- (but-2-ynylfluorenyl) pyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) acetylene ) -1H-pyrazole-4-carboxamide First step (S) -5-Amino-1- (1- (but-2-alkynyl) pyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) acetylene (Syl) -1H-pyrazole-4-carboxamide (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3- Group) -1H-pyrazole-4-carboxamide 7f (50 mg, 0.14 mmol) and 2-butynyl acid (14 mg, 0.17 mmol) were dissolved in dichloromethane, and N, N-diisopropylethylamine was added (54 mg, 0.42 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurenium hexafluorophosphate (HATU) (69 mg, 0.18 mmol), and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by thin-layer silica gel preparative chromatography (dichloromethane / methanol = 20/1) to give the target product (S) -5-amino-1- (1- (but-2-ynylidene) pyrrolidine- 3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 10 (5.1 mg, pale yellow solid), yield: 9%. MS m / z (ESI): 422 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 6.62 (t,J = 2.1 Hz, 2H), 6.47 (t,J = 2.2 Hz, 1H), 4.85-4.81 (m, 1H), 4.01-3.86 (m, 2H), 3.77-3.62 (m, 7.5H), 3.54-3.46 (m, 0.5H), 2.32-2.27 (m , 2H), 1.95-1.93 (m, 3H). Example 11 (S, E) -5-Amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (1- (4-methoxybut-2-enefluorene) Yl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide The first step (E) -4-bromobut-2-enoic acid is methyl (E) -4-bromobut-2-enoate 11a (3g, 16.8mmol), lithium hydroxide monohydrate (1.1g, 25.3 mmol), tetrahydrofuran (50 mL) and water (50 mL) were mixed at 0 ° C and stirring was continued for 2 hours. After the reaction, tetrahydrofuran was washed away with petroleum ether, and the aqueous phase was adjusted to pH = 1 with 2M hydrochloric acid, and then extracted with ethyl acetate (100 mL × 2). After the organic phases were combined, the solvent was removed under reduced pressure to obtain the target product (E) -4-bromobut-2-enoic acid 11b (2.3 g, yellow oil). Yield: 83%. MS m / z (ESI): 163 [M-1] The second step (E) -4-methoxybut-2-enoic acid will compound (E) -4-bromobut-2-enoic acid 11b (100mg After dissolving 0.61 mmmol in methanol (5 mL), a methanol solution of sodium methoxide (30%, 0.55 mL, 3.05 mmol) was added and stirred for 15 hours. After removing the solvent under reduced pressure, the reaction mixture was dissolved in water, adjusted to pH = 1 with dilute hydrochloric acid, and then extracted with dichloromethane (10 mL × 3). After the organic phases were combined, the solvent was removed under reduced pressure to obtain the target product (E) -4-methoxybut-2-enoic acid 11c (50 mg, yellow oil). Yield: 71%.¹ H NMR (400 MHz, CDCl₃ ) δ 7.13-7.03 (m, 1H), 6.15-6.07 (m, 1H), 4.18-4.11 (m, 2H), 3.48-3.38 (s, 3H). The third step (S, E) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (1- (4-methoxybut-2-ene) Group) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide The compound (E) -4-methoxybut-2-enoic acid 11c (22 mg, 0.19 mmol), diisopropylethyl (67mg, 0.52mmol), (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H- Pyrazole-4-carboxamide 7f (50mg, 0.13mmol), 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (72mg, 0.19 mmol) and N, N-dimethylformamide (10 mL) were mixed and stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL) and washed with water and saturated brine in this order. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to obtain the target product (S, E) -5-amino-3-((3,5-dimethyl) Oxyphenyl) ethynyl) -1- (1- (4-methoxybut-2-enylfluorenyl) pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 11 (30mg, White solid), yield: 51%. MS m / z (ESI): 454 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 6.98 (d,J = 15.3 Hz, 1H), 6.86 (brs, 1H), 6.72 (d,J = 2.1 Hz, 2H), 6.54 (s, 1H), 6.39 (dd,J = 27.7, 16.0 Hz, 1H), 5.54 (brs, 1H), 4.73-4.70 (m, 1H), 4.14-4.12 (m, 2H), 4.05-4.00 (m, 2H), 3.95-3.93 (m, 1H ), 3.82 (s, 6H), 3.77-3.68 (m, 1H), 3.43 (d,J = 10.1 Hz, 3H), 2.72 (brs, 0.5H), 2.54 (brs, 0.5H), 2.43-2.35 (m, 1H). Example 12 (S) -5-Amino-1- (1-cyanopyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole 4-formamidine First step (S) -5-amino-1- (1-cyanopyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole 4-Methylpyramine is compound (S) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyridine Azole-4-methylamidine 7f (50mg, 0.14mmol) was dissolved in tetrahydrofuran (2mL), triethylamine (1mL) was added, cooled to 0 ° C, cyanogen bromide (17mg, 0.15mmol) was added, and stirred at 0 ° C After 2 hours, warm to room temperature and continue stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer silica gel preparative chromatography (dichloromethane / methanol = 15/1) to obtain the target product (S) -5-amino-1- (1-cyanopyrrolidine-3). -Yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 12 (18 mg, white solid), yield: 34%. MS m / z (ESI): 381 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 6.77 (brs, 1H), 6.68 (d,J = 1.9 Hz, 2H), 6.50 (s, 1H), 5.75 (s, 2H), 5.67 (brs, 1H), 4.79-4.73 (m, 1H), 3.84-3.73 (m, 9H), 3.61-3.53 ( m, 1H), 2.53-2.43 (m, 1H), 2.37-2.26 (m, 1H). Example 13-16 was synthesized by referring to the operation steps of Example 7: Example 13 (R) -1- (1-propenylpyrrolidin-3-yl) -5-amino-3-((3,5 -Dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamideMS m / z (ESI): 410 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 6.73 (d,J = 1.9 Hz, 2H), 6.71-6.60 (m, 1H), 6.58 (brs, 1H), 6.32 (dd,J = 16.8, 1.7 Hz, 1H), 5.84-5.74 (m, 1H), 5.04-4.91 (m, 1H), 4.09 (m, 0.5H), 3.98 (td,J = 11.1, 4.0 Hz, 1H), 3.91 (dd,J = 7.8, 5.6 Hz, 1H), 3.86 (dd,J = 9.9, 4.4 Hz, 1H), 3.81 (s, 6H), 3.73-3.63 (m, 0.5H), 2.47 (dd,J = 13.2, 6.7 Hz, 1H), 2.38 (dd,J = 13.6, 7.0 Hz, 1H). Example 14 1- (1-propenylazetidin-3-yl) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole 4-formamidineMS m / z (ESI): 396 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 6.75 (d,J = 2.3 Hz, 2H), 6.60 (t,J = 2.2 Hz, 1H), 6.45-6.28 (m, 2H), 5.80 (dd,J = 10.1, 2.1 Hz, 1H), 5.29-5.21 (m, 1H), 4.79-4.64 (m, 2H), 4.54-4.47 (m, 1H), 4.46-4.39 (m, 1H), 3.82 (s, 6H ). Example 15 1- (1-propenylpyridin-4-yl) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4- FormamidineMS m / z (ESI): 424 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 6.88-6.78 (m, 1H), 6.73 (d,J = 2.2 Hz, 2H), 6.58 (t,J = 2.2 Hz, 1H), 6.24 (dd,J = 16.8, 1.7 Hz, 1H), 5.78 (dd,J = 10.7, 1.7 Hz, 1H), 4.73 (d,J = 13.2 Hz, 1H), 4.47-4.36 (m, 1H), 4.30 (d,J = 13.3 Hz, 1H), 3.81 (s, 6H), 3.32-3.24 (m, 1H), 2.91 (t,J = 9.9 Hz, 1H), 2.02 (d, J = 4.5 Hz, 4H). Example 16 1-((1-propenylpyrrolidin-3-yl) methyl) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyridine Azole-4-methylamidineMS m / z (ESI): 424 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 6.73 (s, 2H), 6.66-6.55 (m, 2H), 6.28 (d,J = 16.7 Hz, 1H), 5.75 (d,J = 10.4 Hz, 1H), 4.13-3.99 (m, 2H), 3.82 (s, 6H), 3.78-3.61 (m, 2H), 3.48 (dd,J = 14.8, 7.4 Hz, 1H), 3.39-3.34 (m, 1H), 2.94-2.75 (m, 1H), 2.20-2.02 (m, 1H), 1.94-1.71 (m, 1H). Example 17 (S) -1- (1-propenepyrrolidin-3-yl) -5-amino-3-((2-fluoro-3,5-dimethoxyphenyl) ethynyl) -1H -Pyrazole-4-carboxamide Step 1 1-Ethynyl-2-fluoro-3,5-dimethoxybenzene Dissolve the mixture 1-ethynyl-3,5-dimethoxybenzene 1e (2g, 12.3mmol) in acetonitrile (15mL) , Reduce the temperature to 0 ° C, and add 1-chloromethyl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt (6.6g, 18.5mmol) in portions. And then stirred at room temperature overnight. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Petroleum ether / ethyl acetate = 30/1), the target product 1-ethynyl-2-fluoro-3,5-dimethoxybenzene 17a (800 mg, yellow solid) was obtained, yield: 36%.¹ H NMR (400 MHz, CDCl₃ ) δ 6.46 (dd,J = 6.9, 2.9 Hz, 1H), 6.41 (dd,J = 4.5, 3.0 Hz, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.22 (s, 1H). Example 17 was synthesized with reference to the first to sixth steps of Example 7, but in the third step, 1-ethynyl-3 was substituted with 1-ethynyl-2-fluoro-3,5-dimethoxybenzene , 5-dimethoxybenzene. MS m / z (ESI): 428 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 7.00 (brs, 1H), 6.59-6.57 (m, 2H), 6.49-6.39 (m, 2H), 5.74-5.70 (m, 1H), 5.52 (d,J = 8.5 Hz, 2H), 5.35 (brs, 1H), 4.73-4.64 (m, 1H), 4.07-3.90 (m, 3H), 3.88 (s, 3H), 3.78 (d,J = 5.3 Hz, 3H), 3.75-3.67 (m, 1H), 2.72-2.67 (m, 0.5H), 2.54-2.31 (m, 1.5H). Example 18 (S) -1- (1-propenylpyrrolidin-3-yl) -5-amino-3-((5-chloro-2-fluorophenyl) ethynyl) -1H-pyrazole- 4-formamidine In the first step ((2-fluoro-5-chlorophenyl) ethynyl) trimethylsilane, 2-fluoro-5-chlorobromobenzene 18a (11.0g, 52.8mmol), ethynyltrimethylsilane (7.7g , 79 mmol) and triethylamine (60 mL) were mixed, then cuprous iodide (100 mg, 0.53 mmol) and ditriphenylphosphine palladium chloride (1.86 g, 2.65 mmol) were added. The reaction mixture was heated to 80 ° C under a nitrogen atmosphere and stirring was continued for 4 hours. After the reaction was completed, the solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1) to obtain the target product ((2-fluoro-5-chlorophenyl) ethynyl) trimethyl. Silane 18b (11.0 g, yellow oil), yield: 90%.