CN106317023A

CN106317023A - Preparation method and application of indazole compound

Info

Publication number: CN106317023A
Application number: CN201510406062.7A
Authority: CN
Inventors: 段文虎; 耿美玉; 严伟; 丁健; 艾菁; 赵彬; 范珺; 彭霞; 陈奕
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2015-07-10
Filing date: 2015-07-10
Publication date: 2017-01-11
Also published as: WO2017008708A1

Abstract

The invention provides a preparation method and application of an indazole compound. Specifically, the invention provides a compound shown as a formula (I), wherein definitions of various groups are as shown in the specification. The compound disclosed by the invention has excellent tyrosine kinase inhibitory activity; and compared with the compounds in the prior art, the compound disclosed by the invention has low inhibition concentration, so the compound can be used for preparing a series of medicines capable of treating diseases related to the tyrosine kinase activity. The structural formula is as shown in the specification.

Description

The preparation method of indazole compounds and purposes

Technical field

The present invention relates to as shown in formula the stereoisomer of the indazole compounds of structure, geometric isomer, make a variation mutually Structure body, its pharmaceutical salts, its prodrug and hydrate thereof or solvate, be directed to the preparation method of described compound, bag Pharmaceutical composition containing described compound and it is as protein tyrosine kinase inhibitor, suppresses especially as FGFR Agent, the purposes in the medicine of the relevant diseases such as treatment cancer.

Background technology

Protein kinase is a kind of by the phosphorylation of specific amino acids on protein is regulated the protein of various cell function (enzyme).Protein by the change of conformation regulate activity and with other component binding abilities.The activity of protein kinase refers to , speed that phosphate group is attached on substrate by kinases, this speed can be by being converted into product in detection certain time The amount of substrate be measured.The phosphorylation of substrate occurs on the activation site of protein kinase.

Tyrosine kinase is a kind of protease that can be catalyzed and adenosine triphosphate is transferred to protein-tyrosine residue.These The kinases role that performer is important in somatomedin conduction trigger cell propagation, differentiation and transition process.

Fibroblast growth factor (FGF) has been identified have important regulation effect, such as device in many physiological process Official generates and angiogenesis etc..It is known that have more than 25 kinds of hypotypes, Desmocyte growth factor in FGF family Sub-receptor (FGFR) family comprises four hypotypes (FGFR1-4) altogether, and they are glycoproteins, comprises extracellular para-immunity ball Protein domain, the hydrophobic region of cross-film and intracytoplasmic tyrosine kinase domain.The combination of FGF causes FGFR dimerization, And then there is autophosphorylation and the activation of downstream signaling pathway of receptor.Some specific components of downstream signaling pathway is for cell Growth, metabolism and survival have very important effect.Therefore, FGFR signal path for the breeding of tumor cell, migration, Infiltration and angiogenesis have polyphenic important physiological action.

At present, it has been demonstrated that FGF signal path has with human cancer directly associates.In different types of cancerous cell The FGF process LAN phenomenon that (bladder cancer, renal carcinoma and carcinoma of prostate etc.) is all in the news out different.Therefore, FGF signal leads to Road is a promising therapy target.

In sum, this area is in the urgent need to developing novel tyrosine kinase inhibitor.

Summary of the invention

It is an object of the present invention to provide and there is the stereoisomer of the indazole compounds of structure shown in lower formula (I), several What isomer, tautomer, its pharmaceutical salts, its prodrug and hydrate thereof or solvate

Further object is that and the method preparing above-mentioned indazole compounds is provided.

It is yet a further object of the present invention to provide comprise therapeutically effective amount selected from above-mentioned indazole compounds, its pharmaceutical salts, The pharmaceutical composition of one or more in its prodrug and hydrate thereof or solvate.

A further object of the present invention is to provide selected from the stereoisomer of above-mentioned indazole compounds, geometric isomer, mutually One or more in tautomeric, its pharmaceutical salts, its prodrug and hydrate thereof or solvate are as protein tyrosine kinase Inhibitor, especially as FGFR1-3 inhibitor, prevents in preparation and/or treats and FGF/FGFR signal path exception table Reach the purposes in the medicine of relevant disease.

A first aspect of the present invention, it is provided that a kind of compound as shown in following formula (I):

Wherein:

R¹、R²、R³Be each independently selected from lower group: H, halogen；

R⁹For substituted or unsubstituted 5-7 unit heteroaryl；

R⁸、R¹⁰Be each independently selected from lower group: H, halogen, C1～C3 alkyl, C1～C3 alkoxyl；

R⁴、R⁵、R⁶、R⁷Be each independently selected from lower group: H, halogen, substituted or unsubstituted 3-8 unit heterocycle alkane Base amino, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl, replacement or do not take C1-C8 alkylidene-the hydroxyl in generation, substituted or unsubstituted 3-8 unit heterocyclic radical, substituted or unsubstituted 3-8 unit are miscellaneous Ring group-epoxide, substituted or unsubstituted C1-C8 alkyl-3-8 unit heterocyclic radical, substituted or unsubstituted C1-C8 alkyl Carbamoyl, substituted or unsubstituted 3-8 unit heterocyclic radical-C1-C8 alkyl-carbamoyl, substituted or unsubstituted C1-C8 alkoxy-alkyl-epoxide, orWherein, Ra, Rb are each independently selected from lower group: H, take Generation or unsubstituted C1-C8 alkyl, containing 1-3 selected from the heteroatomic substituted or unsubstituted 5-7 of N, S, O Unit heterocycle, substituted or unsubstituted C2-C8 alkyl-O-alkyl, substituted or unsubstituted C2-C8 amido-alkyl-carbonyl Base, substituted or unsubstituted C2-C8 amido-alkyl, substituted or unsubstituted hydroxyl-C1-C8 alkyl or Ra, Rb collectively forms with the nitrogen-atoms being connected containing 1-3 the heteroatomic substituted or unsubstituted 5-7 selected from N, S, O Unit's heterocycle；

M is selected from lower group: CH₂、CH、NH、N、O、S；

W is selected from O, NH；

Wherein, described replacement refer to the one or more hydrogen atoms on group be selected from lower group substituent group replace: halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 alkylidene-hydroxyl ,-Boc, containing miscellaneous former selected from N, S, O of 1-3 The substituted or unsubstituted 5-7 unit heterocycle of son；

Dotted line represents singly-bound or double bond, and is singly-bound or double bond during two dotted line differences.

In another preference, in two dotted lines at least one be double bond.

In another preference, work as R⁶ForM, W are NH, R¹、R²、R³、R⁴、R⁵、 R⁶、R⁷、R⁸When being H, R⁹It is not the group selected from lower group:

Work as R⁶ForM, W are NH, R¹、R²、R³、R⁴、R^5、R⁶、R⁷、R⁸When being H, R⁹It is not the group selected from lower group:

Work as R⁶For H, M, W are NH, R¹、R²、R³、R⁴、R^5、R⁶、R⁷、R⁸When being H, R⁹It is not Group selected from lower group:

In another preference, R⁹Selected from substituted or unsubstituted five yuan and six membered heteroaryl, it is preferable that described R⁹Choosing From unsubstituted or by 1-4 substituent group replace selected from the group of lower group: pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, Triazine radical, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl；Wherein, described substituent group is selected from lower group: F, Cl, Br, methyl, methoxyl group, amino；

R⁴、R⁵、R⁶、R⁷It is independently selected from H, halogen, substituted or unsubstituted C1-C8 alkyl, replacement or not Substituted C1-C8 alkoxyl, substituted or unsubstituted C1-C8 hydroxyl-alkyl, substituted or unsubstituted 3-8 unit heterocyclic radical, Substituted or unsubstituted 3-8 unit heterocyclic radical-epoxide, substituted or unsubstituted C1-C8 alkyl-hydroxyl-alkyl-hydroxyl, replacement Or unsubstituted C1-C8 alkyl-3-8 unit heterocyclic radical, substituted or unsubstituted C1-C8 alkyl-carbamoyl, replacement or Unsubstituted 3-8 unit heterocyclic radical-C1-C8 alkyl-carbamoyl, orWherein, Ra, Rb are independently of one another Selected from lower group: H, substituted or unsubstituted C1-C8 alkyl, containing 1-3 selected from the heteroatomic replacement of N, S, O or Unsubstituted 5-7 unit heterocycle, substituted or unsubstituted C2-C8 alkyl-O-alkyl, substituted or unsubstituted C2-C8 amido -alkyl-carbonyl, substituted or unsubstituted C2-C8 amido-alkyl, substituted or unsubstituted hydroxyl-C1-C8 alkyl or Ra, Rb collectively forms containing 1-3 the heteroatomic substituted or unsubstituted 5-7 unit selected from N, S, O miscellaneous with the nitrogen-atoms being connected Ring.

In another preference, R⁹For following structure:

Wherein:

R^9a、R^9b、R^9c、R^9d、R^9eIt is each independently selected from H, halogen, C1～C3 alkyl, C1～C3 alkoxyl, And it preferably is selected from H, F, Cl, Br, methyl and methoxyl group；

U, V, X, Y, Z are each independently selected from C, N, and at least one of which is N；And/or

R⁸、R¹⁰It is each independently selected from H, F, Cl, Br, methyl and methoxyl group.

In another preference, described compound has a structure shown in formula (III) or (IV):

Wherein:

R^9a、R^9b、R^9c、R^9d、R^9eSelected from lower group: H, halogen, methyl, ethyl, isopropyl methoxyl group；

R⁴、R⁵、R⁶、R⁷Be each independently selected from lower group: H, halogen, methoxyl group, ethyoxyl, isopropoxy, first ammonia Base, ethylamino, isopropylamino, dimethylamino, diethylamino, diisopropylaminoethyl, (1-methyl piperidine)-methyl- Amino, piperidyl, 1-methyl piperidine base, 1-ethyl piperidine base, 1-isopropyl piperidyl, 1-Boc piperidyl, pyrrolidine Base, piperazinyl, 1-methyl piperazine base, 1-ethyl piperazidine base, 1-isopropyl piperazinyl, 1-hydroxyethylpiperazin base, 1-first Epoxide ethyl piperazidine base, 1-methylaminoethyl piperazinyl, 1-Boc-piperazinyl, 2,6-lupetazin base, homopiperazine base, 1-methylhomopiperazin base, 1-ethyl homopiperazine base, 1-isopropyl homopiperazine base, morpholinyl, C1～C3 dimethylamino alkane Base amino, C1～C3 diethylamino alkyl amino, C1～C3 diisopropylaminoethyl alkyl amino, C1～C3 pyrrolidine Alkyl amino, C1～C3 piperidines alkyl amino, C1～C3 hydroxy alkyl, C1～C3 aminoalkyl, C1～C3 methoxy Base alkyl amino, C1～C3 ethyoxyl alkyl amino, C1～C3 isopropoxy alkyl amino, C1～C3 methoxyalkyl, C1～C3 ethyoxyl alkyl, C1～C3 isopropoxy alkyl, Dimethyl Glycyl amino, diethylamino acetyl Base amino, diisopropylaminoethyl acetyl-amino, dimethylamino propanoylamino, diethylaminopropionylamino, two Isopropylamino propanoylamino, methoxy ethyl epoxide, ethoxyethyl group epoxide, methoxy-propyl epoxide, ethoxy-c Base epoxide.

In another preference, described R⁹For substituted or unsubstituted pyridine radicals, wherein, replace refer on group one Or multiple hydrogen atom is selected from the substituent group of lower group and replaces: halogen, C1-C4 alkyl.

In another preference, described compound is selected from the compound shown in table 1.

A second aspect of the present invention, it is provided that a kind of pharmaceutical composition, described pharmaceutical composition includes: (a) treatment is effectively The compound as described in the first aspect of the invention of amount, or its stereoisomer, geometric isomer, tautomer, pharmacy Upper acceptable salt or prodrug, its hydrate or solvate, or a combination thereof, and optional (b) is pharmaceutically acceptable Carrier.

In another preference, described pharmaceutical composition is used for treating cancer；It is preferred that described cancer is selected from lower group: Breast carcinoma, nonsmall-cell lung cancer, bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, colon cancer, multiple myeloma, liver Cancer, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer and carcinoma of testis etc..

A third aspect of the present invention, it is provided that a kind of compound as described in the first aspect of the invention, or its stereoisomer, Geometric isomer, tautomer, pharmaceutically acceptable salt or prodrug, its hydrate or solvate, or a combination thereof Purposes, it is characterised in that be used for preparing the medicine that (i) prevents and/or treat cancer-related diseases；(ii) as albumen cheese ammonia Acid kinase (preferably FGFR) inhibitor.

In another preference, described tumor is selected from lower group: breast carcinoma, pulmonary carcinoma, bladder cancer, gastric cancer, cancer of pancreas, front Row adenocarcinoma, colon cancer, multiple myeloma AML, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, Glioblast cancer and carcinoma of testis.

In another preference, described tumor is selected from: breast carcinoma, nonsmall-cell lung cancer, bladder cancer, gastric cancer, cancer of pancreas, Carcinoma of prostate, colon cancer, multiple myeloma, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glue Matter blast cell cancer, carcinoma of testis, or a combination thereof.

A fourth aspect of the present invention, it is provided that a kind of protein tyrosine kinase inhibitor alive, described inhibitor contains suppression to be had The compound as described in the first aspect of the invention of effect amount.

In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment) Can be combined with each other between each technical characteristic that body describes, thus constitute new or preferred technical scheme.It is limited to a piece Width, tires out the most one by one at this and states.

Accompanying drawing explanation

Fig. 1 is the compound I-46 growth inhibited exercising result figure to people's pulmonary carcinoma NCI-H1581 Nude Mice.

Detailed description of the invention

The present inventor, through in-depth study for a long time, has prepared a class and has had tyrosine-kinase enzyme inhibition activity Compound of formula I.Compared with tyrosine kinase inhibitor of the prior art, described compound has higher suppression Activity.Based on above-mentioned discovery, inventor completes the present invention.

Term

In this article, in place of special instruction, it is selected that term " replaces " the one or more hydrogen atoms referring on group Replace from the substituent group of lower group: C₁～C₁₀Alkyl, C₃～C₁₀Cycloalkyl, C₁～C₁₀Alkoxyl, halogen, hydroxyl, Carboxyl (-COOH), C₁～C₁₀Aldehyde radical, C₂～C₁₀Acyl group, C₂～C₁₀Ester group, amino, phenyl；Described benzene Base includes unsubstituted phenyl or has the substituted-phenyl of 1-3 substituent group, and described substituent group is selected from: halogen, C₁-C₁₀ Alkyl, cyano group, OH, nitro, C₃～C₁₀Cycloalkyl, C₁～C₁₀Alkoxyl, amino.

In place of special instruction, among all compounds of the present invention, each chiral carbon atom can be optionally R structure Type or S configuration, or R configuration and the mixture of S configuration.

Term " C1～C8 alkyl " refers to the straight or branched alkyl with 1～8 carbon atom, such as methyl, ethyl, Propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.

Term " 3-8 unit heterocyclic radical " refers to that having 1-3 heteroatomic 3～8 yuan of saturated rings selected from lower group loses a hydrogen The group that atom is formed: N, S, O, such as pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or similar group.

Term " C1～C8 alkoxyl " refers to the straight or branched alkoxyl with 1-8 carbon atom, such as methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.

Term " halogen " refers to F, Cl, Br and I.

Term " C2-C8 amido-alkyl-carbonyl " refers to have " carbonyl-C₂～C₈Alkylidene-NH₂", " alkyl-N- Alkylidene-carbonyl (the total number of carbon atoms is 2-8) " or " (alkyl)₂-N-alkylidene-carbonyl (the total number of carbon atoms is 2-8) " knot The group of structure, such as CH₃NH-C (=O)-, C₂H₅NH-C (=O)-, C₃H₇NH-C (=O)-, (CH₃)₂N-C (=O)-, Or similar group.Wherein, C₁～C₄Alkyl defined as described above.

Term " C2-C8 amido-alkyl " refers to have " C₁～C₄Alkylidene-NH₂", " alkyl-N-alkylidene-(carbon Total atom number is 1-4) " or " (alkyl)₂-N-alkylidene-(the total number of carbon atoms is 1-4) " group of structure, such as -CH₂NH₂、-C₂H₅NH₂、-C₃H₇NH₂、-C₂H₄N(CH₃)₂, or similar group.Wherein, C₁～C₄Alkylidene For C₁～C₄Alkyl loses the group that a hydrogen atom is formed, C₁～C₄Alkyl defined as described above.

Unless stated otherwise, structural formula described in the invention be intended to include all of isomeric forms (such as enantiomerism, Diastereo-isomerism and geometric isomer (or conformer): such as contain R, S configuration of asymmetric center, (Z) of double bond, (E) isomer and (Z), the conformer of (E).Therefore distribute the single three-dimensional chemical isomer of bright compound or it is right The mixture reflecting isomer, diastereomer or geometric isomer (or conformer) broadly falls into the scope of the present invention.

Term " tautomer " represents that having the structural isomer of different-energy can exceed low energy barrier, thus mutually Convert.Such as, proton tautomer (i.e. prototropic change) includes being migrated by proton carrying out change, such as 1H-indazole and 2H- Indazole, 1H-benzo [d] imidazoles and 3H-benzo [d] imidazoles, valence tautomers includes by some bonding electricity Son is recombinated and is carried out change.

Formula (I) compound

Specifically, the present invention relates to the logical stereoisomer of the indazole compounds shown in formula (I), geometric isomer, mutually Tautomeric, its pharmaceutical salts, its prodrug and hydrate thereof or solvate:

Wherein:

M is selected from CH₂、CH、NH、N、O、S；

W is selected from O, NH；

Dotted line represents singly-bound or double bond, and is singly-bound or double bond during two dotted line differences；In another preference, two dotted lines In at least one be double bond.

R¹、R²、R³It is independently selected from H, F, Cl, Br；

R⁹Selected from five yuan and six membered heteroaryl, the most substituted or unsubstituted following group: pyridine radicals, pyrimidine radicals, pyrazine Base, pyridazinyl, triazine radical, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, described substituent group is 1-4 substituent group, independently takes from F, Cl, Br, methyl, methoxyl group, amino.

R⁸、R¹⁰It is respectively and independently selected from H, halogen, C1～C3 alkyl, C1～C3 alkoxyl；

R⁴、R⁵、R⁶、R⁷It is independently selected from H, F, Cl, Br, substituted or unsubstituted amino, replacement or does not takes Generation naphthene amino, substituted or unsubstituted heterocyclalkylamino, substituted or unsubstituted alkyl, replacement or do not take The alkoxyl in generation, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted heterocyclylalkoxy groups, replacement or unsubstituted Alkyl cycloheteroalkyl, substituted or unsubstituted alkyl-carbamoyl, substituted or unsubstituted miscellaneous alkyl carbamoyl Base, substituted or unsubstituted heterocycloalkylalkylamino formoxyl, substituted or unsubstituted Heterocyclylalkyl, replacement or not Substituted alkoxyalkyl epoxide.

In preferred implementation, R⁹For following structure:

Wherein:

R^9a、R^9b、R^9c、R^9d、R^9eIt is respectively and independently selected from H, halogen, C1～C3 alkyl, C1～C3 alkoxyl, and preferably From H, F, Cl, Br, methyl and methoxyl group.

U, V, X, Y, Z are respectively and independently selected from C or N, and at least one of which is N；

Preferably, logical indazole compounds shown in formula (I) is the compound shown in lower formula (III):

Wherein:

M is selected from CH₂、CH、NH、N、O、S；

W is selected from O, NH.

R¹、R²、R³It preferably is selected from H, F, Cl, Br；

R⁸、R¹⁰Be respectively and independently selected from H, halogen, C1～C3 alkyl, C1～C3 alkoxyl, and preferably be selected from H, F, Cl, Br, methyl and methoxyl group.；

R⁴、R⁵、R⁶、R⁷It is independently selected from H, F, Cl, Br, substituted or unsubstituted amino, replacement or unsubstituted Naphthene amino, substituted or unsubstituted heterocyclalkylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkane Epoxide, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted alkyl heterocycle Alkyl, substituted or unsubstituted alkyl-carbamoyl, substituted or unsubstituted miscellaneous alkyl-carbamoyl, replacement or do not take The heterocycloalkylalkylamino formoxyl in generation, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted alkoxyalkyl oxygen Base；

Indazole compounds shown in preferred logical formula (I) is the compound shown in lower formula (IV) or (V):

Wherein:

M is selected from CH₂、CH、NH、N、O、S；

W is selected from O, NH.

