FGFR inhibitor compounds and uses thereof

Abstract

This application relates to FGFR inhibitor compounds and their uses. Specifically, this application discloses a compound represented by Formula (I), or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. This application also relates to the medical applications of the compound. #imgabs0#

Description

[0001] This application claims priority to Chinese invention patent application No. 202010800657.1 filed on August 11, 2020, and the entire disclosure of that prior application is incorporated herein by reference. Technical Field

[0002] The present application provides a class of novel compounds with pharmaceutical activity that can be used to inhibit fibroblast growth factor receptor (FGFR). The present application also relates to compositions containing the compounds, and the use of the compounds and the compositions in the preparation of medicaments for treating diseases or conditions associated with FGFR. Background Art

[0003] The fibroblast growth factor receptor (FGFR) family is a class of transmembrane receptor tyrosine kinases (RTKs) consisting of four members: FGFR1, FGFR2, FGFR3, and FGFR4. FGFRs can be activated by binding of their natural ligands. Activated FGFRs can then activate multiple downstream signaling pathways (including Ras-MAPK, AKT-PI3K, and phospholipase C). These signaling pathways are involved in numerous important physiological processes, such as proliferation, differentiation, cell migration, and survival.

[0004] Abnormal constitutive activation of FGFR is found in a variety of tumors. Numerous inhibitors targeting FGFR have been developed for the treatment of various cancers. Preclinical and early clinical trials have demonstrated that multiple FGFR inhibitors effectively reduce tumor size.

[0005] However, one of the major obstacles to the clinical use of FGFR inhibitors for cancer treatment is acquired resistance. This resistance can be acquired through mutations in FGFRs or activation of complementary signaling pathways, among which mutations in gatekeeper residues (referred to as gatekeeper mutations) are one of the most common pathways for acquiring resistance.

[0006] Drug resistance due to gating mutations in FGFRs has been reported in both preclinical and clinical samples. For example, the V561M mutation in FGFR1 confers strong resistance to FIIN-1; the V564F mutation in FGFR2 confers strong resistance to BGJ398; and the V555M mutation in FGFR3 confers resistance to AZ8010, PD173074, and AZD4547.

[0007] It is expected that FGFR inhibitors that still have inhibitory activity against FGFRs carrying gating mutations will be developed to address acquired resistance caused by gating mutations. Recent studies have reported several inhibitors that are effective against FGFR gating mutations, such as FIIN2.

[0008] There is still a need for FGFR inhibitors with better effects (eg, higher inhibition rate, more types of targeted FGFRs and FGFR mutations, higher selectivity for certain FGFRs and FGFR mutations, etc.). Summary of the Invention

[0009] In a first aspect, the present application provides a compound of formula (I) as an FGFR inhibitor, which is capable of inhibiting the activity of wild-type and mutant FGFRs.

[0010]

[0011] or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein:

[0012] A is selected from C 5-8 Aryl, C 7-11 Bicyclic aryl, 5-7 membered heteroaryl, 7-11 membered bicyclic heteroaryl, C 3-8 Cycloalkyl and 4-8 membered heterocycloalkyl; and

[0013] R 1 and R 2 Each independently selected from H, halogen, -CN, -NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; and

[0014] R 3 and R 4 Each independently selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; and

[0015] R 5 The number of R is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and each R 5 Each independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicyclic heteroalkyl), -C 1-4 Alkyl-(C 8-15 -C 1-4 Alkyl-(8-15 membered tricyclic heteroalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicycloheteroalkyl)-C 1-4 Alkyl-(C 8-15 -membered tricycloalkyl) and -C 1-4 alkyl-(8-15 membered tricycloheteroalkyl) each optionally substituted with 0, 1, 2, 3 or 4 R 5a replace;

[0016] R 5a Independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicyclic heteroalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl) and C 1-4 alkyl-(6-12 membered bicycloheteroalkyl) each optionally substituted with 0, 1, 2, 3 or 4 R 5b replace;

[0017] R 5b Independently selected from H, halogen, -OH, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -N(R 7 )(R 8)、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=

[0018] O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 ) and -S(=O)2-N(R 7 )(R 8 ), wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 cycloalkyl) and -C 1-4 Alkyl-(3-10 membered heterocycloalkyl) is optionally substituted with 0, 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; and

[0019] R 6The number of R is 0, 1, 2 or 3, and each R 6 Each independently selected from H, halogen, -CN, -NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and

[0020] R 7 、R 8 and R 9 Each is independently selected at each occurrence from: H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (3-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0021] or R 7 、R 8 and the atoms to which they are attached together form a 3-14 membered ring;

[0022] or R 8 、R 9 and the atoms to which they are attached together form a 3-14 membered ring.

[0023] Unless otherwise indicated, the terms "compound of formula (I)", "compound of formula (I)", "compound of formula (II)", "compound of formula (III)", "compound of formula (IV)", "compound of formula (V)" or "compound of the present application" described herein also include any optical isomers, geometric isomers, tautomers or mixtures of isomers thereof.

[0024] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can exist in the R configuration or the S configuration, and the various isomers thus formed are optical isomers. Optical isomers include all diastereomers, enantiomers, meso-isomers, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0025] The term "geometric isomer" means that when a compound has a double bond, the compound may exist as cis-isomers, trans-isomers, E-isomers and Z-isomers. Geometric isomers include cis-isomers, trans-isomers, E-isomers, Z-isomers or mixtures thereof.

[0026] The term "tautomer" refers to isomers that result from the rapid shift of an atom in a molecule between two positions. Those skilled in the art will appreciate that tautomers can transform into each other and, under certain conditions, may reach an equilibrium state and coexist.

[0027] Unless otherwise indicated, the terms "compound of formula (I)", "compound of formula (I)", "compound of formula (II)", "compound of formula (III)", "compound of formula (IV)", "compound of formula (V)" or "compound of the present application" described herein also cover isotope-labeled compounds obtained by replacing one or more atoms in the compound with its isotope atoms.

[0028] Examples of suitable isotopes for inclusion in the compounds of the present application include isotopes of hydrogen such as 2 H(D) and 3 H(T); isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18O; and isotopes of sulfur, such as 35 S.

[0029] Isotope-labeled compounds (e.g., those containing radioactive isotopes) are useful in drug and / or substrate tissue distribution studies. Radioactive isotopes such as deuterium (i.e., D) and carbon-14 (i.e., C-14) are used for the distribution of substances in the tissues of interest. 14 C) is particularly useful for this purpose.

[0030] Substitution with heavier isotopes such as deuterium (i.e., D) can provide certain therapeutic benefits, such as greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and therefore can be preferred in certain circumstances. Therefore, in some embodiments, the compounds of the present application are isotopically labeled compounds wherein H is optionally replaced by D at each occurrence.

[0031] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission topography (PET) studies to detect substrate receptor occupancy status.

[0032] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0033] The compounds of the present application may exist in the form of pharmaceutically acceptable salts.

[0034] The term "pharmaceutically acceptable" refers to a compound, carrier or molecule that is suitable for administration to a human. Preferably, the term refers to a compound, carrier or molecule that is approved by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA) for use in mammals, preferably humans.

[0035] The pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed with bases which form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

[0036] In addition, the compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The compounds may also exist in one or more crystalline states, i.e., polymorphs, or they may exist as amorphous solids. All of these forms are included within the scope of the present application.

[0037] The present application also includes prodrugs of the compounds of the present application. The term "prodrug" refers to derivatives of the compounds of the present application that are converted into the compounds of the present application by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, such as oxidation, reduction, hydrolysis, etc., each catalyzed by an enzyme. Therefore, certain derivatives of the compounds of the present application may themselves have little or no pharmacological activity, but when administered into or onto the body, they can be converted into the compounds of the present application having the desired activity.

[0038] The present application also includes metabolites of the compounds of the present application. The term "metabolite" refers to all molecules derived from any compound of the present application in a cell or organism, preferably a human.

[0039] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

[0040] As used herein, the term "independently" means that when there are more than one substituent, the substituents may be the same or different.

[0041] As used herein, the term "optional" or "optionally" means that the event it describes may or may not occur. For example, a group "optionally substituted" means that the group may be unsubstituted or substituted.

[0042] The term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0043] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms. For example, the term "C 1-8 "Alkyl" refers to a straight or branched chain radical having 1 to 8 carbon atoms. 1-8 "Alkyl" includes in its definition the term "C 1-6 Alkyl", "C 1-3 Alkyl" and "C 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0044] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms. For example, the term "C 2-8 "Alkenyl" refers to a straight or branched unsaturated atomic group (with at least one carbon-carbon double bond) having 2-8 carbon atoms. The double bond may or may not be the point of attachment to another group. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. The alkenyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents. When the compound of formula (I) contains an alkenyl group, the alkenyl group may be present in pure E form, pure Z form, or any mixture thereof.

[0045] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, or 2-4 carbon atoms. For example, the term "C 2-8 "Alkynyl" refers to a straight or branched unsaturated atomic group (having at least one carbon-carbon triple bond) having 2-8 carbon atoms. The triple bond may or may not be a point of attachment to another group. Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like. Alkynyl groups may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents.

[0046] As used herein, the term “C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms forming a ring. 3-7 "Cycloalkyl" refers to a cycloalkyl group having 3 to 7 carbon atoms forming a ring. 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms forming the ring. The cycloalkyl group may be a monocyclic ring. The definition of cycloalkyl also includes unsaturated non-aromatic cycloalkyl groups. Examples of cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl and cyclooctenyl. Cycloalkyl groups may be optionally substituted by one or more suitable substituents.

[0047] As used in this article, the term “C 6-12 A "bicycloalkyl" group is an alkyl group containing two rings having 6 to 12 carbon atoms forming the rings. The bicycloalkyl groups may be fused and may also include bridged bicycloalkyl systems.

[0048] As used in this article, the term “C 8-15 A "membered tricycloalkyl group" is an alkyl group containing three rings having 8 to 15 carbon atoms forming the ring. The tricycloalkyl group may be fused or bridged.

[0049] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group having m carbon atoms and (nm) heteroatoms forming the ring, wherein the heteroatoms are selected from O, S, and N. For example, the term "4-8 membered heterocycloalkyl" refers to a heterocycloalkyl substituent containing a total of 4 to 8 ring atoms, at least one of which is a heteroatom; the term "4-6 membered heterocycloalkyl" refers to a heterocycloalkyl substituent containing a total of 4 to 6 ring atoms, at least one of which is a heteroatom; and the term "3-10 membered heterocycloalkyl" refers to a heterocycloalkyl substituent containing a total of 3 to 10 ring atoms, at least one of which is a heteroatom. The term "n-membered bicycloheteroalkyl" refers to a bicycloheteroalkyl group having m carbon atoms and (nm) heteroatoms forming the ring, wherein the heteroatoms are selected from O, S, and N. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, thietanyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidine, chromanyl (chro romanyl), isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl, dihydroindole, dihydrobenzofuranyl, tetrahydroquinolinyl, isochromyl, dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanoyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, oxepanyl, thiepanyl, azepanyl, etc. The heterocycloalkyl group may be optionally substituted with one or more suitable substituents.

[0050] As used herein, the term “C 5-8 The term "aryl" refers to an aromatic group having an aromatic ring containing 5 to 8 carbon atoms, such as phenyl.

[0051] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from O, S, and N. For example, 5-7 membered heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The heteroaryl group may be optionally substituted with one or more suitable substituents.

[0052] As used herein, the term “C7-11 The term "bicyclic aryl" refers to a bicyclic aryl group having 7 to 11 carbon atoms, such as naphthyl, indenyl, etc. The bicyclic aryl group may be optionally substituted by one or more suitable substituents.

[0053] As used herein, the term "n-membered bicyclic heteroaryl" refers to a bicyclic heteroaryl group having m carbon atoms forming an aromatic bicyclic ring and (nm) heteroatoms forming an aromatic bicyclic ring, wherein the heteroatoms are selected from O, S and N. For example, 7-11 membered bicyclic heteroaryl groups include, but are not limited to, quinolinyl, isoquinolinyl, indolyl, purinyl, benzothiazolyl, etc. The bicyclic heteroaryl group may be optionally substituted with one or more suitable substituents.

[0054] As used herein, the term "11-15 membered tricyclyl" includes, but is not limited to, acridinyl, etc. The 11-15 membered tricyclyl may be optionally substituted with one or more suitable substituents.

[0055] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); the term "C 1-3 "Haloalkyl" refers to a C 1-3 alkyl groups (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); and the term "C 1-2 "Haloalkyl" refers to a C 1-2 An alkyl group (i.e., methyl or ethyl) (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C1 haloalkyl" refers to a methyl group having 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, and the like.

[0056] As used herein, the term "alkoxy" refers to an alkyl group that is single-bonded to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. The alkoxy group can be depicted as alkyl-O-. The term "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy group containing 1 to 6 carbon atoms. The term "C 1-6"Alkoxy" includes in its definition the term "C 1-3 Alkoxy". Alkoxy includes but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy and the like. Alkoxy may be optionally substituted with one or more suitable substituents.

[0057] As used herein, the term "3- to 14-membered ring" refers to a saturated or unsaturated ring system having 3 to 14 ring atoms.

[0058] Herein, numerical ranges related to the number of substituents, carbon atoms, and ring atoms represent a complete enumeration of all integers within the range, and ranges are used only as a simplified notation. For example, "4-6 membered" means 4, 5, or 6 membered; "5-7 membered" means 5, 6, or 7 membered; "7-11 membered" means 7, 8, 9, 10, or 11 membered; "4-8 membered" means 4, 5, 6, 7, or 8 membered; "3-10 membered" means 3, 4, 5, 6, 7, 8, 9, or 10 membered; "C 1-3 ” means 1 (C1), 2 (C2) or 3 carbon atoms (C3); “C 3-6 ” means 3 (C3), 4 (C4), 5 (C5) or 6 carbon atoms (C6); “C 3-8 ” means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7) or 8 carbon atoms (C8); “C 5-7 ” means 5 (C5), 6 (C6) or 7 carbon atoms (C7); “C 7-11 ” means 7 (C7), 8 (C8), 9 (C9), 10 (C 10 ) or 11 carbon atoms (C 11 ); Therefore, numerical ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also encompass any subranges thereof, and each subrange is also considered to be disclosed herein.

[0059] In the formula (I) described above, R 3 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0060] In some preferred embodiments, R 3 For H.

[0061] In some embodiments, R 3 C 1-3 Alkyl or C 1-3 Haloalkyl, for example, R 3is selected from methyl, ethyl, propyl, isopropyl, which are optionally substituted by one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine). 3 It is a methyl group.