¹ H NMR (400 MHz, CDCl₃ ) δ 7.45 (dd,J = 6.0, 2.7 Hz, 1H), 7.28-7.22 (m, 1H), 7.02 (t,J = 8.8 Hz, 1H), 0.29 (s, 9H). The second step 4-chloro-2-ethynyl-1-fluorobenzene will be ((2-fluoro-5-chlorophenyl) ethynyl) trimethylsilane 18b (11.0 g, 48 mmol), potassium carbonate (8.1 g, 58 mmol), dichloromethane (80 mL) and methanol (40 mL) were mixed and stirred at room temperature for 18 hours. After the reaction, the solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1) to obtain the target product 4-chloro-2-ethynyl-1-fluorobenzene 18c (5.5 g, Yellow solid), yield: 74%.¹ H NMR (400 MHz, CDCl₃ ) δ 7.45 (dd,J = 6.0, 2.7 Hz, 1H), 7.31-7.27 (m, 1H), 7.04 (t,J = 8.0, 1H), 3.35 (s, 1H). Example 18 was synthesized with reference to the first to sixth steps of Example 7, but in the third step, 4-chloro-2-ethynyl-1-fluorobenzene was substituted for 1-ethynyl-3,5-dimethyl Oxybenzene. MS m / z (ESI): 402 [M + 1]¹ H NMR (400 MHz, CD₃ OD) δ 7.62-7.61 (m, 1H), 7.47-7.45 (m, 1H), 7.24 (t,J = 9.0 Hz, 1H), 6.69-6.56 (m, 1H), 6.30 (d,J = 16.8 Hz, 1H), 5.77 (t,J = 9.2 Hz, 1H), 5.02-1.91 (m, 1H), 4.09-3.95 (m, 2H), 3.84-3.78 (m, 2H), 2.46 (dd,J = 13.1, 6.6 Hz, 1H), 2.37 (dd,J = 13.6, 6.9 Hz, 1H). Example 19 (S) -1- (1-propenepyrrolidin-3-yl) -5-amino-3-((2-chloro-5- (methylaminomethyl) phenyl) ethynyl ) -1H-pyrazole-4-carboxamide First step 4-chloro-3-bromobenzoic acid methyl ester 4-chloro-3-bromobenzoic acid 19a (2g, 8.5mmol) was dissolved in methanol (400mL) and cooled to 0 ° C, and then acetamidine was added dropwise. Chlorine (2.3 g, 30 mmol) and stirring was continued for 18 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10/1) to obtain the target product, methyl 4-chloro-3-bromobenzoate 19b (1.2 g, yellow solid). Yield: 57%.¹ H NMR (400 MHz, CDCl₃ ) δ 8.31 (d,J = 1.9 Hz, 1H), 7.93 (dd,J = 8.3, 1.9 Hz, 1H), 7.55 (d,J = 8.3 Hz, 1H), 3.95 (s, 3H). The second step is methyl 4-chloro-3-((trimethylsilyl) ethynyl) benzoate. The compound methyl 4-chloro-3-bromobenzoate 19b (1.2 g, 4.8 mmol), trimethyl Silyl acetylene (0.95 g, 9.7 mmol), palladium acetate (108 mg, 0.48 mmol), triphenylphosphine (254 mg, 0.97 mmol), cuprous iodide (185 mg, 0.97 mmol) and triethylamine (25 mL) Mix in a tube and heat and stir at 100 ° C for 15 hours. After the reaction was completed, the solution was desolvated under reduced pressure, and the residue was purified by column chromatography silica gel chromatography (petroleum ether / ethyl acetate = 10/1) to obtain the target product 4-chloro-3-((trimethylsilyl) ethynyl). Methyl benzoate 19c (1 g, yellow solid), yield: 78%.¹ H NMR (400 MHz, CDCl₃ ) δ 8.19 (d,J = 2.0 Hz, 1H), 7.91 (dd,J = 8.4, 2.1 Hz, 1H), 7.48 (d,J = 8.4 Hz, 1H), 3.94 (s, 3H), 0.30 (s, 9H). The third step is methyl 4-chloro-3-ethynylbenzoate. Methyl 4-chloro-3-((trimethylsilyl) ethynyl) benzoate 19c (1 g, 3.76 mmol) is dissolved in methanol (20 mL). ), Then potassium carbonate (1.04 g, 7.52 mmol) was added. After stirring at room temperature for 1 hour, it was dissolved under reduced pressure. The residue was washed with water and filtered to give the target product, methyl 4-chloro-3-ethynylbenzoate 19d (380 mg, yellow solid), yield: 52%.¹ H NMR (400 MHz, CDCl₃ ) δ 8.23 (d,J = 2.1 Hz, 1H), 7.96 (dd,J = 8.4, 2.0 Hz, 1H), 7.51 (d,J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.44 (s, 1H). Fourth step (S) -3- (5-Amino-3-bromo-4-aminoformamidine-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7c (2.20g, 6.2mmol), aqueous sodium hydroxide solution (0.5M, 12.4 mL, 6.2 mmol), an aqueous hydrogen peroxide solution (30%, 15 mL), and dimethyl sulfene (30 mL) were mixed. After stirring at room temperature for 2 hours, the reaction was diluted with saturated brine (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/1 to 20/1) to obtain the target product (S) -3- (5-amino-3-bromo 4-Aminoformamidine-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19e (1.92 g, pale yellow solid), yield: 83%. MS m / z (ESI): 374 [M + 1] Step 5 (S) -3- (5-Amino-4-aminomethylformamidine-3-((2-chloro-5- (methyl ester) <Methoxycarbonyl>) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (5-amino-3-bromo-4 -Aminoformamidine-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19e (770mg, 2.1mmol), triethylamine (6mL), 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride (307mg, 0.42mmol), cuprous iodide (80mg, 0.42mmol) and N, N-dimethylformamide (20mL) were mixed, deoxygenated, and heated under argon atmosphere to 90 ° C, then a solution of methyl 4-chloro-3-ethynylbenzoate 19d (3.20 g, 16.5 mmol) in N, N-dimethylformamide (2 mL) was added dropwise, and stirring was continued for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to obtain the target product (S) -3- (5-amino-4-aminoformamidine-3-(( 2-chloro-5- (methyl ester <methoxycarbonyl>) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19f (420 mg, yellow solid), Yield: 41%. MS m / z (ESI): 488 [M + 1] Step 6 (S) -3-((5-Amino-1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl) 4-Aminoformamidine-1H-pyrazol-3-yl) ethynyl) -4-chlorobenzoic acid will be (S) -3- (5-amino-4-aminoformamidine-3-(( 2-Chloro-5- (methyl ester <methoxycarbonyl>) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19f (100 mg, 0.2 mmol) dissolved In a mixed solvent of methanol (4 mL) and water (4 mL), sodium hydroxide (25 mg, 0.61 mmol) was added and stirring was continued for 2 hours. After completion of the reaction, the organic solvent was removed under reduced pressure. The residue was adjusted to pH = 4 to 5 with hydrochloric acid (1M), and then extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was desolvated under reduced pressure to give the target product (S) -3-((5-amino-1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl) -4-aminoformamidine-1H -Pyrazol-3-yl) ethynyl) -4-chlorobenzoic acid 19 g (80 mg, brown solid), yield: 84%. MS m / z (ESI): 418 [M + H-56] Step 7 (S) -3- (5-amino-4-aminomethylformamidine-3-((2-chloro-5- (formaldehyde) Methylaminomethyl)) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3-((5-amino-1- (1 -(Tert-butoxycarbonyl) pyrrolidin-3-yl) -4-aminoformamidine-1H-pyrazol-3-yl) ethynyl) -4-chlorobenzoic acid 19g (80mg, 0.17mmol) soluble In N, N-dimethylformamide (2.5mL), then methylamine hydrochloride (34mg, 0.50mmol), diisopropylethylamine (129mg, 1mmol) and 2- (7- Benzotriazole oxide) -N, N, N ', N'-tetramethylurea hexafluorophosphate (64 mg, 0.17 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with water, and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 0/1) to obtain the target product (S) -3- (5-amino-4- Aminoformamidine-3-((2-chloro-5- (methylaminoformamidine) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19h (41 mg, brown solid), Yield: 50%. MS m / z (ESI): 387 [M + H-Boc] Step 8 (S) -5-Amino-3-((2-chloro-5- (methylaminomethyl) phenyl) acetyl) acetylene (Syl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamidine hydrochloride (2-Chloro-5- (methylaminomethane) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19h (40mg, 0.08mmol) dissolved in Ethyl acetate (5 mL), then a solution of hydrogen chloride in ethanol (33%, 3 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solution was desolvated under reduced pressure to obtain the target product (S) -5-amino-3-((2-chloro-5- (methylaminomethylamido) phenyl) ethynyl) -1- (pyrrole Alkyl-3-yl) -1H-pyrazole-4-carboxamide hydrochloride 19i (40 mg, crude, brown solid). This product was used in the next reaction without further purification. MS m / z (ESI): 387 [M + H] Step 9 (S) -1- (1-propenepyrrolidin-3-yl) -5-amino-3-((2-chloro-5 -(Methylaminomethylformamidine) phenyl) ethynyl) -1H-pyrazole-4-carboxamide. Compound (S) -5-amino-3-((2-chloro-5- (methyl Aminoformamidine) phenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamidine hydrochloride 19i (40mg, 0.08mmol, crude), allyl chloride (7.5 mg, 0.08 mmol), an aqueous potassium carbonate solution (0.4M, 1.0 mL, 0.4 mmol) and tetrahydrofuran (5 mL) were mixed at 0 ° C and stirred at this temperature for 0.5 hours. Extract with ethyl acetate (20mL × 2), combine the organic phases and dry over anhydrous sodium sulfate, filter to remove the desiccant, desolvate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 100/1 to 10/1) to obtain the target product (S) -1- (1-propenepyrrolidin-3-yl) -5-amino-3-((2-chloro-5- (methylaminomethylformamidine) Phenyl) ethynyl) -1H-pyrazole-4-carboxamide 19 (18 mg, white solid), yield: 51% in two steps. MS m / z (ESI): 441 [M + H]¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (s, 1H), 8.18 (s, 1H), 7.90 (d,J = 8.0 Hz, 1H), 7.72 (d,J = 8.3 Hz, 1H), 7.43 (s, 1H), 6.70-6.62 (m, 4H), 6.19-6.15 (m, 1H), 5.70 (t,J = 10.2 Hz, 1H), 5.03-4.94 (m, 1H), 3.80-3.54 (m, 4H), 2.78 (d,J = 3.8 Hz, 3H), 2.36-2.25 (m, 2H). Example 20 (S) -1- (1-propenylpyrrolidin-3-yl) -5-amino-3-((3-methoxy-5- (methylaminoformyl) phenyl) (Ethynyl) -1H-pyrazole-4-carboxamide Step 1 3-Bromo-5-methoxy-N-methylbenzidine Dissolve 3-bromo-5-methoxybenzoic acid 20a (500mg, 2.17mmol) in N, N-dimethylformamidine Amine (15mL), then methylamine hydrochloride (291mg, 4.35mmol), diisopropylethylamine (1.12g, 8.68mmol) and 2- (7-benzotriazole) -N were added in that order. , N, N ', N'-tetramethylurea hexafluorophosphate (1.24 g, 3.26 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with water, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to give the target product 3-bromo-5-methoxy- N-methylbenzidine 20b (500 mg, white solid), yield: 95%. MS m / z (ESI): 244 [M + H] The second step 3-methoxy-N-methyl-5-((trimethylsilyl) ethynyl) benzidine gives