R¹、R²、R³It preferably is selected from H, F, Cl, Br；

R¹⁰It is independently selected from H, halogen, C1～C3 alkyl, C1～C3 alkoxyl, and preferably is selected from H, F, Cl, Br, first Base and methoxyl group.；

R⁴、R⁵、R⁶、R⁷It is respectively and independently selected from H, F, Cl, Br, substituted or unsubstituted amino, substituted or unsubstituted Naphthene amino, substituted or unsubstituted heterocyclalkylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alcoxyl Base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted alkyl heterocycle alkane Base, substituted or unsubstituted alkyl-carbamoyl, substituted or unsubstituted miscellaneous alkyl-carbamoyl, replacement or unsubstituted Heterocycloalkylalkylamino formoxyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted alkoxyalkyl epoxide, It preferably is selected from H, F, Cl, Br, methoxyl group, ethyoxyl, isopropoxy, methylamino, ethylamino, isopropylamino, diformazan Base amino, diethylamino, diisopropylaminoethyl, 1 (1-methyl piperidine)-1-methylamino, piperidyl, 1-methyl piperidine Base, 1-ethyl piperidine base, 1-isopropyl piperidyl, 1-Boc piperidyl, pyrrolidinyl, piperazinyl, 1-methyl piperazine base, 1-ethyl piperazidine base, 1-isopropyl piperazinyl, 1-hydroxyethylpiperazin base, 1-methoxy ethyl piperazinyl, 1-methylamino second Base piperazinyl, 1-Boc-piperazinyl, 2,6-lupetazin base, homopiperazine base, 1-methylhomopiperazin base, 1-ethyl height piperazine Piperazine base, 1-isopropyl homopiperazine base, morpholinyl, C1-C3 alkyl, C1～C3 dimethylamino amino, C1～C3 Diethylamino alkyl amino, C1～C3 diisopropylaminoethyl alkyl amino, C1～C3 pyrrolidinealkyl amino, C1～C3 Piperidines alkyl amino, C1～C3 hydroxy alkyl, C1～C3 aminoalkyl, C1～C3 methoxyalkyl amino, C1～C3 Ethyoxyl alkyl amino, C1～C3 isopropoxy alkyl amino, C1～C3 methoxyalkyl, C1～C3 ethyoxyl alkyl, C1～C3 isopropoxy alkyl, Dimethyl Glycyl amino, diethylamino acetyl-amino, diisopropylaminoethyl Acetyl-amino, dimethylamino propanoylamino, diethylaminopropionylamino, diisopropylaminoethyl propanoylamino, Methoxy ethyl epoxide, ethoxyethyl group epoxide, methoxy-propyl epoxide, ethoxycarbonyl propyl epoxide.

Preferably, the present invention leads to the compound in table 1 below of the indazole compounds shown in formula (I)

Table 1

Preferably, the compound of the present invention can be to be prepared as the form of various pharmaceutical salts, the compounds of this invention medicinal The preparation of salt, can use the free alkali of compound, carries out with inorganic or the direct salt-forming reaction of organic acid.Inorganic or have Machine acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, Fluohydric acid., hydrobromic acid, formic acid, acetic acid, picric acid, Fructus Citri Limoniae Acid, maleic acid, Loprazolam, trifluoromethayl sulfonic acid, ethane sulfonic acid and p-methyl benzenesulfonic acid etc..

The preparation method of formula (I) compound

The invention still further relates to four kinds of preparation methoies with the indazole compounds of logical formula (I) structure,

Method 1 comprises the steps:

From compound 1, pyridine ring is replaced and make alcohol, then make sulphonic acid ester, be then replaced to ether, then indole is made The last cyclization of indazole aldehyde obtains target product.

Specifically, described preparation method comprises the steps:

1. compound 1 generates alcohol 2 with corresponding aldehyde reaction in the basic conditions；

2. compound 2 generates sulphonic acid ester 3 with methylsufonyl chloride effect；

3. compound 3 is replaced to ether 4 in the basic conditions with corresponding 5-OHi；

4. compound 4 generates indazole aldehyde 5 with sodium nitrite effect in acid condition；

5. compound 5 obtains target product with corresponding o-phenylenediamine (Ortho-Aminophenol or 2-aminobenzene thioether) compound condensation Thing.

Method 2 comprises the steps:

From compound 1 by corresponding aldehyde (ketone) and corresponding amino indole condensating reductive, then indole is made indazole aldehyde Rear cyclization obtains target product.

Specifically, described preparation method comprises the steps:

1. compound 1 reacts generation indole 2 under reducing agent effect with corresponding 5-amino indole；

2. compound 2 generates indazole aldehyde 3 with sodium nitrite effect in acid condition；

3. compound 5 obtains target product with corresponding o-phenylenediamine (Ortho-Aminophenol or 2-aminobenzene thioether) compound condensation Thing.

Method 3 comprises the steps

Protect from compound 1 by hydroxyl silicon ether, then carry out iodo, protect nitrogen hydrogen, removing with Pentamethylene oxide. the most again Replacing after silicon ether protection group, carry out coupling the most again with corresponding boric acid, finally removing Pentamethylene oxide. protection group obtains mesh Mark product.

Specifically, described preparation method comprises the steps:

1. compound 1 reacts generation silicon ether 2 in the basic conditions with tert-butyl chloro-silicane；

2. compound 2 carries out iodo under the conditions of N-N-iodosuccinimide and obtains compound 3；

3. compound 3 is gone up Pentamethylene oxide. protection group in acid condition and is obtained compound 4；

4. compound 4 deprotection under tetrabutyl ammonium fluoride effect obtains indazole alcohol 5；

5. compound 5 replaces with compound 3 in method 1 in the basic conditions, obtains compound 6；

6. compound 6 carries out coupling reaction under palladium catalyst effect with corresponding boric acid and obtains compound 7；

7. compound 7 deprotection base in acid condition obtains target product.

Method 4 comprises the steps

Compound is compound 3s from method 1, replace through sodium azide, become amine after reduction, then with bromo indole coupling, de- Except protection group, then making aldehyde, last cyclization obtains target product.

Specifically, described preparation method comprises the steps:

1. compound 1 is replaced to azido compound 2 under sodium azide effect；

2. compound 2 is reduced into amine 3 under the conditions of zinc powder ammonium chloride；

3. compound 3 and bromo indole obtain compound 4 through Buchwald coupling；

4. compound 4 generates compound 5 under nitrous acid effect；

Compound 5 obtains target and produces with corresponding o-phenylenediamine (Ortho-Aminophenol or 2-aminobenzene thioether) compound condensation Thing.

Wherein, M, U, V, X, Y, Z, R¹-R¹⁰As defined above and preferably.

The preparation method of the indazole compounds of the present invention has that reaction condition is gentle, abundant raw material is easy to get, operate and after locate The advantages such as reason is simple.

The purposes of formula (I) compound

Indazole compounds has been applied in terms for the treatment of cancer as FGFR inhibitor, such as WO2010129509, US2003207883, US20060079564 etc., it should be pointed out that US2003207883, US20060079564 two parts The claim of patent comprises the compound of the present invention, but in its specific embodiment, in indazole 5 bit substituent not Relate to the embodiment of pyridine alkoxyl, but benzyloxy replaces, and the present inventor is by literature survey and the crystalline substance to FGFR Find after body structural research, compound can be significantly improved after benzyloxy is replaced with pyridine alkoxyl the suppression of FGFR is made With and selectivity because pyridine nitrogen atom can with Asn568 formed hydrogen bond action (Mol Cancer Ther；10(11), 2011), additionally compound physicochemical property is improved, and the reproduction inhibitory activity of different cell strains is become apparent from by it, this point (, relative to I-38, I-37 is relative to I-39 for I-36) can be embodied in an embodiment of the present invention.

The present inventor designs the indazole compounds having synthesized a series of novel structure, passes through structure optimization, it was found that In enzyme, cell and animal body, all there is the little molecule FGFR inhibitor of excellent activity, and FGFR1-3 is all had Strong inhibition effect, this series compound is expected to be used clinically for treating FGF/FGFR signal path unconventionality expression and is drawn The disease risen, such as cancer etc..

The present invention is by the crystal structure of FGFR and the research of other tyrosine kinase inhibitor structure activity relationship, and design is closed Become the compound of a series of novel structure, by molecule, cell and animal model, these compounds have been screened, sent out These compounds existing can substantially suppress FGFR enzymatic activity at molecular level, the various cancerous cell that FGFR is induced by cellular level Propagation also significantly inhibits effect, and can also significantly inhibit tumor growth in animal body.

The invention still further relates to a kind of pharmaceutical composition, described pharmaceutical composition comprise therapeutically effective amount selected from Yin shown in formula (I) In azole compounds, its pharmaceutical salts, its prodrug and hydrate thereof and solvate one or more and optionally, pharmacy Upper acceptable carrier, it can be used for treating the relevant diseases such as cancer.Described pharmaceutical composition can be according to different dosing way Footpath and be prepared as various forms.

The invention still further relates to selected from indazole compounds, its pharmaceutical salts, its prodrug and hydrate thereof shown in above-mentioned formula (I) and molten In agent compound one or more or above-mentioned comprise therapeutically effective amount selected from indazole compounds shown in formula (I), it is medicinal The pharmaceutical composition of one or more in salt, its prodrug and hydrate thereof and solvate is at relevant diseases such as treatment cancers Purposes in medicine, preferably as protein tyrosine kinase inhibitor, especially as FGFR inhibitor.Described FGFR Including one or more in FGFR1, FGFR2, FGFR3.

Described cancer includes breast carcinoma, pulmonary carcinoma, bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, colon cancer, multiple Myeloma AML, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer and carcinoma of testis. More particularly, these cancers are selected from: breast carcinoma, nonsmall-cell lung cancer, bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, Colon cancer, multiple myeloma, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer, And carcinoma of testis.Additionally, the present invention provides a kind of includes that the compounds of this invention or salt are as active component for treat cancer Pharmaceutical composition, wherein cancer is selected from: breast carcinoma, nonsmall-cell lung cancer, bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, Colon cancer, multiple myeloma, hepatocarcinoma, melanoma, head and neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer, With carcinoma of testis etc..

Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate this Bright rather than limit the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to Normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number be by weight Calculate.

Embodiment 1:

3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-(1-3,5 dichloropyridine-4-base) Ethyoxyl)-1H-indazole (I-1)

Step 1: preparation 1-(3,5-dichloropyridine-4-base) ethanol

11.4 milliliters of diisopropylamines are dissolved in 80 milliliters of dry oxolanes, at 0 DEG C, drip 33.8 milliliters of positive fourths The tetrahydrofuran solution (2.4 moles every liter) of base lithium, after dropping, is cooled to-78 DEG C and stirs 1 hour, drip 10 grams 20 milliliters of tetrahydrofuran solutions of 3,5-dichloropyridines, drip off for 30 minutes, after continuing stirring at a temperature of being somebody's turn to do 1 hour, and dropping 20 milliliters of tetrahydrofuran solutions of 7.6 milliliters of acetaldehyde, drip off for 30 minutes, after continuing stirring 2 hours, add 200 milliliters Saturated aqueous ammonium chloride, adds ethyl acetate extraction, organic facies saturated sodium-chloride water solution after separatory after stirring 1 hour After washing, anhydrous sodium sulfate is dried, filtering and concentrating, and residue column chromatography (ethyl acetate: petroleum ether=10:90) separates 12 grams of white solids, yield 92%.

¹H NMR(300MHz,CDCl₃) δ 8.44 (s, 2H), 5.59 5.46 (m, 1H), 2.82 (d, J= 9.6Hz, 1H), 1.63 (d, J=7.8Hz, 3H).

Step 2: preparation 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester

12 grams of 1-(3,5-dichloropyridine-4-base) ethanol is dissolved in 100 milliliters of dichloromethane, adds 8.7 milliliter of three second Amine, drips 6.3 milliliters of methylsufonyl chlorides at 0 DEG C, recover to room temperature, continue stirring 1 hour, add water after dropping With dichloromethane separatory, after the washing of organic facies saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue Column chromatography (ethyl acetate: petroleum ether=10:90) separates to obtain 14.5 grams of white solids, yield 86%.

¹H NMR(300MHz,CDCl₃) δ (ppm): 8.51 (s, 2H), 6.36 (q, J=6.9Hz, 1H), 2.97 (s, 3H), 1.81 (d, J=6.9Hz, 3H).

Step 3: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole

By 10 grams of 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester, 5.4 grams of 5-OHis and 14.47 grams of carbon Acid caesium is dissolved in 200 milliliters of DMFs, is warming up to 80 DEG C, stops heating, reactant liquor after stirring 1 hour Being concentrated to dryness, residue column chromatography (ethyl acetate: petroleum ether=10:90) separates to obtain 11 grams of pale yellow oil, yield 96%.

¹H NMR(400MHz,CDCl₃) δ: 8.40 (s, 2H), 8.11 (s, 1H), 7.23 (d, J=8.8Hz, 1H), 7.14 (t, J=2.8Hz, 1H), 6.99 (d, J=2.4Hz, 1H), 6.88 (dd, J=8.8,2.4 Hz, 1H), 6.40 (m, 1H), 6.02 (q, J=6.7Hz, 1H), 1.79 (d, J=6.7Hz, 3H).

Step 4: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde

11 grams of 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole is dissolved in 560 milliliters of dioxane and 560 In the mixed solution of milliliter water, add 28 grams of sodium nitrite, be cooled to 0 DEG C, drip 120 milliliters of hydrochloride aqueous solutions (2 Mole every liter), after dropping, recover to being stirred at room temperature 3 hours, add ethyl acetate extraction, the saturated chlorine of organic facies After changing sodium water solution washing, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (ethyl acetate: dichloromethane=10: 90) 3.7 grams of brown solids, yield 36% are separated to obtain.

¹H NMR(300MHz,CDCl₃)δ:10.13(s,1H),8.37(s,2H),7.52(s,1H),7.41 (d, J=9.0Hz, 1H), 7.13 (d, J=9.1Hz, 1H), 6.07 (q, J=6.7Hz, 1H), 1.78 (d, J=6.7Hz, 3H).

Step 5: preparation 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline

By 3 grams of 2-nitro-5-fluoroanilines, 3.23 grams of 4-piperidinyl piperidines are dissolved in 50 milliliters of N-Methyl pyrrolidone, add 6.7 milliliters of triethylamines, are heated to 100 DEG C, and 3 as a child stopped heating, recover to room temperature, add ethyl acetate extraction, After separatory, after the washing of organic facies saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (two Chloromethanes: methanol=97:3) separate to obtain 3.53 grams of yellow solids, yield 60%.

Step 6: preparation 3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-(1-3,5 dichloro Pyridin-4-yl) ethyoxyl)-1H-indazole

16 milligrams of 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline is dissolved in 10 ml methanol, adds 3 milligrams 10% palladium carbon, in atmosphere of hydrogen, after stirring 1 hour under room temperature, filtering and concentrating, residue is dissolved in 10 milliliters of ethanol, adds 14 milligrams of 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde stop heating after refluxing 2 hours, instead Liquid is answered to be concentrated to dryness, residue column chromatography (dichloromethane: methanol=95:5), obtain yellow solid 9 milligrams, yield 30%.

¹H NMR(300MHz,CD₃OD)δ8.87(s,2H),8.26(s,1H),8.00(s,1H),7.93- 7.90 (m, 1H), 7.63-7.60 (m, 1H), 7.51-7.48 (m, 1H), 6.67 (q, J=6.4Hz, 1H), 4.14(m,2H),3.22-3.11(m,7H),2.46(m,2H),2.37–2.04(m,8H),1.96(s, 2H).

Embodiment 2:

2 (2 (5 (1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base) ethanol (I-2)

Step 1: preparation 4-nitrobenzophenone alcohol, acetic acid ester

300 milligrams of 4-Nitrophenethyl alcohol are dissolved in 10 milliliters of dichloromethane, add 290 microlitre pyridines, 22 milligrams of 4- Dimethyl aminopyridine, drips 340 microlitre acetic anhydrides under room temperature, after being stirred overnight, reactant liquor adds water separatory, aqueous phase dichloro Methane extracts, and after the washing of organic facies saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (ethyl acetate: petroleum ether=10:90) separates to obtain 323 milligrams of colorless oil, yield 86%.

¹H NMR(300MHz,CDCl₃) δ: 8.17 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 4.32 (t, J=6.7Hz, 2H), 3.05 (t, J=6.7Hz, 2H), 2.03 (s, 3H).

Step 2: preparation 4-aminophenyl alcohol, acetic acid ester

310 milligrams of 4-nitrobenzophenone alcohol, acetic acid esters are dissolved in 10 ml methanol, add 933 milligrams of ammonium formates, 150 Milligram 10% palladium carbon, is heated to reflux 1 hour, recovers to room temperature, filtering and concentrating, residue column chromatography (ethyl acetate: Petroleum ether=20:80) separate to obtain 220 milligrams of light brown grease, yield 83%.

¹H NMR(30MHz,CDCl₃) δ: 7.01 (d, J=8.4Hz, 2H), 6.66 (d, J=8.4Hz, 2H), 4.21 (t, J=7.1Hz, 2H), 3.11 (s, 3H), 2.82 (t, J=7.1Hz, 2H), 2.03 (s, 3H).

Step 3: preparation 2-(4-amino-3-nitrobenzophenone) ethanol

At 0 DEG C, in 3 milliliters of trifluoroacetic anhydride, drip 200 milligrams of 4-aminophenyl alcohol, acetic acid esters, stir 10 minutes After, 135 milligrams of potassium nitrate of disposable addition, recover to stirred overnight at room temperature, decompression is distilled off excess trifluoroacetic anhydride, Residue add in saturated sodium bicarbonate aqueous solution and after, ethyl acetate extracts, after organic facies is washed with saturated sodium-chloride water solution Anhydrous sodium sulfate is dried, filtering and concentrating, obtains 260 milligrams of rufous grease, adds 5 ml methanol, 324 milligrams of carbonic acid Potassium, stirs half an hour under room temperature, and filtering and concentrating obtains 130 milligrams of orange solids, two step yields 82%.

¹H NMR (300MHz, Acetone) δ: 7.86 (d, J=2.0Hz, 1H), 7.29 (dd, J=8.6, 2.0Hz, 1H), 6.95 (d, J=8.6Hz, 1H), 6.84 (s, 1H), 3.74 3.63 (m, 3H), 2.69 (m,6.4Hz,2H).

Step 4:2 (2 (5 (1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] Imidazoles-6-base) ethanol

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 2-(4-amino-3-nitrobenzophenone) ethanol, remaining Needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain beige solid 2 (2 (5 (1-(3,5-bis- Chloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) ethanol

¹H NMR(300MHz,DMSO)δ:13.44(s,1H),12.72(s,1H),8.61-8.60(m,1H), 7.82 (s, 1H), 7.64-7.35 (m, 1H), 7.56-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.57 7.51 (m, 1H), 7.54 (d, J=9.0Hz, 1H), 7.30 (s, 1H), 7.15 (dd, J=9.0, 2.4Hz, 1H), 7.07 (dd, J=8.2,1.4Hz, 1H), 6.10 (q, J=6.7Hz, 1H), 4.71 4.61 (m, 1H), 3.74 3.60 (m, 2H), 2.91 2.81 (m, 2H), 1.78 (d, J=6.6Hz, 3H).

Embodiment 3:

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-methylpiperazine-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-3)

Step 1: preparation 5-(4-methylpiperazine-1-yl)-2-nitroaniline

Changing 4-piperidinyl piperidine into 4-methyl piperazine, remaining needed raw material, reagent and preparation method are with in embodiment 1 Step 5, obtains yellow solid 5-(4-methylpiperazine-1-yl)-2-nitroaniline.

¹H NMR (300MHz, DMSO) δ 7.80 (d, J=9.7Hz, 1H), 7.25 (s, 2H), 6.39 (dd, J=9.8,2.6Hz, 1H), 6.21 (d, J=2.6Hz, 1H), 3.30 (m, 4H), 2.43 2.37 (m, 4H),2.20(s,3H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-methylpiperazine-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(4-methylpiperazine-1-yl)-2-Nitrobenzol Amine, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloros Pyridin-4-yl) ethyoxyl)-3-(6-(4-methylpiperazine-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ:13.41-13.36(m,1H),12.60-12.55(m,1H),8.60 (s, 2H), 7.84-7.80 (m, 1H), 7.58-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19 -6.88 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 6.99-6.98 (m, 1H), 6.10 (q, J=6.7 Hz, 1H), 3.13 (s, 4H), 2.24 (s, 4H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 4

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-4)

Step 1: preparation 5-(piperidin-1-yl)-2-nitroaniline

Change 4-piperidinyl piperidine into piperidines, remaining needed raw material, reagent and preparation method with the step 5 in embodiment 1, Obtain yellow solid 5-(piperidin-1-yl)-2-nitroaniline.

¹H NMR(300MHz,CDCl₃) δ: 7.98 (d, J=9.7Hz, 1H), 6.26 (dd, J=9.7,2.4 Hz, 1H), 6.14 (s, 2H), 5.91 (d, J=2.4Hz, 1H), 3.36 (s, 4H), 1.65 (m, 6H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, remaining Needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloropyridine-4- Base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ13.40-13.35(m,1H),12.58-12.52(m,1H),8.60 (s, 2H), 7.84-7.80 (m, 1H), 7.57-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19 -6.88 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 6.99-6.98 (m, 1H), 6.10 (q, J=6.7 Hz, 1H), 3.15-3.07 (m, 4H), 1.78 (d, J=6.7Hz, 3H), 1.73-1.69 (m, 4H), 1.58 -1.50(m,2H),

Embodiment 5

3-(1H-benzo [d] imidazoles-2-base-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole (I-5)

By molten to 67 milligrams of 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde, 22 milligrams of o-phenylenediamines In 2 milliliters of ethanol, stopping heating after refluxing 2 hours, reactant liquor is concentrated to dryness, residue column chromatography (dichloromethane: Methanol=97:3), obtain faint yellow solid 67 milligrams, yield 79%.

¹H NMR (300MHz, DMSO) δ: 13.48 (s, 1H), 12.86 (s, 1H), 8.61 (s, 2H), 7.83 (d, J=2.3Hz, 1H), 7.78 7.72 (m, 1H), 7.55 (d, J=9.0Hz, 1H), 7.51 7.45 (m, 1H), 7.22 (dd, J=5.9,3.2Hz, 2H), 7.16 (dd, J=9.0,2.4Hz, 1H), 6.10 (q, J=6.6Hz, 1H), 1.78 (d, J=6.6Hz, 3H).