[0062] In some embodiments, R 3 C 1-3 Alkoxy, for example, R 3 Selected from methoxy, ethoxy, propoxy, isopropoxy.

[0063] In some embodiments, R 3 C 3-6 Cycloalkyl, for example, R 3 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0064] In some embodiments, R 3 is a 4-6 membered heterocycloalkyl group, for example, R 3 Selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.

[0065] It should be understood that any of the above R 3 The embodiments can be combined with any of the R 1 、R 2 ,A,R 4 、R 5 、R 6 、R 7 and R 8 The implementation methods are combined together.

[0066] In the formula (I) described above, R 1 Selected from H, halogen, -CN, -NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0067] In some embodiments, R 1 For H.

[0068] In some embodiments, R 1 is a halogen, such as R 1 Selected from F, Cl, Br, I.

[0069] In some embodiments, R 1 It is -CN.

[0070] In some embodiments, R 1 It is -NO2.

[0071] In some embodiments, R 1 C 1-3 Alkyl or C 1-3 Haloalkyl, for example, R 1 Selected from methyl, ethyl, propyl, isopropyl, which are optionally substituted by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine).

[0072] In some embodiments, R 1 C 1-3 Alkoxy, for example, R 1 Selected from methoxy, ethoxy, propoxy, isopropoxy.

[0073] In some embodiments, R 1 C 3-6 Cycloalkyl, for example, R 1 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0074] In some embodiments, R 1 is a 4-6 membered heterocycloalkyl group, for example, R 1 Selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.

[0075] It should be understood that any of the above R 1 The embodiments can be combined with any of the R 2 、R 3 ,A,R 4 、R 5 、R 6 、R 7 and R 8 The implementation methods are combined together.

[0076] In the formula (I) described above, R 2 Selected from H, halogen, -CN, -NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0077] In some embodiments, R 2 For H.

[0078] In some embodiments, R 2 is a halogen, such as R 2 Selected from F, Cl, Br, I.

[0079] In some embodiments, R2 It is -CN.

[0080] In some embodiments, R 2 It is -NO2.

[0081] In some embodiments, R 2 C 1-3 Alkyl or C 1-3 Haloalkyl, for example, R 2 Selected from methyl, ethyl, propyl, isopropyl, which are optionally substituted by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine).

[0082] In some embodiments, R 2 C 1-3 Alkoxy, for example, R 2 Selected from methoxy, ethoxy, propoxy, isopropoxy.

[0083] In some embodiments, R 2 C 3-6 Cycloalkyl, for example, R 2 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0084] In some embodiments, R 2 is a 4-6 membered heterocycloalkyl group, for example, R 2 Selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.

[0085] It should be understood that any of the above R 2 The embodiments can be combined with any of the R 1 、R 3 ,A,R 4 、R 5 、R 6 、R 7 and R 8 The implementation methods are combined together.

[0086] In some embodiments, R 1 and R 2 can be the same. For example, R 1 and R 2 are all halogens, such as Cl; for example, R 1 and R 2 In a preferred embodiment, R 1 and R 2 All are Cl.

[0087] In other embodiments, R 1and R 2 Can be different.

[0088] In the formula (I) described above, R 4 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0089] In some preferred embodiments, R 4 For H.

[0090] In some embodiments, R 4 C 1-3 Alkyl or C 1-3 Haloalkyl, for example, R 4 Selected from methyl, ethyl, propyl, isopropyl, which are optionally substituted by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine).

[0091] In some embodiments, R 4 C 1-3 Alkoxy, for example, R 4 Selected from methoxy, ethoxy, propoxy, isopropoxy.

[0092] In some embodiments, R 4 C 3-6 Cycloalkyl, for example, R 4 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0093] In some embodiments, R 4 is a 4-6 membered heterocycloalkyl group, for example, R 4 Selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.

[0094] It should be understood that any of the above R 4 The embodiments can be combined with any of the R 1 、R 2 ,A,R 3 、R 5 、R 6 、R 7 and R 8 The implementation methods are combined together.

[0095] In the formula (I) described above, R 6 The number of can be 0, 1, 2 or 3. 6 When each R 6Each independently selected from H, halogen, -CN, -NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0096] In some preferred embodiments, R 6 For H.

[0097] In some embodiments, R 6 is a halogen, such as R 6 Selected from F, Cl, Br, I.

[0098] In some embodiments, R 6 It is -CN.

[0099] In some embodiments, R 6 It is -NO2.

[0100] In some embodiments, R 6 C 1-3 Alkyl or C 1-3 Haloalkyl, such as R 6 Selected from methyl, ethyl, propyl, isopropyl, which are optionally substituted by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine).

[0101] In some embodiments, R 6 C 1-3 Alkoxy, such as R 6 Selected from methoxy, ethoxy, propoxy, isopropoxy.

[0102] In some embodiments, R 6 C 3-6 Cycloalkyl, such as R 6 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl.

[0103] In some embodiments, R 6 is a 4-6 membered heterocycloalkyl group, for example, R 6 Selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl.

[0104] In some preferred embodiments, R 6 For 1.

[0105] It should be understood that any of the above R 6 The embodiments can be combined with any of the R 1 、R 2 ,A,R3 、R 4 、R 5 、R 7 and R 8 The implementation methods are combined together.

[0106] In the formula (I) as described above, A is selected from C 5-8 Aryl, C 7-11 Bicyclic aryl, 5-7 membered heteroaryl, 7-11 membered bicyclic heteroaryl, C 3-8 cycloalkyl and 4-8 membered heterocycloalkyl.

[0107] In some embodiments, A is C 5-8 Aryl, for example A is phenyl.

[0108] In some embodiments, A is C 7-11 Bicyclic aryl, for example, A is selected from naphthyl and indenyl.

[0109] In some embodiments, A is a 5-7 membered heteroaryl group, for example, A is selected from furandidazine, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0110] In some embodiments, A is a 7-11 membered bicyclic heteroaryl group, for example, A is selected from quinolinyl, isoquinolinyl, and benzothiazolyl.

[0111] In some embodiments, A is C 3-8 Cycloalkyl, for example A, is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl and cyclooctenyl.

[0112] In some embodiments, A is a 4-8 membered heterocycloalkyl group, for example, A is selected from oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, and piperazinyl.

[0113] In some preferred embodiments, A is phenyl.

[0114] In some preferred embodiments, A is pyridyl.

[0115] In some preferred embodiments, A is pyridazinyl.

[0116] In some preferred embodiments, A is pyrazolyl.

[0117] Those skilled in the art should understand that in this application, the various substituents or groups listed for A should be understood in a broad sense (i.e., covering the monovalent form, divalent form, trivalent form, etc. of the substituent or group) to meet the valence rules of the compound. For example, when R 5 Does not exist (R 5 The number of 0) or R 5 The number of is 1 and R 5 =H, A is a monovalent group; when R 5 The number of is 1 and R 5 When it is not H, A is a divalent group; when R 5 When the number of is 2 and none of them is H, A is a trivalent group. For example, the "phenyl" listed above for A may represent a monovalent phenyl group, a divalent phenyl group, or a trivalent phenyl group in different situations; the same applies to other substituents or groups.

[0118] It should be understood that any of the above embodiments of A can be combined with any of the above and below described R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 The implementation methods are combined together.

[0119] In the formula (I) described above, R 5 The number of can be 0, 1, 2, 3, 4, 5, 6, 7, 8 or more. 5 When each R 5 Each independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicyclic heteroalkyl), -C 1-4 Alkyl-(C 8-15 -C 1-4 Alkyl-(8-15 membered tricyclic heteroalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicycloheteroalkyl)-C 1-4 Alkyl-(C 8-15 -membered tricycloalkyl) and -C 1-4alkyl-(8-15 membered tricycloheteroalkyl) each optionally substituted with 0, 1, 2, 3 or 4 R 5a replace;

[0120] R 5a Independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicyclic heteroalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl) and C 1-4 alkyl-(6-12 membered bicycloheteroalkyl) each optionally substituted with 0, 1, 2, 3 or 4 R 5b replace;

[0121] R 5b Independently selected from H, halogen, -OH, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8) and -S(=O)2-N(R 7 )(R 8 ), wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 cycloalkyl) and -C 1-4 Alkyl-(3-10 membered heterocycloalkyl) is optionally substituted with 0, 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; and

[0122] R 7 、R 8 and R 9 Each is independently selected at each occurrence from: H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (3-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4Alkyl-, wherein each option within the group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0123] or R 7 、R 8 and the atoms to which they are attached together form a 3-14 membered ring;

[0124] or R 8 、R 9 and the atoms to which they are attached together form a 3-14 membered ring.

[0125] In some embodiments, each R 5 Each independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, 3, 4 or more substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 .

[0126] Among them, R 7 and R 8 Each is independently selected at each occurrence from: H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, C3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (3-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy or R 7 、R 8 and the atoms to which they are attached together form a 3-14 membered ring.

[0127] In some embodiments, R 5 is a 3-10 membered heterocycloalkyl group, for example, R 5Selected from azetidinyl, thietanyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazinyl , tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidine, chromanyl, isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl, dihydroindole, dihydrobenzofuranyl, tetrahydroquinolinyl, isochromanyl, dihydro-1H-isoindolyl, oxepanyl, thiepanyl, azepanyl. The 3-10 membered heterocycloalkyl group may be optionally substituted with 1, 2, 3, 4 or more substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , where R 7 and R 8 As defined above.

[0128] In some embodiments, R 5 C 1-6 Alkyl groups, such as R 5 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, and hexyl. 1-6The alkyl group may be optionally substituted with 1, 2, 3, 4 or more substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , where R 7 and R 8 As defined above.

[0129] In some embodiments, R 5 C 3-7 Cycloalkyl, such as R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohexadienyl, cyclopentenyl, and cycloheptenyl. 3-7 The cycloalkyl group may be optionally substituted with 1, 2, 3, 4 or more substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R7 )(R 8 ),-SR 7 AND-OR 7 , where R 7 and R 8 As defined above.

[0130] In some preferred embodiments, R 5 is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, azetidinyl. The piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl and azetidinyl may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH. For example, in some preferred embodiments, R 5 Selected from 3,5-dimethylpiperazinyl, morpholinyl, 3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-hydroxypiperidinyl, 1-methylpiperidinyl, 1-ethylpiperidin-4-yl, 1-methylazetidin-3-yl.

[0131] In some preferred embodiments, R 5 is selected from methyl, ethyl, propyl, isopropyl, and cyclobutyl groups. The methyl, ethyl, propyl, isopropyl, or cyclobutyl groups may be optionally substituted with 0, 1, or 2 substituents independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, and piperidinyl, which may in turn be optionally substituted with 0, 1, or 2 substituents independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH. For example, in some preferred embodiments, R 5 Selected from (1-hydroxycyclopropyl)ethyl, 3-hydroxycyclobutyl, 2-cyanoethyl, 2-hydroxyethyl, 2-cyano-1-cyclopentylethyl, 1-cyanopropane, 2-morpholinoethyl, ethyl and (1-methylpiperidin-4-yl)methyl.

[0132] In some preferred embodiments, R 5 is selected from halogen, such as F.

[0133] In some preferred embodiments, R 5 The number of is 1.

[0134] In some preferred embodiments, R 5 The number of is 2. In some preferred embodiments, R 5 The number of them is 2, of which 1 is R 5is selected from piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl and azetidinyl, wherein the piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl and azetidinyl may be optionally substituted with 0, 1 or 2 substituents each independently selected from the group consisting of methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH; another R 5 In some preferred embodiments, R 5 The number of them is 2, of which 1 is R 5 is selected from methyl, ethyl, propyl, isopropyl, cyclobutyl groups, wherein the methyl, ethyl, propyl, isopropyl or cyclobutyl groups may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, wherein the substituents may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH; another R 5 Selected from halogen.

[0135] It should be understood that any of the above R 5 The embodiments can be combined with any of the R 1 、R 2 、R 3 、R 4 ,A,R 6 、R 7 and R 8 The implementation methods are combined together.

[0136] In some embodiments, the compound described herein is a compound selected from Formula (II), Formula (III), Formula (IV) and Formula (V), or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

[0137]

[0138]

[0139] Among them, R 4 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; and

[0140] R 5 The number of R is 0, 1, 2, 3, 4, 5, 6, 7 or 8, and each R 5Each independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicyclic heteroalkyl), -C 1-4 Alkyl-(C 8-15 -C 1-4 Alkyl-(8-15 membered tricyclic heteroalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicycloheteroalkyl)-C 1-4 Alkyl-(C 8-15 -membered tricycloalkyl) and -C 1-4 alkyl-(8-15 membered tricycloheteroalkyl) each optionally substituted with 0, 1, 2, 3 or 4 R 5a replace;

[0141] R 5a Independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl), -C 1-4 Alkyl-(6-12 membered bicyclic heteroalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-12 Bicycloalkyl, 6-12 membered bicycloheteroalkyl, C 8-15 8-15 membered tricyclic alkyl, 8-15 membered tricyclic heteroalkyl, C 5-8 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -C 1-4 Alkyl-(C 6-12 Bicycloalkyl) and C 1-4 alkyl-(6-12 membered bicycloheteroalkyl) each optionally substituted with 0, 1, 2, 3 or 4 R 5b replace;

[0142] R 5b Independently selected from H, halogen, -OH, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-N(R 7 )(C(=O)-OR 8 )、-N(R 7 )(C(=O)-N(R 8 )(R 9 ))、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=

[0143] O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 ) and -S(=O)2-N(R 7 )(R 8 ), wherein said -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-4 Alkyl-(C 3-7 cycloalkyl) and -C 1-4 Alkyl-(3-10 membered heterocycloalkyl) is optionally substituted with 0, 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C1-4 haloalkoxy; and

[0144] R 6 The number of R is 0, 1, 2 or 3, and each R 6 Each independently selected from H, halogen, -CN, -NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and

[0145] R 7 、R 8 and R 9 Each is independently selected at each occurrence from: H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (3-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy;

[0146] or R 7 、R 8 and the atoms to which they are attached together form a 3-14 membered ring;

[0147] or R 8 、R9 and the atoms to which they are attached together form a 3-14 membered ring.

[0148] X1 and X2 are each independently selected from -CH, N and R 5 C in case of connection.

[0149] In the above formula (I), R 4 、R 5 and R 6 The embodiments and preferences of the same apply to formula (II), formula (III), formula (IV) and formula (V).

[0150] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is benzene; R 5 The number of is 1 and is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, and the azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, Morpholinyl, piperidinyl , said substituent may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.

[0151] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is pyridine; R 5 The number of is 1 and is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, and the azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, Morpholinyl, piperidinyl , said substituent may be optionally substituted by 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.