compound 3-bromo -5-methoxy-N-methylbenzidine 20b (500mg, 2.1mmol), trimethylsilylacetylene (302mg, 3.1mmol), palladium acetate (47mg, 0.21mmol), triphenylphosphine (110mg , 0.42 mmol), cuprous iodide (80 mg, 0.42 mmol) and triethylamine (20 mL) were mixed in a sealed tube, heated to 100 ° C, and stirred for 15 hours. After the reaction was completed, the solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 3-methoxy-N-methyl-5-((trimethyl Methylsilyl) ethynyl) benzidine 20c (220 mg, yellow solid), yield: 41%. MS m / z (ESI): 262 [M + H] The third step 3-ethynyl-5-methoxy-N-methylbenzidine will be 3-methoxy-N-methyl-5- ( (Trimethylsilyl) ethynyl) benzidine 20c (220 mg, 0.84 mmol) was dissolved in methanol (8 mL), and potassium carbonate (233 mg, 1.68 mmol) was added. After stirring at room temperature for 1 hour, it was dissolved under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 3-ethynyl-5-methoxy-N-methylbenzidine 20d (140 mg, pale yellow solid). Yield: 88%. MS m / z (ESI): 190 [M + H] Step 4 (S) -3- (5-Amino-4-aminomethylhydrazone-3-((3-methoxy-5- (methyl Methylaminomethyl)) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester (S) -3- (5-amino-3-bromo-4 -Aminoformamidine-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 19e (329mg, 0.88mmol), triethylamine (2mL), 1,1'-bisdiphenylphosphine Ferrocene palladium dichloride (129 mg, 0.2 mmol), cuprous iodide (34 mg, 0.18 mmol) and N, N-dimethylformamide (8 mL) were mixed, deoxidized, and heated to argon 90 ° C. Then a solution of 3-ethynyl-5-methoxy-N-methylbenzidine 20d (1.00 g, 5.3 mmol) in N, N-dimethylformamide (2 mL) was added dropwise and stirring was continued for 12 hours . The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20/1) to obtain the target product (S) -3- (5-amino-4-aminomethyl-3--3- ( (3-Methoxy-5- (methylaminomethane) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl 20e (400mg, crude, brown solid). MS m / z (ESI): 383 [M + H-100] Step 5 (S) -5-Amino-3-((3-methoxy-5- (methylaminoformamidine) phenyl) ) Ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamidine hydrochloride (S) -3- (5-amino-4-aminoformamidine-3 -((3-methoxy-5- (methylaminomethane) phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 20e (400mg, crude ) Was dissolved in dichloromethane (5 mL), then a solution of hydrogen chloride in ethanol (30%, 3 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solution was desolvated under reduced pressure to obtain the target product (S) -5-amino-3-((3-methoxy-5- (methylaminomethylamido) phenyl) ethynyl) -1- (Pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide hydrochloride 20f (300 mg, crude, brown solid). The product was used without further purification in the next reaction. MS m / z (ESI): 383 [M + H] Step 6 (S) -1- (1-propenepyrrolidin-3-yl) -5-amino-3-((3-methoxy -5- (methylaminomethylformamidine) phenyl) ethynyl) -1H-pyrazole-4-carboxamide will compound (S) -5-amino-3-((3-methoxy-5 -(Methylaminoformyl) phenyl) ethynyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-formamidine hydrochloride 20f (150mg, 0.39mmol, crude), Allyl chloride (42 mg, 0.47 mmol), sodium bicarbonate (131 mg, 1.56 mmol), water (4 mL) and tetrahydrofuran (8 mL) were mixed at 0 ° C and stirred at this temperature for 0.5 hours. Extract with ethyl acetate (20mL × 2), combine the organic phases and dry over anhydrous sodium sulfate, remove the desiccant by filtration, desolvate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 20/1) To give the target product (S) -1- (1-propenepyrrolidin-3-yl) -5-amino-3-((3-methoxy-5- (methylaminomethylformamidine) phenyl) ) Ethynyl) -1H-pyrazole-4-carboxamide 20 (60 mg, white solid), yield: 35% in two steps. MS m / z (ESI): 437 [M + H]¹ H NMR (400 MHz, CD₃ OD) δ 7.59 (s, 1H), 7.45 (s, 1H), 7.28 (s, 1H), 6.73-6.58 (m, 1H), 6.36-6.28 (m, 1H), 5.83-5.75 (m, 1H) , 5.04-4.93 (m, 1H), 4.12-3.91 (m, 2H), 3.89 (s, 3H), 3.86-3.66 (m, 2H), 2.93 (s, 3H), 2.51-2.44 (m, 1H) , 2.42-2.34 (m, 1H). Example 21 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (methylamino) -1H -Pyrazole-4-carboxamide First step (S) -3- (3-bromo-4-cyano-5- (methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester S) -3- (5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7c (178 mg, 0.5 mmol) and p-methyl The benzenesulfonic acid monohydrate (12 mg, 0.07 mmol) was dissolved in triethyl orthoformate (4 mL) and heated under reflux for 2 hours. After the reaction was completed, the solution was desolvated under reduced pressure, and the residue was dispersed in water and then extracted with ethyl acetate (30 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was desolvated under reduced pressure, and the residue was dissolved in ethanol (10 mL). After cooling to 0 ° C, sodium borohydride (89 mg, 2.35 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with saturated brine, and then extracted with ethyl acetate (30 mL × 2). After the organic phases were combined and desolvated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 1/1) to obtain the target product (S) -3- (3-bromo-4- Cyano-5- (methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 21a (178 mg, white solid), yield: 100%. MS m / z (ESI): 314 [M + H-56] Second step (S) -3- (4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -5 -(Methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (3-bromo-4-cyano-5- (methylamine Group) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 21a (1.85 g, 5.0 mmol), triethylamine (20 mL), 1,1'-bisdiphenylphosphine dicene Iron palladium dichloride (816mg, 1mmol), cuprous iodide (190mg, 1mmol) and N, N-dimethylformamide (20mL) were mixed, deoxidized, and heated to 90 ° C in an argon atmosphere. A solution of 1-ethynyl-3,5-dimethoxybenzene (4.86 g, 30 mmol) in N, N-dimethylformamide (10 mL) was then added dropwise and stirring was continued for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1 to 0/1) to obtain the target product (S) -3- (4-cyano-3-((3, 5-Dimethoxyphenyl) ethynyl) -5- (methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 21b (2.1g, brown solid), produced Rate: 80%. MS m / z (ESI): 496 [M + H-56] The third step (S) -3- (5-((third butoxycarbonyl) (methyl) amino) -4-cyano- 3-((3,5-Dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (4-cyano- 3-((3,5-Dimethoxyphenyl) ethynyl) -5- (methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 21b (225mg, 0.5 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (150 mg, 1.5 mmol), Boc anhydride (218 mg, 1 mmol), and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added in this order. After stirring at room temperature for 2 hours, saturated brine (10 mL) was added and extracted with ethyl acetate (20 mL × 2). After the organic phases were combined and desolvated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1 to 1/1) to obtain the target product (S) -3- (5-((third Butoxycarbonyl) (methyl) amino) -4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1- Third butyl formate 21c (200 mg, pale yellow solid), yield: 72%. MS m / z (ESI): 440 [M + H-112] Fourth step (S) -3- (5-((third butoxycarbonyl) (methyl) amino) -4-aminomethyl)醯 -3-((3,5-Dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (5- ( (Third butoxycarbonyl) (methyl) amino) -4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine Tertiary-butyl 1-formate 21c (55mg, 0.1mmol), aqueous sodium hydroxide solution (0.5M, 0.1mL, 0.05mmol), aqueous hydrogen peroxide solution (30%, 0.5mL), and dimethylsulfine (1mL) ) Mix and stir at room temperature for 2 hours. The reaction was diluted with saturated brine (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 1/100) to obtain (S) -3- (5-((third butoxy (Carbonyl) (methyl) amino) -4-aminomethylhydrazine-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid Third butyl ester 21d (30 mg, brown solid), yield: 50%. MS m / z (ESI): 414 [M + H-156] Step 5 (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (methylamino)- 1- (Pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide hydrochloride will be (S) -3- (5-((third butoxycarbonyl) (methyl) amino) 4-Aminoformamidine-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 21d (570mg, 1mmol ) Was dissolved in ethyl acetate (10 mL), then a solution of hydrogen chloride in ethanol (33%, 5 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solution was desolvated under reduced pressure to obtain the target product (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (methylamino) -1- (pyrrolidine-3 -Yl) -1H-pyrazole-4-carboxamide hydrochloride 21e (400 mg, crude, brown solid). This product was used in the next reaction without further purification. MS m / z (ESI): 370 [M + H] Step 6 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) Ethynyl) -5- (methylamino) -1H-pyrazole-4-carboxamide will compound (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5- ( Methylamino) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide hydrochloride 21e (870 mg, 2.35 mmol, crude), allyl chloride (254 mg, 2.82 mmol) , Potassium carbonate aqueous solution (2.5M, 4.7mL, 11.78mmol) and tetrahydrofuran (10mL) were mixed at 0 ° C and stirred at this temperature for 0.5 hours. It was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/1 to 10/1) to obtain the target product (S) -1- (1-propenepyrrolidin-3-yl) -3-((3 , 5-Dimethoxyphenyl) ethynyl) -5- (methylamino) -1H-pyrazole-4-carboxamide 