Embodiment 6

2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-methyl-N-(1-methyl piperidine-4- Base)-1H-benzo [d] imidazoles-6-amine (I-6)

Step 1: preparation N¹-methyl-N¹-(1-methyl piperidine-4-base)-4-Nitrobenzol-1,3-diamidogen

4-piperidinyl piperidine changes into N, 1-lupetidine-4-amine, and remaining needed raw material, reagent and preparation method are with implementing Step 5 in example 1, obtains yellow solid N¹-methyl-N¹-(1-methyl piperidine-4-base)-4-Nitrobenzol-1,3-diamidogen.

¹H NMR (300MHz, DMSO) δ: 7.80 (d, J=9.8Hz, 1H), 7.23 (s, 2H), 6.29 (dd, J=9.8,2.7Hz, 1H), 6.07 (d, J=2.6Hz, 1H), 3.72 3.59 (m, 1H), 2.85-2.80 (m, 5H), 2.17 (s, 3H), 2.01 (t, J=10.8Hz, 2H), 1.77 (qd, J=12.1,3.6Hz, 2H), 1.56(m,2H).

Step 2:2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-methyl-N-(1-methyl Piperidin-4-yl)-1H-benzo [d] imidazoles-6-amine

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into N1-methyl-N1-(1-methyl piperidine-4-base 4- Nitrobenzol-1,3-diamidogen, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-methyl-N-(1-methyl piperidine-4- Base)-1H-benzo [d] imidazoles-6-amine.

¹H NMR(300MHz,DMSO)δ13.38-13.31(m,1H),12.52-12.38(m,1H),8.60 -8.58 (m, 2H), 7.83 (dd, J=15.9,2.1Hz, 1H), 7.57 7.27 (m, 2H), 7.15 (d, J=2.4Hz, 1H), 7.14 6.84 (m, 2H), 6.79 (d, J=2.1Hz, 1H), 6.09 (q, J=6.7 Hz, 1H), 3.52 (m, 6.6Hz, 1H), 2.85 (d, J=11.8Hz, 2H), 2.83-2.74 (s, 3H), 2.18 (s, 3H), 1.99 (t, J=10.3Hz, 2H), 1.83 1.56 (m, 7H).

Embodiment 7

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-methoxyl group-1H-benzo [d] imidazoles-2-base)-1H-indazole (I-7)

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 2-nitro-4-aminoanisole, former needed for remaining Material, reagent and preparation method, with the step 6 in embodiment 1, obtain light pink solid 5-(1-(3,5-dichloropyridine-4-base) Ethyoxyl)-3-(6-methoxyl group-1H-benzo [d] imidazoles-2-base)-1H-indazole.

¹H NMR(300MHz,DMSO)δ:13.43-13.39(m,1H),12.70(s,1H),8.60(s,2H), 7.83-7.79 (m, 1H), 7.62-7.34 (m, 1H), 7.53 (d, J=8.1Hz, 1H), 7.24-6.94 (m, 1H), 7.14 (d, J=8.8Hz, 1H), 6.85 (d, J=8.1Hz, 1H), 6.10 (q, J=6.7Hz, 1H), 3.86-3.80 (m, 3H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 8

2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-methyl isophthalic acid H-benzo [d] imidazoles-6 -amine (I-8)

Step 1: preparation N¹-methyl-4-Nitrobenzol-1,3-diamidogen

Changing 4-piperidinyl piperidine into methylamine hydrochloride, remaining needed raw material, reagent and preparation method are with in embodiment 1 Step 5, obtains yellow solid N¹-methyl-4-Nitrobenzol-1,3-diamidogen

¹H NMR (400MHz, DMSO) δ 7.72 (d, J=9.5Hz, 1H), 7.37 (s, 2H), 6.95 (d, J=2.4Hz, 1H), 5.99 (dd, J=9.5,2.4Hz, 1H), 5.77 (d, J=2.0Hz, 1H), 2.69 (d,3H).

Step 2: preparation 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-methyl isophthalic acid H-benzene And [d] imidazoles-6-amine

5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline is changed into N1-methyl-4-Nitrobenzol-1,3-diamidogen, remaining Needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain beige solid 2-(5-(1-(3,5-dichloropyridines -4-base) ethyoxyl)-1H-indazole-3-base)-N-methyl isophthalic acid H-benzo [d] imidazoles-6-amine

¹H NMR(300MHz,DMSO)δ13.29(s,1H),12.29(s,1H),8.60(s,2H),7.81 (s, 1H), 7.50 (d, J=9.0Hz, 1H), 7.41 (s, 1H), 7.12 (dd, J=9.0,2.4Hz, 1H), 6.58 (dd, J=8.7,2.0Hz, 1H), 6.49 (s, 1H), 6.08 (q, J=6.7Hz, 1H), 2.73 (s, 3H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 9

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-fluoro-1H-benzo [d] imidazoles-2-base)-1H-indazole (I-9)

5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline is changed into 2-nitro-5-fluoroaniline, remaining needed raw material, Reagent and preparation method, with the step 6 in embodiment 1, obtain white solid 5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-3-(6-fluoro-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ:13.53-13.51(m,1H),12.99(s,1H),8.62-8.61 (m, 2H), 7.78 (s, 1H), 7.74-7.43 (m, 1H), 7.55 (d, J=8.1Hz, 1H), 7.51-7.19 (m, 1H), 7.16 (dd, J=9.0,2.4Hz, 1H), 7.11-7.04 (m, 1H), 6.10 (q, J=6.7Hz, 1H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 10

N-(2-(5-(1-(3,5 dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base)-2-(dimethylamino)-N-methylacetamide (I-10)

Step 1: the preparation bromo-N-of 2-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H- Benzo [d] imidazoles-6-base)-N-methylacetamide

By 400 milligrams of 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl))-1H-indazole-3-base)-N-methyl isophthalic acid H-benzene And [d] imidazoles-6-amine, 0.25 milliliter of triethylamine is dissolved in 10 milliliters of N,N-dimethylacetamide, drips 88 microlitres under ice bath Bromoacetyl chloride, moves to stirred overnight at room temperature, adds water and is extracted with ethyl acetate, and after separatory, organic facies saturated sodium-chloride is water-soluble Liquid washing after anhydrous sodium sulfate be dried, filtering and concentrating, residue column chromatography (dichloromethane: methanol=97:3) separate 260 The milligram bromo-N-of yellow solid 2-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base)-N-methylacetamide, yield 51%.

Step 4: preparation N-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzene And [d] imidazoles-6-base)-2-(dimethylamino)-N-methylacetamide

By 260 milligrams of bromo-N-of 2-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzene And [d] imidazoles-6-base)-N-methylacetamide is dissolved in the tetrahydrofuran solution of 10 milliliters of dimethylamine of 2M concentration, room temperature Be stirred overnight, be spin-dried for reactant liquor, residue column chromatography (dichloromethane: methanol=97:3) separate 180 milligrams of yellow are solid Body N-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base)-2-(dimethylamino)-N-methylacetamide, yield 74%

¹H NMR(300MHz,CDCl₃) δ 8.31 (s, 2H), 7.82 (s, 1H), 7.66 (d, J=7.9Hz, 1H), 7.53 (s, 1H), 7.41 (d, J=9.0Hz, 1H), 7.07 (dd, J=9.1,2.0Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 6.09 (q, J=6.5Hz, 1H), 3.55 (s, 2H), 3.24 (s, 3H), 2.66 (s, 6H), 1.75 (d, J=6.5Hz, 3H).

Embodiment 11

5-(1-(3-chloropyridine-4-base) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-Yin Azoles (I-11)

Step one: preparation 1-(3-chloropyridine-4-base) ethanol

By 3,5-dichloropyridine changes 3-chloropyridine into, and remaining needed raw material, reagent and preparation method are with the step in embodiment 1 Rapid 1, obtain beige crystals 1-(3-chloropyridine-4-base) ethanol

¹H NMR(300MHz,CDCl₃) δ: 8.32 (m, 2H), 7.54 (d, J=5.0Hz, 1H), 5.15 (q, J=6.5Hz, 1H), 1.42 (d, J=6.5Hz, 3H).

Step 2: preparation 1-(3-chloropyridine-4-base) ethyl methane sulfonate ester

Change 1-(3,5-dichloropyridine-4-base) ethanol into 1-(3-chloropyridine-4-base) ethanol, remaining needed raw material, reagent And preparation method is with the step 2 in embodiment 1, obtain pale brown oil thing 1-(3-chloropyridine-4-base) ethyl methane sulfonate ester.

¹H NMR(300MHz,CDCl₃) δ: 8.59 (s, 1H), 8.55 (d, J=5.1Hz, 1H), 7.47 (d, J=5.1Hz, 1H), 6.03 (q, J=6.5Hz, 1H), 2.99 (s, 3H), 1.68 (d, J=6.5Hz, 3H).

Step 3: preparation 5-(1-(3-chloropyridine-4-base) ethyoxyl)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 1-(3-chloropyridine-4-base) ethyl methane sulfonate ester, its Remaining needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain colorless oil 5-(1-(3-chloropyridine-4- Base) ethyoxyl)-1H-indole

¹H NMR(300MHz,CDCl₃) δ: 8.56 (s, 1H), 8.41 (d, J=5.0Hz, 1H), 8.06 (s, 1H), 7.50 (d, J=5.0Hz, 1H), 7.28 7.22 (m, 1H), 7.16 (m, 1H), 6.89 (m, 1H), 6.84 (dd, J=8.7,2.3Hz, 1H), 6.40 (s, 1H), 5.64 (q, J=6.4Hz, 1H), 1.64 (d, J=6.4Hz, 3H).

Step 4: preparation 5-(1-(3-chloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(3-chloropyridine-4-base) ethoxy Base)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain colorless oil 5-(1-(3-chloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde.

¹H NMR(400MHz,CDCl₃) δ: 10.21 (s, 1H), 8.60 (s, 1H), 8.43 (d, J=5.1Hz, 1H), 7.55 (m, 1H), 7.46 (m, 2H), 7.15 (dd, J=9.1,2.3Hz, 1H), 5.76 (q, J=6.4 Hz, 1H), 1.67 (d, J=6.4Hz, 3H).

Step 5: preparation 5-(1-(3-chloropyridine-4-base) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-(1-(3-chloropyridine-4-base) ethoxy into Base)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid Body 5-(1-(3-chloropyridine-4-base) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,CDCl₃) δ 11.11 (s, 1H), 8.55 (s, 1H), 8.37 (d, J=5.0Hz, 1H), 7.98 (s, 1H), 7.62 7.51 (m, 1H), 7.44 (d, J=5.0Hz, 1H), 7.29-7.26 (m, 2H), 7.14 6.94 (m, 3H), 5.77 (dd, J=12.4,6.0Hz, 1H), 3.20 3.06 (m, 4H), 1.75 (s, 5H), 1.60 (d, J=6.4Hz, 4H).

Embodiment 12

5-(1-(3-fluorine pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-Yin Azoles (I-12)

Step one: preparation 1-(3-fluorine pyridin-4-yl) ethanol

By 3,5-dichloropyridine changes 3-fluorine pyridine into, and remaining needed raw material, reagent and preparation method are with the step in embodiment 1 Rapid 1, obtain colorless oil 1-(3-fluorine pyridin-4-yl) ethanol

¹H NMR(400MHz,CDCl₃) δ: 8.41 (d, J=4.8Hz, 1H), 8.38 (s, 1H), 7.50 (t, J=5.5Hz, 1H), 5.26 5.18 (m, 1H), 2.26 (d, J=4.2Hz, 1H), 1.52 (d, J=6.5 Hz,3H).

Step 2: preparation 1-(3-fluorine pyridin-4-yl) ethyl methane sulfonate ester

Change 1-(3,5-dichloropyridine-4-base) ethanol into 1-(3-fluorine pyridin-4-yl) ethanol, remaining needed raw material, reagent And preparation method is with the step 2 in embodiment 1, obtain pale brown oil thing 1-(3-fluorine pyridin-4-yl) ethyl methane sulfonate ester.

¹H NMR(300MHz,CDCl₃) δ 8.49:(m, 2H), 7.43 (t, J=5.5Hz, 1H), 5.99 (q, J=6.6Hz, 1H), 3.00 (s, 3H), 1.73 (d, J=6.6Hz, 3H).

Step 3: preparation 5-(1-(3-fluorine pyridin-4-yl) ethyoxyl)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 1-(3-fluorine pyridin-4-yl) ethyl methane sulfonate ester, its Remaining needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain colorless oil 5-(1-(3-fluorine pyridine-4- Base) ethyoxyl)-1H-indole

¹H NMR(300MHz,CDCl₃) δ: 8.43 (d, J=1.6Hz, 1H), 8.35 (d, J=4.9Hz, 1H), 8.07(s,1H),7.52–7.45(m,1H),7.29–7.23(m,1H),7.19–7.14(m,1H), 6.98 (d, J=2.2Hz, 1H), 6.87 (dd, J=8.8,2.4Hz, 1H), 6.41 (s, 1H), 5.64 (q, J=6.5Hz, 1H), 1.66 (d, J=6.5Hz, 3H).

Step 4: preparation 5-(1-(3-fluorine pyridin-4-yl) ethyoxyl)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(3-fluorine pyridin-4-yl) ethoxy Base)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown oil 5-(1-(3-fluorine pyridin-4-yl) ethyoxyl)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃) δ 10.21 (s, 1H), 8.50 (s, 1H), 8.40 (d, J=5.0Hz, 1H), 7.61 (d, J=2.2Hz, 1H), 7.49 (m, 2H), 7.18 (dd, J=9.0,2.3Hz, 1H), 5.77 (q, J=6.4Hz, 1H), 1.70 (d, J=6.4Hz, 3H).

Step 5: preparation 5-(1-(3-fluorine pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-(1-(3-fluorine pyridin-4-yl) ethoxy into Base)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid Body 5-(1-(3-fluorine pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ:13.45-13.40(m,1H),12.62-12.55(m,1H),8.60 (s, 1H), 8.41 (d, J=4.8Hz, 1H) 7.91-7.88 (m, 1H), 7.59-7.39 (m, 3H), 7.33 -6.90 (m, 1H), 7.20-7.17 (m), 6.99-6.92 (m, 1H), 5.81 (q, J=6.7Hz, 1H), 1.67-1.66(m,7H),1.57-1.53(m,2H).

Embodiment 13

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-((3R, 5S)-3,5-lupetazin-1-base)-1H-benzene And [d] imidazoles-2-base)-1H-indazole (I-13)

Step 1: preparation 5-((3R, 5S)-3,5-lupetazin-1-base)-2-nitroaniline

Changing 4-piperidinyl piperidine into (2R, 6S)-2,6-dimethyl-piperizine, remaining needed raw material, reagent and preparation method are same Step 5 in embodiment 1, obtains yellow solid 5-((3R, 5S)-3,5-lupetazin-1-base)-2-nitroaniline.

¹H NMR (300MHz, DMSO) δ 7.78 (d, J=9.8Hz, 1H), 7.23 (s, 2H), 6.40 (dd, J=9.8,2.2Hz, 1H), 6.20 (d, J=2.2Hz, 1H), 3.69 (d, J=11.7Hz, 2H), 2.82 2.67 (m, 2H), 2.31 (t, J=11.4Hz, 2H), 1.01 (d, J=6.2Hz, 6H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-((3R, 5S)-3,5-lupetazin -1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-((3R, 5S)-3,5-lupetazin-1- Base)-2-nitroaniline, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-((3R, 5S)-3,5-lupetazin-1-base)-1H-benzo [d] Imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ13.43-13.38(m,1H),12.62-12.54(m,1H),8.60 (s, 2H), 7.87-7.80 (m, 1H), 7.58-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19 -6.86 (m, 1H), 7.18-7.12 (m, 1H), 6.99-6.96 (m, 1H), 6.10 (q, J=6.7Hz, 1H), 3.51-3.47 (m, 2H), 2.97 (s, 2H), 2.26-2.17 (m, 2H), 1.78 (d, J=6.7Hz, 3H), 1.11-1.06(m,6H).

Embodiment 14

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-(4-methyl isophthalic acid, 4-Diazesuberane-1-base)-1H- Benzo [d] imidazoles-2 base)-1H-indazole (I-14)

Step 1: preparation 5-(4-methyl isophthalic acid, 4-Diazesuberane-1-base)-2-nitroaniline

4-piperidinyl piperidine changes into 1-methyl isophthalic acid, 4-Diazesuberane, and remaining needed raw material, reagent and preparation method are same Step 5 in embodiment 1, obtains yellow solid 5-(4-methyl isophthalic acid, 4-Diazesuberane-1-base)-2-nitroaniline

¹H NMR (300MHz, DMSO) δ 7.79 (d, J=9.8Hz, 1H), 7.22 (s, 2H), 6.24 (dd, J=9.8,2.6Hz, 1H), 6.02 (d, J=2.6Hz, 1H), 3.57 3.51 (m, 2H), 3.47 (t, J=6.2Hz, 2H), 2.62 2.55 (m, 2H), 2.47 2.40 (m, 2H), 2.25 (s, 3H), 1.92 –1.81(m,2H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-(4-methyl isophthalic acid, 4-Diazesuberane -1-base)-1H-benzo [d] imidazoles-2 base)-1H-indazole

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(4-methyl isophthalic acid, 4-Diazesuberane-1- Base)-2-nitroaniline, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-(4-methyl isophthalic acid, 4-Diazesuberane-1-base)-1H-benzo [d] Imidazoles-2 base)-1H-indazole.

¹H NMR(300MHz,DMSO)δ13.38-13.30(m,1H),12.45-12.32(m,1H),8.60 -8,58 (m, 2H), 7.86-7.80 (m, 1H), 7.53-7.26 (m, 2H), 7.13 (dd, J=9.0,2.2 Hz, 1H), 6.95-6.63 (m, 1H), 6.76-6.71 (m, 1H), 6.10 (q, J=6.7Hz, 1H), 3.57 -3.54 (m, 2H), 3.47 (t, J=6.0Hz, 2H), 2.72-2.67 (m, 2H), 2.50 (s, 2H), 2.28 (s, 3H), 2.07-1.90 (m, 2H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 15

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-ethyl piperazidine-1-base)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-15)

Step 1: preparation 5-(4-ethyl piperazidine-1-base)-2-nitroaniline

Changing 4-piperidinyl piperidine into 4-ethyl piperazidine, remaining needed raw material, reagent and preparation method are with in embodiment 1 Step 5, obtains yellow solid 5-(4-ethyl piperazidine-1-base)-2-nitroaniline.

¹H NMR (300MHz, DMSO) δ: 7.80 (d, J=9.7Hz, 1H), 7.27 (s, 2H), 6.38 (d, J=9.7Hz, 1H), 6.21 (s, 1H), 3.34 3.24 (m, 4H), 2.48 2.40 (m, 4H), 2.35 (q, J=7.0Hz, 2H), 1.02 (t, J=7.1Hz, 3H) ..

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-ethyl piperazidine-1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(4-ethyl piperazidine-1-base)-2-Nitrobenzol Amine, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloros Pyridin-4-yl) ethyoxyl)-3-(6-(4-ethyl piperazidine-1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ:13.42-13.37(m,1H),12.62-12.56(m,1H),8.60 (s, 2H), 7.84-7.80 (m, 1H), 7.58-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19 -6.88 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 6.99-6.98 (m, 1H), 6.10 (q, J=6.7 Hz, 1H), 3.12 (s, 4H), 2.55 (s, 4H), 2.41-2.35 (m, 2H), 1.78 (d, J=6.7Hz, 3H), 1.09-1.02(m,3H).

Embodiment 16

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-isopropyl piperazine-1-base)-1H-benzo [d] imidazoles -2-base)-1H-indazole (I-16)

Step 1: preparation 5-(4-isopropyl piperazine-1-base)-2-nitroaniline

4-piperidinyl piperidine changes into 4-isopropyl piperazine, and remaining needed raw material, reagent and preparation method are with in embodiment 1 Step 5, obtain yellow solid 5-(4-isopropyl piperazine-1-base)-2-nitroaniline.

¹H NMR (300MHz, DMSO) δ: 7.80 (d, J=9.7Hz, 1H), 7.27 (s, 2H), 6.38 (dd, J=9.7,2.5Hz, 1H), 6.19 (d, J=2.5Hz, 1H), 3.32 3.25 (m, 4H), 2.71--2.62 (m, 1H), 2.56 2.47 (m, 4H), 0.98 (d, J=6.5Hz, 6H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-isopropyl piperazine-1-base)-1H- Benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(4-isopropyl piperazine-1-base)-2-Nitrobenzol Amine, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloros Pyridin-4-yl) ethyoxyl)-3-(6-(4-isopropyl piperazine-1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,DMSO)δ13.42-13.37(m,1H),12.61-12.55(m,1H),8.60 (s, 2H), 7.84-7.80 (m, 1H), 7.58-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19 -6.88 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 6.99-6.98 (m, 1H), 6.10 (q, J=6.7 Hz, 1H), 3.12 (s, 4H), 2.63 (m, 5H), 1.78 (d, J=6.7Hz, 3H), 1.02 (d, J=6.0 Hz,3H).

Embodiment 17

3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(1-(pyridin-4-yl) ethyoxyl)-1H-indazole (I-17)

Step 1: preparation 1-(pyridin-4-yl) ethanol

1.21 grams of 4-acetylpyridine are dissolved in 25 ml methanol, under ice-water bath, are dividedly in some parts 757 milligrams of sodium borohydrides, After charging, recovering to being stirred at room temperature 2 hours, reactant liquor is concentrated to dryness, and adds ethyl acetate, successively with water, saturated After sodium-chloride water solution washing, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography for separation (dichloromethane: first Alcohol=98:2) obtain 1.08 grams of white solid 1-(pyridin-4-yl) ethanol, yield 88%

¹H NMR(400MHz,CDCl₃) δ: 8.52 (d, J=4.8Hz, 2H), 7.31 (d, J=4.8Hz, 2H), 4.96-4.83 (m, IH), 1.50 (d, J=6.5Hz, 3H).