[0152] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is pyridazine; R 5 The number of is 1 and is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, the azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups can be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, the substituents can be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.

[0153] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is pyrazole; R 5 The number of is 1 and is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, the azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups can be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, the substituents can be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH.

[0154] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is benzene; R 5 The number of them is 2, of which 1 is R 5R is selected from the group consisting of methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, and cyclobutyl groups, wherein the azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, and cyclobutyl groups may be optionally substituted with 0, 1, or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, and piperidinyl, wherein the substituents may be optionally substituted with 0, 1, or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, and -OH; another R 5 Selected from halogen.

[0155] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is pyridine; R 5 The number of them is 2, of which 1 is R 5 R is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, said azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, said substituents may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH; another R 5 Selected from halogen.

[0156] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is pyridazine; R 5 The number of them is 2, of which 1 is R 5R is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, said azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, said substituents may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH; another R 5 Selected from halogen.

[0157] In some embodiments, in the formula (I) as described above, R 1 and R 2 All are Cl; R 3 is methyl; R 4 H; R 6 is H; A is pyrazole; R 5 The number of them is 2, of which 1 is R 5 R is selected from methyl, azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups, said azetidinyl, piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl, ethyl, propyl, isopropyl, cyclobutyl groups may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH, morpholinyl, piperidinyl, said substituents may be optionally substituted with 0, 1 or 2 substituents each independently selected from the following groups: methyl, ethyl, cyclopentyl, cyclopropyl, -CN, -OH; another R 5 Selected from halogen.

[0158] In some embodiments, the compound of the present application is selected from:

[0159] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

[0160] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0161] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide,

[0162] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide,

[0163] N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide,

[0164] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

[0165] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0166] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide,

[0167] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

[0168] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

[0169] N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide,

[0170] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0171] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide,

[0172] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0173] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0174] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-3-carboxamide,

[0175] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide,

[0176] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide,

[0177] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0178] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0179] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0180] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0181] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0182] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0183] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0184] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0185] N-(1-cyclobutyl-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide,

[0186] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0187] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0188] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(morpholinomethyl)phenyl)-1H-indazole-3-carboxamide,

[0189] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0190] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((S)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0191] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((R)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0192] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0193] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0194] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0195] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0196] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0197] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0198] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0199] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0200] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0201] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0202] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0203] 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0204] 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0205] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0206] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0207] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide,

[0208] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, and

[0209] (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide.

[0210] The compounds of the present application can be synthesized by conventional organic synthesis methods according to the specific structures of the compounds by those skilled in the art.

[0211] Synthesis route (I)

[0212]

[0213] For example, the compound of formula (I) can be prepared by the method shown in the above-mentioned synthetic route (I). G in the intermediate Int-2 is selected from halogen, hydroxyl, mesyl (OMs), p-toluenesulfonyl (OTs), etc. PG is an amino protecting group, such as tetrahydropyran (THP), benzyl (Bn), p-methoxybenzyl (PMB), etc. When G is halogen, OMs, or OTs, the intermediate Int-1 and Int-2 can be subjected to an SN2 coupling reaction under alkaline conditions to produce the intermediate Int-3. When G is OH, the intermediate Int-3 can be obtained by a Mitsunobu reaction between Int-1 and Int-2. Under the action of an oxidizing agent (such as, but not limited to, KMnO4), the aldehyde group in Int-3 is converted into a carboxylic acid to produce the intermediate Int-4. Under typical amide formation reaction conditions (such as, but not limited to, in the presence of DIPEA / HATU), Int-4 reacts with Int-5 to produce the amide Int-6. Under appropriate deprotection conditions, Int-6 can be converted into the target compound of formula (I). In addition, those skilled in the art can refer to the synthetic routes of the specific compounds in the specific examples of this application and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain synthetic methods for other compounds.

[0214] The compound of the present application can suppress the activity of FGFR. For example, the compound of the present application can be used for selectively suppressing the activity of FGFR1 and / or FGFR2 and / or FGFR3 and / or FGFR4 and / or their mutants (such as gating mutants, such as FGFR1 V561M mutant, FGFR2 V564F mutant, FGFR3 V555M mutant, FGFR3 K650E mutant etc.) in a cell or an individual or patient who needs to suppress FGFR, and this is achieved by applying the compound of the present application of an inhibitory amount to the cell, individual or patient.

[0215] In some embodiments, the compounds of the present application have excellent inhibitory activity against FGFR1, FGFR2, FGFR3 and their gating mutants (eg, FGFR1 V561M mutant, FGFR2 V564F mutant and FGFR3 V555M mutant of FGFR).

[0216] As used herein, "gatekeeper mutations" have the meaning generally known in the art and are mutations that prevent drug binding and can lead to drug resistance. Gatekeeper mutations of FGFR include, but are not limited to, FGFR1 V561M, FGFR2 V564F, FGFR2 V564I, FGFR2 N550K, FGFR2 V565I, FGFR3 V555M, FGFR4 V550L, FGFR4 V550M, FGFR4 V555M, FGFR4 V555L, and the like.

[0217] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of the present application as described above or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0218] The pharmaceutical composition of the present application can be prepared in a manner well known in the pharmaceutical field and can be applied by a variety of routes, depending on whether local treatment or systemic treatment is desired and on the site to be treated. Administration can be local (including ophthalmic and to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by a nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by a balloon catheter or ophthalmic insert placed in the conjunctival sac with a surgical method. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders.

[0219] If a solid carrier is used, the preparation can be tableted, placed in a hard gel capsule in the form of a powder or granules, or in the form of a lozenge or pastille. Solid carriers may include conventional excipients, such as adhesives, fillers, tableting lubricants, disintegrants, wetting agents, etc. If necessary, the tablets may be film-coated by conventional techniques. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, ointment, soft gel capsule, a sterile carrier for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product reconstituted with water or other appropriate carriers before use. Liquid preparations may include conventional additives, such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavorings and / or coloring agents. For parenteral administration, typically the carrier at least comprises sterile water for the most part, but saline solutions, glucose solutions, etc. may also be used. Injectable suspensions may also be used, in which case conventional suspending agents may be used. Conventional preservatives, buffering agents, etc. may also be added to parenteral dosage forms. Pharmaceutical compositions are prepared by conventional techniques appropriate to the desired formulation containing appropriate amounts of the active ingredient (ie, the compound of the present application).

[0220] Compositions suitable for parenteral injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate).

[0221] These compositions can also include various excipients, for example, preservatives, wetting agents, emulsifiers and dispersants. The inhibition of the effect of microorganisms can be ensured by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents can also be included, for example, sugar, sodium chloride, etc. The absorption of injectable pharmaceutical dosage forms can be extended by using delayed absorption agents (for example, aluminum monostearate and gel).

[0222] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate) and may also include: (a) fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar); (e.g., fat-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retarding agents (e.g., paraffin); (f) absorption accelerators (e.g., quaternary ammonium compounds); (i) wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) adsorbents (e.g., kaolin and bentonite); and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), or mixtures thereof.

[0223] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, lactose and high molecular weight polyethylene glycols as excipients.

[0224] Solid dosage forms (e.g., tablets, dragees, capsules, pills, and granules) can be prepared using coatings and shells (e.g., enteric coatings and others known in the art). They may contain opacifiers, and they may also be compositions that release the active compound or compounds in a delayed manner in a certain part of the intestine. Examples of useful embedding compositions are polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0225] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof, etc., commonly used in the art.

[0226] Besides such inert diluents, the composition may also include, for example, wetting agents, emulsifying and suspending agents, perfuming, flavoring, and perfuming agents.

[0227] In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0228] The topical dosage forms of the compound of the present application include ointments, powders, sprays and inhalants. The active ingredient is mixed with a physiologically acceptable carrier and any required preservative, buffer or propellant under aseptic conditions. Ophthalmic formulations, eye ointments, powders and solutions are also included in the scope of the present application.

[0229] The amount of the compound of the present application in the pharmaceutical composition and dosage form can be appropriately determined by those skilled in the art as needed. For example, the compound of the present application can be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.

[0230] In a third aspect, the present application provides the use of the compound of the present application or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or the pharmaceutical composition as described above in the preparation of a medicament for treating a disease or condition associated with FGFR.

[0231] The present application also provides a method for treating a disease or condition associated with FGFR, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present application or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition as described above. The patient is preferably a mammal, more preferably a human patient. The route of administration may be oral, topical (including but not limited to topical application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical, and intravenous), intrabronchial, or nasal administration, etc.

[0232] In some embodiments, the disease or condition associated with FGFR is cancer. The compounds of the present application can be used, for example, to inhibit the proliferation and metastasis of cancer cells.

[0233] Exemplary cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancer (e.g., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip and oral cavity), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocellular carcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchogenic carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0234] Additional exemplary cancers include hematopoietic malignancies, such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin or non-Hodgkin lymphoma, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0235] Additional exemplary cancers include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0236] In some preferred embodiments, the disease or condition associated with FGFR is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer and rhabdomyosarcoma.

[0237] In other embodiments, the FGFR-related disease or condition is selected from skeletal disorders and chondrocyte disorders, such skeletal disorders and chondrocyte disorders include but are not limited to achondroplasia, hypochondrogenesis, dwarfism, thanatophoric achondroplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and premature suture closure syndrome.

[0238] In other embodiments, the FGFR-related disease or condition is a hypophosphatemia disorder, including, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteromaLacia.

[0239] In other embodiments, the disease or disorder associated with FGFR is selected from fibrotic diseases. Exemplary fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0240] In some embodiments, the FGFR-associated disease or disorder is a disease or disorder that is resistant to FGFR inhibitors that do not target the gating mutation due to a gating mutation in FGFR.

[0241] The present application is further illustrated and described below in conjunction with specific embodiments. Example

[0242] The following examples are provided herein for illustrative purposes only, to illustrate various aspects and embodiments of the present invention, and are not intended to limit the scope of the present invention in any way.

[0243] Unless otherwise stated, all reactants were obtained from commercial sources. The instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0244] Example 1: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazine- Synthesis of 1-(1-amino)phenyl)-1H-indazole-3-carboxamide (1)

[0245]

[0246] Compound 1 Synthesis route:

[0247]

[0248] Synthesis method:

[0249] synthetic intermediates 1-1 :1H-indole-5-acetate

[0250] Dissolve 5-hydroxyindole (240.0 mg, 1.80 mmol) in 20 ml of pyridine, add acetic anhydride (202.4 mg, 1.98 mmol) dropwise, and stir at room temperature for 16 hours. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude intermediate. 1-1 276.6 mg, yield 87.4%.

[0251] synthetic intermediates 1-2 :3-Formyl-1H-indazole-5-acetate

[0252] Sodium nitrite (157.5 mg, 2.28 mmol) was dissolved in 10 ml of water, 10 ml of DMF was added, 3 M HCl (0.7 ml, 2.05 mmol) was added dropwise at 0 °C, and stirred for 10 minutes. A solution of 1H-indole-5-acetate (50.0 mg, 0.29 mmol) in DMF (10 ml) was added to the reaction solution and reacted at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain the intermediate. 1-2 37.6 mg, yield 63.5%.

[0253] 1 H NMR (400MHz, CDCl3) δ10.25(s,1H),8.01(s,1H),7.49(d,J=9.0Hz,1H),7.21(d,J=9.0Hz,1H),2.36(s,3H).

[0254] synthetic intermediates 1-3 :3-Formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-acetate

[0255] Will 1-2 (190.0 mg, 0.93 mmol) was dissolved in 20 ml of DCM, p-toluenesulfonic acid (177.0 mg, 0.93 mmol) was added, and stirred for 2 minutes. A solution of 3,4-dihydro-2H-pyran (117.4 mg, 1.40 mmol) in DCM (3 ml) was added to the reaction solution, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain the intermediate. 1-3 160.2 mg, yield 59.6%.

[0256] synthetic intermediates 1-4 :5-Hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0257] Will 1-3 (160.2 mg, 0.56 mmol) was dissolved in 20 ml of methanol, potassium carbonate (115.1 mg, 0.83 mmol) was added to the solution and reacted at room temperature for 30 minutes. The reaction solution was filtered and the filtrate was concentrated to obtain a crude intermediate. 1-4 130.5 mg, yield 95.1%.

[0258] synthetic intermediates 1-5 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0259] Dissolve 1-(3,5-dichloropyridin-4-yl)ethane-1-ol (93.6 mg, 0.49 mmol) and triethylamine (148.6 mg, 1.47 mmol) in 20 ml of DCM, add methanesulfonyl chloride (57.3 mg, 0.50 mmol) dropwise to the reaction solution at 0 degrees, and react at room temperature for 1 hour. Add water to the reaction solution to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. 1-4 (100.0 mg, 0.41 mmol) and the concentrate were dissolved in 20 ml DMF, cesium carbonate (264.6 mg, 0.82 mmol) was added, and the reaction was carried out at 60 degrees for 16 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain the intermediate. 1-5 64.3 mg, yield 37.5%.

[0260] 1 H NMR (400MHz, CDCl3) δ10.16(s,1H),8.42(s,2H),7.59–7.53(m,2H),7.18–7.15(m,1H),6.11(q,J=6.7Hz,1H),5.77–5.72(m ,1H),4.01–3.94(m,1H),3.77–3.70(m,1H),2.54–2.46(m,1H),2.22–2.06(m,2H),1.81(d,J=6.7Hz,3H),1.76–1.68(m,3H).

[0261] synthetic intermediates 1-6 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid

[0262] Will 1-5(24.0 mg, 0.06 mmol) was dissolved in 12 ml of acetonitrile and 4 ml of water, potassium permanganate (18.1 mg, 0.12 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was filtered through celite, the filtrate was adjusted to pH 3 with 3M hydrochloric acid, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain the intermediate. 1-6 16.3 mg, yield 64.2%.

[0263] 1 H NMR (400MHz, CDCl3) δ8.46 (s, 2H), 7.60–7.57 (m, 1H), 7.50 (s, 1H), 7.16 (d, J = 9.1Hz, 1H), 6.11 (q, J = 6.7Hz, 1H), 5.77–5.72 ( m,1H),4.01–3.98(m,1H),3.74–3.71(m,1H),2.54–2.46(m,1H),2.07–2.04(m,2H),1.82(d,J=6.7Hz,3H),1.76–1.66(m,3H).

[0264] Synthetic compounds 1 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0265] Will 1-6 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)aniline (20.0 mg, 0.05 mmol) and 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)aniline (11.3 mg, 0.06 mmol) were dissolved in 10 ml of DMF. HATU (20.9 mg, 0.06 mmol) and DIPEA (17.8 mg, 0.12 mmol) were added to the solution and allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, and the reaction was carried out at 50 degrees Celsius for 1 hour. The mixture was concentrated and dissolved in 5 ml of methanol. 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. Purification on a preparative plate gave 11.2 mg of the final product in a yield of 50.8%.