21 (720 mg, white solid), yield: 76%. MS m / z (ESI): 424 [M + H]¹ HNMR (400 MHz, CDCl₃ ) δ 6.88 (s, 1H), 6.69 (d,J = 2.3 Hz, 2H), 6.51 (t,J = 2.2 Hz, 1H), 6.46-6.40 (m, 2H), 5.74-5.72 (m, 1H), 5.52-5.48 (m, 1H), 5.06-5.01 (m, 1H), 4.09-3.94 (m, 3H ), 3.80 (s, 6H), 3.72-3.70 (m, 1H), 3.00 (s, 3H), 2.71-2.56 (m, 1H), 2.45-2.35 (m, 1H). Example 22 (S) -1- (1-propenepyrrolidin-3-yl) -3-((2-fluoro-3,5-dimethoxyphenyl) ethynyl) -5- (methylamine ) -1H-pyrazole-4-carboxamideExample 22 was synthesized with reference to the procedure of Example 21, but in the second step, 1-ethynyl-2-fluoro-3,5-dimethoxybenzene was substituted for 1-ethynyl-3,5-dimethoxy Benzene. MS m / z (ESI): 442 [M + H]¹ H NMR (400 MHz, CDCl₃ ) δ 7.08 (s, 1H), 6.68 (d,J = 7.2 Hz, 1H), 6.60-6.57 (m, 2H), 6.51-6.40 (m, 2H), 5.74-5.69 (m, 1H), 5.35 (s, 1H), 5.08-4.99 (m, 1H), 4.11-4.08 (m, 1H), 4.05-3.94 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.75-3.65 (m, 1H), 3.00 (t,J = 5.2 Hz, 3H), 2.72-2.58 (m, 1H), 2.44-2.33 (m, 1H). Example 23 (S) -1- (1-propenepyrrolidin-3-yl) -3-((5-chloro-2-fluorophenyl) ethynyl) -5- (methylamino) -1H -Pyrazole-4-carboxamideExample 23 was synthesized with reference to the procedures of Example 21, but in the second step, 4-chloro-2-ethynyl-1-fluorobenzene was used to replace 1-ethynyl-3,5-dimethoxybenzene. MS m / z (ESI): 416 [M + H]¹ H NMR (400 MHz, CDCl₃ ) δ 7.56-7.52 (m, 1H), 7.35-7.33 (m, 1H), 7.08 (t,J = 8.8 Hz, 1H), 7.02-6.92 (m, 1H), 6.51-6.39 (m, 2H), 5.74 (d,J = 9.3 Hz, 1H), 5.55-5.44 (m, 1H), 5.09-4.98 (m, 1H), 4.14-3.90 (m, 3H), 3.80-3.65 (m, 1H), 3.01 (s, 3H), 2.74-2.55 (m, 1H), 2.49-2.34 (m, 1H). Example 24 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (ethylamino) -1H -Pyrazole-4-carboxamide (S) -3- (5-ethylamino-4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrole Alkane-1-carboxylic acid third butyl ester will mix (S) -3- (5-amino-4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyridine Azol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (500 mg, 1.14 mmol) and sodium hydride (91 mg, 2.28 mmol, 60%) were added to N, N-diethylacetamide (5 mL ), Stir for 10 minutes, add iodoethane (106 mg, 0.68 mmol), and stir for 0.5 hours. The reaction solution was poured into water and concentrated under reduced pressure. The residue was purified by reversed-phase high-performance liquid chromatography [acetonitrile / water (containing 0.1% formic acid): 50% -90%] to obtain the target product (S) -3- ( 5-ethylamino-4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 24a (70 mg, white solid), yield: 22%. MS m / z (ESI): 410 [M + 1-56] Second step (S) -3- (5-ethylamino-4-aminomethylhydrazine-3-((3,5-dimethyl Oxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (5-ethylamino-4-cyano-3- ( (3,5-Dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester 24a (55mg, 0.12mmol) was dissolved in dimethylsulfinium (3mL ), Add hydrogen peroxide (2mL) and sodium hydroxide (300mg, 7.5mmol), stir at room temperature for 10 minutes, then raise the temperature to 40^o C. After the reaction is completed, after cooling, it is diluted with water (20 mL), extracted with ethyl acetate (30 mL), and washed with water (20 mL × 3). The organic phase is concentrated under reduced pressure, and the residue is purified by reversed-phase high-performance liquid chromatography [acetonitrile / water (Containing 0.1% formic acid): 50% -90%] to obtain the target product (S) -3- (5-ethylamino-4-aminomethylhydrazine-3-((3,5-dimethoxybenzene Group) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester 24b (15 mg), yield: 26%. MS m / z (ESI): 484 [M + 1] Step 3 (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (ethylamino) -1- (Pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide (S) -3- (5-ethylamino-4-aminoformamidine-3-((3,5-di Methoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 24b (15mg, 0.031mmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (0.5 mL) and stirred for half an hour. After the reaction is completed, the solution is concentrated under reduced pressure to obtain the target product (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (ethylamino) -1- (pyrrolidine-3- Yl) -1H-pyrazole-4-carboxamide 24c (20 mg, crude, brown oil), yield:> 100%. The product was used in the next reaction without purification. MS m / z (ESI): 384 [M + 1] Step 4 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) Ethynyl) -5- (ethylamino) -1H-pyrazole-4-carboxamide will compound (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5- ( Ethylamino) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 24c (20mg, 0.031mmol, crude) was dissolved in tetrahydrofuran (5mL), and a saturated sodium bicarbonate solution ( 2 mL), and then added a solution of propylene chloride (2.7 mg, 0.03 mmol) in tetrahydrofuran and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL) and washed with water (20 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by reversed-phase high performance liquid chromatography [acetonitrile / water (containing 0.1% formic acid): 20% -70%] to obtain the target product (S) -1- (1-propenepyrrole Alk-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (ethylamino) -1H-pyrazole-4-carboxamide 24 (4.7 mg, white (Solid), yield: 24%. MS m / z (ESI): 438 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.87 (brs, 1H), 6.74 (s, 2H), 6.54 (s, 1H), 6.52 (s, 1H), 6.48-6.40 (m, 2H), 5.74-5.69 (m, 1H), 5.06- 4.97 (m, 2H), 4.13-3.93 (m, 3H), 3.84 (s, 6H), 3.80-3.67 (m, 1H), 3.42 (brs, 2H), 2.75-2.35 (m, 2H), 1.31- 1.25 (m, 3H). Example 25 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5- (isopropylamino)- 1H-pyrazole-4-carboxamide First step (S) -3- (4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -5- (isopropylamino) -1H-pyrazole-1- Propyl) pyrrolidine-1-carboxylic acid tert-butyl ester The mixture (S) -3- (5-amino-4-cyano-3-((3,5-dimethoxyphenyl) ethynyl)- 1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (600 mg, 1.37 mmol), cesium carbonate (893 mg, 2.74 mmol), and acetonitrile (25 mL) were stirred for 10 minutes, and 2-bromo was quickly added Propane (186mg, 1.51mmol), heated to 72^o C, stir for 6 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to give the target product (S) -3- (4-cyano-3-((3 , 5-Dimethoxyphenyl) ethynyl) -5- (isopropylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 25a (600mg, light yellow solid) Yield: 91%. MS m / z (ESI): 424 [M + 1-56] 合成 Example 25 was synthesized with reference to the second to fourth steps in Example 24. MS m / z (ESI): 452 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 6.88 (brs, 1H), 6.70 (s, 2H), 6.54 (s, 1H), 6.51-6.39 (m, 2H), 6.03 (t,J = 10.3 Hz, 1H), 5.74-5.69 (m, 1H), 5.49 (brs, 1H), 4.96-4.87 (m, 1H), 4.09-3.86 (m, 3H), 3.80-3.66 (m, 7H), 3.45-3.43 (m, 1H), 2.69-2.32 (m, 2H), 1.27-1.15 (m, 6H). Example 26 (S) -1- (1-propenepyrrolidin-3-yl) -5-((cyclopropylmethyl) amino) -3-((3,5-dimethoxyphenyl) (Ethynyl) -1H-pyrazole-4-carboxamide First step (S) -1- (1-propenepyrrolidin-3-yl) -5-((cyclopropylmethyl) amino) -3-((3,5-dimethoxyphenyl) (Ethynyl) -1H-pyrazole-4-carboxamide will compound (S) -1- (1-propenylpyrrolidin-3-yl) -5-amino-3-((3,5-dimethyl Oxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 7 (50 mg, 0.12 mmol) was dissolved in acetonitrile (2 mL), and cesium carbonate (80 mg, 0.24 mmol) and (bromomethyl) cyclopropane were added. (19mg, 0.13mmol), heated to 70^o C, stir for 4 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. Dichloromethane / methanol = 12/1) purification to give the target product (S) -1- (1-propenepyrrolidin-3-yl) -5-((cyclopropylmethyl) amino) -3- ((3,5-Dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 26 (14 mg, white solid), yield: 28%. MS m / z (ESI): 464 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 6.89 (brs, 1H), 6.71 (s, 2H), 6.54 (s, 1H), 6.51-6.37 (m, 2H), 5.76-5.71 (m, 1H), 5.40 (brs, 1H), 5.03- 4.95 (m, 1H), 4.06-3.89 (m, 3H), 3.82 (s, 6H), 3.78-3.67 (m, 1H), 3.06-3.02 (m, 2H), 2.69-2.52 (m, 1H), 2.46-2.35 (m, 1H), 1.15-0.98 (m, 1H), 0.63-0.60 (m, 2H), 0.29-0.27 (m, 2H). Example 27 (S) -1- (1-propenylpyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2,2,2- Trifluoroethyl) amino) -1H-pyrazole-4-carboxamide First step (S) -3- (4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -5-((2,2,2-trifluoroethyl) amino ) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester (S) -3- (5-amino-4-cyano-3-((3,5-dimethoxy Phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (430mg, 0.98mmol), trifluoroacetaldehyde aqueous solution (75%) (304mg, 1.96mmol ) And tetraethyl titanate (448 mg, 1.96 mmol) were added to dichloromethane (15 mL) and stirred for 2 hours. After the reaction was completed, sodium borohydride (75 mg, 1.96 mmol) was added to the reaction solution, and stirring was continued for 1 hour at normal temperature. The reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by a flash column to obtain the target product (S)- 3- (4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -5-((2,2,2-trifluoroethyl) amino) -1H-pyrazole- 1-yl) Pyrrolidine-1-carboxylic acid tert-butyl ester 27a (120 mg, yellow oil), yield: 26%. MS m / z (ESI): 464 [M + 1-56] 合成 Example 27 was synthesized by referring to the operation steps of the second step to the fourth step in Example 24. MS m / z (ESI): 492 