Step 2: preparation 1-(pyridin-4-yl) ethyl methane sulfonate ester

Change 1-(3,5-dichloropyridine-4-base) ethanol into 1-(pyridin-4-yl) ethanol, remaining needed raw material, reagent and system Preparation Method, with the step 2 in embodiment 1, obtains pale brown oil thing 1-(pyridin-4-yl) ethyl methane sulfonate ester.

¹H NMR(300MHz,CDCl₃) δ 8.64 (d, J=4.5Hz, 2H), 7.30 (d, J=4.5Hz, 2H), 5.70 (q, J=6.6Hz, 1H), 2.92 (s, 3H), 1.70 (d, J=6.6Hz, 3H).

Step 3: preparation 5-(1-(pyridin-4-yl) ethyoxyl)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 1-(pyridin-4-yl) ethyl methane sulfonate ester, remaining institute Need raw material, reagent and preparation method with the step 3 in embodiment 1, obtain rufous grease 5-(1-(pyridin-4-yl) ethoxy Base)-1H-indole

¹H NMR(300MHz,CDCl₃) δ 8.56 (d, J=4.8Hz, 2H), 7.34 (d, J=4.7Hz, 2H), 7.23 (s, 1H), 7.15 (t, J=2.7Hz, 1H), 6.97 (s, 1H), 6.86 (dd, J=8.8,2.4Hz, 1H), 6.40-6.38 (m, 1H), 5.29 (q, J=6.5Hz, 1H), 1.64 (d, J=6.5Hz, 3H).

Step 4: preparation 5-(1-(pyridin-4-yl) ethyoxyl)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(pyridin-4-yl) ethyoxyl)-1H- Indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain colorless oil 5-(1-(pyridine -4-base) ethyoxyl)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃) δ 10.20 (s, 1H), 8.59 (d, J=5.4Hz, 2H), 7.56 (d, J=1.4Hz, 1H), 7.44 (d, J=9.0Hz, 1H), 7.39 (d, J=5.4Hz, 2H), 7.15 (dd, J=9.0,1.4Hz, 1H), 5.45 (q, J=6.3Hz, 1H), 1.66 (d, J=6.4Hz, 3H).

Step 5: preparation 5-(1-(pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-(1-(pyridin-4-yl) ethoxy into Base)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid Body 5-(1-(pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR (400MHz, DMSO) δ 13.42 (s, 1H), 12.60 (s, 1H), 8.55 (d, J=5.9Hz, 2H), 7.87 (s, 1H), 7.53-7.50 (m, 3H), 7.46 (s, 1H), 7.18 (dd, J=9.0,2.3Hz, 1H), 6.96 (m, 2H), 5.60 (q, J=6.4Hz, 1H), 3.11 (s, 4H), 1.69 (s, 4H), 1.61 (d, J=6.4Hz, 3H), 1.55 (m, 2H).

Embodiment 18

5-(1-(3-chloro-5-fluorine pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-18)

Step one: preparation 1-(3 chloro-5-fluorine pyridin-4-yl) ethanol

By 3,5-dichloropyridine changes 3-chloro-5-fluorine pyridine into, and remaining needed raw material, reagent and preparation method are with embodiment 1 In step 1, obtain colorless oil 1-(3-chloro-5-fluorine pyridin-4-yl) ethanol

¹H NMR(300MHz,CDCl₃) δ 8.39 (s, 1H), 8.35 (d, J=1.5Hz, 1H), 5.41 5.29 (m, 1H), 2.49 (d, J=8.2Hz, 1H), 1.63 (d, J=6.8Hz, 3H).

Step 2: preparation 1-(3-chloro-5-fluorine pyridin-4-yl) ethyl methane sulfonate ester

1-(3,5-dichloropyridine-4-base) ethanol is changed into 1-(3-chloro-5-fluorine pyridin-4-yl) ethanol, remaining needed raw material, Reagent and preparation method, with the step 2 in embodiment 1, obtain white waxy solid 1-(3-chloro-5-fluorine pyridin-4-yl) ethyl first Sulphonic acid ester.

¹H NMR(300MHz,CDCl₃) δ 8.46 (s, 1H), 8.42 (s, 1H), 6.19 (q, J=6.7Hz, 1H), 2.98 (s, 3H), 1.79 (d, J=6.7Hz, 3H).

Step 3: preparation 5-(1-(3-chloro-5-fluorine pyridin-4-yl) ethyoxyl)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 1-(3-chloro-5-fluorine pyridin-4-yl) ethyl methane sulfonate Ester, remaining needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain colorless oil 5-(1-(the chloro-5-of 3- Fluorine pyridin-4-yl) ethyoxyl)-1H-indole

¹H NMR(300MHz,CDCl₃)δ8.36(s,1H),8.29(s,1H),8.07(s,1H),7.23(d, J=9.0Hz, 1H), 7.18 7.12 (m, 1H), 7.05 (s, 1H), 6.88 (dd, J=8.8,2.2Hz, 1H), 6.42 (s, 1H), 5.86 (q, J=6.6Hz, 1H), 1.79 (d, J=6.6Hz, 3H).

Step 4: preparation 5-(1-(3-chloro-5-fluorine pyridin-4-yl) ethyoxyl)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(3-chloro-5-fluorine pyridin-4-yl) second Epoxide)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown oil 5-(1-(3-chloro-5-fluorine pyridin-4-yl) ethyoxyl)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃)δ11.37(s,1H),10.20(s,1H),8.39(s,1H),8.30 (s, 1H), 7.64 (s, 1H), 7.44 (d, J=9.0Hz, 1H), 7.17 (dd, J=9.0,1.9Hz, 1H), 5.95 (q, J=6.5Hz, 1H), 1.81 (d, J=6.5Hz, 3H).

Step 5: preparation 5-(1-(3-chloro-5-fluorine pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] Imidazoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-(1-(3-chloro-5-fluorine pyridin-4-yl) into Ethyoxyl)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow Color solid 5-(1-(3-chloro-5-fluorine pyridin-4-yl) ethyoxyl)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ 8.39 (s, 1H), 8.34 (d, J=1.9Hz, 1H), 7.90 (d, J=2.2Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.48 (d, J=9.3Hz, 1H), 7.23 (s, 1H), 7.15 (dd, J=9.1,2.3Hz, 1H), 7.09 (dd, J=8.9,2.2Hz, 1H), 6.10 (q, J=6.1 Hz,1H),3.20–3.12(m,4H),1.82(m,7H),1.62(m,2H).

Embodiment 19

2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base) benzo [d] azoles (I-19)

Step 1:2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base) benzo [d] azoles

By 100 milligrams of preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde, 36 milligrams of 2-ammonia Base phenol is dissolved in 5 milliliters of ethanol, stops heating, recover to room temperature after refluxing 4 hours, and reactant liquor is concentrated to dryness, and adds Entering 5 milliliters of chloroform, 150 milligram 2,3-bis-chloro-5,6-dicyano p-benzoquinone, under room temperature, 2 hours post-heating of stirring return Flow 2 hours, recover to room temperature to add 50 milliliters of chloroform, with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water After solution washing, anhydrous sodium sulfate is dried, and column chromatography for separation (dichloromethane: methanol=98:2) obtains 90 milligrams of ecrus Solid, yield 60%.

¹H NMR(300MHz,CDCl₃) δ 12.39:(s, 1H), 8.44 (s, 2H), 7.87 7.80 (m, 1H), 7.71 (d, J=2.0Hz, 1H), 7.65 7.60 (m, 1H), 7.57 (d, J=9.1Hz, 1H), 7.46 7.36 (m, 2H), 7.20 (dd, J=9.1,2.4Hz, 1H), 6.17 (q, J=6.7Hz, 1H), 1.85 (d, J=6.7Hz, 3H).

Embodiment 20

2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base) benzo [d] thiazole (I-20)

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 2-aminothiophenol, remaining needed raw material, examination Agent and preparation method, with the step 6 in embodiment 1, obtain white solid 2-(5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-1H-indazole-3-base) benzo [d] thiazole

¹H NMR(300MHz,CDCl₃) δ 8.40:(s, 2H), 8.13 (d, J=8.1Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 7.81 (d, J=2.2Hz, 1H), 7.56 7.48 (m, 1H), 7.43 7.34 (m, 2H), 7.17 (dd, J=9.0,2.4Hz, 1H), 6.16 (q, J=6.7Hz, 1H), 1.82 (d, J=6.7 Hz,3H).

Embodiment 21

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(1H-indole-2-base)-1H-indazole (I-21)

Step 1: preparation 5-((t-butyldimethylsilyl) epoxide)-1H-indazole

By 1.34 grams of 1H-indazole-5-alcohol, 1.2 grams of imidazoles are dissolved in 100 milliliters of DMFs, divide at 0 DEG C Criticize and add 2.3 grams of tert-butyl chloro-silicanes, recover after charging to stirred overnight at room temperature, in 0 DEG C of downhill reaction liquid Adding water, ethyl acetate extracts, and after the washing of organic facies saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, and filtering and concentrating is residual Excess column chromatography (ethyl acetate: petroleum ether=30:70) separates to obtain 2.4 grams of yellow solids, yield 97%.

¹H NMR(300MHz,CDCl₃) δ: 7.96 (s, 1H), 7.35 (d, J=8.8Hz, 1H), 7.12 (s, 1H), 6.98 (dd, J=8.8,2.1Hz, 1H), 1.01 (s, 9H), 0.21 (s, 6H).

Step 2: preparation 5-((t-butyldimethylsilyl) epoxide)-3-iodo-1H-indazole

2 grams of 5-((t-butyldimethylsilyl) epoxide)-1H-indazole is dissolved in 50 milliliters of dichloromethane, is cooled to 10 DEG C, it is dividedly in some parts 2.24 grams of N-N-iodosuccinimides, after charging, recovers to being stirred at room temperature 5 hours, cooling To 0 DEG C, add a small amount of hypo solution, separatory after stirring 1 hour, aqueous phase dichloromethane extracts, and merges organic facies, After washing with saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (ethyl acetate: oil Ether=10:90) separate to obtain 3.03 grams of yellow solids, yield 99%.

¹H NMR(300MHz,CDCl₃) δ: 7.34 (d, J=8.9Hz, 1H), 7.03 (dd, J=8.9,2.2 Hz, 1H), 6.85 (d, J=2.2Hz, 1H), 1.01 (s, 9H), 0.22 (s, 6H).

Step 3: preparation 5-((t-butyldimethylsilyl) epoxide) the iodo-1-of-3-(tetrahydrochysene-2H-pyrans-2-base)-1H- Indazole

2 grams of 5-((t-butyldimethylsilyl) epoxide)-3-iodo-1H-indazole is dissolved in 30 milliliters of dichloromethane, 30 Milliliter oxolane in, be cooled to 10 DEG C, drip successively 175 microlitre Loprazolams, 1.5 milliliter 3,4-dihydro-2H-pyrrole Muttering, recover to stirred overnight at room temperature, reactant liquor adds 20 milliliters of saturated sodium bicarbonate aqueous solution cancellation, separatory, and aqueous phase is used Dichloromethane extracts, and merges organic facies, and after washing with saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, and filtering and concentrating is residual Excess column chromatography (ethyl acetate: petroleum ether=3:97) separates to obtain 2 grams of colorless oil, yield 82%.

¹H NMR(300MHz,CDCl₃) δ 7.42 (d, J=9.0Hz, 1H), 7.01 (dd, J=8.9,2.3 Hz, 1H), 6.81 (d, J=2.2Hz, 1H), 5.63 (dd, J=9.4,2.6Hz, 1H), 4.02 (d, J= 11.3Hz,1H),3.73(m,1H),2.61–2.45(m,1H),2.08(m,2H),1.81–1.61(m, 3H),1.01(s,9H),0.21(s,6H).

Step 4: the preparation iodo-1-of 3-(tetrahydrochysene-2H-pyrans-2-base)-1H-indazole-5-alcohol

By 600 milligrams of 5-((t-butyldimethylsilyl) epoxide) the iodo-1-of-3-(tetrahydrochysene-2H-pyrans-2-base)-1H-Yin Azoles is dissolved in 12 milliliters of oxolanes, adds 2 milliliters of tetrahydrofuran solutions of 410 milligrams of tetrabutyl ammonium fluorides, under room temperature Stirring 1 hour, reactant liquor is concentrated to dryness, and adds 50 milliliters of ethyl acetate, washes with water, saturated sodium-chloride water solution successively After washing, anhydrous sodium sulfate is dried, filtering and concentrating, and residue column chromatography (ethyl acetate: petroleum ether=10:90) separates 450 milligrams of white solids, yield 100%.

¹H NMR(300MHz,CDCl₃) δ 7.37 (d, J=9.0Hz, 1H), 7.01 (dd, J=9.0,2.0 Hz, 1H), 6.74 (d, J=2.0Hz, 1H), 5.58 (d, J=9.6Hz, 1H), 3.98 (d, J=10.1 Hz, 1H), 3.67 (t, J=9.4Hz, 1H), 2.451-2.41 (m, 1H), 2.17 1.95 (m, 2H), 1.73 -1.60(m,3H).

Step 5: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the iodo-1-of-3-(tetrahydrochysene-2H-pyrans-2-base)-1H- Indazole

5-OHi is changed into the iodo-1-of 3-(tetrahydrochysene-2H-pyrans-2-base)-1H-indazole-5-alcohol, remaining needed raw material, examination Agent and preparation method, with the step 3 in embodiment 1, obtain white solid 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3- Iodo-1-(tetrahydrochysene-2H-pyrans-2-base)-1H-indazole.

¹H NMR(300MHz,CDCl₃) δ 8.42 (s, 2H), 7.44 (dd, J=9.1,2.1Hz, 1H), 7.15 (dd, J=9.1,2.4Hz, 1H), 6.70 (d, J=2.2Hz, 1H), 6.06 (q, J=6.6Hz, 1H), 5.64–5.55(m,1H),4.06–3.92(m,1H),3.75–3.62(m,1H),2.56–2.39 (m, 1H), 2.20 1.95 (m, 3H), 1.81 (d, J=6.7Hz, 3H), 1.75 1.61 (m, 4H).

Step 6: preparation 1H-indole-1-carboxylic acid tert-butyl ester

By 500 milligrams of indole, 1.02g Bis(tert-butoxycarbonyl)oxide, it is dissolved in 20 milliliters of dichloromethane, adds 52 milligrams of 4- Dimethyl aminopyridine, is stirred overnight under room temperature, and reactant liquor adds water separatory, and aqueous phase dichloromethane extracts, and merges organic facies, After washing with saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (ethyl acetate: oil Ether=2:98) separate to obtain 810 milligrams of colorless oil, yield 87%.

Step 7: preparation (1-(tertbutyloxycarbonyl)-1H-indole-2-base) boric acid

300 milligrams of 1H-indole-1-carboxylic acid tert-butyl esters are dissolved in 5 milliliters of oxolanes, add 1.5 milliliters of triisopropyls Borate, is cooled to 0 DEG C, drips 760 microlitre lithium diisopropylamine solution (2 moles every liter), drips and continues under complete room temperature Stirring 6 hours, add saturated aqueous ammonium chloride cancellation, add ethyl acetate extraction, organic facies saturated sodium-chloride is water-soluble After liquid washing, anhydrous sodium sulfate is dried, and filtering and concentrating obtains 480 milligrams of yellow-brown solid, yield 100%.

¹H NMR(300MHz,CDCl₃) δ: 8.02 (d, J=8.5Hz, 1H), 7.61 (d, J=7.8Hz, 1H), 7.49 (s, 1H), 7.36 (t, J=7.8Hz, 1H), 7.29 7.22 (m, 2H), 7.10 (s, 2H), 1.75 (s,9H).

Step 8: preparation 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1-(tetrahydrochysene-2H-pyrans-2-base)-1H- Indazole-3-base)-1H-indole-1-carboxylic acid tert-butyl ester

By 25 milligrams of 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the iodo-1-of-3-(tetrahydrochysene-2H-pyrans-2-base)-1H-Yin Azoles, 25 milligrams of (1-(tertbutyloxycarbonyl)-1H-indole-2-base) boric acid, 31 milligrams of cesium carbonates are dissolved in 3 milliliters of dioxane, Add 7 milligrams of [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chlorides after argon displacement, stir 2 hours at 80 DEG C, recover To room temperature, reactant liquor is concentrated to dryness, and column chromatography (ethyl acetate: petroleum ether=5:95) separates to obtain 23 milligrams of white solids, Yield 78%

¹H NMR(300MHz,CDCl₃) δ 8.38 (s, 1H), 8.29 (d, J=8.5Hz, 1H), 7.60 (d, J=7.8Hz, 1H), 7.49 (dd, J=9.0,2.8Hz, 1H), 7.39 (t, J=7.8Hz, 1H), 7.29 (d, J=7.0Hz, 1H), 7.11 (dd, J=9.0,2.3Hz, 1H), 6.92 (s, 1H), 6.74 (d, J= 5.3Hz, 1H), 5.94 (q, J=6.3Hz, 1H), 5.72 5.63 (m, 1H), 4.04 (d, J=9.8Hz, 1H),3.79–3.67(m,1H),2.63–2.47(m,1H),2.20–2.00(m,2H),1.75(d, J=6.7Hz, 4H), 1.68 (dd, J=11.5,5.6Hz, 2H), 1.02 (d, J=9.1Hz, 8H).

Step 9: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(1H-indole-2-base)-1H-indazole

By 30 milligrams of 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1-(tetrahydrochysene-2H-pyrans-2-base)-1H-indazole -3-base)-1H-indole-1-carboxylic acid tert-butyl ester is dissolved in 3 ml methanol, adds 1 milliliter of hydrogen chloride/ethanol solution (4 moles Every liter), stir 48 hours under room temperature, be concentrated to dryness, 30% sodium hydrate aqueous solution extracts with rear ethyl acetate, organic After washing with saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (dichloromethane: first Alcohol=97:3) separate to obtain 10 milligrams of pale pink solids, yield 48%.

¹H NMR(300MHz,CDCl₃) δ: 9.05 (s, 1H), 8.45 (s, 2H), 7.71 (d, J=7.6Hz, 1H), 7.39 (t, J=8.5Hz, 2H), 7.31 (d, J=2.0Hz, 1H), 7.24 7.12 (m, 2H), 6.97 (s, 1H), 6.14 (q, J=6.7Hz, 1H), 1.86 (d, J=6.7Hz, 3H).

Embodiment 22

N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles-6- Base)-N²,N²-dimethyl ethane-1,2-diamidogen (I-22)

Step 1: preparation N¹,N¹-(2-(dimethylamino) ethyl)-4-Nitrobenzol-1,2-diamidogen

Change 4-piperidinyl piperidine into N¹,N¹-dimethyl ethane-1,2-diamidogen, remaining needed raw material, reagent and preparation method With the step 6 in embodiment 1, obtain yellow solid N¹,N¹-(2-(dimethylamino) ethyl)-4-Nitrobenzol-1,2-diamidogen.

¹H NMR (300MHz, DMSO) δ: 7.71 (d, J=9.6Hz, 1H), 7.34 (s, 2H), 6.81 (t, J=5.2Hz, 1H), 6.05 (dd, J=9.6,2.4Hz, 1H), 5.83 (d, J=2.4Hz, 1H), 3.12 (q, 6.7Hz, 2H), 2.42 (t, J=6.7Hz, 2H), 2.18 (s, 6H).

Step 2: preparation N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] Imidazoles-6-base)-N²,N²-dimethyl ethane-1,2-diamidogen

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into N¹,N¹-(2-(dimethylamino) ethyl)-4-nitre Base benzene-1,2-diamidogen, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles-6- Base)-N²,N²-dimethyl ethane-1,2-diamidogen

¹H NMR(300MHz,DMSO)δ:13.43-13.27(m,1H),12.40-12.30(m,1H),8.60 (s,2H),7.83-7.79(m,1H),7.53-7.50(m,1H),7.45-7.17(m,1H),7.14- 7.10 (m, 1H), 6.86-6.54 (m, 1H), 6.64-6.61 (m, 1H), 6.08 (q, J=6.7Hz, 1H), 5.30 (t, J=6.0Hz, 1H), 3.19-3.09 (m, 2H), 2.55-2.47 (m, 2H), 2.25-1.78 (d, J=6.7Hz, 3H).

Embodiment 23

N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles-6- Base)-N²,N²-diethyl ethane-1,2-diamidogen (I-23)

Step 1: preparation N¹,N¹-(2-(diethylamino) ethyl)-4-Nitrobenzol-1,2-diamidogen

Change 4-piperidinyl piperidine into N¹,N¹-diethyl ethane-1,2-diamidogen, remaining needed raw material, reagent and preparation method With the step 5 in embodiment 1, obtain yellow solid N¹,N¹-(2-(diethylamino) ethyl)-4-Nitrobenzol-1,2-diamidogen.

¹H NMR (300MHz, DMSO) δ: 7.71 (d, J=9.5Hz, 1H), 7.34 (s, 2H), 6.78 (t, J=5.2Hz, 1H), 6.03 (dd, J=9.6,2.4Hz, 1H), 5.84 (d, J=2.4Hz, 1H), 3.10 (q, 6.7Hz, 2H), 2.62 2.50 (m, 6H), 0.96 (t, J=7.1Hz, 6H).