[0266] 1H NMR (400MHz, DMSO-d6) δ13.65(s,1H),10.04(s,1H),8.60(s,2H),7.73–7.70(m,2H),7.56(d,J=9.0Hz,1H),7.50(s,1H),7.17–7.14(m,1H),7 .00(d,J=8.8Hz,2H),6.07(q,J=6.6Hz,1H),3.78(d,J=12.7Hz,2H),3.31(s,2H),2.67–2.58(m,2H),1.75(d,J=6.6Hz,3H),1.27–1.23(m,6H).

[0267] Example 2: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl) Synthesis of (4-amino-1H-indazole-3-carboxamide (2)

[0268]

[0269] Synthesis method:

[0270] Compound 2 Synthesis route:

[0271]

[0272] synthetic intermediates 2-1 : 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole 4-nitro-1H-pyrazole (200 mg, 1.77 mmol) was dissolved in 25 ml of acetonitrile, potassium carbonate (733 mg, 5.31 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (508 mg, 2.12 mmol) were added to the reaction solution, and the mixture was heated to 80 degrees to react. After the reaction was completed, 50 ml of water was added to the system, extracted with EA, separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 470 mg of the intermediate 2-1 , yield 97.9%.

[0273] 1 H NMR (400MHz, CDCl3) δ8.20 (s, 1H), 8.07 (s, 1H), 4.24 (t, J = 4.9Hz, 2H), 3.95 (t, J = 4.9Hz, 2H), 0.83 (s, 9H), -0.04 (s, 6H).

[0274] synthetic intermediates 2-2 :1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-amine intermediate 2-1(450mg, 1.66mmol) was dissolved in 10ml of methanol, 10% Pd / C (45mg) was added to the system, the system was replaced with hydrogen three times, and then reacted at room temperature. After the reaction was completed, the system was filtered and concentrated to obtain 390mg of the intermediate 2-2 , yield 97.4%.

[0275] Synthesis of compound 2: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide 1-6 (30.0 mg, 0.069 mmol) was dissolved in 4 ml of DMF, HATU (28.8 mg, 0.076 mmol) and DIPEA (17.8 mg, 0.138 mmol) were added to the system, stirred at room temperature for one hour, and then the intermediate was added to the system. 2-2 (16.7 mg, 0.069 mmol), the reaction was carried out at room temperature. After the reaction was completed, water was added to the system to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved in 4 ml of methanol, and then 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50 degrees to react. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was dissolved in 2 ml of methanol and neutralized with 0.5 ml of ammonia water. After neutralization, the mixture was concentrated and purified by column chromatography to obtain 14.0 mg of the compound. 2 , yield 44.1%.

[0276] 1 H NMR (400MHz, DMSO-d6) δ13.62(s,1H),10.42(s,1H),8.60(s,2H),8.06(s,1H),7.66(s,1H),7.55(d,J=5.2Hz,1H),7.54(s, 1H), 7.15 (dd, J=2.3, 9.1Hz, 1H), 6.09 (q, J=6.6Hz, 1H), 4.12 (t, J=5.6Hz, 2H), 3.95 (t, J=5.6Hz, 2H), 1.76 (d, J=6.6Hz, 3H).

[0277] Example 3: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl) Synthesis of (phenyl)-1H-indazole-3-carboxamide (3)

[0278]

[0279] Compound 3 Synthesis route:

[0280]

[0281] Synthesis method:

[0282] Synthetic compounds 3 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0283] Will 1-6 The product was dissolved in 10 ml of DMF. HATU (32.7 mg, 0.09 mmol) and DIPEA (22.2 mg, 0.17 mmol) were added to the solution and allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50 degrees for 1 hour. The mixture was concentrated and dissolved in 5 ml of methanol. 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. Purification on a preparative plate gave 11.5 mg of the final product in a yield of 63.8%.

[0284] 1 H NMR (400MHz, DMSO-d6) δ13.57(s,1H),9.83(s,1H),8.60(s,2H),7.62–7.50(m,4H),7.15–7.13(m,1H),6.51–6.49(m,2H),6.07( q,J=6.6Hz,1H),4.41(s,1H),3.43–3.23(m,3H),3.08–3.05(m,1H),2.09–1.95(m,1H),1.92–1.86(m,1H),1.75(d,J=6.6Hz,3H).

[0285] Example 4: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole- Synthesis of 3-formamide (4)

[0286]

[0287] Compound 4 Synthesis route:

[0288]

[0289] Synthesis method:

[0290] Synthetic compounds 4 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide

[0291] 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (20.0 mg, 0.05 mmol) and 6-morpholinopyridin-3-amine (10.8 mg, 0.06 mmol) were dissolved in 5 mL of DMF. HATU (20.9 mg, 0.06 mmol) and DIPEA (17.8 mg, 0.14 mmol) were added to the solution and allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was dissolved in 4 mL of methanol, 2 mL of concentrated hydrochloric acid was added, and the reaction was continued at 50°C for 1 hour. The reaction was concentrated, dissolved in 5 mL of methanol, 0.5 mL of aqueous ammonia was added, and the mixture was concentrated. Purification on a preparative plate yielded 6.4 mg of the product, with a total yield of 19.6% for the two steps.

[0292] 1 H NMR (400MHz, DMSO-d6) δ13.68(s,1H),10.18(s,1H),8.60(s,2H),8.56(d,J= 4.0Hz,1H),8.01(dd,J=4.0Hz,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.50(d,J =4.0Hz, 1H), 7.16 (dd, J = 4.0Hz, J = 8.0Hz, 1H), 6.90 (d, J = 12.0Hz, 1H), 6.07 ( q,J=6.6Hz,1H),3.73-3.71(m,4H),3.42-3.39(m,4H),1.75(d,J=8.0Hz,3H).

[0293] Example 5: N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl) Synthesis of (ethoxy)-1H-indazole-3-carboxamide (5)

[0294]

[0295] Compound 5 Synthesis route:

[0296]

[0297] Synthesis method:

[0298] synthetic intermediates 5-1 :3-(4-amino-1H-pyrazol-1-yl)butanenitrile

[0299] 4-Nitro-1H-pyrazole (25 mg, 0.22 mmol) and 3-bromobutyronitrile (42.5 mg, 0.29 mmol) were dissolved in 5 ml of acetonitrile, potassium carbonate (92.1 mg, 0.66 mmol) was added to the solution, and the mixture was reacted at 80 degrees for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. 3 ml of methanol was added, and 2.5 mg of palladium carbon was added to replace the hydrogen. The mixture was reacted at 40 degrees for 1 hour. After the reaction was completed, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain 20 mg of the intermediate. 5-1 , yield 60.24%.

[0300] 1 H NMR (400MHz, CDCl3) δ8.27 (s, 1H), 8.15 (s, 1H), 4.66-4.71 (m, 1H), 2.99-3.01 (m, 2H), 1.75 (d, J = 8Hz, 3H).

[0301] Synthetic compounds 5 :N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide

[0302] The intermediate 5-1 (20 mg, 0.13 mmol) and intermediate 1-6 (52.8 mg, 0.12 mmol), dissolved in DMF (3 ml), added HATU (50.6 mg, 0.13 mmol) and DIPEA (31.2 mg, 0.24 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of aqueous ammonia, concentrated, and purified on a preparative plate to obtain 9 mg of the final product with a yield of 15.5%.

[0303] 1 H NMR (400MHz, MeOD-d4) δ8.46(s,2H),8.08(s,1H),7.70(s,1H),7.58(d,J=4Hz,1H),7.48(d,J=8Hz,1H),7.16(d,J=8Hz,1H ),6.14-6.19(m,1H),3.64(m,1H),2.96-3.02(m,1H),2.82-2.87(m,1H),1.82(d,J=4Hz,3H),1.55(d,J=8Hz,3H).LC-MS:C 22H 20 Cl2N7O2[M+H] + The calculated m / z value is 484.1, and the detected value is 484.1.

[0304] Example 6: 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethyl Synthesis of (1-piperazin-1-yl)phenyl)-1H-indazole-3-carboxamide (6)

[0305]

[0306] Compound 6 Synthesis route:

[0307]

[0308] Synthesis method:

[0309] synthetic intermediates 6-1 :5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0310] Dissolve (S)-1-(3,5-dichloropyridin-4-yl)ethan-1-ol (200.0 mg, 1.05 mmol) and triethylamine (317.6 mg, 3.14 mmol) in 20 ml of DCM. Add methanesulfonyl chloride (131.9 mg, 1.15 mmol) dropwise to the reaction solution at 0 degrees and react at room temperature for 1 hour. Add water to the reaction solution to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. 1-4 (270.0 mg, 1.09 mmol) and the concentrate were dissolved in 20 ml DMF, cesium carbonate (684.2 mg, 2.10 mmol) was added, and the reaction was carried out at 60 degrees for 16 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 289.3 mg of the intermediate. 6-1 , yield 65.5%.

[0311] 1 H NMR (400MHz, CDCl3) δ10.16(s,1H),8.42(s,2H),7.59–7.53(m,2H),7.18–7.15(m,1H),6.11(q,J=6.7Hz,1H),5.77–5.72(m ,1H),4.01–3.94(m,1H),3.77–3.70(m,1H),2.54–2.46(m,1H),2.22–2.06(m,2H),1.81(d,J=6.7Hz,3H),1.76–1.68(m,3H).

[0312] synthetic intermediates 6-2 :5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid

[0313] Will 6-1 (289.3 mg, 0.69 mmol) was dissolved in 12 ml of acetonitrile and 4 ml of water, potassium permanganate (218.1 mg, 1.38 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was filtered through celite, the filtrate was adjusted to pH 3 with 3M hydrochloric acid, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain 246.5 mg of the intermediate. 6-2 , yield 81.8%.

[0314] 1 H NMR (400MHz, CDCl3) δ8.46 (s, 2H), 7.60–7.57 (m, 1H), 7.50 (s, 1H), 7.16 (d, J = 9.1Hz, 1H), 6.11 (q, J = 6.7Hz, 1H), 5.77–5.72 ( m,1H),4.01–3.98(m,1H),3.74–3.71(m,1H),2.54–2.46(m,1H),2.07–2.04(m,2H),1.82(d,J=6.7Hz,3H),1.76–1.66(m,3H).

[0315] Synthetic compounds 6 :5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0316] Will 6-2 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)aniline (40.0 mg, 0.09 mmol) and 4-((3S,5R)-3,5-dimethylpiperazin-1-yl)aniline (22.5 mg, 0.12 mmol) were dissolved in 10 ml of DMF. HATU (41.8 mg, 0.12 mmol) and DIPEA (35.6 mg, 0.26 mmol) were added to the solution and allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, and the reaction was carried out at 50 degrees Celsius for 1 hour. The mixture was concentrated and dissolved in 5 ml of methanol. 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. Purification on a preparative plate gave 37.2 mg of the final product in a yield of 76.3%.

[0317] 1H NMR (400MHz, DMSO-d6) δ13.66(s,1H),10.00(s,1H),8.59(s,2H),7.70(d,J=8.6Hz,2H),7.56(d,J=9.0Hz,1H),7.50(s,1H),7.16–7.13(m,1H),6. 98(d,J=8.7Hz,2H),6.07(q,J=6.6Hz,1H),3.73(d,J=12.7Hz,2H),3.26– 3.17(m,2H),2.57–2.54(m,2H),1.75(d,J=6.6Hz,3H),1.26–1.23(m,6H).

[0318] Example 7: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazole- Synthesis of 4-amino-1H-indazole-3-carboxamide (7)

[0319]

[0320] Compound 7 Synthesis route:

[0321]

[0322] Synthesis method:

[0323] Synthetic compounds 7 :(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0324] Will 6-2 (40.0 mg, 0.09 mmol) and 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-amine (24.4 mg, 0.10 mmol) were dissolved in 10 ml of DMF. HATU (41.8 mg, 0.12 mmol) and DIPEA (35.6 mg, 0.26 mmol) were added to the solution and reacted at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was dissolved in 6 ml of methanol, 3 ml of concentrated hydrochloric acid was added, and the mixture was reacted at 50 degrees for 1 hour. The mixture was concentrated and dissolved in 5 ml of methanol. 0.5 ml of aqueous ammonia was added, and the mixture was concentrated. Purification on a preparative plate gave 17.6 mg of the final product with a yield of 42.4%.

[0325] 1H NMR (400MHz, DMSO-d6) δ13.60(s,1H),10.39(s,1H),8.60(s,2H),8.05(s,1H),7.66(s,1H),7.56–7.53(s,2H),7.16–7.13 (m,1H),6.08(q,J=6.6Hz,1H),4.88(t,J=5.3Hz,1H),4.12(t,J=5.7Hz,2H),3.72(q,J=5.6Hz,2H),1.76(d,J=6.6Hz,3H).

[0326] Example 8: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S,5R)-3,5-dimethylpiperazine- Synthesis of 1-(1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide (8)

[0327]

[0328] Compound 8 Synthesis route:

[0329]

[0330] Synthesis method:

[0331] synthetic intermediates 8-1 :6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-amine

[0332] 2-Fluoro-5-nitropyridine (20 mg, 0.14 mmol) and (2S,6R)-2,6-dimethylpiperazine (24.1 mg, 0.21 mmol) were dissolved in 3 ml of DMSO. Potassium carbonate (39.1 mg, 0.28 mmol) was added to the solution and the mixture was reacted at 40 degrees for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 3 ml of methanol was added. 2.5 mg of 10% palladium carbon was added and the atmosphere was replaced with hydrogen three times. The mixture was reacted at 40 degrees for 1 hour. After the reaction was complete, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain 20 mg of the intermediate. 8-1 , yield 68.9%.

[0333] 1 H NMR (400MHz, CDCl3) δ7.78 (s, 1H), 6.99 (d, J = 8Hz, 1H), 6.57 (d, J = 8Hz, 1H), 3.93-4.01(m,2H),3.08-3.18(m,2H),2.51-2.62(m,2H),1.29-1.35(m,6H).

[0334] Synthetic compounds 8:5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide

[0335] The intermediate 8-1 (20 mg, 0.10 mmol) and intermediate 1-6 (38.5 mg, 0.09 mmol) were dissolved in DMF (3 ml), and HATU (33.5 mg, 0.09 mmol) and DIPEA (22.74 mg, 0.18 mmol) were added. The reaction was allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, 0.5 ml of aqueous ammonia was added, concentrated, and purified on a preparative plate to obtain 8 mg of the final product with a yield of 15.3%.