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 6.92 (brs, 1H), 6.70 (s, 2H), 6.52 (s, 1H), 6.47-6.39 (m, 2H), 6.31-6.25 (m, 1H), 5.75-5.65 (m, 1H), 5.65 (brs, 1H), 5.05-4.98 (m, 1H), 4.10-3.88 (m, 3H), 3.80 (s, 6H), 3.75-3.61 (m, 3H), 2.63-2.34 (m, 2H). Example 28 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-methoxyethyl (Amino) amino) -1H-pyrazole-4-carboxamideExample 28 was synthesized with reference to the procedures of Example 25, but in the first step, 2-bromopropane was replaced with 1-bromo-2-methoxyethane. MS m / z (ESI): 468 [M + 1]¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.32 (brs, 1H), 6.74 (d,J = 2.2 Hz, 2H), 6.64 (dd,J = 16.8, 10.4 Hz, 1H), 6.60 (t,J = 2.2 Hz, 1H), 6.50 (t,J = 6.0 Hz, 1H), 6.16 (dd,J = 16.8, 5.0 Hz, 1H), 5.68 (t,J = 10.8 Hz, 1H), 5.15-5.05 (m, 1H), 4.05-4.01 (m, 0.5H), 3.86-3.81 (m, 1.5H), 3.77 (s, 6H), 3.70-3.61 (m, 1H ), 3.59-3.50 (m, 1H), 3.46 (t,J = 5.1 Hz, 2H), 3.39-3.34 (m, 2H), 3.26 (s, 3H), 2.42-2.23 (m, 2H). Example 29 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl) Amine group) -1H-pyrazole-4-carboxamide First step (S) -3- (5-((2-Ethyloxyethyl) amino) -4-cyano-3-((3,5-dimethoxyphenyl) ethynyl)- 1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester The mixture (S) -3- (5-amino-4-cyano-3-((3,5-dimethoxy) Phenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (300 mg, 0.685 mmol), 2-bromoethyl acetate (126 mg, 0.753 mmol), Cesium carbonate (447mg, 1.37mmol) and acetonitrile (4mL) were heated to 90^o C, and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was subjected to silica gel. Purification by column chromatography (dichloromethane / methanol = 15/1) to obtain the target product (S) -3- (5-((2-ethylamidooxyethyl) amino) -4-cyano-3- ((3,5-Dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester 29a (148 mg, yellow solid), yield: 41%. MS m / z (ESI): 468 [M + 1-56] Second step (S) -3- (4-Aminoformamidine-3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl) amino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (5-((2-ethyl Ethoxyethyl) amino) -4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid Butyl ester 29a (68mg, 0.146mmol), ethanol (5mL) and dimethyl sulfene (1mL), add saturated sodium hydroxide solution (3mL) and hydrogen peroxide (4mL), 30^o Stir at C for 1 hour. After the reaction is completed, the reaction solution is poured into a saturated sodium sulfite solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases are combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the target product. (S) -3- (4-Aminoformamidine-3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl) amino) -1H-pyrazole -1-yl) Pyrrolidine-1-carboxylic acid third butyl ester 29b (110 mg, crude, yellow oil), yield:> 100%, the product was used in the next reaction without purification. MS m / z (ESI): 444 [M + 1-56] The third step (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl ) Amino) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide. Compound (S) -3- (4-aminoformamidine-3-((3,5- Dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl) amino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 29b (110mg, 0.146mmol, Crude) dissolved in hydrochloric acid in methanol (5mL), heated to 40^o C for 1 hour. After the reaction is completed, it is concentrated under reduced pressure to obtain the target product (S) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl) amino) -1- (Pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 29c (160 mg, crude, white solid), yield:> 100%, the product was used in the next reaction without purification. MS m / z (ESI): 400 [M + 1] Fourth step (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) Ethynyl) -5-((2-hydroxyethyl) amino) -1H-pyrazole-4-carboxamide will compound (S) -3-((3,5-dimethoxyphenyl) ethynyl ) -5-((2-hydroxyethyl) amino) -1- (pyrrolidin-3-yl) -1H-pyrazole-4-carboxamide 29c (160 mg, 0.146 mmol, crude) was dissolved in tetrahydrofuran ( 5 mL), a saturated sodium bicarbonate solution (10 mL) was added, and then propylene chloride (12 mg, 0.13 mmol) was added, followed by stirring at room temperature for 10 minutes. After the reaction is completed, the reaction solution is poured into water (50mL) and extracted with ethyl acetate (30mL × 3). The organic phases are combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. -Phase high performance liquid chromatography [acetonitrile / water (containing 0.2% formic acid): 20% -60%] was purified to obtain the target product (S) -1- (1-propenepyrrolidin-3-yl) -3- ( (3,5-Dimethoxyphenyl) ethynyl) -5-((2-hydroxyethyl) amino) -1H-pyrazole-4-carboxamide 29 (6 mg, white solid), Yield: 9%. MS m / z (ESI): 454 [M + 1]¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.36 (brs, 1H), 6.76 (brs, 1H), 6.74 (s, 2H), 6.70-6.60 (m, 2H), 6.55-6.52 (m, 1H), 6.17 (d,J = 16.9 Hz, 1H), 5.69 (t,J = 10.9 Hz, 1H), 5.16-5.10 (m, 1H), 4.87 (s, 1H), 4.06-4.0 (m, 0.5H), 3.83-3.81 (m, 1.5H), 3.77 (s, 6H), 3.68-3.63 (m, 2H), 3.55-3.53 (m, 2H), 3.28-3.26 (m, 2H), 2.38-2.27 (m, 2H). Example 30 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((3-morpholinopropane (Amino) amino) -1H-pyrazole-4-carboxamide Step 1 3-morpholinopropyl 4-methylbenzenesulfonate Dissolve the compound 3-morpholinopropane-1-ol 30a (500 mg, 3.45 mmol) in dichloromethane (100 ml) and add 4-di Methylaminopyridine (42 mg, 0.34 mmol), triethylamine (1.04 g, 10.3 mmol) and p-toluenesulfonyl chloride (988 mg, 5.17 mmol) were stirred overnight at room temperature. After the reaction is completed, the reaction solution is poured into water (50mL) and extracted with dichloromethane (50mL × 3). The organic phases are combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue is applied to a silica gel column. Chromatographic purification (petroleum ether / ethyl acetate = 2/1, the target product 3-morpholinopropyl 4-methylbenzenesulfonate 30b (660 mg, yellow oil) was obtained, yield: 64%. MS m / z (ESI): 300 [M + 1] 合成 Example 30 was synthesized with reference to the procedure of Example 25, but in the first step, 2-morpholinopropyl 4-methylbenzenesulfonate was used instead of Bromopropane. MS m / z (ESI): 537 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.23 (brs, 1H), 7.12 (brs, 1H), 6.94 (brs, 1H), 6.69 (s, 2H), 6.52 (s, 1H), 6.49-6.40 (m, 2H), 5.92 (brs, 1H), 5.74-5.70 (m, 1H), 5.03-4.96 (m, 1H), 4.09-3.90 (m, 3H), 3.80-3.68 (m, 11H), 3.28 (brs, 2H), 2.89 (brs, 6H), 2.69-2.33 (m, 2H), 1.93 (brs, 2H). Example 31 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2-morpholinoethyl (Amino) amino) -1H-pyrazole-4-carboxamideExample 31 was synthesized with reference to the procedures of Example 25, but in the first step, 4- (2-chloroethyl) morpholine was substituted for 2-bromopropane. MS m / z (ESI): 523 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.14 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 2H), 6.63 (brs, 1H), 6.52 (s, 1H), 6.49-6.39 (m, 2H), 6.14 (brs, 1H), 5.75-5.70 (m, 1H), 5.06-4.98 (m, 1H), 4.11-3.85 (m, 3H), 3.80-3.72 (m, 11H), 3.37-3.33 (m, 2H), 2.80- 2.73 (m, 2H), 2.65 (brs, 4H), 2.45-2.32 (m, 2H). Example 32 (S) -1- (1-propenylpyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((2- (pyrrolidine- 1-yl) ethyl) amino) -1H-pyrazole-4-carboxamide In the first step, 2-bromoethyl 4-methylbenzenesulfonate compound 2-bromoethanol 32a (500 mg, 4.0 mmol), 4-dimethylaminopyridine (246 mg, 2.02 mmol) and triethylamine (1.22 g , 12.1 mmol) was dissolved in dichloromethane (50 mL), and the temperature was reduced to 0.^o C, p-toluenesulfonyl chloride (1.15 g, 6.05 mmol) was added in portions. After the addition was completed, the mixture was warmed to room temperature and stirred overnight. After the reaction is completed, the reaction solution is poured into water (50mL) and extracted with dichloromethane (50mL × 3). The organic phases are combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue is applied to a silica gel column layer. Analytical and purified (petroleum ether / ethyl acetate = 10/1) to obtain the target product 2-bromoethyl 4-methylbenzenesulfonate 32b (600 mg, yellow oil), yield: 53%. MS m / z (ESI): 277 [M + 1] Second step (S) -3- (5-((2-bromoethyl) amino) -4-cyano-3-((3,5 -Dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (S) -3- (5-amino-4-cyano-3 -((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (400 mg, 0.92 mmol), 2-bromoethyl 4-methylbenzenesulfonate (380mg, 1.37mmol), cesium carbonate (600mg, 1.84mmol) and acetonitrile (10mL) were heated to 70^o C, and stirred for 2 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was separated through a flash column to obtain the target. Product (S) -3- (5-((2-bromoethyl) amino) -4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole- 1-yl) Pyrrolidine-1-carboxylic acid tert-butyl ester 32c (240 mg, brown oil), yield: 48%. MS m / z (ESI): 408 [M + 1-56-80] Third step (S) -3- (4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -5-((2- (pyrrolidin-1-yl) ethyl) amino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester will be mixed with (S) -3- ( 5-((2-bromoethyl) amino) -4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1 -Third butyl formate 32c (240mg, 0.44mmol), pyrrolidine (47mg, 0.66mmol), cesium carbonate (288mg, 0.88mmol) and acetonitrile (5mL) heated to 70^o C and stirred for 1.5 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Dichloromethane / methanol = 10/1) to give the target product (S) -3- (4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -5-((2- (Pyrrolidin-1-yl) ethyl) amino) -1H-pyrazol-1-yl) third butyl pyrrolidine-1-carboxylic acid 32d (200 mg, yellow oil), yield: 85%. MS m / z (ESI): 479 [M + 1-56] 合成 Example 32 was synthesized with reference to the second to fourth steps in Example 24. MS m / z (ESI): 507 [M + 1]¹ H NMR (400 MHz, CDCl₃ ) δ 8.38 (s, 1H), 6.99 (brs, 1H), 6.69 (s, 2H), 6.51 (s, 1H), 6.47-6.36 (m, 2H), 5.72-5.67 m, 2H), 5.16-5.08 (m, 1H), 4.12-3.86 (m, 3H), 3.80-3.62 (m, 9H), 3.33-3.29 (m, 6H), 2.62-2.34 (m, 2H), 2.07 (brs, 4H). Example 33 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((tetrahydro-2H-pyridine Alan-4-yl) amino) -1H-pyrazole-4-carboxamide Step 4 4-iodotetrahydro-2H-pyran 4-hydroxytetrahydro-2H-pyran 33a (2.04g, 20mmol), triphenylphosphine (6.81g, 26) and imidazole (2.04g, 30mmol) Dissolved in dichloromethane (100mL) and cooled to 0^o C, then add iodine (6.09g, 24mmol), and add^o Stir at C for 14 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was desolvated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1/1) to obtain the target product 4-iodotetrahydro-2H-pyran 33b (2.12 g, white solid), yield: 50%.¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.62 (dt,J = 13.9, 4.5 Hz, 1H), 3.68-3.64 (m, 2H), 3.47-3.42 (m, 2H), 2.13-1.97 (m, 4H).合成 Example 33 was synthesized with reference to the procedures of Example 24, but in the first step, 4-iodotetrahydro-2H-pyran was used instead of iodoethane. MS m / z (ESI): 494 [M + H]¹ H NMR (400 MHz, CD₃ OD) δ 6.74 (t,J = 2.2 Hz, 2H), 6.71-6.62 (m, 1H), 6.60-6.58 (m, 1H), 6.36-6.30 (m, 1H), 5.82-5.77 (m, 1H), 5.18-5.12 (m, 1H ), 4.04-3.94 (m, 6H), 3.81 (s, 6H), 3.52-3.46 (m, 3H), 2.55-2.39 (m, 2H), 1.94-1.92 (m, 2H), 1.60-1.55 (m , 2H). Example 34 (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -5-((1-methylpyridine -4-yl) amino) -1H-pyrazole-4-carboxamide The first step 4-iodo-1-methylpyridine is 4-hydroxy-1-methylpyridine 34a (2.3g, 20mmol), triphenylphosphine (6.81g, 26mmol), imidazole (2.04g, 30mmol) Mix with dichloromethane (100mL) and cool to 0^o C, then add iodine (6.09 g, 24 mmol) and continue stirring for 18 hours. After the reaction was completed, it was quenched with water and then extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was then dissolved under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1) to obtain the target product 4-iodo-1-methylpyridine 34b (2.25 g, white solid), yield: 50%. MS m / z (ESI): 226 [M + H] Step (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) Ethynyl) -5-((1-methylpyridin-4-yl) amino) -1H-pyrazole-4-carboxamide will compound (S) -1- (1-propenepyrrolidine-3 -Yl) -5-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxamide 7 (210mg, 0.5mmmol), 4-iodo-1 -Methylpyridine 34b (450 mg, 2 mmol), potassium carbonate (207 mg, 1.5 mmol) and acetonitrile (10 mL) were mixed and mixed at 90^o Heat and stir at C for 13 hours. The reaction mixture was dissolved under reduced pressure, dissolved in water, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined and desolvated under reduced pressure. The residue was purified by reverse preparative liquid chromatography to obtain the target product (S) -1- (1-propenepyrrolidin-3-yl) -3-((3,5-di Methoxyphenyl) ethynyl) -5-((1-methylpyridin-4-yl) amino) -1H-pyrazole-4-carboxamide 34 (8.1 mg, white solid), Yield: 3.2%. MS m / z (ESI): 507 [M + H]¹ H NMR (400 MHz, CD₃ OD) δ 6.77 (s, 2H), 6.68-6.65 (m, 1H), 6.59 (s, 1H), 6.34-6.30 (m, 1H), 5.81-5.78 (m, 1H), 5.69-5.67 (m, 1H), 5.03-5.00 (m, 1H), 4.98-5.95 (m, 1H), 4.92-4.90 (m, 1H), 4.36 (s, 2H), 4.12-4.07 (m, 1H), 4.00-3.98 ( m, 1H), 3.93-3.90 (m, 1H), 3.86-3.84 (m, 1H), 3.81 (s, 6H), 3.72-3.68 (m, 1H), 2.53-2.47 (m, 3H), 2.40- 2.38 (m, 1H), 2.32 (s, 3H), 2.27-2.21 (m, 1H).生物学 Biological experiments FGFR activity inhibition test Using the HTRF kinase detection kit to evaluate the effect of the compounds of the present invention on the in vitro activity of FGFR by detecting the level of substrate phosphorylation in the kinase reaction (Table 1). FGFR1 activity inhibition test The experimental method is summarized as follows: The reaction buffer contains the following components: 5-fold diluted enzyme buffer / kinase 5X (Cisbio, article number 62EZBFDD) (the main component is 50mM HEPES, pH7.0), 5mM MgCl₂ And 1mM DTT; human recombinant FGFR1 catalytic domain protein (amino acid 308-731) was purified by the company itself and diluted with a reaction buffer to a 0.6ng / uL kinase solution; the substrate reaction solution included a 400nM dilution with a reaction buffer Biotin-labeled tyrosine kinase substrate (Cisbio, article number 62TK0PEC) and 40uM ATP; the test solution includes dilution with detection buffer (Cisbio, article number 62SDBRDF) to 0.125ng / uL Eu³⁺ Labeled cage antibody (Cisbio, Cat. No. 61T66KLB), 25nM streptavidin-labeled XL665 (Cisbio, Cat. No. 610SAXLB).化合物 The compound was dissolved and diluted to 1 mM with DMSO, and then serially diluted 4 times with DMSO to a minimum concentration of 0.061 uM, and each concentration point was diluted 40 times with reaction buffer. If the compound IC₅₀ The values are very low, reducing the starting concentration of the compound. Add 4uL of compound solution and 2uL of FGFR1 kinase solution to a 384-well assay plate (Thermo, Cat. No. 264706), mix well and incubate at room temperature for 15 minutes; then add 4uL of substrate reaction solution, and incubate the reaction mixture at room temperature for 60 minutes ; Then add an equal volume of 10uL of detection solution to the reaction to stop the reaction, mix well and leave it at room temperature. After 60 minutes, the phosphorylated product was simultaneously Eu³⁺ Recognition of labeled cage antibodies (donors) and streptavidin-labeled XL665 antibodies (acceptors). After laser excitation, nearby donors and acceptors undergo energy resonance transfer, which is transferred from the donor (620nm) to The energy of the acceptor (665nm) was measured with a microplate reader EnVision (Perkin Elmer). The ratio of 665/620 is positively correlated with the degree of substrate phosphorylation, and thus the activity of FGFR1 kinase is detected. In this experiment, the group without enzyme was regarded as a 100% inhibition group, and the group without enzyme was added as a 0% inhibition group. The percentage inhibition of FGFR1 activity by the compound was calculated using the following formula: Percent inhibition = 100-100 * (ratio_Compound -ratio_{100% inhibition} )/(ratio_{0% inhibition} -ratio_{100% inhibition} ) IC₅₀ Values were calculated from 10 concentration points using the XLfit software in Excel using the following formula: Y = Bottom + (Top-Bottom) / (1 + 10 ^ ((logIC₅₀ -X) * slope factor)) where Y is the inhibition percentage, Bottom is the bottom plateau value of the S-shaped curve, Top is the top plateau value of the S-shaped curve, X is the logarithmic value of the concentration of the test compound, and slope factor is the slope coefficient of the curve . FGFR2 activity inhibition test The experimental method is summarized as follows: The reaction buffer contains the following components: 5-fold diluted enzyme buffer / kinase 5X (Cisbio, article number 62EZBFDD) (the main component is 50mM HEPES, pH7.0), 5mM MgCl₂ And 1mM DTT; human recombinant FGFR2 catalytic domain protein (amino acid 400-821) was purchased from Yiqiao Shenzhou Biotechnology Co., Ltd. and diluted to 0.45ng / uL of kinase solution with reaction buffer; the substrate reaction solution included the reaction Buffer was diluted to 800nM biotin-labeled tyrosine kinase substrate (Cisbio, Cat. No. 62TK0PEC) and 50uM ATP; detection solution included diluted to 0.125ng / uL Eu with detection buffer (Cisbio, Cat. 62SDBRDF)³⁺ Labeled cage antibody (Cisbio, Cat. No. 61T66KLB), 50nM streptavidin-labeled XL665 (Cisbio, Cat. No. 610SAXLB).化合物 The compound was dissolved and diluted to 1 mM with DMSO, and then serially diluted 4 times with DMSO to a minimum concentration of 0.061 uM, and each concentration point was diluted 40 times with reaction buffer. If the compound IC₅₀ The values are very low, reducing the starting concentration of the compound. Add 4uL of compound solution and 2uL of FGFR2 kinase solution to a 384-well detection plate (Thermo, Cat. No. 264706), mix well and incubate at room temperature for 15 minutes; then add 4uL of substrate reaction solution, and incubate the reaction mixture at room temperature for 60 minutes ; Then add an equal volume of 10uL of detection solution to the reaction to stop the reaction, mix well and leave it at room temperature. After 60 minutes, the phosphorylated product was simultaneously Eu³⁺ Recognition of labeled cage antibodies (donors) and streptavidin-labeled XL665 antibodies (acceptors). After laser excitation, the nearby donor and acceptor undergo energy resonance transfer, and the energy transferred from the donor (620nm) to the acceptor (665nm) is detected with a microplate reader EnVision (Perkin Elmer). The ratio of 665/620 is positively correlated with the degree of substrate phosphorylation, and thus the activity of FGFR2 kinase is detected. In this experiment, the group without enzyme was regarded as a 100% inhibition group, and the group without enzyme was added as a 0% inhibition group. The percentage inhibition of FGFR2 activity of the compound was calculated using the following formula: Percent inhibition = 100-100 * (ratio_Compound -ratio_{100% inhibition} )/(ratio_{0% inhibition} -Ratio_{100% inhibition} ) IC₅₀ Values were calculated from 10 concentration points using the XLfit software in Excel using the following formula: Y = Bottom + (Top-Bottom) / (1 + 10 ^ ((logIC₅₀ -X) * slope factor)) where Y is the inhibition percentage, Bottom is the bottom plateau value of the S-shaped curve, Top is the top plateau value of the S-shaped curve, X is the logarithmic value of the concentration of the test compound, and slope factor is the slope coefficient of the curve .