Step 2:N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles -6-base)-N²,N²-diethyl ethane-1,2-diamidogen

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into N¹,N¹-(2-(diethylamino) ethyl)-4-nitre Base benzene-1,2-diamidogen, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles-6- Base)-N²,N²-diethyl ethane-1,2-diamidogen

¹H NMR(400MHz,DMSO)δ:13.39-13.31(m,1H),12.46-12.36(m,1H),8.60 (s,2H),7.83-7.79(m,1H),7.53–7.49(m,1H),7.47–7.20(m,1H),7.14 -7.12(m,1H),6.90-6.58(m,1H),6.65-6.61(m,1H),6.10-6.06(m,1H),3.24 (s, 2H), 3.10 2.62 (m, 6H), 1.77 (d, J=6.7Hz, 3H), 1.09 (m, 6H).

Embodiment 24

N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles-6- Base)-N³,N³-dimethylpropane-1,3-diamidogen (I-24)

Step 1: preparation N¹,N¹-(3-(dimethylamino) propyl group)-4-Nitrobenzol-1,3-diamidogen

Change 4-piperidinyl piperidine into N¹,N¹-dimethylpropane-1,3-diamidogen, remaining needed raw material, reagent and preparation method With the step 5 in embodiment 1, obtain yellow solid N¹,N¹-(2-(dimethylamino) propyl group)-4-Nitrobenzol-1,3-diamidogen.

¹H NMR (300MHz, DMSO) δ: 7.71 (d, J=9.6Hz, 1H), 7.34 (s, 2H), 6.95 (t, J=4.3Hz, 1H), 6.01 (dd, J=9.6,2.1Hz, 1H), 5.81 (d, J=2.1Hz, 1H), 3.05 (q, 6.2Hz, 2H), 2.27 (t, J=7.0Hz, 2H), 2.13 (s, 6H), 1.74 1.61 (m, 2H).

Step 2:N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles -6-base)-N³,N³-dimethylpropane-1,3-diamidogen

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into N¹,N¹-(3-(dimethylamino) propyl group)-4-nitre Base benzene-1,3-diamidogen, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid N¹-(2-(5-(1-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indol-3-yl)-1H-benzo [d] imidazoles-6- Base)-N³,N³-dimethylpropane-1,3-diamidogen

¹H NMR(300MHz,DMSO)δ13.34-13.27(m,1H),12.40-12.28(m,1H),8.60 (s,2H),7.83-7.79(m,1H),7.50-7.48(m,1H),7.43-7.16(m,1H),7.13- 7.11 (m, 1H), 6.82-6.50 (m, 1H), 6.60-6.58 (m, 1H), 6.08 (q, J=6.7Hz, 1H), 5.54(s,1H),3.12-3.04(m,2H),2.35(m,2H),2.20-2.17(m,6H),1.78-1.76 (m,5H).

Embodiment 25

4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) Piperazine-1-carboxylic acid tert-butyl ester (I-25)

Step 1: preparation 4-(3-amino-4-nitrobenzophenone) piperazine-1-carboxylic acid tert-butyl ester

4-piperidinyl piperidine is changed into piperazine-1-carboxylic acid tert-butyl ester, the same embodiment of remaining needed raw material, reagent and preparation method Step 5 in 1, obtains yellow solid 4-(3-amino-4-nitrobenzophenone) piperazine-1-carboxylic acid tert-butyl ester.

¹H NMR(400MHz,CDC1₃) δ: 8.02 (d, J=9.6Hz, 1H), 6.22 (dd, J=9.6,2.4 Hz, 1H), 6.15 (s, 2H), 5.91 (d, J=2.4Hz, 1H), 3.42-3.47 (m, 4H), 3.31-3.35 (m,4H),1.41(s,9H).

Step 2: preparation 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] Imidazoles-6-base) piperazine-1-carboxylic acid tert-butyl ester

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 4-(3-amino-4-nitrobenzophenone) piperazine-1-carboxylic Tert-butyl acrylate, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain beige solid 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) piperazine -1-carboxylic acid tert-butyl ester

¹H NMR(300MHz,DMSO)δ:13.43-13.38(m,1H),12.65-12.62(m,1H),8.61 (s, 2H), 7.83-7.79 (m, 1H), 7.59-7.32 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.23 -6.90 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 6.99-6.98 (m, 1H), 6.09 (q, J=6.7 Hz, 1H), 3.52 (s, 4H), 3.09 (s, 4H), 1.78 (d, J=6.7Hz, 3H), 1.43 (s, 9H).

Embodiment 26

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperazine-1-base)-1H-benzo [d] imidazoles-2- Base)-1H-indazole hydrochloride (I-26)

By 12 milligrams of 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] miaow Azoles-6-base) piperazine-1-carboxylic acid tert-butyl ester is dissolved in 1 ml methanol, and (4 moles are every to add 1 milliliter of hydrogen chloride/ethanol solution Rise), stir 48 hours under room temperature, reactant liquor is concentrated to dryness, dried 5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-3-(6-(piperazine-1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole hydrochloride

¹H NMR (300MHz, DMSO) δ: 9.19 (s, 2H), 8.59 (s, 1H), 7.98 (s, 1H), 7.74 7.63 (m, 2H), 7.29 (d, J=7.1Hz, 1H), 7.19 (d, J=9.2Hz, 2H), 6.20 (q, J= 6.6Hz, 1H), 3.45 (s, 4H), 3.30 (s, 4H), 1.80 (d, J=6.6Hz, 2H).

Embodiment 27

4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) Piperidines-1-t-butyl formate (I-27)

Step 1: preparation 4-oxo-piperidine-1-carboxylic acid tert-butyl ester

2 grams of 4-oxo-piperidine keto hydrochlorides are dissolved in 25 ml methanol, add 3.1 milliliters of triethylamines, be sequentially added into 4.4 Gram Bis(tert-butoxycarbonyl)oxide, 95 milligrams of 4-dimethylaminopyridines, after stirring 4 hours under room temperature, reactant liquor concentrates, and adds second Acetoacetic ester dissolves, and after organic facies saturated sodium bicarbonate solution and water wash successively, anhydrous sodium sulfate is dried, filtering and concentrating, Obtain Off-white solid 2.57 grams, yield 8%

1H NMR (300MHz, CDCl3) δ: 3.71 (t, J=6.2Hz, 4H), 2.44 (t, J=6.2Hz, 4H),1.49(s,9H).

Step 2: preparation 4-trimethyl fluoride sulfonyl epoxide-5,6-dihydropyridine-1 (2H)-t-butyl formate

6.5 milliliters of lithium diisopropylamine solution (2 moles every liter) are dissolved in 10 milliliters of oxolanes, drip at-78 DEG C 15 milliliters of tetrahydrofuran solutions of 2 grams of 4-oxo-piperidine-1-carboxylic acid tert-butyl esters, drip and finish, continuation stirring 30 minutes, and-78 Drip 15 milliliters of tetrahydrofuran solutions of double (fluoroform sulphonyl) imines of 3.26 grams of N-phenyl at DEG C, at a temperature of being somebody's turn to do, stir 1 Recovering after hour to room temperature, reactant liquor adds ethyl acetate extraction, anhydrous sulfur after the washing of organic facies saturated ammonium chloride solution Acid sodium is dried, and filtering and concentrating, residue column chromatography (ethyl acetate: petroleum ether=5:95) separates to obtain 2.26 grams of shallow brown oils Shape thing, yield 75%.

¹H NMR(300MHz,CDCl₃) δ: 5.76 (s, 1H), 4.05 (s, 2H), 3.63 (s, 2H), 2.44 (s, 2H),1.47(s,9H).

Step 3: preparation 4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base)-5,6-dihydropyridine-1 (2H)- T-butyl formate

By 330 milligrams of 4-trimethyl fluoride sulfonyl epoxide-5,6-dihydropyridine-1 (2H)-t-butyl formate, 356 milligrams of connection boric acid Pinacol ester, in 10 milliliters of Isosorbide-5-Nitrae-dioxane of 324 milligrams of liquor kalii aceticis, adds 37 milligram 1,1 '-bis-diphenyl Phosphine ferrocene palladium chloride, stirs 2 hours at 80 DEG C, recovers to room temperature, filtering and concentrating, residue column chromatography (acetic acid Ethyl ester: petroleum ether=5:95) separate to obtain 250 milligrams of white solids, yield 81%.

¹H NMR(300MHz,CDCl₃) δ: 6.46 (s, 1H), 3.94 (d, J=2.6Hz, 2H), 3.43 (t, J=5.4Hz, 2H), 2.22 (s, 2H), 1.45 (s, 9H), 1.26 (s, 12H).

Step 4: preparation 4-(4-amino-3-nitrobenzophenone)-5,6-dihydropyridine-1 (2H)-t-butyl formate

By 50 milligrams of 2-nitro-4-bromanilines, 85 milligrams of 4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2- Base)-5,6-dihydropyridine-1 (2H)-t-butyl formate, 95 milligrams of potassium carbonate are dissolved in 4 milliliters of DMFs, Add 15 milligram 1,1 '-bis-Diphenyl phosphino ferrocene palladium chlorides, stir 2 hours at 80 DEG C, recover to room temperature, mistake Filter concentrates, and residue column chromatography (ethyl acetate: petroleum ether=20:80) separates to obtain 250 milligrams of brown solids 29 milligrams, receives Rate 40%.

¹H NMR(300MHz,CDCl₃) δ: 8.09 (s, 1H), 7.46 (dd, J=8.7,1.9Hz, 1H), 6.79 (d, J=8.7Hz, 1H), 6.09 (s, 2H), 6.01 (s, 1H), 4.07 (d, J=2.3Hz, 2H), 3.63 (t, J=5.7Hz, 2H), 2.48 (s, 2H), 1.49 (s, 9H).

Step 5: preparation 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] Imidazoles-6-base) piperidines-1-t-butyl formate

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 4-(4-amino-3-nitrobenzophenone)-5,6-dihydro Pyridine-1 (2H)-t-butyl formate, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow Color solid 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base) piperidines-1-t-butyl formate

¹H NMR(300MHz,DMSO)δ13.45(s,1H),12.76(s,1H),8.60(s,2H),7.82 (m,1H),7.67-7.37(m,1H),7.53-7.28(m,2H),7.17-7.10(m,2H),6.10(q, J=6.7Hz, 1H), 4.11 (s, 2H), 2.84 (s, 3H), 1.88-1.77 (m, 2H), 1.78 (d, J= 6.7Hz,3H),1.44(s,9H).

Embodiment 28

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperidin-4-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole hydrochloride (I-28)

By 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base) piperazine-1-carboxylic acid tert-butyl ester changes 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-into Base)-1H-benzo [d] imidazoles-6-base) piperidines-1-t-butyl formate, remaining needed raw material, reagent and preparation method are with implementing Example 25, obtains 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperidin-4-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole hydrochloride

¹H NMR (400MHz, DMSO) δ: 9.15 (s, 2H), 8.58 (s, 2H), 8.12 (s, 1H), 7.80 (d, J=7.8Hz, 1H), 7.73 7.61 (m, 2H), 7.40 (d, J=7.6Hz, 1H), 7.19 (d, J =8.5Hz, 1H), 6.24 (q, J=6.5Hz, 1H), 3.40 (d, J=12.5Hz, 2H), 3.05 (s, 3H), 2.01 (s, 4H), 1.80 (d, J=6.5Hz, 3H).

Embodiment 29

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(1-methyl piperidine-4-base)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-29)

Step 1: preparation N-(4-bromophenyl) acetamide

5 grams of 4-bromanilines are dissolved in 50 milliliters of dichloromethane 13 milliliters of triethylamines of addition, under ice-water bath, drip 2.7 millis Rising chloroacetic chloride, drip and finish, stir 2 hours under room temperature, add water separatory, anhydrous after the washing of organic facies saturated sodium-chloride water solution Sodium sulfate is dried, filtering and concentrating, residue column chromatography (ethyl acetate: petroleum ether=40:60) separate 3.6 grams of yellow are solid Body, yield 58%.

¹H NMR(300MHz,CDCl₃) δ: 7.40 (m, 4H), 2.16 (s, 3H).

Step 2: preparation N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) acetamide

Change 4-trimethyl fluoride sulfonyl epoxide-5,6-dihydropyridine-1 (2H)-t-butyl formate into N-(4-bromophenyl) acetyl Amine, remaining needed raw material, reagent and preparation method, with embodiment 28, step 3, obtain yellow oil N-(4-(4,4,5,5- Tetramethyl-1,3-dioxolanes-2-base) phenyl) acetamide.

¹H NMR(300MHz,CDCl₃) δ: 7.76 (d, J=8.0Hz, 2H), 7.51 (d, J=8.0Hz, 2H), 2.18(s,3H),1.33(s,12H).

Step 3: preparation N-(4-(pyridin-4-yl) phenyl) acetamide

By 1.95 grams of 4-pyridine hydrochlorides, 3.13 grams of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) Phenyl) acetamide, 4.3 grams of sodium carbonate are dissolved in 20 ml deionized water, 80 milliliters of oxolanes, add 360 milligrams 1,1 '-bis-Diphenyl phosphino ferrocene palladium chlorides, stop heating after refluxing 4 hours, recover to room temperature to concentrate, residue Column chromatography (dichloromethane: methanol=97:3) obtains 1.96 grams of yellow solids, yield 84%.

¹H NMR(300MHz,CDCl₃) δ 8.63 (d, J=6.2Hz, 2H), 7.68 7.57 (m, 4H), 7.49 (d, J=6.2Hz, 2H), 2.22 (s, 3H).

Step 4: preparation 4-(4-acetylamino phenyl)-1-picoline-1-Methylsulfate

1.4 grams of N-(4-(pyridin-4-yl) phenyl) acetamide is dissolved in 20 milliliters of DMFs, adds 1.2 Milliliter dimethyl sulfate, stirs 6 hours under room temperature, adds 40 milliliters of ether, after stirring 10 minutes, add 20 milliliters Ethanol, filters after stirring 10 minutes, filter cake washing with alcohol, is dried to obtain 1.7 grams of yellow solids, yield 76%.

¹H NMR (400MHz, DMSO) δ: 10.35 (s, 1H), 8.93 (d, J=6.8Hz, 2H), 8.43 (d, J=6.8Hz, 2H), 8.08 (d, J=8.8Hz, 2H), 7.82 (d, J=8.8Hz, 2H), 4.28 (s, 3H), 2.11(s,3H).

Step 5: preparation N-(4-(1-methyl piperidine-4-base) phenyl) acetamide

200 milligrams of 4-(4-acetylamino phenyl)-1-picoline-1-Methylsulfate is dissolved in 20 milliliters of ethanol, Adding 550 milligrams of ammonium formates, 100 milligram of 10% palladium carbon, reflux 18 hours, recover to room temperature, reactant liquor concentrates, and 2 After mole of every liter sodium hydrate aqueous solution alkalization, dichloromethane extracts, anhydrous after the washing of organic facies saturated sodium-chloride water solution Sodium sulfate is dried, filtering and concentrating, obtains 116 milligrams of white solids, yield 84%.

¹H NMR(400MHz,CDCl₃) δ 7.40 (d, J=8.2Hz, 2H), 7.29 (s, 1H), 7.16 (d, J=8.2Hz, 2H), 2.97 (d, J=11.2Hz, 2H), 2.49 2.39 (m, 1H), 2.32 (s, 3H), 2.15(s,3H),2.08–2.00(m,2H),1.84–1.74(m,4H).

Step 6: preparation N-(4-(1-methyl piperidine-4-base)-2-nitrobenzophenone) acetamide

Add in 2 milliliters of acetic acid, 5 ml acetic anhydride mixed solutions under ice bath 140 microlitre 65% nitric acid, two droplets 98% dense Sulphuric acid, after stirring 10 minutes, drips 3 milliliters of second of 232 milligrams of N-(4-(1-methyl piperidine-4-base) phenyl) acetamide Acid solution, drips and finishes, and recovers to being stirred at room temperature 4 hours, after adding 2 moles of every liter of sodium hydrate aqueous solution alkalization, and dichloromethane Alkane extract, organic facies saturated sodium-chloride water solution washing after anhydrous sodium sulfate be dried, filtering and concentrating, obtain 300 milligrams orange Grease, yield 100%.

¹H NMR(300MHz,CDCl₃) δ: 10.21 (s, 1H), 8.67 (d, J=8.7Hz, 1H), 8.05 (d, J=1.7Hz, 1H), 7.53 (dd, J=8.7,1.7Hz, 1H), 3.24 (d, J=11.7Hz, 2H), 2.70 –2.55(m,1H),2.47(s,3H),2.40–2.24(m,5H),2.11–1.83(m,7H).

Step 7: preparation 4-(1-methyl piperidine-4-base)-2-nitroaniline

277 milligrams of N-(4-(1-methyl piperidine-4-base)-2-nitrobenzophenone) acetamide is dissolved in 5 ml methanol, adds 1 Milliliter 20% potassium hydroxide aqueous solution, is stirred overnight under room temperature, and reactant liquor is concentrated to dryness, and adds dichloromethane and dissolves, organic After washing mutually, saturated sodium-chloride water solution washing, anhydrous sodium sulfate is dried, and filtering and concentrating obtains 300 milligrams of orange, Yield 100%.

¹H NMR (300MHz, DMSO) δ: 7.74 (d, J=1.8Hz, 1H), 7.34 (dd, J=8.7,1.8 Hz, 1H), 7.31 (s, 2H), 6.97 (d, J=8.7Hz, 1H), 2.83 (d, J=11.3Hz, 2H), 2.43 –2.30(m,1H),2.17(s,3H),1.98–1.86(m,2H),1.75–1.64(m,2H),1.64 –1.48(m,2H).

Step 8: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(1-methyl piperidine-4-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 4-(1-methyl piperidine-4-base)-2-Nitrobenzol Amine, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloros Pyridin-4-yl) ethyoxyl)-3-(6-(1-methyl piperidine-4-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole.

¹H NMR(300MHz,DMSO)δ:13.44(s,1H),12.73(s,1H),8.60(s,2H),7.82 (m,1H),7.66-7.36(m,1H),7.55-7.29(m,2H),7.16-7.10(m,2H),6.10(q, J=6.7Hz, 1H), 2.94-2.89 (m, 2H), 2.60-2.50 (m, 2H), 2.23-2.21 (m, 3H), 2.01-1.96(m,2H),1.79-1.69(m,7H).

Embodiment 30

4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) Morpholine (I-30)

Step 1: preparation 5-morpholine-2-nitroaniline

Change 4-piperidinyl piperidine into morpholine, remaining needed raw material, reagent and preparation method with the step 5 in embodiment 1, Obtain yellow solid 5-morpholine-2-nitroaniline

¹H NMR (400MHz, DMSO) δ: 7.73:(d, J=9.7Hz, 1H), 7.20 (s, 2H), 6.30 (dd, J=2.7,9.7Hz, 1H), 6.12 (d, J=2.7Hz, 1H), 3.61 (t, J=4.8Hz, 4H), 3.18 (t, J=5.0Hz, 4H).

Step 2: preparation 4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] Imidazoles-6-base) morpholine

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-morpholine-2-nitroaniline, former needed for remaining Material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 4-(2-(5-(1-(3,5-dichloropyridine-4- Base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) morpholine.

¹H NMR(300MHz,DMSO)δ:13.40(s,1H),12.61(s,1H),8.61(s,2H),7.81 (s, 1H), 7.57 (s, 1H), 7.53 (d, J=9.0Hz, 1H), 7.14 (dd, J=9.0,2.4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.91 (s, 1H), 6.10 (q, J=6.7Hz, 1H), 3.80 (s, 4H), 3.12 (s, 4H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 31

2-(4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base) piperazine-1-base) ethanol (I-31)

Step 1: preparation 2-(4-(3-amino-4-nitrobenzophenone) piperazine-1-base) ethanol

¹H NMR (300MHz, DMSO) δ 7.80:(d, J=9.7Hz, 1H), 7.26 (s, 2H), 6.39 (d, J=9.9Hz, 1H), 6.20 (s, 1H), 4.46 (s, 1H), 3.53 (t, J=6.2Hz, 2H), 3.36 3.26 (m, 6H), 2.53 2.48 (m, 2H), 2.42 (t, J=5.9Hz, 2H).

Step 2: preparation 2-(4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) piperazine-1-base) ethanol

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 2-(4-(3-amino-4-nitrobenzophenone) piperazine -1-base) ethanol, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 2-(4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) piperazine Piperazine-1-base) ethanol

¹H NMR(300MHz,DMSO)δ:13.41-13.36(m,1H),12.60-12.55(m,1H),8.60 (s, 2H), 7.84-7.80 (m, 1H), 7.58-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19 -6.88 (m, 1H), 7.14 (d, J=8.8Hz, 1H), 6.70-6.95 (m, 1H), 6.10 (q, J=6.7 Hz,1H),4.47-4.42(m,1H),3.60-3.52(m,2H),3.13(m,4H),2.61(m,4H), 2.48-2.43 (m, 2H), 1.78 (d, J=6.7Hz, 3H).