[0336] 1 H NMR (400MHz, MeOD-d4) δ8.45 (s, 3H), 7.93 (d, J = 8Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 12Hz, 1H), 7.17 (d, J = 8Hz, 1H), 6.88 (d, J = 8H z,1H),6.12-6.17(m,1H),4.16(d,J=12Hz,2H),2.95-3.01(m,2H),2.42-2.48(m,2H),1.81(d,J=4Hz,3H),1.20(d,J=4Hz,6H).

[0337] Example 9: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)- Synthesis of 1H-indazole-3-carboxamide (9)

[0338]

[0339] Compound 9 Synthesis route:

[0340]

[0341] Synthesis method:

[0342] synthetic intermediates 9-1 :4-(4-methylpiperazin-1-yl)aniline

[0343] 4-Nitrofluorobenzene (25 mg, 0.18 mmol) and 1-methylpiperazine (26.6 mg, 0.27 mmol) were dissolved in 3 ml of DMSO. Potassium carbonate (49.3 mg, 0.35 mmol) was added to the solution and the mixture was reacted at 40 degrees for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 3 ml of methanol was added. 2.5 mg of palladium carbon was added to replace the hydrogen. The mixture was reacted at 40 degrees for 1 hour. After the reaction was complete, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain 20 mg of the intermediate. 9- 1 , yield 73.8%.

[0344] 1 H NMR (400MHz, CDCl3) δ6.82 (d, J = 8Hz, 2H), 6.65 (d, J = 8Hz, 2H), 3.08-3.10 (m, 4H), 2.60-2.63 (m, 4H), 2.37 (s, 3H).

[0345] Synthetic compounds 9 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0346] The intermediate 9-1 (20 mg, 0.10 mmol) and intermediate 1-6 (41.5 mg, 0.09 mmol) were dissolved in DMF (3 ml), and HATU (36.1 mg, 0.09 mmol) and DIPEA (24.5 mg, 0.19 mmol) were added. The reaction was allowed to react at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, 0.5 ml of ammonia water was added, concentrated, and purified on a preparative plate to obtain 10 mg of the final product with a yield of 18.2%.

[0347] 1 H NMR (400MHz, DMSO-d6) δ13.60(s,1H),9.94(s,1H),8.59(s,2H),7.66(d,J=8Hz,2H),7.55(d,J=8Hz,1H),7.50(d,J=4Hz,1H),7. 14(d,J=8Hz,1H),6.92(d,J=8Hz,2H),6.04-6.09(m,1H),3.10-3.13(m,4H),2.49-2.52(m,4H),2.26(s,3H),1.75(d,J=4Hz,3H).

[0348] Example 10: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)- Synthesis of 1H-indazole-3-carboxamide (10)

[0349]

[0350] Compound 10 Synthesis route:

[0351]

[0352] Synthesis method:

[0353] synthetic intermediates 10-1 :4-(4-ethylpiperazin-1-yl)aniline

[0354] 4-Nitrofluorobenzene (25 mg, 0.18 mmol) and 1-ethylpiperazine (30.4 mg, 0.27 mmol) were dissolved in 3 ml of DMSO. Potassium carbonate (49.3 mg, 0.35 mmol) was added to the solution and the mixture was allowed to react at 40°C for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 3 ml of methanol was added. 2.5 mg of 10% palladium carbon was added and the atmosphere was replaced with hydrogen three times. The mixture was allowed to react at 40°C for 1 hour. After the reaction was complete, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain 20 mg of the intermediate. 10-1 , yield 68.7%.

[0355] 1 H NMR (400MHz, CDCl3) δ6.82 (d, J = 8Hz, 2H), 6.65 (d, J = 8Hz, 2H), 3.09-3.12 (m, 4H), 2.64-2.66 (m, 4H), 2.48-2.54 (m, 2H), 1.15 (t, J = 8Hz, 3H).

[0356] Synthetic compounds 10 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0357] The intermediate 10-1 (20 mg, 0.10 mmol) and intermediate 1-6(38.6 mg, 0.09 mmol), dissolved in DMF (3 ml), added HATU (33.7 mg, 0.09 mmol) and DIPEA (22.9 mg, 0.18 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 12 mg of the final product with a yield of 22.8%.

[0358] 1 H NMR (400MHz, DMSO-d6) δ13.60(s,1H),9.95(s,1H),8.59(s,2H),7.66(d,J=8Hz,2H),7.55(d,J=8Hz,1H),7.50(d,J=4Hz,1H),7.14(d,J=8Hz, 1H),6.92(d,J=8Hz,2H),6.04-6.09(m,1H),3.09-3.14(m,4H),2.51-2 .55(m,4H),2.41-2.44(m,2H),1.75(d,J=4Hz,3H),1.06(t,J=4Hz,3H).

[0359] Example 11: N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy Synthesis of (4-amino-1H-indazole-3-carboxamide (11)

[0360]

[0361] Compound 11 Synthesis route:

[0362]

[0363] Synthesis method:

[0364] synthetic intermediates 11-1 :3-(4-nitro-1H-pyrazol-1-yl)propionitrile

[0365] 4-Nitro-1H-pyrazole (200 mg, 1.77 mmol) was dissolved in 25 ml of acetonitrile. Potassium carbonate (733 mg, 5.31 mmol) and bromopropionitrile (284 mg, 2.12 mmol) were added to the reaction solution. After the addition was complete, the mixture was heated to 80 degrees to react. After the reaction was completed, 50 ml of water was added to the system, and EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 270 mg of the intermediate. 11-1 , yield 91.9%.

[0366] 1 H NMR (400MHz, CDCl3) δ8.28(s,1H),8.15(s,1H),4.44(t,J=6.5Hz,2H),3.04(t,J=6.5Hz,2H).

[0367] Synthetic intermediate 11-2: 3-(4-amino-1H-pyrazol-1-yl)propionitrile

[0368] The intermediate 11-1 (200 mg, 1.20 mmol) was dissolved in 10 ml of methanol, 10% Pd / C (20 mg) was added to the system, the system was replaced with hydrogen three times, and then reacted at room temperature. After the reaction was completed, the system was filtered and concentrated to obtain 156 mg of the intermediate 11-2 , yield 95.4%.

[0369] Synthesis of compound 11: N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide

[0370] The intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30.0 mg, 0.069 mmol) was dissolved in 4 ml of DMF, and HATU (28.8 mg, 0.076 mmol) and DIPEA (17.8 mg, 0.138 mmol) were added to the system. The mixture was stirred at room temperature for one hour, and then the intermediate 15-2 (9.37 mg, 0.069 mmol) was added to the system. After the addition was complete, the mixture was reacted at room temperature. After the reaction was completed, water was added to the system to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. 4 ml of methanol was added to dissolve the residue, and then 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50 degrees to react. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was dissolved in 2 ml of methanol and neutralized with 0.5 ml of ammonia water. After neutralization, the residue was concentrated and purified by column chromatography to obtain 5.3 mg of the compound. 11 , yield 18.4%.

[0371] 1H NMR (400MHz, CDCl3) δ10.26(s,1H),8.63(s,1H),8.42(s,2H),8.09(s,1H),7.77(d,J=2.3Hz,1H),7.57(s,1H),7.39(d,J=9.0Hz,1 LC-MS:C 21 H 18 Cl2N7O2[M+H] + The calculated m / z value is 470.1, and the detected value is 470.1.

[0372] Example 12: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazole- Synthesis of 4-amino-1H-indazole-3-carboxamide (12)

[0373]

[0374] Synthesis route of compound 12:

[0375]

[0376] Synthesis method:

[0377] synthetic intermediates 12-1 :1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-4-nitro-1H-pyrazole

[0378] 4-Nitro-1H-pyrazole (149 mg, 1.32 mmol) was dissolved in 25 ml of acetonitrile. Potassium phosphate (839 mg, 3.95 mmol) and cyclobutyl 3-((tert-butyldimethylsilyl)oxy)-4-methylbenzenesulfonate (470 mg, 1.32 mmol) were added to the reaction solution. After the addition was complete, the mixture was heated to 80 degrees to react. After the reaction was completed, 50 ml of water was added to the system, and EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 223 mg of the intermediate. 12-1 , yield 56.8%.

[0379] 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),8.04(s,1H),4.86-4.79(m,1H),4.64-4. 58(m,1H),2.75-2.69(m,2H),2.52-2.45(m,2H),0.84(s,9H),0.02(s,6H).

[0380] synthetic intermediates 12- 2: 1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-1H-pyrazol-4-amine

[0381] The intermediate 12-1 (50mg, 0.168mmol) was dissolved in 5ml of methanol, 10% Pd / C (5mg) was added to the system, the system was replaced with hydrogen three times, and then reacted at room temperature. After the reaction was completed, the system was filtered and concentrated to obtain 43mg of the intermediate 12- 2 , yield 95.6%.

[0382] Synthetic compounds 12 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0383] The intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (36.0 mg, 0.082 mmol) was dissolved in 4 ml of DMF, HATU (34.4 mg, 0.091 mmol) and DIPEA (21.2 mg, 0.165 mmol) were added to the system, stirred at room temperature for one hour, and then the intermediate was added to the system. 12- 2 (22.0 mg, 0.082 mmol), the reaction was carried out at room temperature. After the reaction was completed, water was added to the system to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration was dissolved in 4 ml of methanol, and then 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50 degrees to react. After the reaction was completed, the reaction solution was evaporated under reduced pressure, and the residue was dissolved in 2 ml of methanol and neutralized with 0.5 ml of ammonia water. After neutralization, the mixture was concentrated and purified by column chromatography to obtain 16.0 mg of the compound. 12 , yield 42.3%.

[0384] 1 H NMR (400MHz, MeOD-d4) δ8.46(s,2H),8.09(s,1H),7.73(s,1H),7.58(d,J=2.2Hz,1H),7.48(d,J=9.1Hz,1H),7.16(dd,J=2.3,9.0 Hz,1H),6.16(q,J=6.7Hz,1H),5.02-4.94(m,1H),4.62-4.56(m,1H),2.82-2.75(m,2H),2.54-2.47(m,2H),1.81(d,J=6.7Hz,3H).

[0385] Example 13: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)- Synthesis of 1H-indazole-3-carboxamide (13)

[0386]

[0387] Compound 13 Synthesis route:

[0388]

[0389] Synthesis method:

[0390] synthetic intermediates 13-1 :1-(4-aminophenyl)piperidin-4-ol

[0391] 4-Nitrofluorobenzene (25 mg, 0.18 mmol) and piperidin-4-ol (26.9 mg, 0.27 mmol) were dissolved in 3 ml of DMSO. Potassium carbonate (49.3 mg, 0.35 mmol) was added to the solution and the mixture was reacted at 40 degrees for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 3 ml of methanol was added. 2.5 mg of palladium carbon was added to replace the hydrogen. The mixture was reacted at 40 degrees for 1 hour. After the reaction was complete, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain 20 mg of the intermediate. 13- 1 , yield 73.4%.

[0392] 1 H NMR (400MHz, CDCl3) δ6.85 (d, J = 8Hz, 2H), 6.64 (d, J = 8Hz, 2H), 3.79-3.83 (m, 1H ),3.33-3.39(m,2H),2.77-2.83(m,2H),2.01-2.05(m,2H),1.68-1.77(m,2H).

[0393] Synthetic compounds 13 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide

[0394] The intermediate 13-1 (20 mg, 0.10 mmol) and intermediate 1-6(41.3 mg, 0.09 mmol), dissolved in DMF (3 ml), added HATU (35.9 mg, 0.09 mmol) and DIPEA (24.4 mg, 0.18 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 8 mg of the final product with a yield of 14.60%.

[0395] 1 H NMR (400MHz, DMSO-d6) δ13.58(s,1H),9.92(s,1H),8.59(s,2H),7.63(d,J=12Hz ,2H), 7.55(d,J=8Hz,1H),7.50(d,J=4Hz,1H),7.14(d,J=8Hz,1H),6.90(d,J=12H z,2H),6.04-6.09(m,1H),4.63-4.65(m,1H),3.61-3.63(m,1H),3.47-3.50(m,2 H),2.77-2.83(m,2H),1.81-1.84(m,2H),1.75(d,J=4Hz,3H),1.48-1.52(m,2H).

[0396] Example 14: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyridin- Synthesis of (4-oxazol-1H-indazole-3-carboxamide (14)

[0397]

[0398] Compound 14 Synthesis route:

[0399]

[0400] Synthesis method:

[0401] synthetic intermediates 14-1 :1-methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine

[0402] 4-Nitro-1H-pyrazole (100 mg, 0.884 mmol) was dissolved in 20 ml of acetonitrile, and potassium phosphate (563 mg, 2.65 mmol) and 1-methylpiperidin-4-yl-4-methylbenzenesulfonate (238 mg, 0.884 mmol) were added to the reaction solution. After the addition was complete, the mixture was heated to 80 degrees to react. After the reaction was completed, 50 ml of water was added to the system, and EA was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 112 mg of the intermediate. 14-1 , yield 60.1%.

[0403] 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),8.08(s,1H),4.18-4.10(m,1H),3.02-2.98(m,2H),2.51(s,3H),2.22-2.13(m,4H),2.09-1.99(m,2H).

[0404] synthetic intermediates 14-2 :1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine

[0405] The intermediate 14-1 (50.0 mg, 0.238 mmol) was dissolved in 5 ml of methanol, 10% Pd / C (5 mg) was added to the system, the system was replaced with hydrogen three times, and then reacted at room temperature. After the reaction was completed, the system was filtered and concentrated to obtain 37.0 mg of intermediate 14-2 , yield 86.3%.

[0406] Synthetic compounds 14 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0407] The intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30.0 mg, 0.069 mmol) was dissolved in 4 ml of DMF, HATU (28.7 mg, 0.076 mmol) and DIPEA (17.8 mg, 0.138 mmol) were added to the system, stirred at room temperature for one hour, and then the intermediate was added to the system. 14- 2(12.4 mg, 0.069 mmol), the reaction was allowed to proceed at room temperature. After the reaction was complete, water was added to the system to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration was dissolved in 4 ml of methanol, and then 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50 degrees to react. After the reaction was complete, the reaction solution was evaporated under reduced pressure, and the residue was dissolved in 2 ml of methanol and neutralized with 0.5 ml of ammonia water. After neutralization, the mixture was concentrated and purified by column chromatography to obtain 14.0 mg of the compound. 14 , yield 39.6%.