测试 FGFR3 activity inhibition test The experimental method is summarized as follows: The reaction buffer contains the following components: 5-fold diluted enzyme buffer / kinase 5X (Cisbio, article number 62EZBFDD) (the main component is 50mM HEPES, pH7.0), 5mM MgCl₂ And 1mM DTT; human recombinant FGFR3 catalytic domain protein (amino acid 399-806) was purchased from Yiqiao Shenzhou Biotechnology Co., Ltd. and diluted to 0.3 ng / uL of kinase solution with reaction buffer; the substrate reaction solution included the reaction Buffer was diluted to 1000nM biotin-labeled tyrosine kinase substrate (Cisbio, Cat. No. 62TK0PEC) and 90uM ATP; detection solution included diluted to 0.125ng / uL Eu with detection buffer (Cisbio, Cat. 62SDBRDF)³⁺ Labeled cage antibody (Cisbio, Cat. No. 61T66KLB), 62.5nM streptavidin-labeled XL665 (Cisbio, Cat. No. 610SAXLB).化合物 The compound was dissolved and diluted to 1 mM with DMSO, and then serially diluted 4 times with DMSO to a minimum concentration of 0.061 uM, and each concentration point was diluted 40 times with reaction buffer. If the compound IC₅₀ The values are very low, reducing the starting concentration of the compound. Add 4uL of compound solution and 2uL of FGFR3 kinase solution to a 384-well detection plate (Thermo, Cat. No. 264706), mix well and incubate at room temperature for 15 minutes; then add 4uL of substrate reaction solution, and incubate the reaction mixture at room temperature for 60 minutes ; Then add an equal volume of 10uL of detection solution to the reaction to stop the reaction, mix well and leave it at room temperature. After 60 minutes, the phosphorylated product was simultaneously Eu³⁺ Recognition of labeled cage antibodies (donors) and streptavidin-labeled XL665 antibodies (acceptors). After laser excitation, the nearby donor and acceptor undergo energy resonance transfer, and the energy transferred from the donor (620nm) to the acceptor (665nm) is detected with a microplate reader EnVision (Perkin Elmer). The ratio of 665/620 is positively correlated with the degree of substrate phosphorylation, and thus the activity of FGFR3 kinase is detected. In this experiment, the group without enzyme was regarded as a 100% inhibition group, and the group without enzyme was added as a 0% inhibition group. The percentage inhibition of FGFR3 activity of the compound was calculated using the following formula: Percent inhibition = 100-100 * (ratio_Compound -ratio_{100% inhibition} )/(ratio_{0% inhibition} -Ratio_{100% inhibition} ) IC₅₀ Values were calculated from 10 concentration points using the XLfit software in Excel using the following formula: Y = Bottom + (Top-Bottom) / (1 + 10 ^ ((logIC₅₀ -X) * slope factor)) where Y is the inhibition percentage, Bottom is the bottom plateau value of the S-shaped curve, Top is the top plateau value of the S-shaped curve, X is the logarithmic value of the concentration of the test compound, and slope factor is the slope coefficient of the curve . FGFR4 activity inhibition test The experimental method is summarized as follows: The reaction buffer contains the following components: 5-fold diluted enzyme buffer / kinase 5X (Cisbio, article number 62EZBFDD) (the main component is 50mM HEPES, pH7.0), 5mM MgCl₂ And 1mM DTT; human recombinant FGFR4 catalytic domain protein (amino acid 460-802) was purchased from the Protein Research and Technology Center of Tsinghua University, diluted with reaction buffer to a 0.5ng / uL kinase solution; the substrate reaction solution included the use of reaction buffer The solution was diluted to 500nM biotin-labeled tyrosine kinase substrate (Cisbio, article number 62TK0PEC) and 90uM ATP; the detection solution was diluted to 0.125ng / uL Eu with detection buffer (Cisbio, article number 62SDBRDF).³⁺ Labeled cage antibody (Cisbio, Cat. No. 61T66KLB), 31.25nM streptavidin-labeled XL665 (Cisbio, Cat. No. 610SAXLB).化合物 The compound was dissolved and diluted to 1 mM with DMSO, and then serially diluted 4 times with DMSO to a minimum concentration of 0.061 uM, and each concentration point was diluted 40 times with reaction buffer. If the compound IC₅₀ The values are very low, reducing the starting concentration of the compound. Add 4uL of compound solution and 2uL of FGFR4 kinase solution to a 384-well assay plate (Thermo, Cat. No. 264706), mix well and incubate at room temperature for 15 minutes; then add 4uL of substrate reaction solution, and incubate the reaction mixture at room temperature for 60 minutes ; Then add an equal volume of 10uL of detection solution to the reaction to stop the reaction, mix well and leave it at room temperature. After 60 minutes, the phosphorylated product was simultaneously Eu³⁺ Recognition of labeled cage antibodies (donors) and streptavidin-labeled XL665 antibodies (acceptors). After laser excitation, the nearby donor and acceptor undergo energy resonance transfer, and the energy transferred from the donor (620nm) to the acceptor (665nm) is detected with a microplate reader EnVision (Perkin Elmer). The ratio of 665/620 is positively correlated with the degree of substrate phosphorylation, and thus the activity of FGFR4 kinase is detected. In this experiment, the group without enzyme was regarded as a 100% inhibition group, and the group without enzyme was added as a 0% inhibition group. The percentage inhibition of FGFR4 activity of the compound was calculated using the following formula: Percent inhibition = 100-100 * (ratio_Compound -ratio_{100% inhibition} )/(ratio_{0% inhibition} -Ratio_{100% inhibition} ) IC₅₀ Values were calculated from 10 concentration points using the XLfit software in Excel using the following formula: Y = Bottom + (Top-Bottom) / (1 + 10 ^ ((logIC₅₀ -X) * slope factor)) where Y is the inhibition percentage, Bottom is the bottom plateau value of the S-shaped curve, Top is the top plateau value of the S-shaped curve, X is the logarithmic value of the concentration of the test compound, and slope factor is the slope coefficient of the curve . Table 1 A ﹤ 10nM; 10 nM ≤ B <100nM; 100 nM ≤ C <1000nM The compounds of the embodiments of the present invention have a significant inhibitory effect on the activity of FGFR, preferably IC₅₀ 100 to 1000nM, better IC₅₀ Less than 100nM, best IC₅₀ Less than 10nM. Measurement of Hep3B Cell Proliferation Inhibition The effect of the compound of the present invention on the cell proliferation of Hep3B hepatocellular carcinoma cell line was evaluated using a luminescent cell viability test experiment (Table 2). The experimental method is summarized as follows: CellTilter-Glo reagent (Promega, article number G7572) consists of CTG lyophilized powder and CTG buffer, and the lyophilized powder can be dissolved in the buffer when used. The compound was dissolved and diluted to 5 mM in DMSO (Sigma, Cat. No. D5879), and then serially diluted 4 times with DMSO to a minimum concentration of 0.31 uM, and each concentration point was further treated with FMEM-free DMEM medium (ThermoFisher, Cat. ) Dilute 50 times. If the compound's IC50 value is very low, the starting concentration of the compound can be reduced. Hep3B cells (from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) in DMEM complete medium containing 10% FBS (GBICO, Cat. No. 10099-141) and 100U / mL penicillin-streptomycin mixed solution (ThermoFisher, Cat. No. 15140122) Medium culture, when the cell coverage in the culture container reaches 80-90%, digest with 0.25% trypsin (containing EDTA) (ThermoFisher, Cat. No. 25200056) and then disperse and plant it in a white 384-well plate (ThermoFisher, Cat. No. 164610) ), 1000 cells per well (27uL DMEM complete medium), and then place the 384-well plate at 37ºC, 5% CO₂ Incubate overnight (18-20 hours) in the incubator. After overnight, add 3uL of DMEM diluted compound to each well, mix by centrifugation gently, and then place the 384-well plate at 37ºC, 5% CO.₂ The culture was continued in the incubator, and after 72 hours, it was taken out and left at room temperature. For 30 minutes, add 15uL of CTG reagent equilibrated to room temperature to each well, and gently shake on the shaker for 3 minutes to ensure sufficient cell lysis. Leave for 10 minutes to stabilize the cold light signal, and then read the cold light signal with EnVision (Perkin Elmer) . Among them, add 10uM Blueprint's BLU9931 (Cancer Discovery 2015, 5, 424) group as the signal_{100% inhibition} , Plus the cold light signal of the 0.2% DMSO group as the signal_{0% inhibition} . The percentage of the inhibition of Hep3B cell proliferation by compounds can be calculated by the following formula:% inhibition = 100-100 * (signal_Compound -signal_{100% inhibition} ) / (signal_{0% inhibition} -signal_{100% inhibition} ) The IC50 value of the hydrazone compound is calculated from the 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software through the following formula: Y = Bottom + (Top-Bottom) / (1 + 10 ^ ((logIC₅₀ -X) * slope factor)) where Y is the inhibition percentage, Bottom is the bottom plateau value of the S-shaped curve, Top is the top plateau value of the S-shaped curve, X is the logarithmic value of the concentration of the test compound, and slope factor is the slope coefficient of the curve .