Embodiment 32

2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-(2-(pyrrolidin-1-yl) second Base)-1H-benzo [d] imidazoles-6-amine (I-32)

Step 1: preparation 4-nitro-N¹-(2-(pyrrolidin-1-yl) ethyl) benzene-1,3-diamidogen

4-piperidinyl piperidine changes into 2-(pyrrolidin-1-yl) ethamine, and remaining needed raw material, reagent and preparation method are with implementing Step 5 in example 1, obtains yellow solid 4-nitro-N¹-(2-(pyrrolidin-1-yl) ethyl) benzene-1,3-diamidogen

¹H NMR (300MHz, DMSO) δ: 7.70 (d, J=9.6Hz, 1H), 7.32 (s, 2H), 6.87 (s, 1H), 6.03 (d, J=9.6Hz, 1H), 5.82 (s, 1H), 3.14 (s, 2H), 2.58 (s, 2H), 2.46 (s, 4H),1.67(s,4H).

Step 2: preparation 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-(2-(pyrrolidine -1-base) ethyl)-1H-benzo [d] imidazoles-6-amine

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into 4-nitro-N¹-(2-(pyrrolidin-1-yl) ethyl) Benzene-1,3-diamidogen, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-(2-(pyrrolidin-1-yl) ethyl)-1H- Benzo [d] imidazoles-6-amine.

¹H NMR(400MHz,DMSO)δ13.35-13.28(m,1H),12.41-12.30(m,1H),8.60 (s,2H),7.83-7.80(m,1H),7.52-7.49(m,1H),7.44-7.17(m,1H),7.14- 7.11 (m, 1H), 6.85-6.53 (m, 1H), 6.63-6.60 (m, 1H), 6.08 (q, J=6.7Hz, 1H), 5.39 (t, J=6..0Hz, 1H), 3.17-3.12 (m, 2H), 2.68-2.64 (m, 2H), 2.55 (m, 4H), 1.77 (d, J=6.7Hz, 3H), 1.71 (s, 2H).

Embodiment 33

2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-(2-methoxy ethyl)-1H-benzene And [d] imidazoles-6-amine (I-33)

Step 1: preparation N¹-(2-methoxy ethyl)-4-Nitrobenzol-1,3-diamidogen

Changing 4-piperidinyl piperidine into 2-methoxyethyl amine, remaining needed raw material, reagent and preparation method are with in embodiment 1 Step 5, obtain yellow solid N¹-(2-methoxy ethyl)-4-Nitrobenzol-1,3-diamidogen.

¹H NMR (300MHz, DMSO) δ 7.72 (dd, J=9.5,2.1Hz, 1H), 7.33 (s, 2H), 6.99 (s, 1H), 6.06 (d, J=9.5Hz, 1H), 5.85 (s, 1H), 3.51 3.44 (m, 2H), 3.28 (d, J=2.5Hz, 3H), 3.25 3.18 (m, 2H).

Step 2: preparation 2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-(2-methoxyl group second Base)-1H-benzo [d] imidazoles-6-amine

Change 5-([1,4 '-connection piperidines]-1 '-yl)-2-nitroaniline into N¹-(2-methoxy ethyl)-4-Nitrobenzol-1,3- Diamidogen, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 2-(5-(1-(3,5- Dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-N-(2-methoxy ethyl)-1H-benzo [d] imidazoles-6-amine.

¹H NMR(300MHz,DMSO)δ13.34-13.27(m,1H),12.42-12.30(m,1H),8.60 (s, 2H), 7.80 (s, 1H), 7.50 (d, J=8.1Hz, 1H), 7.44-7.19 (m, 1H), 7.14- 7.10 (m, 1H), 6.88-6.55 (m, 1H), 6.64 (d, J=7.5Hz, 1H), 6.08 (q, J=6.7Hz, 1H), 5.55 (s, 1H), 3.55 (s, 2H), 3.31 (s, 3H), 3.22 (s, 2H0,1.78 (d, J=6.7Hz, 3H).

Embodiment 34

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-6 fluoro-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-34)

Step 1: preparation 1-benzyloxy-2-fluoro-4-Nitrobenzol

3 grams of 2-fluoro-4-nitrophenols, 7.9 grams of potassium carbonate and 2.5 milliliters of bromobenzyls are dissolved in 100 milliliters of acetone, heat back Flow 3 hours, filtering and concentrating, residue column chromatography (petroleum ether: dichloromethane=70:30) separate 3.85 grams of whites are solid Body 1-benzyloxy-2-fluoro-4-Nitrobenzol, yield 82%.

¹H NMR(300MHz,DMSO)δ8.23–8.07(m,2H),7.55–7.32(m,6H),5.35(s, 2H).

Step 2: preparation 2-(5-(benzyloxy)-4-fluoro-2-Nitrobenzol) acetonitrile

By 3 grams of 1-benzyloxy-2-fluoro-4-Nitrobenzol, 2.28 grams of 4-chlorobenzene oxygen acetonitriles are dissolved in 50 milliliters of dry N, N-bis- In methylformamide, be cooled to after-10 DEG C drip 3 grams of potassium tert-butoxides DMF solution 10 milliliters, 2 hours Rear reaction terminates.Pour in the hydrochloric acid ice bath that 100 milliliters of concentration is 1M.Being extracted with ethyl acetate, after separatory, organic facies is used After saturated sodium-chloride water solution washing, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (petroleum ether: dichloromethane= 40:60) separate to obtain 2.9 grams of products and the mixture of 2-(3-(benzyloxy)-2-fluoro-6-Nitrobenzol) acetonitrile, yield 84%.

Step 3: preparation 6-fluoro-1-H-indole-5-alcohol

2.9 grams of 2-(5-(benzyloxy)-4-fluoro-2-Nitrobenzol) acetonitrile is dissolved in the mixed of 85 ml methanol and 15 milliliters of acetic acid Close in solution, add palladium charcoal.Pressurize 3 kilograms, heat 50 DEG C and react 10 hours.Filtering and concentrating, residue column chromatography (stone Oil ether: ethyl acetate=90:10) separate to obtain 850 milligrams of products and the mixture of 4-fluoro-1-H-indole-5-alcohol, yield 55%.

Step 4: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-6-fluoro-1H-indole

5-OHi changes into 6-fluoro-1-H-indole-5-alcohol, and remaining needed raw material, reagent and preparation method are with real Execute the step 3 in example 1, obtain colorless oil 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-6-fluoro-1H-indole 1.2 gram.

¹H NMR(300MHz,CDCl3)δ8.43(s,2H),8.20(s,1H),7.14–7.08(m,2H), 6.97 (d, J=8.1Hz, 1H), 6.41 6.34 (m, 1H), 5.98 (q, J=6.7Hz, 1H), 1.83 (d, J=6.7Hz, 3H).

Step 5: preparation 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-6-fluoro-1H-indole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(3,5-dichloropyridine-4-base) second Epoxide)-6-fluoro-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid Body 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-6-fluoro-1H-indole-3-formaldehyde.

¹H NMR(300MHz,DMSO)δ14.13(s,1H),10.05(s,1H),8.63(s,2H),7.64 (d, J=10.6Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 6.10 (q, J=6.7Hz, 1H), 1.79 (d, J=6.7Hz, 3H).

Step 6:5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the fluoro-3-of-6-(6-(piperidin-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde changes 5-(1-(3,5-dichloropyridine-4-base) third into Epoxide)-6-fluoro-1H-indole-3-formaldehyde, remaining needed raw material, reagent and preparation method with the step 6 in embodiment 1, Obtain white solid 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the fluoro-3-of-6-(6-(piperidin-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole

¹H NMR(400MHz,DMSO)δ13.49-13.44(m,1H),12.65-12.58(m,1H),8.63 (s, 2H), 7.92-7.86 (m, 1H), 7.57-7.30 (m, 1H), 7.53 (d, J=9.0Hz, 1H), 7.19 -6.88 (m, 1H), 6.97-6.95 (m, 1H), 6.12 (q, J=6.6Hz, 1H), 3.10 (s, 4H), 1.81 (d, J=6.6Hz, 3H), 1.68 (s, 4H), 1.54 (m, 2H).

Embodiment 35

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the fluoro-3-of-4-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-35)

Step 1: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-4-fluoro-1H-indole

5-OHi changes into 4-fluoro-1-H-indole-5-alcohol, and remaining needed raw material, reagent and preparation method are with real Execute the step 3 in example 1, obtain colorless oil 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-4-fluoro-1H-indole.

¹H NMR(300MHz,CDCl3)δ8.42(s,2H),7.15(m,1H),6.94(m,1H),6.80 (m, 1H), 6.60 (m, 1H), 5.98 (q, J=6.7Hz, 1H), 1.83 (d, J=6.7Hz, 3H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-4-fluoro-1H-indole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(3,5-dichloropyridine-4-base) second Epoxide)-4-fluoro-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid Body 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-4-fluoro-1H-indole-3-formaldehyde.

¹H NMR (400MHz, DMSO) δ 10.10 (d, J=4.0Hz, 1H), 8.61 (s, 2H), 7.41 (d, J=8.9Hz, 1H), 7.26 7.10 (m, 1H), 6.04 (q, J=6.6Hz, 1H), 1.79 (d, J=6.7 Hz,3H).

Step 3: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the fluoro-3-of-4-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde changes 5-(1-(3,5-dichloropyridine-4-base) third into Epoxide)-4-fluoro-1H-indole-3-formaldehyde, remaining needed raw material, reagent and preparation method with the step 6 in embodiment 1, Obtain yellow solid 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl) the fluoro-3-of-4-(6-(piperidin-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole.

¹H NMR(300MHz,DMSO)δ13.78(m,1H),12.59-12.52(m,1H),8.62(s,2H), 7.50(m,1H),7.33-7.30(m,1H),7.21–7.08(m,1H),6.92(m,2H),5.99(q, J=6.7Hz, 1H), 3.09 (s, 4H), 1.81 (d, J=6.7Hz, 3H), 1.67 (s, 4H), 1.54 (m, 2H).

Embodiment 36

3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((3,5 dichloropyridine-4-base) first Epoxide)-1H-indazole (I-36)

Step 1: preparation 3,5-dichloropyridine formaldehyde

Changing acetaldehyde into DMF, remaining needed raw material, reagent and preparation method are with the step in embodiment 1 Rapid 1, obtain white solid 3,5-dichloropyridine formaldehyde

¹H NMR(300MHz,CDCl3)δ:10.45(s,1H),8.63(s,2H).

Step 2: preparation (3,5-dichloropyridine-4-base) methanol

By 2 gram 3,5-dichloropyridine formaldehyde is dissolved in 100 ml methanol, adds such as 650 milligrams of sodium borohydrides at 0 DEG C in batches, After being stirred at room temperature 2 hours, reaction terminates.It is spin-dried for solvent, adds 200 milliliters of ethyl acetate, then wash with water, have after separatory After the washing of machine saturated sodium-chloride water solution, anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography (petroleum ether: second Acetoacetic ester=70:30) separate to obtain 1.665 grams of (3,5-dichloropyridine-4-base) methanol, yield 82%.

¹H NMR(300MHz,CDCl₃)δ:10.45(s,1H),8.63(s,2H).

Step 3: preparation 3,5-bis-chloro-4-(chloromethyl) pyridine hydrochloride

20 milligrams of (3,5-dichloropyridine-4-base) methanol are dissolved in 5 milliliters of thionyl chlorides, reflux 1 hour, obtain yellow under argon Color solid, concentrating under reduced pressure solvent obtains 22 milligram 3,5-bis-chloro-4-(chloromethyl) pyridine hydrochloride

¹H NMR(300MHz,DMSO)δ8.72(s,2H),4.87(s,2H).

Step 4:5-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into (3,5-dichloropyridine-4-base) methylmethanesulfonate ester, Remaining needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain yellow oil 5-(3,5-dichloropyridines -4-base) methoxyl group)-1H-indole.

¹H NMR(300MHz,CDCl₃) δ 8.55 (s, 2H), 8.14 (s, 1H), 7.31 (d, J=8.8Hz, 1H), 7.27 (d, J=2.4Hz, 1H), 7.22 (m, 1H), 6.94 (dd, J=8.8,2.4Hz, 1H), 6.51 (m,1H),5.29(s,2H).

Step 5: preparation 5-(3,5-dichloropyridine-4-base) methoxyl group)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(3,5-dichloropyridine-4-base) methoxy Base)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(3,5- Dichloropyridine-4-base) methoxyl group)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃) δ 10.27 (s, 1H), 8.55 (s, 2H), 7.84 (d, J=2.3Hz, 1H), 7.48 (d, J=9.1Hz, 1H), 7.16 (dd, J=9.1,2.4Hz, 1H), 5.32 (s, 2H).

Step 6:3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((3,5 dichloropyridines -4-base) methoxyl group)-1H-indazole

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde into 5-(3,5-dichloropyridine-4-base) Methoxyl group)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow Color solid 3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((2,6 benzyl dichloride) epoxide) -1H-indazole

¹H NMR(300MHz,CD₃OD) δ: 8.61 (s, 2H), 8.11 (d, J=2.2Hz, 1H), 7.61-7.53 (m,2H),7.30(s,1H),7.19–7.09(m,2H),5.45(s,2H),4.14(m,2H),3.22- 3.11(m,7H),2.46(m,2H),2.37–2.04(m,8H),1.96(s,2H).

Embodiment 37

5-((3,5-dichloropyridine-4-base) methoxyl group)-3-(6-(piperidin-1-yl-1H-benzo [d] imidazoles-2-base)-1H-Yin Azoles (I-37)

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde into 5-(3,5-dichloropyridine-4- Base) methoxyl group)-1H-indazole-3-formaldehyde, 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline changes 5-(piperidines-1-into Base)-2-nitroaniline, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-((3,5-dichloropyridine-4-base) methoxyl group)-3-(6-(piperidin-1-yl-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ: 8.61 (s, 2H), 8.11 (d, J=2.2Hz, 1H), 7.61-7.53 (m,2H),7.30(s,1H),7.19–7.09(m,2H),5.45(s,2H),3.26–3.14(m,4H), 1.89–1.75(m,4H),1.68–1.57(m,2H).

Embodiment 38

3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((2,6 dichloro-benzyloxy)-1H- Indazole (I-38)

Step 1: preparation 5-(2,6-dichloro-benzyloxy)-1H-indole

1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester is changed into 2,6-dichloro bromobenzyl, remaining needed raw material, reagent and Preparation method, with the step 3 in embodiment 1, obtains yellow oil 5-(2,6-dichloro-benzyloxy)-1H-indole.

¹H NMR(300MHz,CDCl3)δ8.11(s,1H),7.40–7.17(m,6H),6.97(m,1H), 6.51(s,1H),5.32(s,2H).

Step 2: preparation 5-(2,6-dichloro-benzyloxy)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(2,6-dichloro-benzyloxy)-1H-indole, Remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(2,6-dichloro benzyloxies Base)-1H-indazole-3-formaldehyde.

¹H NMR (300MHz, DMSO) δ 10.18 (s, 1H), 7.71 (d, J=2.3Hz, 1H), 7.65 (d, J=9.0Hz, 1H), 7.59 (m, 1H), 7.56 (s, 1H), 7.48 (m, 1H), 7.19 (m, 1H), 5.31 (s, 2H).

Step 3:3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((2,6 dichloro-benzyloxy) -1H-indazole

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde into 5-(2,6-dichloro benzyloxy Base)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid Body 3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((2,6 benzyl dichloride) epoxide)-1H- Indazole

¹H NMR(300MHz,CD₃OD) δ: 8.11 (d, J=2.0Hz, 1H), 7.62 7.45 (m, 4H), 7.41-7.35(m,1H),7.28-7.27(m,1H),7.17-7.09(m,2H),5.47(s,2H),4.15 (m,2H),3.23-3.11(m,7H),2.47(m,2H),2.38–2.04(m,8H),1.97(s,2H)

Embodiment 39

5-((2,6-dichloro benzyl) epoxide)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole (I-39)

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde into 5-(2,6-dichloro benzyloxy Base)-1H-indazole-3-formaldehyde, 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline changes 5-(piperidin-1-yl)-2-into Nitroaniline, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((2,6 benzyl dichloride) epoxide)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ: 8.11 (d, J=2.0Hz, 1H), 7.62 7.45 (m, 4H), 7.41-7.35(m,1H),7.28-7.27(m,1H),7.17-7.09(m,2H),5.47(s,2H),3.22 –3.14(m,4H),1.86–1.75(m,4H),1.68–1.58(m,2H).

Embodiment 40

3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-2-methoxyl group)-1H-indazole (I-40)

Step 1: preparation 2-chloromethyl pyridine hydrochloride

5 milliliters of thionyl chlorides are cooled with an ice bath, drip the 2-piconol of 1 gram.After dropping, back flow reaction 2 is little Time.It is spin-dried for reactant liquor and obtains yellow solid 2-chloromethyl pyridine hydrochloride.

¹H NMR (300MHz, CDCl₃) δ: 4.68 (2H, s), 7.25 (m, 1H), 7.49 (d, J=7.8Hz, 1H), 7.71 7.76 (td, J=7.7,1.8Hz, 1H), 8.58 (m, 1H).

Step 2: preparation 5-(pyridine-2-methoxyl group)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 2-chloromethyl pyridine hydrochloride, remaining needed raw material, Reagent and preparation method, with the step 3 in embodiment 1, obtain green solid thing 5-(pyridine-2-methoxyl group)-1H-indole.

Step 3: preparation 5-(pyridine-2-methoxyl group)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(pyridine-2-methoxyl group)-1H-indole, Remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(pyridine-2-methoxy Base)-1H-indazole-3-formaldehyde.

¹H NMR (300MHz, CDCl₃) δ 10.23 (s, 1H), 8.64 (d, J=4.0Hz, 1H), 7.76 (m, 2H), 7.56 (d, J=7.7Hz, 1H), 7.43 (d, J=8.9Hz, 1H), 7.18 (d, J=8.8Hz, 1H), 5.28 (d, J=7.3Hz, 2H).

Step 4:3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-2-methoxyl group)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde changes 5-(pyridine-2-methoxyl group)-1H-indazole into -3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 3-(6-(piperazine Pyridine-1-base)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-2-methoxyl group)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ: 8.57 (d, J=4.9Hz, 1H), 8.02 (d, J=2.0Hz, 1H), 7.90 (td, J=7.7,1.7Hz, 1H), 7.71-7.69 (m, 1H), 7.62 7.50 (m, 2H), 7.44 7.35 (m, 1H), 7.29 7.21 (m, 2H), 7.11 (dd, J=8.8,2.2Hz, 1H), 5.32 (s, 2H),3.25–3.11(m,4H),1.89–1.74(m,4H),1.69–1.56(m,2H).

Embodiment 41

3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-3-methoxyl group)-1H-indazole (I-41)

Step 1: preparation 3-chloromethyl pyridine hydrochloride

Being dissolved in 15 milliliters of dichloromethane by the 3-piconol of 1 gram, ice bath cools down.Dropping thionyl chloride 2 milliliters, moves To being stirred at room temperature 3 hours.It is spin-dried for reactant liquor and obtains yellow solid 3-chloromethyl pyridine hydrochloride.

¹H NMR (300MHz, CDCl₃) δ 4.60 (s, 2H), 7.33 (dd, J=3.0,4.8Hz, 1H), 7.74 (1H, dt, J=7.9,1.9Hz), 8.58 (1H, dd, J=3.3,1.5Hz), 8.63 (1H, d, J=2.0 Hz)。

Step 2:5-(pyridine-3-methoxyl group)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 3-chloromethyl pyridine hydrochloride, remaining needed raw material, Reagent and preparation method, with the step 3 in embodiment 1, obtain green solid thing 5-(pyridine-3-methoxyl group)-1H-indole.

Step 3: preparation 5-(pyridine-3-methoxyl group)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(pyridine-3-methoxyl group)-1H-indole, Remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(pyridine-3-methoxy Base)-1H-indazole-3-formaldehyde.

¹H NMR (300MHz, CDCl₃) δ 10.28 (s, 1H), 8.77 (s, 1H), 8.63 (d, J=4.6Hz, 1H), 7.85 (d, J=7.6Hz, 1H), 7.79 (s, 1H), 7.50 (d, J=9Hz, 1H), 7.43 7.34 (m, 1H), 7.20 (d, J=9Hz, 1H), 5.17 (s, 2H).

Step 4:3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-3-methoxyl group)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde changes 5-(pyridine-3-methoxyl group)-1H-indazole into -3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 3-(6-(piperazine Pyridine-1-base)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-3-methoxyl group)-1H-indazole.

¹H NMR(300MHz,CD₃OD) δ: 8.72 (s, 1H), 8.51 (d, J=5.0Hz, 1H), 8.08 7.97 (m, 2H), 7.63 7.45 (m, 3H), 7.28 (s, 1H), 7.22 (dd, J=9.1,2.2Hz, 1H), 7.12 (dd, J=8.8,2.1Hz, 1H), 5.30 (s, 2H), 3.24 3.15 (m, 4H), 1.86 1.74 (m, 4H), 1.64 (d, J=5.2Hz, 2H).

Embodiment 42

3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-4-methoxyl group)-1H-indazole (I-42)

Step 1: preparation 4-chloromethyl pyridine hydrochloride

Being dissolved in 15 milliliters of dichloromethane by the 4-piconol of 1 gram, ice bath cools down.Dropping thionyl chloride 2 milliliters, moves To being stirred at room temperature 3 hours.It is spin-dried for reactant liquor and obtains yellow solid 4-chloromethyl pyridine hydrochloride.

¹H NMR (300MHz, CDCl₃) δ 4.55 (s, 2H), 7.34 (d, J=5.9Hz, 2H), 8.62 (d, J=5.9Hz, 2H).

Step 2:5-(pyridine-4-methoxyl group)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 4-chloromethyl pyridine hydrochloride, remaining needed raw material, Reagent and preparation method, with the step 3 in embodiment 1, obtain green solid thing 5-(pyridine-4-methoxyl group)-1H-indole.