[0408] 1 H NMR (400MHz, MeOD-d4) δ8.45(s,2H),8.10(s,1H),7.70(s,1H),7.58(d,J=2.3Hz,1H),7.48(d,J=9.1Hz,1H),7.16(dd,J=2.4,9.1Hz,1H) ,6.16(q,J=6.7Hz,1H),4.23-4.03(m,1H),3.08-2.99(m,2H),2.37(s,3H),2.33-2.26(m,2H),2.19-2.05(m,4H),1.81(d,J=6.7Hz,3H).

[0409] Example 15: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)- Synthesis of 1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (15)

[0410]

[0411] Compound 15 Synthesis route:

[0412]

[0413] Synthesis method:

[0414] synthetic intermediates 15-1 :1-(2-bromoethyl)cyclopropane-1-ol

[0415] Methyl 3-bromopropionate (1 g, 5.99 mmol) and tetraisopropyl titanate (170.2 mg, 0.60 mmol) were dissolved in 30 ml THF (dry), nitrogen was replaced, the temperature was lowered to 0 degrees, ethyl magnesium bromide (13.2 ml, 1 mol / L) was added dropwise to the solution, and the mixture was reacted at room temperature for 2 hours. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and concentrated by column chromatography to obtain the intermediate. 15-1 230 mg, yield 23.3%.

[0416] 1H NMR (400MHz, CDCl3) δ3.62 (t, J = 6Hz, 2H), 2.13 (t, J = 8Hz, 2H), 0.81-0.84 (m, 2H), 0.54-0.57 (m, 2H).

[0417] synthetic intermediates 15-2 :1-(2-(4-amino-1H-pyrazol-1-yl)ethyl)cyclopropane-1-ol

[0418] 4-Nitro-1H-pyrazole (100 mg, 0.88 mmol) was dissolved in 15 ml of acetonitrile, and cesium carbonate (864.9 mg, 2.65 mmol) was added to the reaction solution. 15-1 (230mg, 1.39mmol), after adding, heat to 60 degrees to react. React for 3 hours, add 30ml of water to the system, extract with EA, separate the liquid, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate column chromatography to obtain 100mg of product dissolved in 5ml of methanol, add 10mg of palladium carbon, replace hydrogen, react at room temperature for 1 hour, complete the reaction, filter, concentrate, and concentrate column chromatography to obtain 60mg of intermediate 15-2 , yield 40.6%.

[0419] 1 H NMR (400MHz, CDCl3) δ7.16 (s, 1H), 7.03 (s, 1H), 4.26 (t, J = 6Hz, 2H), 1.95 (t, J = 6Hz, 2H), 0.67-0.70 (m, 2H), 0.27-0.30 (m, 2H).

[0420] Synthetic compounds 15 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0421] The intermediate 1-6 (50 mg, 0.11 mmol) was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 3 hours, concentrated, added 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified by column chromatography to obtain the product and intermediate 15-2 (14.2 mg, 0.08 mmol) was dissolved in DMF (3 ml), and HATU (38.8 mg, 0.10 mmol) and DIPEA (22.0 mg, 0.17 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 2.8 mg of the final product in a yield of 7%.

[0422] 1 H NMR (400MHz, DMSO-d6) δ13.61(s,1H),10.39(s,1H),8.60(s,2H),8.05(s,1H),7.64(s,1H),7.54-7.56(m,2H),7.15(d,J=8H z,1H),6.06-6.11(m,1H),4.25(t,J=6Hz,2H),1.94(t,J=6Hz,2H),1.76(d,J=8Hz,3H),0.50-0.53(m,2H),0.25-0.28(m,2H).

[0423] Example 16: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S,5R)-3,5-dimethylpiperid ... Synthesis of (1-oxazine-1-yl)pyridin-2-yl)-1H-indazole-3-carboxamide (16)

[0424]

[0425] Compound 16 Synthesis route:

[0426]

[0427] Synthesis method:

[0428] synthetic intermediates 16-1 :(3S,5R)-3,5-dimethyl-1-(6-nitropyridin-3-yl)piperazine

[0429] 5-Fluoro-2-nitropyridine (100 mg, 0.70 mmol) and (2S,6R)-2,6-dimethylpiperazine (88.4 mg, 0.77 mmol) were dissolved in 2 ml of DMF. DIPEA (181.6 mg, 1.41 mmol) was added to the solution and reacted at 50°C for 3 hours. Water was added to the reaction solution and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 155 mg of the intermediate. 16-1 , yield 93.2%.

[0430] 1 H NMR (400MHz, CDCl3) δ8.16-8.12(m,2H),7.20-7.17(m,1H),3.76-3.72(m,2H),3.04-2.99(m,2H),2.60-2.54(m,2H),0.90(dd,J=4Hz,J=8Hz,6H).

[0431] synthetic intermediates 16-2 :5-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-amine

[0432] Intermediate 16-1 (155 mg, 0.66 mmol) was dissolved in 10 ml of methanol, 20 mg of 10% palladium carbon was added, and hydrogen was replaced 3 times. The mixture was reacted at room temperature for 2 hours, filtered, and concentrated to obtain 130 mg of intermediate 16-2 , yield 96.1%.

[0433] Synthetic compounds 16 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-3-carboxamide

[0434] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and intermediate 16-2 (15.6 mg, 0.08 mmol), dissolved in DMF (1 ml), added HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of aqueous ammonia, concentrated, and purified on a preparative plate to obtain 4 mg of the final product with a total yield of 10.8% for two steps.

[0435] 1 H NMR (400MHz, DMSO-d6) δ9.45 (s, 1H), 8.60 (s, 2H), 8.05-8.03 (m, 2H), 7.59 (d, J = 8Hz, 1H), 7.49-7.46 (m, 2H), 7.18 (dd, J = 4Hz, J =8Hz,1H),6.11-6.06(m,1H),3.56-3.51(m,2H),2.90-2.85(m,2H),2.18-2.12(m,2H),1.77(d,J=8Hz,3H),1.04(d,J=4Hz,6H).

[0436] Example 17: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperid ... Synthesis of (1-oxazine-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide (17)

[0437]

[0438] Compound 17 Synthesis route:

[0439]

[0440] Synthesis method:

[0441] synthetic intermediates 17-1 :4-((3S,5R)-3,5-dimethylpiperazine-1-yl)-3-fluoroaniline 1,2-difluoro-4-nitrobenzene (50mg, 0.31mmol) and (2S,6R)-2,6-dimethylpiperazine (39.5mg, 0.34mmol) were dissolved in 5ml of acetonitrile, DIPEA (81.1mg, 0.63mmol) was added to the solution, and the mixture was reacted at 80 degrees for 2 hours. Water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, 3ml of methanol was added, 5mg of 10% palladium carbon was added, hydrogen was replaced, and the mixture was reacted at 40 degrees for 1 hour. After the reaction was complete, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain 44mg of the intermediate. 17-1 , yield 62.7%.

[0442] 1 H NMR (400MHz, CDCl3) δ6.79 (t, J = 8Hz, 1H), 6.37-6.43 (m, 2H), 3.07-3.16 (m, 4H), 2.26 (t, J = 10Hz, 2H), 1.10 (d, J = 8Hz, 6H).

[0443] Synthetic compounds 17 : 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide

[0444] The intermediate 17-1 (18.4 mg, 0.08 mmol) and intermediate 1-6 (30 mg, 0.06 mmol), dissolved in DMF (3 ml), added HATU (31.4 mg, 0.08 mmol) and DIPEA (17.7 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 10 mg of the final product with a yield of 26.1%.

[0445] 1H NMR (400MHz, CDCl3) δ10.48(s,1H),8.71(s,1H),8.43(s,2H),7.77(s,1H),7.67(d,J=12Hz,1H),7.39(d,J=8Hz,1H),7.16-7.24(m,2H ), 6.94 (t, J = 10Hz, 1H), 6.13-6.18 (m, 1H), 3.28-3.31 (m, 2H), 3.16-3.20 (m, 2H), 2.40 (m, 2H), 1.81 (d, J = 8Hz, 3H), 1.18 (d, J = 4Hz, 6H).

[0446] Example 18: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)- Synthesis of 1H-indazole-3-carboxamide (18)

[0447]

[0448] Compound 18 Synthesis route:

[0449]

[0450] Synthesis method:

[0451] synthetic intermediates 18-1 :1-ethyl-4-phenylpiperidine

[0452] 4-Phenylpiperidine (100 mg, 0.62 mmol) and triethylamine (188.4 mg, 1.86 mmol) were dissolved in 10 ml of dichloromethane, and acetyl chloride (58.4 mg, 0.74 mmol) was added dropwise to the solution. The mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a solid, dissolved in dry THF, cooled to 0 degrees, and lithium aluminum tetrahydride (61.7 mg, 1.62 mmol) was added. The mixture was reacted at room temperature for 3 hours. A small amount of water was added to quench the reaction, anhydrous sodium sulfate was added, stirred for 20 minutes, filtered, and concentrated to obtain the intermediate. 18-1 96 mg, total yield of two steps 82.1%.

[0453] 1 H NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 5H), 3.11-3.06 (m, 2H), 2.50-2.42 (m, 3H), 2.05-2.01 (m, 2H), 1.99-1.79 (m, 4H), 1.11 (t, J = 8 Hz, 3H). Synthetic intermediate 18-2 :1-ethyl-4-(4-nitrophenyl)piperidine

[0454] intermediates 18-1(96 mg, 0.51 mmol) was dissolved in 196 mg of concentrated sulfuric acid, cooled to 0 degrees, and concentrated nitric acid (56.7 mg, 0.90 mmol) was added dropwise. The reaction was allowed to proceed overnight at room temperature. Water was added and the pH was adjusted to 8 with sodium hydroxide solution. The product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the intermediate. 18-2 83 mg, yield 70.9%.

[0455] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8Hz,2H),7.39(d,J=8Hz,2H),3.13-3.10(m,2H),2.64-2 .60(m,1H),2.50-2.45(m,2H),2.07-2.01(m,2H),1.89-1.81(m,4H),1.13(t,J=8Hz,3H).

[0456] synthetic intermediates 18-3 :4-(1-ethylpiperidin-4-yl)aniline

[0457] intermediates 18-2 (83 mg, 0.35 mmol) was dissolved in 10 ml of methanol, 8 mg of 10% palladium carbon was added, hydrogen was replaced 3 times, and the reaction was carried out at room temperature for 2 hours. The intermediate was obtained after filtration and concentration. 18-3 49 mg, yield 67.7%.

[0458] Synthetic compounds 18 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide

[0459] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and intermediate 18-3 (15.5 mg, 0.08 mmol), dissolved in DMF (1 ml), added HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 11 mg of the final product, with a total yield of 29.7% for two steps.

[0460] 1H NMR (400MHz, DMSO-d6) δ13.65 (s, 1H), 10.10 (s, 1H), 8.60 (s, 2H), 7.74 (d, J = 8Hz ,2H),7.58(d,J=8Hz,1H),7.51(d,J=4Hz,1H),7.22(d,J=8Hz,2H),7.17-7.14(m ,1H),6.10-6.07(m,1H),3.00-2.97(m,2H),2.50-2.46(m,1H),2.37-2.33(m,2H ), 2.01-1.94(m,3H), 1.77(d,J=8Hz,3H), 1.68-1.63(m,3H), 1.04(t,J=8Hz,3H).

[0461] Example 19: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazole- Synthesis of 4-amino-1H-indazole-3-carboxamide (19)

[0462]

[0463] Compound 19 Synthesis route:

[0464]

[0465] Synthesis method:

[0466] synthetic intermediates 19-1 :4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)morpholine

[0467] 4-Nitro-1H-pyrazole (70 mg, 0.62 mmol) was dissolved in 10 ml of acetonitrile, potassium carbonate (256.7 mg, 1.86 mmol) and 4-(2-bromoethyl)morpholine hydrobromide (187.7 mg, 0.68 mmol) were added to the reaction solution, and the mixture was heated to 80 degrees for 4 hours. After the reaction was completed, 50 ml of water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 103 mg of the intermediate. 19-1 , yield 73.5%.

[0468] 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.08 (s, 1H), 4.27 (t, J = 8Hz, 2H), 3.73-3.71 (m, 4H), 2.84 (t, J = 8Hz, 2H), 2.52-2.50 (m, 4H).

[0469] synthetic intermediates 19-2 :1-(2-morpholinoethyl)-1H-pyrazol-4-amine

[0470] intermediates 19-1 (103 mg, 0.46 mmol) was dissolved in 10 ml of methanol, 10 mg of 10% palladium carbon was added, hydrogen was replaced 3 times, the reaction was carried out at room temperature for 2 hours, filtered, and concentrated to obtain the intermediate 19-2 92 mg, yield 91.8%.

[0471] Synthetic compounds 19 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0472] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and intermediate 19-2 (16.2 mg, 0.08 mmol), dissolved in DMF (1 ml), added HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 23 mg of the final product, with a total yield of 63.0% for two steps.

[0473] 1 H NMR (400MHz, MeOD-d4) δ8.48 (s, 2H), 8.17 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 4Hz, 1H), 7.51 (d, J = 8Hz, 1H), 7.20 (dd, J = 4Hz, J = 8H z, 1H), 6.21-6.16 (m, 1H), 4.31 (t, J = 4Hz, 2H), 3.74-3.71 (m, 4H), 2.84 (t, J = 8Hz, 2H), 2.55-2.52 (m, 4H), 1.83 (d, J = 4Hz, 3H).

[0474] Example 20: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H- Synthesis of indazole-3-carboxamide (20)

[0475]

[0476] Compound 20 Synthesis route:

[0477]

[0478] Synthesis method:

[0479] synthetic intermediates 20-1 :1-ethyl-4-nitro-1H-pyrazole

[0480] 4-Nitro-1H-pyrazole (100 mg, 0.88 mmol) was dissolved in 15 ml of acetonitrile, potassium carbonate (366.7 mg, 2.65 mmol) and bromoethane (217.6 mg, 1.77 mmol) were added to the reaction solution, and the mixture was heated to 80 degrees for reaction. After the reaction was completed, 50 ml of water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 110 mg of the intermediate. 20-1 , yield 88.1%.

[0481] 1 H NMR (400MHz, CDCl3) δ8.16 (s, 1H), 8.10 (s, 1H), 4.27 (dd, J = 8Hz, J = 12Hz, 2H), 1.59-1.56 (m, 3H).

[0482] synthetic intermediates 20-2 :1-ethyl-1H-pyrazol-4-amine

[0483] intermediates 20-1 (110 mg, 0.78 mmol) was dissolved in 10 ml of methanol, 20 mg of 10% palladium carbon was added, hydrogen was replaced 3 times, the reaction was carried out at room temperature for 2 hours, filtered, and concentrated to obtain the intermediate 20-2 73 mg, yield 84.3%.