的 Measurement of RT4 cell proliferation inhibition The effect of the compound of the present invention on the proliferation of RT4 bladder cancer cell line cells was evaluated using a luminescent cell viability test experiment (Table 2). The summary of the experimental method refers to the method for measuring the inhibition of Hep3B cell proliferation, in which RT4 cells (from the Cell Resource Center of the Shanghai Academy of Life Sciences, Chinese Academy of Sciences) and the positive control are Example 1 ((S) -1- (1) in Taiho patent application WO2015008844A1 3- (4-amino-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidine-1- Group) prop-2-en-1-one). Measurement of SNU-16 Cell Proliferation Inhibition The luminous cell viability test was used to evaluate the effect of the compound of the present invention on the cell proliferation of SNU-16 gastric cancer cell line (Table 2).概述 Summary of experimental methods Refer to the measurement method of Hep3B cell proliferation inhibition, in which SNU-16 cells (ATCC, HB-8064) and positive control are BJG398 of Novartis. Table 2 Note: A ﹤ 10nM; 10nM≤B <100nM; 100nM≤C <1000Nm N.D .: Not tested The compounds of the examples of the present invention have significant inhibitory effects on the cell proliferation of Hep3B, RT4 and SNU-16, respectively, and the preferred IC is₅₀ 100 to 1000nM, better IC₅₀ Less than 100nM.

Claims (12)

A compound represented by the general formula (I) or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof: (I) wherein: A is N or CR ² ; ring B is a benzene ring or a 5- to 6-membered heteroaryl ring, wherein the benzene ring and the heteroaryl ring are optionally substituted with one or more G ¹ ; R ^{1 is} independent Is independently selected from H, halogen, cyano, C _1-6 alkyl or -NHR ³ ; R ^{2 is} independently selected from H, halogen, cyano or C _1-6 alkyl, wherein said alkyl is optionally halogen , Cyano, hydroxy, or -OC _1-6 alkyl; R ^{3 is} independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein Alkyl, cycloalkyl and heterocyclyl are optionally halogen, cyano, -OR ⁴ , -NR ⁵ R ⁶ , C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclyl Substituted; X is absent or is C _1-6 alkylene; Y is absent or is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclo, aryl or heteroaryl, wherein The cycloalkyl, heterocyclo, cycloaryl, and cycloaryl are optionally substituted with one or more G ² ; Z is independently selected from cyano, -NR ⁷ CN, , , or Bond a is a double or triple bond; when bond a is a double bond, each of R ^a , R ^b and R ^{c is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 ring Alkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more G ³ ; R ^a and R ^b or R ^b and R ^{c are} optionally the carbon atoms they are attached form a 3-6 membered ring optionally containing a heteroatom; when bond a is a triple bond, R ^a and R ^c are absent, R ^b are independently selected from H, cyano, halo, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more G ⁴ ; R ^{7 is} independent Is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl may be optionally substituted by one or more G ⁵ ; G ¹ , G ² , G ³ , G ⁴ and G ⁵ are each independently selected from halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ⁸ , -OC (O) NR ⁸ R ⁹ , -C (O) OR ⁸ , -C (O) NR ⁸ R ⁹ , -C (O) R ⁸ , -NR ⁸ R ⁹ , -NR ⁸ C (O) R ⁹ , -NR ⁸ C (O) NR ⁹ R ¹⁰ , -S (O) _m R ⁸ or -NR ⁸ S (O) _m R ⁹ , wherein the alkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from one or more of halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic Base, -OR ¹¹ , -OC (O) NR ¹¹ R ¹² , -C (O) OR ¹¹ , -C (O) NR ¹¹ R ¹² , -C (O) R ¹¹ , -NR ¹¹ R ¹² , -NR ¹¹ C (O) R ¹² , -NR ¹¹ C (O) NR ¹² R ¹³ , -S (O) _m R ¹¹ or -NR ¹¹ S (O) _m R ¹² is substituted by a substituent; R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered monocyclic hetero A cyclic group, a monocyclic heteroaryl group, or a phenyl group; and m is 1 or 2. The compound or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, or a mixture thereof according to claim 1, wherein A is N or CH, and preferably N. The compound or a prodrug, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer thereof, or a mixture thereof according to claim 1 or 2, wherein ring B is a benzene ring. The compound or a prodrug, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer and a mixture thereof according to claim 1, which are compounds of the following general formula (II): (II) wherein: G ^a , G ^b , G ^c and G ^d are each independently selected from H, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group -OR ⁸ , -NR ⁸ R ⁹ or -C (O) NR ⁸ R ⁹ , wherein the alkyl, cycloalkyl and heterocyclic group are optionally selected from one or more selected from halogen, cyano, C _{1 -6} alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -OR ¹¹ or -NR ¹¹ R ¹² substituted with G ^a , G ^b , G ^c and G ^d each independently Preferred are -OC _1-2 alkyl or halogen; A, R ¹ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , X, Y, Z are as defined in claim 1. The compound or a prodrug, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, or a mixture thereof according to claim 1, which is a compound of the following general formula (III): (III) wherein: G ^a and G ^b are each independently selected from H, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, -OR ⁸ ,- NR ⁸ R ⁹ or -C (O) NR ⁸ R ⁹ , wherein the alkyl group, cycloalkyl group and heterocyclic group are optionally one or more selected from halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -OR ¹¹ or -NR ¹¹ R ¹² substituted with substituents, and G ^a and G ^b are each independently preferably -OC _1-2 alkyl; The definitions of A, R ¹ , R ⁸ , R ⁹ , R ¹¹ , R ¹² , X, Y, Z are as described in claim 1. The compound or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, or a mixture thereof according to any one of the preceding claims 1-2 and 4-5, wherein R ^{1 is} independently selected from H, -NH ₂ or -NHR ³ ; R ^{3 is} independently selected from C _1-6 alkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and hetero The cyclic group is optionally substituted with halogen, cyano, -OR ⁴ , -NR ⁵ R ⁶ , C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclic group. The compound or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, or a mixture thereof according to any one of the preceding claims 1-2 and 4-5, wherein R ^{1 is} independently selected from H, -NH ₂ or -NHC _1-6 alkyl. The compound or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, or a mixture thereof according to any one of the preceding claims 1-2 and 4-5, wherein: X is absent or is C _1-6 alkylene; Y is absent or selected from C _3-8 cycloalkyl or 3-8 membered heterocyclo; Z is independently selected from cyano, -NR ⁷ CN, or Bond a is a double or triple bond; when bond a is a double bond, each of R ^a , R ^b and R ^{c is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 ring Alkyl or 3-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are optionally selected from one or more independently selected from halogen, cyano, C _1-6 alkyl, C _{3- 6} -cycloalkyl, 3-6 membered heterocyclyl, -OR ⁸ or -NR ⁸ R ⁹ are substituted by the substituent; when the bond a is a triple bond, R ^a and R ^{c are} not present, and R ^{b is} independently selected from H, cyano, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally one or more Independently substituted by a substituent selected from halogen, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR ⁸ or -NR ⁸ R ⁹ ; R ⁴ , R ⁸ and R ⁹ are each independently selected from H or C _1-6 alkyl. The compound or prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer and mixture thereof according to claim 1, which is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer and a mixture thereof, and a pharmacy Acceptable carriers and excipients. A compound according to any one of claims 1-9 or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof, or a pharmaceutical composition according to claim 10 in Prepared for the treatment and / or prevention of FGFR-related diseases, preferably tumors (e.g. non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, renal cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, intrauterine Membrane cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, and liver cancer, more preferably, drugs for liver cancer, gastric cancer, non-small cell lung cancer, and bladder cancer). A compound according to any one of claims 1 to 9 or a prodrug thereof, a stable isotope derivative, a pharmaceutically acceptable salt, an isomer, and a mixture thereof, or a pharmaceutical composition according to claim 10, for use as a medicament .