Step 3: preparation 5-(pyridine-4-methoxyl group)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(pyridine-4-methoxyl group)-1H-indole, Remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(pyridine-4-methoxy Base)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃) δ 10.15 (s, 1H), 8.59 (d, J=5.1Hz, 2H), 7.67 (d, J=9.1Hz, 1H), 7.59 (s, 1H), 7.50 (d, J=5.2Hz, 2H), 7.30 7.24 (m, 1H), 5.27 (s, 2H).

Step 4: preparation 3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-4-methoxyl group)-1H-Yin Azoles

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde changes 5-(pyridine-4-methoxyl group)-1H-indazole into -3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 3-(6-(piperazine Pyridine-1-base)-1H-benzo [d] imidazoles-2-base)-5-(pyridine-4-methoxyl group)-1H-indazole.

¹H NMR(300MHz,CD₃OD) δ: 8.55-8.54 (m, 2H), 8.00 (d, J=2.0Hz, 1H), 7.61 (d, J=6.0Hz, 2H), 7.60-7.53 (m, 2H), 7.25 (dd, J=9.1,2.4Hz, 1H), 7.24 -7.23 (m, 1H), 7.08 (dd, J=8.8,2.1Hz, 1H), 5.31 (s, 2H), 3.19 3.08 (m, 4H),1.87–1.71(m,4H),1.66–1.55(m,2H).

Embodiment 43

5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-43)

Step one: preparation 1-(3,5-dichloropyridine-4-base) propanol

Changing acetaldehyde into propionic aldehyde, remaining needed raw material, reagent and preparation method, with the step 1 in embodiment 1, obtain yellow color Grease 1-(3,5-dichloropyridine-4-base) propanol

Step 2: preparation 1-(3,5-dichloropyridine-4-base) propyl Methanesulfonate

1-(3,5-dichloropyridine-4-base) ethanol is changed into 1-(3,5-dichloropyridine-4-base) propanol, remaining needed raw material, Reagent and preparation method, with the step 2 in embodiment 1, obtain white waxy solid 1-(3,5-dichloropyridine-4-base) propyl group first Sulphonic acid ester.

¹H NMR(300MHz,CDCl₃) δ 8.51 (s, 2H), 6.09 (m, 1H), 2.94 (s, 3H), 2.35-2.23 (m, 1H), 2.04 (m, 1H) 1.03 (t, J=7.4,3H).

Step 3:5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 1-(3,5-dichloropyridine-4-base) propyl group methanesulfonic acid Ester, remaining needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain colorless oil 5-(1-(3,5- Dichloropyridine-4-base) propoxyl group)-1H-indole

¹H NMR (300MHz, CDCl₃) δ 8.52 (s, 2H), 7.42-7.31 (m, 1H), 7.26 (s, 1H) 7.12 (s, 1H), 7.01 (m, 1H), 6.53 (m, 1H), 5.92-5.84 (m, 1H), 2.47 (m, 1H), 2.25-2.10 (m, 1H), 1.24 (t, J=7.4Hz, 3H).

Step 4: preparation 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-1H-indole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(3,5-dichloropyridine-4-base) third Epoxide)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-1H-indole-3-formaldehyde.

¹H NMR (300MHz, CDCl₃) δ 10.20 (s, 1H), 8.43 (s, 2H), 7.62 (d, J=2.1Hz, 1H), 7.43 (d, J=9.1Hz, 1H), 7.20 (dd, J=9.1,2.1Hz, 1H), 5.86 (m, 1H), 2.35 (m, 7.6Hz, 1H), 2.16 2.00 (m, 1H), 1.11 (t, J=7.4Hz, 3H).

Step 5: preparation 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-3-(6-(piperidin-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde changes 5-(1-(3,5-dichloropyridine-4-base) third into Epoxide)-1H-indole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow Solid 5-(1-(3,5-dichloropyridine-4-base) propoxyl group)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole

¹H NMR (400MHz, MeOD) δ: 8.41 (s, 2H), 7.84 (d, J=2.1Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.46 (d, J=9.0Hz, 1H), 7.25 (s, 1H), 7.16 (dd, J=9.0,1.7 Hz, 1H), 7.09 (dd, J=8.8,2.0Hz, 1H), 6.04 5.90 (m, 1H), 3.23 3.05 (m, 4H),2.46–2.27(m,1H),2.16–2.01(m,1H),1.89–1.70(m,4H),1.62-1.58 (m, 2H), 1.13 (t, J=7.4Hz, 3H).

Embodiment 44

(R)-2 (2 (5 (1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] miaow Azoles-6-base) ethanol (I-44)

Change 1-(3,5-dichloropyridine-4-base) ethanol into (S)-1-(3,5-dichloropyridine-4-base) ethanol, remaining institute Need raw material, reagent and preparation method with embodiment 2, obtain (R)-2 (2 (5 (1-(3,5-dichloropyridine-4-base) Ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6-base) ethanol

Embodiment 45

(R)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-48)

Change 1-(3,5-dichloropyridine-4-base) ethanol into (S)-1-(3,5-dichloropyridine-4-base) ethanol, remaining institute Need raw material, reagent and preparation method with embodiment 4, obtain (R)-5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole.

¹H NMR(300MHz,DMSO)δ13.40-13.35(m,1H),12.58-12.52(m,1H), 8.60 (s, 2H), 7.84-7.80 (m, 1H), 7.57-7.30 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.19-6.88 (m, 1H), 7.13 (d, J=8.8Hz, 1H), 6.99-6.98 (m, 1H), 6.10 (q, J=6.7Hz, 1H), 3.15-3.07 (m, 4H), 1.78 (d, J=6.7Hz, 3H), 1.73- 1.69(m,4H),1.58-1.50(m,2H)

Embodiment 46

(R)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-methylpiperazine-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole (I-46)

Change 1-(3,5-dichloropyridine-4-base) ethanol into (S)-1-(3,5-dichloropyridine-4-base) ethanol, former needed for remaining Material, reagent and preparation method, with embodiment 3, obtain (R)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-first Base piperazine-1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Embodiment 47

(R)-N-(2-(5-(1-(3,5 dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-base)-1H-benzo [d] imidazoles-6- Base)-2-(dimethylamino)-N-methylacetamide (I-50)

Change 1-(3,5-dichloropyridine-4-base) ethanol into (S)-1-(3,5-dichloropyridine-4-base) ethanol, former needed for remaining Material, reagent and preparation method, with embodiment 10, obtain (R)-N-(2-(5-(1-(3,5 dichloropyridine-4-base) ethyoxyl)-1H- Indazole-3-base)-1H-benzo [d] imidazoles-6-base)-2-(dimethylamino)-N-methylacetamide

¹H NMR(300MHz,CDCl₃) δ 8.31 (s, 2H), 7.82 (s, 1H), 7.66 (d, J=7.9Hz, 1H), 7.53 (s, 1H), 7.41 (d, J=9.0Hz, 1H), 7.07 (dd, J=9.1,2.0Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 6.09 (q, J=6.5Hz, 1H), 3.55 (s, 2H), 3.24 (s, 3H), 2.66 (s, 6H), 1.75 (d, J=6.5Hz, 3H)

Embodiment 48

5-(1-(2,4-dichloropyridine-3-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-48)

Step 1: preparation 1-(2,4-dichloropyridine-3-base) ethanol

By 3,5-dichloropyridine changes 2 into, and 4-dichloropyridine, remaining needed raw material, reagent and preparation method are with in embodiment 1 Step 1, obtain colorless oil 1-(2,4-dichloropyridine-3-base) ethanol.

¹H NMR(300MHz,CDCl₃) δ: 8.19 (d, J=5.2Hz, 1H), 7.28 (d, J=5.2Hz, 1H), 5.56 (dq, J=9.7,6.9Hz, 1H), 2.84 (d, J=9.7Hz, 1H), 1.66 (d, J=6.9Hz, 3H).

Step 2: preparation 1-(2,4-dichloropyridine-3-base) ethyl methane sulfonate ester

1-(3,5-dichloropyridine-4-base) ethanol is changed into 1-(2,4-dichloropyridine-3-base) ethanol, remaining needed raw material, Reagent and preparation method, with the step 2 in embodiment 1, obtain white waxy solid 1-(2,4-dichloropyridine-3-base) ethyl first Sulphonic acid ester

¹H NMR(300MHz,CDCl₃) δ: 8.27 (d, J=5.3Hz, 1H), 7.33 (d, J=5.3Hz, 1H), 6.43 (q, J=6.9Hz, 1H), 2.96 (s, 3H), 1.84 (d, J=6.9Hz, 3H).

Step 3: preparation 5-(1-(2,4-dichloropyridine-3-base) ethyoxyl)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into 1-(2,4-dichloropyridine-3-base) ethyl methane sulfonate Ester, remaining needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain colorless oil 5-(1-(2,4- Dichloropyridine-3-base) ethyoxyl)-1H-indole

1H NMR (300MHz, CDCl3) δ: 8.12 (d, J=5.2Hz, 1H), 8.04 (s, 1H), 7.23 (d, J=8.9Hz, 1H), 7.20 (d, J=5.2Hz, 1H), 7.16 7.13 (m, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.89 (dd, J=8.8,2.4Hz, 1H), 6.41-6.39 (m, 1H), 6.05 (q, J=6.7Hz, 1H), 1.81 (d, J=6.7Hz, 3H).

Step 4: preparation 5-(1-(2,4-dichloropyridine-3-base) ethyoxyl)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-(1-(2,4-dichloropyridine-3-base) second Epoxide)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-(1-(2,4-dichloropyridine-3-base) ethyoxyl)-1H-indazole-3-formaldehyde.

1H NMR (300MHz, CDCl3) δ 10.91 (s, 1H), 10.20 (s, 1H), 8.15 (d, J=5.2Hz, 1H), 7.65 (d, J=2.4Hz, 1H), 7.43 (d, J=9.1Hz, 1H), 7.26 (d, J=5.2Hz, 1H), 7.20 (dd, J=9.1,2.4Hz, 1H), 6.15 (q, J=6.7Hz, 1H), 1.84 (d, J=6.7Hz, 3H).

Step 5: preparation 5-(1-(2,4-dichloropyridine-3-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-(1-(2,4-dichloropyridine-3-base) second into Epoxide)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow Solid 5-(1-(2,4-dichloropyridine-3-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole.

¹H NMR(300MHz,CD₃OD) δ: 8.12 (d, J=5.3Hz, 1H), 7.85 (d, J=2.0Hz, 1H), 7.57 (d, J=8.4Hz, 1H), 7.47 (d, J=9.0Hz, 1H), 7.39 (d, J=5.1Hz, 1H), 7.23 (s, 1H), 7.17 (dd, J=9.0,2.3Hz, 1H), 7.09 (d, J=8.6Hz, 1H), 6.26 (q, J= 6.6Hz,1H),3.17(s,4H),1.89–1.75(m,7H),1.62(s,2H).

Embodiment 49

3-(5,6-bis-chloro-1H-benzo [d] imidazoles-2-base)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole (I-49)

Step 1: preparation 4,5-dichloro-benzenes-1,2-diamidogen

By 400 milligram 4,5-bis-chloro-2-nitroaniline is dissolved in 10 ml methanol, adds 80 milligram of 10% palladium carbon hydrogenation and urges Agent, under room temperature, normal pressure hydrogenation reacts 8 hours, filtering and concentrating, residue silica gel column chromatography (ethyl acetate: petroleum ether=30: 70) 140 milligrams of yellow-brown solid, yield 41% are separated to obtain.

¹H NMR (300MHz, DMSO) δ: 6.62 (s, 2H), 4.85 (s, 4H).

Step 2: preparation 3-(5,6-bis-chloro-1H-benzo [d] imidazoles-2-base)-5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-1H-indazole

O-phenylenediamine is changed into 4,5-dichloro-benzenes-1,2-diamidogen, remaining needed raw material, reagent and preparation method with embodiment 5, Obtain yellow solid 3-(5,6-bis-chloro-1H-benzo [d] imidazoles-2-base)-5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-1H-indazole

¹H NMR (300MHz, DMSO) δ: 13.64 (s, 1H), 13.21 (s, 1H), 8.63 (s, 2H), 7.93 (s, 1H), 7.74 (d, J=2.4Hz, 1H), 7.64 (s, 1H), 7.57 (d, J=9.0Hz, 1H), 7.17 (dd, J=9.0,2.4Hz, 1H), 6.10 (q, J=6.7Hz, 1H), 1.79 (d, J=6.7Hz, 3H).

Embodiment 50

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-(piperidin-1-yl)-6-fluoro-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-50)

Step 1: preparation 4-fluoro-2-nitro-5-(piperidin-1-yl) aniline

By 500 milligram 4,5-bis-fluoro-2-nitroaniline is dissolved in 5 milliliters of piperidines, and 100 DEG C are heated 2 hours, adds 50 millis Rising water, ethyl acetate extracts, and organic facies is washed, and saturated common salt is washed, and anhydrous sodium sulfate is dried, evaporating column chromatography (second Acetoacetic ester: petroleum ether=20:80) separate to obtain 570 milligrams of orange solids, yield 83%.

¹H NMR(300MHz,CDCl₃) δ 7.75 (d, J=14.1Hz, 1H), 6.06 (s, 2H), 6.02 (d, J=7.6Hz, 1H), 3.26 3.15 (m, 4H), 1.77 1.61 (m, 6H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-fluoro-5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 4-fluoro-2-nitro-5-(piperidin-1-yl) aniline, Remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloropyridines -4-base) ethyoxyl)-3-(5-(piperidin-1-yl)-6-fluoro-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ 8.43 (s, 2H), 7.80 (d, J=2.4Hz, 1H), 7.47 (d, J=9.0Hz, 1H), 7.43 7.35 (m, 1H), 7.27 7.19 (m, 1H), 7.17 (dd, J=9.0, 2.4Hz, 1H), 6.22 (q, J=6.7Hz, 1H), 3.11 2.98 (m, 4H), 1.89 1.74 (m, 7H), 1.63(m,2H).

Embodiment 51

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(7-methyl isophthalic acid H-benzo [d] imidazoles-2-base)-1H-indazole (I-51)

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 2-methyl-6-nitroaniline, former needed for remaining Material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow-brown solid 5-(1-(3,5-dichloropyridine-4-base) Ethyoxyl)-3-(7-methyl isophthalic acid H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ 8.42 (s, 2H), 7.73 (s, 1H), 7.49 (d, J=9.0Hz, 1H), 7.36 (s, 1H), 7.23 7.12 (m, 2H), 7.05 (d, J=7.2Hz, 1H), 6.21 (q, J= 6.7Hz, 1H), 2.68 (m, 3H), 1.82 (d, J=6.7Hz, 3H).

Embodiment 52

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-methyl isophthalic acid H-benzo [d] imidazoles-2-base)-1H-indazole (I-52)

O-phenylenediamine is changed into 4-methyl isophthalic acid, 2-phenylenediamine, remaining needed raw material, reagent and preparation method with embodiment 5, Obtain yellow solid 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-methyl isophthalic acid H-benzo [d] imidazoles-2-base)-1H- Indazole

¹H NMR(300MHz,CD₃OD)δ8.43(s,2H),7.81(s,1H),7.67–7.32(m,3H), 7.17 (dd, J=9.0,2.1Hz, 1H), 7.11 (d, J=7.8Hz, 1H), 6.24 (q, J=6.6Hz, 1H), 2.50 (s, 3H), 1.83 (d, J=6.6Hz, 3H).

Embodiment 53

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-(2-methoxy ethoxy)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-53)

Step 1: preparation 4-(2-methoxy ethoxy)-2-nitroaniline

500 milligrams of 3-nitro-PAPs, 541 milligrams of 1-bromo-2-Ethyl Methyl Ethers are dissolved in 10 milliliters of N, N-diformazans In base Methanamide, adding 1.34 grams of potassium carbonate, be warming up to 60 DEG C of reactions overnight, reactant liquor is concentrated to dryness, residue post layer Analysis (ethyl acetate: petroleum ether=20:80), 350 milligrams of orange solids, yield 50%.

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(5-(2-methoxy ethoxy)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 4-(2-methoxy ethoxy)-2-nitroaniline, Remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloropyridines -4-base) ethyoxyl)-3-(5-(2-methoxy ethoxy)-1H-benzo [d] imidazoles-2-base)-1H-indazole

¹H NMR(300MHz,CD₃OD) δ 8.44 (s, 2H), 7.81 (s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.48 (d, J=8.5Hz, 1H), 7.18 (m, 2H), 6.96 (dd, J=8.8,2.2Hz, 1H), 6.24 (q, J=6.6Hz, 1H), 4.25 4.16 (m, 2H), 3.85 3.77 (m, 2H), 3.47 (s, 3H), 1.84 (d, J=6.6Hz, 3H).

Embodiment 54

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(7-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base-1H- Indazole (I-54)

Step 1: preparation 2-nitro-3-(piperidin-1-yl) aniline

By 4,5-bis-fluoro-2-nitroaniline changes 2-nitro-3-chloroaniline into, and remaining needed raw material, reagent and preparation method are same Step 1 in embodiment 1, obtains brown slurry 2-nitro-3-(piperidin-1-yl) aniline

¹H NMR(300MHz,CDCl₃) δ 7.09 (t, J=8.1Hz, 1H), 6.34 (m, 2H), 4.76 (s, 2H),3.03–2.90(m,4H),1.73–1.61(m,4H),1.56(m,2H).

Step 2: preparation 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(7-(piperidin-1-yl)-1H-benzo [d] Imidazoles-2-base-1H-indazole

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 2-nitro-3-(piperidin-1-yl) aniline, remaining Needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 5-(1-(3,5-dichloropyridine-4- Base) ethyoxyl)-3-(7-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base-1H-indazole.

¹H NMR(300MHz,DMSO)δ13.45(s,1H),12.76(s,1H),8.56(s,2H),8.08 (s, 1H), 7.54 (d, J=9.1Hz, 1H), 7.20 (d, J=8.7Hz, 1H), 7.05 (t, J=7.7Hz, 1H), 6.98 (d, J=7.7Hz, 1H), 6.53 (d, J=7.5Hz, 1H), 6.20 (q, J=6.7Hz, 1H), 3.60(s,4H),1.81(m,7H),1.66(s,2H).

Embodiment 55

3-(7-chloro-1H-benzo [d] imidazoles-2-base)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole (I-55)

Step 1: preparation 3-chloro-1,2-phenylenediamine

500 milligrams of 2-nitro-3-chloroanilines are dissolved in 8 milliliters of ethanol, add 5 milliliters of hydrochloric acid (3 moles every liter), then Add 3.27 grams of stannous chloride dihydrates, reflux three hours.Reactant liquor concentrates, with rear addition second in saturated sodium bicarbonate solution Acetoacetic ester, separatory after filtration, organic facies washing, after saturated sodium-chloride water solution washing, anhydrous sodium sulfate is dried, and filters dense Contracting, residue column chromatography obtains 367 milligrams of brown liquid 3-chloro-1,2-phenylenediamine, yield 89%.

¹H NMR (300MHz, DMSO) δ: 6.55 6.44 (m, 2H), 6.38 (t, J=7.8Hz, 1H), 4.80(s,2H),4.60(s,2H).

Step 2: preparation 3-(7-chloro-1H-benzo [d] imidazoles-2-base)-5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-1H-indazole

O-phenylenediamine changes into 3-chloro-1,2-phenylenediamine, and remaining needed raw material, reagent and preparation method, with embodiment 5, obtain Yellow solid 3-(7-chloro-1H-benzo [d] imidazoles-2-base)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-Yin Azoles.

¹H NMR(300MHz,CD₃OD)δ8.42(s,2H),7.77(s,1H),7.48(m,2H),7.30– 7.16 (m, 3H), 6.23 (q, 6.6Hz, 1H), 3.35 (s, 2H), 1.82 (d, J=6.6Hz, 3H).

Embodiment 56

3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-N-(pyridin-4-yl methyl)-1H-indazole-5-amine (I-56)

Step 1: preparation 5-amino indole

1 gram of 5-nitroindoline is dissolved in 40 milliliters of ethanol, adds 200 milligram of 10% palladium carbon, under atmosphere of hydrogen, stir 6 Hour, filtering and concentrating obtains 680 milligrams of pink solid 5-amino indoles, yield 86%

¹H NMR (300MHz, DMSO) δ 10.55 (s, 1H), 7.09 (dd, J=12.9,5.6Hz, 2H), 6.68 (s, 1H), 6.48 (dd, J=8.5,2.0Hz, 1H), 6.12 (d, J=2.0Hz, 1H), 4.40 (s, 2H).

Step 2: preparation N-(pyridin-4-yl methyl)-1H-indole-5-amine

50 milligrams of 5-amino indoles are dissolved in 2 ml methanol, add 50 milligrams of 4-pyridine carboxaldehydes, stirred under room temperature At night, add 30 milligrams of sodium borohydrides, add saturated sodium bicarbonate solution cancellation after stirring 1 hour, after ethyl acetate extraction Washing, saturated sodium-chloride water solution washs, and the dried filtering and concentrating of anhydrous sodium sulfate, residue column chromatography obtains 60 milligrams of palm fibres Color grease N-(pyridin-4-yl methyl)-1H-indole-5-amine, yield 71%.

¹H NMR (300MHz, DMSO) δ 10.60 (s, 1H), 8.46 (d, J=5.9Hz, 2H), 7.37 (d, J=5.4Hz, 2H), 7.12 (m, 2H), 6.56 (dd, J=8.8,2.0Hz, 1H), 6.50 (s, 1H), 6.10 (s, 1H), 5.78 (t, J=6.4Hz, 1H), 4.30 (d, J=6.1Hz, 2H).