[0484] Synthetic compounds 20 :5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0485] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and intermediate 20-2(8.4 mg, 0.08 mmol), dissolved in DMF (1 ml), added HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added with 0.5 ml of aqueous ammonia, concentrated, and purified on a preparative plate to obtain 19 mg of the final product, with a total yield of 62.0% for two steps.

[0486] 1 H NMR (400MHz, MeOD-d4) δ8.48 (s, 2H), 8.08 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 4Hz, 1H), 7.51 (d, J = 8Hz, 1H), 7.20 (d d, J=4Hz, J=8Hz, 1H), 6.21-6.16 (m, 1H), 4.24 (dd, J=8Hz, J=16Hz, 2H), 1.85 (d, J=8Hz, 3H), 1.52 (t, J=8Hz, 3H).

[0487] Example 21: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidine-3-yl)- Synthesis of 1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (21)

[0488]

[0489] Compound 21 Synthesis route:

[0490]

[0491] Synthesis method:

[0492] synthetic intermediates 21-1 : tert-Butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate

[0493] 4-Nitro-1H-pyrazole (230 mg, 2.04 mmol) was dissolved in 4 ml of DMF. Cesium carbonate (1.33 g, 4.08 mmol) and tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (614.4 mg, 2.45 mmol) were added to the reaction solution. The mixture was heated to 100 degrees and reacted overnight. After the reaction was completed, 50 ml of water was added to the system and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 480 mg of the intermediate. 21-1 , yield 87.6%.

[0494] 1H NMR (400MHz, CDCl3) δ8.30(s,1H),8.18(s,1H),5.09-5.05(m,1H),4.47-4.42(m,2H),4.36-4.33(m,2H),1.46(s,9H).

[0495] synthetic intermediates 21-2 :1-(1-methylazetidin-3-yl)-4-nitro-1H-pyrazole

[0496] Intermediate 21-1 (460 mg, 1.72 mmol) was dissolved in 10 ml of dichloromethane, 2.5 ml of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 0.5 hours, concentrated, and the residue was dissolved in dichloromethane, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the product (83 mg, 0.49 mmol). Dichloromethane was added to dissolve the mixture, and formaldehyde aqueous solution (0.12 ml, 1.48 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. NaBH (OAc) 3 (627.9 mg, 2.96 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added for extraction, dried over anhydrous sodium sulfate, and concentrated to obtain the intermediate 21-2 42 mg, total yield of two steps 13.5%.

[0497] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.13(s,1H),4.97-4.90(m,1H),3.83-3.79(m,2H),3.58-3.54(m,2H),2.47(s,3H).

[0498] synthetic intermediates 21-3 :1-(1-methylazetidin-3-yl)-1H-pyrazol-4-amine

[0499] intermediates 21-2 The compound (42 mg, 0.23 mmol) was dissolved in 5 ml of methanol, 5 mg of 10% palladium carbon was added, and the hydrogen atmosphere was replaced three times. The reaction was carried out at room temperature for 2 hours, filtered, and concentrated to obtain 29 mg of intermediate 21-3 with a yield of 82.9%.

[0500] Synthetic compounds 21 :Synthesis of 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0501] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and intermediate 21-3 (12.6 mg, 0.08 mmol), dissolved in DMF (1 ml), added HATU (31.4 mg, 0.08 mmol) and DIPEA (17.8 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of aqueous ammonia, concentrated, and purified on a preparative plate to obtain 3.6 mg of the final product with a total yield of 10.8% for two steps.

[0502] 1 H NMR (400MHz, MeOD-d4) δ8.48(s,2H),8.19(s,1H),7.79(s,1H),7.60(d,J=4Hz,1H),7.51(d,J=8Hz,1H),7.20(dd,J=4Hz,J=8H z,1H),6.21-6.16(m,1H),5.06-5.02(m,1H),3.94-3.90(m,2H),3.68-3.65(m,2H),2.52(s,3H),1.52(d,J=4Hz,3H).LC-MS:C 22 H 22 Cl2N7O2[M+H] + The calculated m / z value is 486.1, and the detected value is 486.1.

[0503] Example 22: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl Synthesis of 1H-pyrazol-4-yl)-1H-indazole-3-carboxamide (22)

[0504]

[0505] Compound 22 Synthesis route:

[0506]

[0507] Synthesis method:

[0508] synthetic intermediates 22-1 : tert-Butyl 4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0509] Dissolve tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (130.0 mg, 0.47 mmol) and 4-nitro-1H-pyrazole (48.0 mg, 0.42 mmol) in 20 ml of acetonitrile, add cesium carbonate (276.8 mg, 0.85 mmol) to the reaction solution, heat to 80 degrees and react for 2 hours. After the reaction is completed, water is added to the system, extracted with ethyl acetate, separated, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain the intermediate 22-1 130.3 mg, yield 98.6%.

[0510] synthetic intermediates 22-2 :1-methyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine

[0511] The intermediate 22-1 (130.3 mg, 0.41 mmol) was dissolved in 10 ml of dichloromethane, 2 ml of trifluoroacetic acid was added to the solution, and the mixture was reacted at room temperature for 30 minutes. The reaction solution was concentrated, and the concentrate was dissolved in 10 ml of dichloromethane. Formaldehyde aqueous solution (0.10 ml, 1.25 mmol) was added and stirred at room temperature for 20 minutes. NaBH(OAc)3 (265.1 mg, 1.25 mmol) was added and stirred at room temperature for 2 hours. Water was added for extraction, and the mixture was dried over anhydrous sodium sulfate and concentrated to obtain the intermediate. 22-2 90.2 mg, yield 95.8%.

[0512] 1 H NMR(400MHz,MeOD-d4)δ8.61(s,1H),8.14(s,1H),4.14(d,J=7.2Hz,2H),3.09–3.04(m,2H) ,2.44(s,3H),2.32–2.21(m,2H),2.08–2.01(m,1H),1.71–1.66(m,2H),1.48–1.40(m,2H).

[0513] Synthetic compounds 22-3 :1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-amine

[0514] intermediates 22-2 (50.0 mg, 0.22 mmol) was dissolved in 5 ml of methanol, 5 mg of 10% palladium carbon was added, hydrogen was replaced 3 times, and the reaction was carried out at room temperature for 2 hours. The reaction solution was filtered and the filtrate was concentrated to obtain the intermediate 22-3 42.9 mg, yield 99.2%.

[0515] Synthetic compounds 22:5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0516] Intermediate 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (30 mg, 0.07 mmol) and intermediate 22-3 The crude product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50°C for 2 hours, concentrated, dissolved in 3 ml of methanol, added with 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 7.6 mg of the final product with a total yield of 35.2% for two steps.

[0517] 1 H NMR (400MHz, MeOD-d4) δ8.47 (s, 2H), 8.08 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 2.4Hz, 1 H), 7.50 (d, J = 9.1Hz, 1H), 7.18 (dd, J = 9.1Hz, 2.4Hz, 1H), 6.18 (q, J = 6.6Hz, 1H), 4. 06(d,J=7.2Hz,2H),2.94(d,J=11.7Hz,2H),2.32(s,3H),2.09(t,J=11.3Hz,2H),2 .00–1.89(m,1H), 1.83(d,J=6.7Hz,3H), 1.64(d,J=13.1Hz,2H), 1.44–1.37(m,2H).

[0518] Example 23: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1 ... (4-(2-Yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0519]

[0520] Compound 23 Synthesis route:

[0521]

[0522] Synthesis method:

[0523] synthetic intermediates 23-1 :2-(4-amino-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)ethan-1-one

[0524] 2-(4-nitro-1H-pyrazol-1-yl)acetic acid (50 mg, 0.29 mmol) and pyrrolidine (24.9 mg, 0.35 mmol) were dissolved in DMF, HATU (133.3 mg, 0.35 mmol) and DIPEA (75.4 mg, 0.58 mmol) were added to the solution, and the mixture was reacted at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel plate. The obtained product was dissolved in 3 ml of methanol, 5 mg of 10% palladium carbon was added, and the hydrogen was replaced. The mixture was reacted at 40 degrees for 1 hour. After the reaction was completed, the mixture was filtered, concentrated, and purified on a silica gel plate to obtain the intermediate. 23-1 40 mg, yield 70.4%.

[0525] 1 H NMR (400MHz, CDCl3) δ7.17 (d, J = 4Hz, 2H), 4.78 (s, 2H), 3.42-3.50 (m, 4H), 2.00–1.93 (m, 2H), 1.88-1.81 (m, 2H).

[0526] Synthesis of compound 23: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0527] The intermediate 23-1 (16.0 mg, 0.08 mmol) and intermediate 1-6 (30 mg, 0.07 mmol), dissolved in DMF (3 ml), added HATU (31.3 mg, 0.08 mmol) and DIPEA (17.7 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 6 mg of the final product with a yield of 16.5%.

[0528] 1H NMR(400MHz,DMSO)δ13.62(s,1H),10.45(s,1H),8.60(s,2H),8.03(s,1H),7.66(s,1H),7.57-7.54(m,2H),7.17-7.14 (m,1H),6.11-6.06(m,1H),5.01(s,2H),3.49(t,J=8Hz,2H),3.36-3.34(m,2H),1.96-1.89(m,2H),1.83-1.76(m,5H).

[0529] Example 24 to Example 30

[0530] According to the synthetic route and method similar to Example 23, the compounds of each example shown in the table below were prepared by changing the starting materials, and the 1 H NMR or mass spectral data.

[0531]

[0532]

[0533]

[0534] Example 31: (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethylazetidine- 3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0535]

[0536] Compound 31 Synthesis route:

[0537]

[0538] Synthesis method:

[0539] synthetic intermediates 31-1 :1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-amine

[0540] 4-Nitro-1H-pyrazole (50 mg, 0.44 mmol) and tert-butyl 3-bromoazetidine-1-carboxylate (114.8 mg, 0.47 mmol) were dissolved in DMF, K2CO3 (184.4 mg, 1.33 mmol) was added to the solution, and the mixture was reacted at 80 degrees for 4 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel plate. The obtained product was dissolved in 5 ml of dichloromethane, and 1 ml of trifluoroacetic acid was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated and the obtained product was dissolved in 5 ml of dichloromethane. Acetaldehyde (21.4 mg, 0.49 mmol) was added to the solution and stirred at room temperature for half an hour. Sodium triacetylborohydride (186.5 mg, 0.88 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, water was added to the reaction solution and the mixture was extracted twice with dichloromethane. The organic phases were combined, concentrated, and purified on a silica gel plate. The obtained product was dissolved in 5 ml of methanol and 5 mg of palladium carbon was added. The mixture was replaced with hydrogen and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was filtered and concentrated to obtain the intermediate. 31-1 29 mg, yield 39.5%.

[0541] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.13(s,1H),4.98-4.96(m,1H),3.82-3.79(m,2H),3.53-3.50(m,2H),2.64-2.62(m,2H),1.05(t,J=8Hz,3H).

[0542] Synthetic compounds 31 :(R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0543] The intermediate 31-1 (13.7 mg, 0.08 mmol) and intermediate 6-2 (30 mg, 0.07 mmol), dissolved in DMF (3 ml), added HATU (31.3 mg, 0.08 mmol) and DIPEA (17.7 mg, 0.14 mmol), reacted at room temperature for 3 hours, water was added to the reaction solution, extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid, reacted at 50 degrees for 2 hours, concentrated, dissolved in 3 ml of methanol, added 0.5 ml of ammonia water, concentrated, and purified on a preparative plate to obtain 12 mg of the final product with a yield of 34.9%.

[0544] 1 H NMR (400MHz, MeOD) δ8.47(s,2H),8.20(s,1H),7.80(s,1H),7.59(s,1H),7.50(d,J=8Hz,1H),7.18(d,J=8Hz,1H),6.20-6.15 (m,1H),5.13-5.05(m,1H),3.98-3.93(m,2H),3.70-3.35(m,2H),2.80-2.75(m,2H),1.83(d,J=8Hz,3H),1.09(t,J=8Hz,3H).

[0545] Examples 32-45 and Examples 47-51

[0546] According to the synthetic route and method similar to Example 31, the compounds of each example shown in the table below were prepared by changing the starting materials and measuring 1 H NMR or mass spectral data.

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554] Example 46: 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H- Indazole-3-carboxamide

[0555]

[0556] Compound 46 Synthesis route:

[0557]

[0558] Synthesis method:

[0559] synthetic intermediates 46-1 :1-(3,5-dichloropyridin-4-yl)propan-1-ol

[0560] Dissolve DIEA (6.35g, 0.049mol) in 20ml THF, replace with nitrogen, cool to below -50℃, add n-butyllithium (20ml, 0.049mol) dropwise, and react for 10min; control the temperature from -70℃ to -50℃, add 3,5-dichloropyridine (6.0g, 0.041mol) dissolved in THF dropwise, and react for 20min; finally, add anhydrous propionaldehyde (4.7g, 0.082mol) dropwise, react at -50℃ for 2h, then return to room temperature naturally. LCMS monitoring shows that the reaction is complete. Add 30ml of ammonium chloride solution to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, purify on a silica gel column, and concentrate to obtain the intermediate. 46-1 7.8g, yield 93.9%.

[0561] synthetic intermediates 46-2 :1-(3,5-dichloropyridin-4-yl)propyl 4-methylbenzenesulfonate

[0562] The intermediate 46-1 (7.8g, 0.038mol) and TEA (11.5g, 0.114mol) were dissolved in 20ml DCM, cooled to 0°C, and p-toluenesulfonyl chloride (8.7g, 0.045mol) and DMAP (0.48g, 0.0038mol) were added. The reaction was allowed to react overnight at room temperature. Water was added to the reaction solution to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the intermediate. 46-2 Crude product 10.3g, yield 75.7%.

[0563] synthetic intermediates 46-3 :5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1H-indole

[0564] The intermediate 46-2 (10.3g, 0.028mol) and 5-hydroxyindole (4.6g, 0.034mol) were dissolved in 20ml DMF, cesium carbonate (28.0g, 0.086mol) was added, and the mixture was reacted at 60℃ for 2h. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to obtain the intermediate. 46-3 4.51 g, yield 49.1%. LC-MS m / z (ESI) [M+H] + Targeting C 15 H 13 The calculated value of Cl2N3O is: 322.04; the measured value is: 322.04.

[0565] synthetic intermediates 46-4:5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1H-indazole-3-carbaldehyde

[0566] Sodium nitrite (8.1 g, 0.117 mol) was dissolved in 20 ml of water, 20 ml of DMF was added, the temperature was lowered to 0 ° C, 3M HCl (24 ml, 0.073 mol) was added dropwise, and the temperature was removed after the addition, and the mixture was stirred at room temperature for 10 minutes. The intermediate dissolved in 20 ml of DMF was added dropwise. 46-3 (4.51g, 0.015mol), react at room temperature for 3h. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude intermediate 46-4 4.63 g, yield 94.3%. LC-MS m / z (ESI) [M+H] + Targeting C 15 H 12 The calculated value of Cl2N4O2 is: 351.03; the measured value is: 351.03.

[0567] synthetic intermediates 46-5 :5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde

[0568] Dissolve 46-4 (4.63 g, 0.013 mol) in 20 ml of DCM, add p-toluenesulfonic acid (2.26 g, 0.013 mol), stir for 2 minutes, add 3,4-dihydro-2H-pyran (1.32 g, 0.015 mol) in DCM (5 ml) to the reaction solution, and react at room temperature for 2 hours. Add water to the reaction solution, extract twice with DCM, combine the organic phases, wash with saturated sodium bicarbonate solution and saturated brine, respectively, dry over anhydrous sodium sulfate, concentrate, and purify on a silica gel column to obtain the intermediate 46-5 2.61 g, yield 45.6%. LC-MS m / z (ESI) [M+H] + Targeting C 20 H 20 The calculated value of N4O3 is: 435.09; the measured value is: 435.09.

[0569] synthetic intermediates 46-6 :5-(1-(3,5-dichloropyridin-4-yl)propoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid

[0570] 46-5 (100.0 mg, 0.221 mmol) was dissolved in 24 ml of acetonitrile and 8 ml of water, potassium permanganate (87.1 mg, 0.442 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. The reaction solution was filtered through celite, and the filtrate was adjusted to pH 3 with 3M hydrochloric acid. The mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to obtain the intermediate. 46-6 91 mg, yield 88.1%. LC-MS m / z (ESI) [M+H] + Targeting C 20 H 20 The calculated value of N4O4 is: 451.09; the measured value is: 451.09.

[0571] Synthetic compounds 46 :5-(1-(3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide

[0572] The intermediate 46-6 The product (40.0 mg, 0.088 mmol) was dissolved in 5 ml of DMF. HATU (40.5 mg, 0.11 mmol) and DIPEA (16.1 mg, 0.12 mmol) were added to the mixture and stirred at room temperature for one hour. Then, 1-methyl-1H-pyrazol-4-amine (8.6 mg, 0.088 mmol) was added to the mixture and allowed to react at room temperature for one hour. After completion of the reaction, the mixture was quenched with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was dissolved in 4 ml of methanol, followed by the addition of 2 ml of concentrated hydrochloric acid and heating to 50°C. After completion of the reaction, the reaction solution was evaporated under reduced pressure, the residue was dissolved in 2 ml of methanol, and neutralized with 0.5 ml of aqueous ammonia. After neutralization, the mixture was concentrated and purified on a preparative plate to obtain 6.0 mg of the final product in a yield of 15.4%. LC-MS m / z (ESI) [M+H] + Targeting C 20 H 18 The calculated value of Cl2N6O2 is: 445.09; the measured value is: 445.09.

[0573] Experimental assay 1: Determination of inhibitory activity against FGFR mutants

[0574] 1. Reagents and consumables

[0575]

[0576] 2. Experimental Procedure

[0577] 2.1 Prepare 1x kinase reaction buffer:

[0578] Prepare 1x kinase reaction buffer with 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT.

[0579] 2.2 Reaction conditions:

[0580]

[0581] 2.3 Compound Screening:

[0582] 1. Dilute the compound 4-fold in DMSO in a dilution plate, starting at a compound concentration of 2 mM (4 mM for nintedanib).

[0583] 2. Dilute the compound 40-fold into 1X kinase reaction buffer and shake on a shaker for 20 minutes.

[0584] 3. Prepare 2X FGFR1 V561M / FGFR2 V564F / FGFR3 K650E / VEGFR2 using 1X enzyme reaction buffer.

[0585] 4. Add 2 μl of FGFR1 V561M / FGFR2 V564F / FGFR3 K650E / VEGFR2 kinase (prepared in step 3) to each well of the reaction plate.

[0586] 5. Add 1 μl of compound diluted in buffer to each well, seal the plate with sealing film, centrifuge at 1000g for 30 seconds, and let it stand at room temperature for 10 minutes.

[0587] 6. Prepare 2.5x TK-substrate-biotin and ATP mixture using 1X enzyme reaction buffer and add 2μl of K-substrate-biotin / ATP mixture to the reaction plate.

[0588] 7. Seal the plate with sealing film and centrifuge at 1000g for 30 seconds. Incubate at room temperature for 50 minutes.

[0589] 8. Prepare 4X Sa-XL 665 (250 nM) in HTRF detection buffer.

[0590] 9. Add 5 μl of Sa-XL 665 and 5 μl of TK-antibody-Cryptate to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 1 hour.

[0591] 10. Use Biotek to read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665).

[0592] 3. Data Analysis

[0593] 3.1 Calculate the ratio for each well: The ratio is calculated as 665 / 615 nm.

[0594] 3.2 Inhibition rate was calculated as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%. The positive control was 20,000 nM nintedanib or infigratinib, and the negative control was 0.5% DMSO.

[0595] 3.3 Calculate IC50 and draw the inhibition curve of the compound:

[0596] The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: Data analysis was performed using Graphpad 6.0 software.

[0597] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*Hill Slope))

[0598] X: log value of compound concentration Y: inhibition rate (% inh)

[0599] 3.4 Result Verification

[0600] Data were exported from Envision and analyzed manually. Ratios were converted to inhibition percentages, and IC50 values ​​were calculated using inhibition percentages using PrismGraphPad 6.0. IC50 values ​​were recalculated using ratios to verify the accuracy of the results.

[0601] 3.5 Quality Control

[0602] Z factor>0.5; S / B>2

[0603] Positive control IC50 is within 3 times of the average value of all previous times

[0604] 4. Results

[0605] Table 1: Inhibitory effects of the compounds of Examples 1-22 on FGFR mutants

[0606]

[0607]

[0608] The compounds of the examples tested above all showed good inhibitory activity against FGFR1 V561M / FGFR2 V564F / FGFR3 V555M, while having relatively weak inhibition against VEGFR2.

[0609] Experimental assay 2: Determination of inhibitory activity against wild-type FGFR

[0610] 1. Reagents and consumables

[0611]

[0612] 2. Experimental Procedure

[0613] 2.1 Prepare 1x kinase reaction buffer:

[0614] Prepare 1x kinase reaction buffer with 1 volume of 5X kinase reaction buffer and 4 volumes of water; 5 mM MgCl2; 1 mM DTT.

[0615] 2.2 Reaction conditions:

[0616]

[0617] 2.3 Compound Screening:

[0618] 1. Dilute the compound 4-fold in DMSO in a dilution plate, starting at a compound concentration of 2 mM (4 mM for nintedanib).

[0619] 2. Dilute the compound 40-fold into 1X kinase reaction buffer and shake on a shaker for 20 minutes.

[0620] 3. Prepare 2X FGFR1 / FGFR2 / FGFR3 using 1X enzyme reaction buffer.

[0621] 4. Add 2 μl of FGFR1 / FGFR2 / FGFR3 kinase (prepared in step 3) to each well of the reaction plate.

[0622] 5. Add 1 μl of compound diluted in buffer to each well, seal the plate with sealing film, centrifuge at 1000g for 30 seconds, and let it stand at room temperature for 10 minutes.

[0623] 6. Prepare 2.5x TK-substrate-biotin and ATP mixture using 1X enzyme reaction buffer and add 2μl of K-substrate-biotin / ATP mixture to the reaction plate.

[0624] 7. Seal the plate with sealing film and centrifuge at 1000g for 30 seconds. Incubate at room temperature for 50 minutes.

[0625] 8. Prepare 4X Sa-XL 665 (250 nM) in HTRF detection buffer.

[0626] 9. Add 5 μl of Sa-XL 665 and 5 μl of TK-antibody-Cryptate to each well, centrifuge at 1000 g for 30 seconds, and react at room temperature for 1 hour.

[0627] 10. Use Biotek to read the fluorescence signals at 615 nm (Cryptate) and 665 nm (XL665).

[0628] 3. Data Analysis

[0629] 3.1 Calculate the ratio of each well. The ratio is calculated as 665 / 615 nm.

[0630] 3.2 Inhibition rate was calculated as follows: Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%. The positive control was 20,000 nM nintedanib; the negative control was 0.5% DMSO.

[0631] 3.3 Calculate IC50 and draw the inhibition curve of the compound:

[0632] The IC50 (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: Data analysis was performed using Graphpad 6.0 software.

[0633] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*Hill Slope))

[0634] X: log value of compound concentration Y: inhibition rate (% inh)

[0635] 3.4 Result Verification

[0636] Data were exported from Envision and analyzed manually. Ratios were converted to inhibition percentages, and IC50 values ​​were calculated using inhibition percentages using PrismGraphPad 6.0. IC50 values ​​were recalculated using ratios to verify the accuracy of the results.

[0637] 3.5 QC

[0638] Z factor>0.5; S / B>2

[0639] Positive control IC50 is within 3 times of the average value of all previous times

[0640] 4. Results

[0641] Table 2: Inhibitory effects of example compounds on wild-type FGFR

[0642]

[0643] The tested compounds of the examples also showed similar or better inhibitory activity against wild-type FGFR1 / FGFR2 / FGFR3 than nintedanib.

[0644] Experimental assay 3: Determination of inhibitory activity against FGFR mutants

[0645] According to the experimental procedure described in "Experimental Assay 1: Determination of Inhibitory Activity against FGFR Mutants", the inhibitory activity of Example Compounds 23-50 and the control compound Infigratinib against various FGFR mutants was measured using the same test method and equipment, but the operation was performed by different experimenters. The measurement results are shown in Table 3 below.

[0646] Table 3: Inhibitory effects of the compounds of Examples 23-50 on FGFR mutants

[0647]

[0648]

[0649] The data in the above table show that the compounds of Examples 23-50 all exhibited good inhibitory activity against FGFR1 V561M / FGFR2 V564F / FGFR3 V555M, while their inhibition against VEGFR2 was relatively weak.

[0650] While specific embodiments of the present invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the present invention. Rather, the words used in this specification are merely descriptive and are not restrictive. It will be apparent to those skilled in the art that various other changes and modifications may be made without departing from the general scope of this disclosure. Therefore, the appended claims are intended to include all such changes and modifications within the scope of the present invention.

Claims

1. A compound or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, which is a compound selected from formula (II) or formula (III), or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof: R 4 is H; R 6 is H; and R 5 The number of R is 0, 1, 2, 3, and each R 5 Each independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 ;and R 7 and R 8 Each is independently selected at each occurrence from: C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (3-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, or R 7 、R 8 and the atoms to which they are attached together form a 3-14 membered ring, X1 and X2 are each independently selected from -CH, N and R 5 C in case of connection.

2. A compound or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, which is a compound selected from formula (IV) or formula (V), or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof: R 4 is H; R 6 is H; and R 5 The number of R is 0, 1, 2, 3, and each R 5 Each independently selected from H, halogen, -OH, -NO2, -CN, -SF5, -SH, -SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 Bicyclic aryl, 7-11 membered bicyclic heteroaryl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 , wherein the-SC 1-4 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, -C 1-4 Alkyl-(C 3-7 Cycloalkyl), -C 1-4 Alkyl-(3-10 membered heterocycloalkyl), C 5-7 Aryl, 5-7 membered heteroaryl, C 7-11 The bicyclic aryl and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, -N(R 7 )(R 8 )、-N(R 7 )(C(=O)R 8 )、-C(=O)-N(R 7 )(R 8 ),-C(=O)-R 7 、-C(=O)-OR 7 、-OC(=O)R 7 、-N(R 7 )(S(=O)2R 8 )、-S(=O)2-N(R 7 )(R 8 ),-SR 7 AND-OR 7 ;and R 7 and R 8 Each is independently selected at each occurrence from: C 1-4 Halogenated alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, (C 3-7 Cycloalkyl)-C 1-4 Alkyl-, (3-10 membered heterocycloalkyl)-C 1-4 Alkyl-, (C 6-10 Aryl)-C 1-4 Alkyl- and (5-10 membered heteroaryl)-C 1-4 Alkyl-, wherein each option within the group is optionally substituted with 0, 1, 2, 3 or 4 substituents independently selected from the following groups: halogen, -OH, -NH2, -NH(CH3), -N(CH3)2, -CN, -NO2, -SF5, -SH, -SC 1-4 Alkyl, oxo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-4 Hydroxyalkyl, -SC 1-4 Alkyl, -C(=O)H, -C(=O)-C 1-4 Alkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NH2, -C(=O)-N(C 1-4 Alkyl)2, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, or R 7 、R 8 and the atoms to which they are attached together form a 3-14 membered ring, X1 and X2 are each independently selected from -CH, N and R 5 C in case of connection.

3. The compound according to claim 1 or 2, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-10 membered heterocycloalkyl are each optionally substituted with 0, 1, 2, 3 or 4 substituents each independently selected from the following groups: halogen, -CN, -OH, C 1-4 Alkyl, C 3-6 Cycloalkyl. 4 . The compound according to claim 1 , or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, which is an isotope-labeled compound wherein H is optionally substituted by D at each occurrence.

5. The compound according to claim 1 or 2, or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((R)-3-hydroxypyrrolidin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-morpholinopyridin-3-yl)-1H-indazole-3-carboxamide, N-(1-(1-cyanopropan-2-yl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxamide, N-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(4-hydroxypiperidin-1-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(1-hydroxycyclopropyl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(5-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-fluorophenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(1-ethylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, N-(1-cyclobutyl-1H-pyrazol-4-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(4-(morpholinomethyl)phenyl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-ethylazetidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((S)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((R)-2-hydroxypropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-ethyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylpiperidin-2-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, 5-(1-(3,5-dichloropyridin-4-yl)propoxy)-N-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide, and (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-N-(1-((1-methylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or its isotope-labeled compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

7. Use of the compound according to any one of claims 1 to 5 or its isotope-labeled compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating a disease or condition associated with FGFR.

8. The use according to claim 7, wherein the diseases and disorders associated with FGFR are selected from the group consisting of cancer, bone disorders or cartilage cell disorders, hypophosphatemic disorders and fibrotic diseases.

9. The method of claim 7, wherein the diseases and conditions associated with FGFR are selected from the group consisting of hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

10. The use according to any one of claims 7 to 9, wherein the disease or disorder associated with FGFR is a disease or disorder resistant to FGFR inhibitors that do not target the gating mutations due to gating mutations in FGFR.

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