Step 3: preparation 5-((pyridin-4-yl methyl) amino)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into N-(pyridin-4-yl methyl)-1H-indole -5-amine, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain yellow solid 5-((pyridine-4- Ylmethyl) amino)-1H-indazole-3-formaldehyde.

¹H NMR (300MHz, DMSO) δ 10.19 (s, 1H), 8.48 (d, J=5.4Hz, 2H), 8.23 (s, 1H), 7.87 (m, 2H), 7.11 (d, J=5.4Hz, 2H), 5.46 (s, 2H).

Step 4: preparation 3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-N-(pyridin-4-yl methyl)-1H-Yin Azoles-5-amine

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-((pyridin-4-yl methyl) ammonia into Base)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid Body 3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-N-(pyridin-4-yl methyl)-1H-indazole-5-amine

¹H NMR(300MHz,CD₃OD) δ: 8.61 (d, J=2.0Hz, 1H), 8.45 (d, J=6.2Hz, 2H), 7.85 (dd, J=9.1,2.1Hz, 1H), 7.75 (d, J=9.0Hz, 1H), 7.56 (s, 1H), 7.27 (d, J=6.1Hz, 2H), 7.20 (s, 1H), 7.09 (dd, J=8.6,2.1Hz, 1H), 5.53 (s, 2H), 3.21 –3.12(m,4H),1.80(m,4H),1.63(m,2H).

Embodiment 57

N-((3,5-dichloropyridine-4-base) methyl)-3-(5 (piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole -5-amine (I-57)

Step 1: preparation N-((3,5-dichloropyridine-4-base) methyl)-1H-indole-5-amine

4-pyridine carboxaldehyde changes into 3, and 5-bis-chloro-4-pyridine carboxaldehyde, remaining remaining needed raw material, reagent and preparation method are with real Execute the step 2 in example 56, obtain light brown grease N-((3,5-dichloropyridine-4-base) methyl)-1H-indole-5-amine.

¹H NMR(400MHz,CDCl₃) δ 8.46 (s, 2H), 8.00 (s, 1H), 7.22 (d, J=8.6Hz, 1H), 7.14 (t, J=2.7Hz, 1H), 7.03 (d, J=1.8Hz, 1H), 6.73 (dd, J=8.8,2.1 Hz, 1H), 6.41 (d, J=0.4Hz, 1H), 4.63 (s, 2H).

Step 2: preparation 5-(((3,5-dichloropyridine-4-base) methyl) amino)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into N-((3,5-dichloropyridine-4-base) first Base)-1H-indole-5-amine, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain yellow solid 5-(((3,5-dichloropyridine-4-base) methyl) amino)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃) δ 10.26 (s, 1H), 8.35 (d, J=2.6Hz, 3H), 7.68 (dd, J=8.9,2.1Hz, 1H), 7.59 (d, J=9.1Hz, 1H), 5.56 (s, 2H).

Step 3: preparation N-((3,5-dichloropyridine-4-base) methyl)-3-(5 (piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole-5-amine

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-(((3,5-dichloropyridine-4-base) first into Base) amino)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain Yellow solid N-((3,5-dichloropyridine-4-base) methyl)-3-(5 (piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H- Indazole-5-amine.

¹H NMR(300MHz,CD₃OD)δ8.61(s,1H),8.38(s,2H),7.65(s,2H),7.57(d, J=9.0Hz, 1H), 7.22 (s, 1H), 7.09 (dd, J=8.8,2.0Hz, 1H), 5.65 (s, 2H), 3.21 –3.12(m,4H),1.85–1.74(m,4H),1.62(m,2H).

Embodiment 58

N-(1-(3,5-dichloropyridine-4-base) ethyl)-3-(5 (piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-Yin Azoles-5-amine (I-58)

Step 1: preparation 1-(3,5-dichloropyridine-4-base) ethamine

3 grams of 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester is dissolved in 60 milliliters of DMFs, adds Enter 1.08 grams of Hydrazoic acid,sodium salt, be heated to 50 DEG C and react 1 hour, recover to room temperature to add 100 milliliters of ethyl acetate, have Machine is micro-dry with being concentrated into after 300 milliliters of water washings mutually, adds 60 milliliters of ethanol, 20 milliliters of water, adds 1.48 grams of chlorine Change ammonium, 1.08 grams of zinc powders, be stirred overnight under room temperature, concentrate after reacting liquid filtering, add 100 milliliters of ethyl acetate, have Machine is dried with anhydrous sodium sulfate after washing with water and saturated sodium-chloride water solution the most successively, and filtering and concentrating, residue column chromatography obtains 1.5 grams of light yellow oil 1-(3,5-dichloropyridine-4-base) ethamine, yield 70.7%

¹H NMR (300MHz, DMSO) δ 8.53 (s, 1H), 4.63 (q, J=7.2Hz, 1H), 2.30 (s, 2H), 1.40 (d, J=7.1Hz, 3H).

Step 2: prepare the tert-butyl group-5-bromo-1H-indole-1-carboxylate

1 gram of 5-bromo indole is dissolved in 50 milliliters of dichloromethane, adds 1.22 grams of Bis(tert-butoxycarbonyl)oxides, 60 milligrams of 4-bis- Methylamino pyridine, stirs 1 hour under room temperature, and reactant liquor concentrates, the residue column chromatography give light yellow oil tert-butyl group-5- Bromo-1H-indole-1-carboxylate 1.34 grams, yield 88.7%

¹H NMR(400MHz,CDCl₃) δ 8.02 (d, J=7.7Hz, 1H), 7.69 (s, 1H), 7.59 (d, J=3.4Hz, 1H), 7.39 (d, J=8.7Hz, 1H), 6.50 (d, J=3.7Hz, 1H), 1.67 (s, 9H).

Step 3: prepare the tert-butyl group-5-((1-(3,5-dichloropyridine-4-base) ethyl) amino)-1H-indole-1-carboxylate

By 20 milligrams of 1-(3,5-dichloropyridine-4-base) ethamine, the 30 milligrams of tert-butyl group-5-bromo-1H-indole-1-carboxylates are molten In 1.5 milliliters of dry toluenes, it is sequentially added into 6 milligrams of tri-tert tetrafluoride borates, 24 milligrams of sodium tert-butoxides and 9 Milligram three (dibenzalacetone) two palladium, is warming up to 100 DEG C after argon displacement and reacts 1 hour, and reactant liquor concentrates, residue Column chromatography obtains the 24 milligrams of colorless oil tert-butyl group-5-((1-(3,5-dichloropyridine-4-base) ethyl) amino)-1H-indole -1-carboxylate, yield 60.7%

¹H NMR(300MHz,CDCl₃) δ 8.35 (s, 2H), 7.86 (d, J=10.1Hz, 1H), 7.46 (d, J=3.1Hz, 1H), 6.64 (d, J=8.3Hz, 2H), 6.35 (d, J=3.6Hz, 1H), 5.49 5.35 (m, 1H), 4.61 (d, J=9.2Hz, 1H), 1.66 (d, J=7.0Hz, 3H), 1.62 (s, 9H).

Step 4: preparation N-(-(3,5-dichloropyridine-4-base) ethyl) indole-5-amine

The 10 milligrams of tert-butyl group-5-((1-(3,5-dichloropyridine-4-base) ethyl) amino)-1H-indole-1-carboxylate is dissolved in 1 In the ethanol solution of hydrogen chloride of milliliter 4 moles every liter, stirring 3 hours under room temperature, reactant liquor concentrates, and adds 1 ml methanol, 20 milligrams of potassium carbonate, are heated to reflux 2 hours, and reacting liquid filtering is concentrated to give N-(-(3,5-dichloropyridine-4-base) ethyl) Yin Diindyl-5-amine.

¹H NMR(300MHz,CDCl₃) δ 8.33 (s, 2H), 7.91 (s, 1H), 7.15 (d, J=8.6Hz, 1H), 7.07 (t, J=2.6Hz, 1H), 6.76 (s, 1H), 6.61 (dd, J=8.6,2.0Hz, 1H), 6.33 (s, 1H), 5.44 (q, J=7.1Hz, 1H), 1.66 (d, J=7.0Hz, 3H).

Step 5: preparation 5-((1-(3,5-dichloropyridine-4-base) ethyl) amino)-1H-indazole-3-formaldehyde

5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole is changed into N-(-(3,5-dichloropyridine-4-base) ethyl) Indole-5-amine, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain yellow solid 5-((1-(3,5-dichloropyridine-4-base) ethyl) amino)-1H-indazole-3-formaldehyde.

¹H NMR(300MHz,CDCl₃)δ10.30(s,1H),8.49(s,1H),8.43(s,2H),8.09(s, 2H), 7.71 7.59 (m, 2H), 6.12 (q, J=7.5Hz, 1H), 1.62 (d, J=7.3Hz, 3H).

Step 6: preparation N-(1-(3,5-dichloropyridine-4-base) ethyl)-3-(5 (piperidin-1-yl)-1H-benzo [d] imidazoles -2-base)-1H-indazole-5-amine

Change 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline into 5-(piperidin-1-yl)-2-nitroaniline, 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indazole-3-formaldehyde changes 5-((1-(3,5-dichloropyridine-4-base) into Ethyl) amino)-1H-indazole-3-formaldehyde, remaining needed raw material, reagent and preparation method with the step 6 in embodiment 1, Obtain yellow solid N-(1-(3,5-dichloropyridine-4-base) ethyl)-3-(5 (piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole-5-amine.

Embodiment 59

5-((3-chloropyridine-4-base) methoxyl group)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole (I-59)

Step 1: preparation 3-chlorine different cigarette aldehyde

By 3,5-dichloropyridine changes 3-chloropyridine into, and acetaldehyde changes DMF into, remaining needed raw material, reagent And preparation method is with the step 1 in embodiment 1, obtain light yellow solid 3-chlorine different cigarette aldehyde.

¹H NMR(400MHz,CDCl₃) δ 10.49 (s, 1H), 8.79 (s, 1H), 8.69 (d, J=4.9Hz, 1H), 7.71 (d, J=4.9Hz, 1H).

Step 2: preparation (3-chloropyridine-4-base) methanol

By 3,5-dichloropyridine formaldehyde changes 3-chlorine different cigarette aldehyde into, and remaining needed raw material, reagent and preparation method are with embodiment 36 In step 2, obtain white solid (3-chloropyridine-4-base) methanol.

¹H NMR(400MHz,CDCl₃) δ 8.50-8.48 (m, 2H), 7.54 (d, J=4.9Hz, 1H), 4.82 (s,2H).

Step 3: preparation (3-chloropyridine-4-base) methylmethanesulfonate ester

1-(3,5-dichloropyridine-4-base) ethanol is changed into (3-chloropyridine-4-base) methanol, remaining needed raw material, reagent and Preparation method, with the step 2 in embodiment 1, obtains white solid (3-chloropyridine-4-base) methylmethanesulfonate ester.

¹H NMR(300MHz,CDCl₃) δ 8.55 (d, J=5.0Hz, 1H), 7.45 (d, J=5.0Hz, 1H), 5.33(s,2H),3.12(s,3H).

Step 4:5-((3-chloropyridine-4-base) methoxyl group)-1H-indole

Change 1-(3,5-dichloropyridine-4-base) ethyl methane sulfonate ester into (3-chloropyridine-4-base) methylmethanesulfonate ester, remaining Needed raw material, reagent and preparation method, with the step 3 in embodiment 1, obtain white solid 5-((3-chloropyridine-4-base) methoxy Base)-1H-indole.

¹H NMR(300MHz,CDCl₃) δ 8.58 (s, 1H), 8.50 (d, J=5.0Hz, 1H), 8.18 (s, 1H), 7.63 (dd, J=5.0,0.6Hz, 1H), 7.33 (d, J=8.8Hz, 1H), 7.21 (t, J=2.8 Hz, 1H), 7.15 (d, J=2.5Hz, 1H), 6.96 (dd, J=8.8,2.4Hz, 1H), 6.49 (t, J= 3.0Hz,1H),5.21(s,2H).

Step 5: preparation 5-((3-chloropyridine-4-base) methoxyl group)-1H-indazole-3-formaldehyde

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole into 5-((3-chloropyridine-4-base) methoxy Base)-1H-indole, remaining needed raw material, reagent and preparation method, with the step 4 in embodiment 1, obtain brown solid 5-((3- Chloropyridine-4-base) methoxyl group)-1H-indazole-3-formaldehyde.

¹H NMR (300MHz, DMSO) δ 10.16 (s, 1H), 8.69 (s, 1H), 8.57 (d, J=4.7Hz, 1H), 7.71 7.58 (m, 3H), 7.30 (d, J=8.9Hz, 1H), 5.31 (s, 2H).

Step 6:5-((3-chloropyridine-4-base) methoxyl group)-3-(5-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole

Change 5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-indole-3-formaldehyde into 5-((3-chloropyridine-4-base) first Epoxide)-1H-indazole-3-formaldehyde, 5-([Isosorbide-5-Nitrae '-connection piperidines]-1 '-yl)-2-nitroaniline changes 5-(piperidines-1-into Base)-2-nitroaniline, remaining needed raw material, reagent and preparation method, with the step 6 in embodiment 1, obtain yellow solid 3-(6-([1,4 ' connection piperidines]-1 '-yl)-1H-benzo [d] imidazoles-2-base)-5-((2,6 benzyl dichloride) epoxide))-1H-Yin Azoles

¹H NMR(300MHz,CD₃OD) δ 8.59 (s, 1H), 8.51 (d, J=5.0Hz, 1H), 8.03 (s, 1H), 7.76 (d, J=4.9Hz, 1H), 7.58 (d, J=3.6Hz, 1H), 7.55 (d, J=3.9Hz, 1H), 7.30 7.23 (m, 2H), 7.10 (d, J=8.8Hz, 1H), 5.37 (s, 2H), 3.22 3.13 (m, 4H),1.85–1.75(m,4H),1.67–1.58(m,2H).

Embodiment 60

(S)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2- Base)-1H-indazole (I-48)

Change 1-(3,5-dichloropyridine-4-base) ethanol into (R)-1-(3,5-dichloropyridine-4-base) ethanol, remaining institute Need raw material, reagent and preparation method with embodiment 4, obtain (S)-5-(1-(3,5-dichloropyridine-4-base) ethoxy Base)-3-(6-(piperidin-1-yl)-1H-benzo [d] imidazoles-2-base)-1H-indazole.

Embodiment 61

(S)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-methylpiperazine-1-yl)-1H-benzo [d] miaow Azoles-2-base)-1H-indazole (I-46)

Change 1-(3,5-dichloropyridine-4-base) ethanol into (R)-1-(3,5-dichloropyridine-4-base) ethanol, former needed for remaining Material, reagent and preparation method, with embodiment 3, obtain (S)-5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-3-(6-(4-first Base piperazine-1-base)-1H-benzo [d] imidazoles-2-base)-1H-indazole

Embodiment 62

The impact that FGFR1 and FGFR2 enzyme is lived by compound molecule level

1, test method

By enzyme reaction substrate Poly (Glu, Tyr) 4:1 with without potassium ion PBS (10mM sodium phosphate buffer, 150mM NaCl, PH7.2-7.4) it is diluted to 20 μ g/mL, 125 μ L/ hole coated elisa plates, puts 37 DEG C and react 12-16 hour.Discard hole Wash plate after middle liquid, wash plate three times with the T-PBS (PBS containing 0.1%Tween-20) in 200 μ L/ holes, each 5 minutes. ELISA Plate 1-2 hour it is dried in 37 DEG C of baking ovens.

Every hole adds with reaction buffer (50mM HEPES pH 7.4,50mM MgCl₂,0.5mM MnCl₂,0.2mM Na₃VO₄, 1mM DTT) the ATP solution 50 μ L that dilutes, final concentration 5 μMs.Compound DMSO is diluted to suitable concentration, 1 μ L/ Hole or or containing the DMSO (negative control hole) of respective concentration, add dilute with 49 μ L reaction buffers FGFR1, FGFR2 kinases territory recombiant protein starts reaction, and experiment need to set without ATP control wells holes every time.Put 37 DEG C of shaking tables (100rpm) React 1 hour.T-PBS washes plate three times.Adding an anti-PY99 diluent 100 μ L/ hole, it is little that 37 DEG C of shaking tables react 0.5 Time.T-PBS washes plate three times.Add the IgG diluent 100 μ L/ hole of two anti-horseradish peroxidase-labeled sheep anti mouses, 37 DEG C Shaking table reacts 0.5 hour.T-PBS washes plate three times.Add the OPD nitrite ion 100 μ L/ hole of 2mg/ml (with containing 0.03% H₂O₂0.1M citric acid-sodium citrate buffer (pH=5.4) dilution), 25 DEG C of lucifuges are reacted 1-10 minute.Add 2M H₂SO₄50 μ L/ hole stopped reactions, decline orifice plate microplate reader SPECTRA MAX 190 reading with wavelengthtunable, and wavelength is 490 nm。

The suppression ratio of sample is tried to achieve by following equation:

IC₅₀Value uses the random bundled software of microplate reader to return with four parametric methods and tries to achieve.

2, experimental result

Molecular level enzymatic activity test show, the indazole compounds of the present invention when concentration is nM level to FGFR1 Tyrosine kinase has good inhibition, part of compounds to the half-inhibition concentration of FGFR1 at about 1nM, It it is the potent FGFR1 tyrosine kinase inhibitor of a class.

Wherein when concentration is 10nM, pyridine ring compound I-36 and I-37 is alive to FGFR1 enzyme, and inhibitory action (presses down Rate processed is respectively 100%, and 55.4%) it is significantly stronger than benzene ring compound I-38 and I-39 (suppression ratio is respectively 50%, 2.4%). This experimental result confirms, relative to two parts of patents of US2003207883, US20060079564, the present invention more invasive The property made.

Table 2. compound inhibitory activity alive to FGFR1 and FGFR2 enzyme

Compound in embodiment	FGFR1	FGFR2
			I-1	A	–
I-2	A	–
			I-3	A	–
I-4	A	–
			I-5	A	–
I-6	A	–
			I-7	A	–
I-8	A	–
			I-9	A	–
I-10	A	–
			I-11	A	A
I-12	B	A
			I-13	A	A
I-14	A	A
			I-15	A	A
I-16	A	A
			I-17	B	A
I-18	A	A
			I-19	A	A
I-20	B	–

I-21	A	A
			I-22	A	–
I-23	A	–
			I-24	A	–
I-25	A	–
			I-26	A	–
I-27	B	–
			I-28	A	–
I-29	A	–
			I-30	A	–
I-31	A	–
			I-32	A	–
I-33	A	–
			I-34	A	–
I-35	B	–
			I-36	A (100%@10nM)	–
I-37	A (55.4%@10nM)	–
			I-38	B (50%@10nM)	–
I-39	B (2.4%@10nM)	–
			I-40	B	–
I-41	A	–
			I-42	B	–
I-43	A	–
			I-44	A	–
I-45	A	–
			I-46	A	–
I-47	A	–
			I-58	A	–

Wherein: A represents IC₅₀Less than 10nM

B represents IC₅₀Less than 100nM

C represents IC₅₀More than 100nM

Embodiment 63

The impact of the BaF3/TEL-FGFR1 cell proliferation that FGFR1 is relied on by compound

1, test method

Compound to BaF3/TEL-FGFR1 cell, (in cell, stably express by TEL-FGFR1 kinases district fusion protein In endochylema, FGFR1 sustained activation, for FGFR1 dependent cell strain) growth inhibited detection CCK-8 cell counting Test kit (Dojindo) detects.Specifically comprise the following steps that the BaF3/TEL-FGFR1 cell being in exponential phase is by conjunction Suitable density is seeded in 96 well culture plates, every hole 90 μ L, and after overnight incubation, the compound adding variable concentrations is made With 72hr, and setting solvent matched group (negative control).After compound effects cell 72h, compound on intracellular The impact of propagation uses CCK-8 Cell counting Kit (Dojindo) detection, and every hole adds 10 μ L CCK-8 reagent, After being placed in 37 DEG C of incubators placement 2-4 hour, decline orifice plate microplate reader SpectraMax 190 reading by all-wave length, Mensuration wavelength is 450nm.Use with the following equation computerized compound suppression ratio (%) to growth of tumour cell: suppression Rate (%)=(OD negative control hole-OD dosing holes)/OD negative control hole × 100%.IC50 value uses microplate reader random Bundled software returns with four parametric methods and tries to achieve.

2, experimental result

By table 3 result it can be seen that the indazole compounds of the present invention is when concentration is nM level pair BaF3/TEL-FGFR1 cell has good proliferation inhibiting effect, and part of compounds is to BaF3/TEL-FGFR1 cell Half-inhibition concentration is at about 1nM.

Wherein when concentration is 200nM, pyridine ring compound I-36 is to BaF3/TEL-FGFR1 cell inhibitory effect Effect (suppression ratio 79%) is significantly stronger than benzene ring compound I-38 (suppression ratio 3%).This experimental result is further characterized by, Relative to compound (wherein R disclosed in two parts of patents of US2003207883, US20060079564⁹Part is benzene Base), the compounds of this invention has more preferable inhibitory activity.

The impact on BaF3/TEL-FGFR1 cell proliferation of table 3. compound

Compound in embodiment	Activity
		I-2	A
I-3	A
		I-4	A
I-5	B
		I-6	A
I-10	A
		I-12	D
I-13	A
		I-14	B
I-15	A
		I-16	A
I-17	D
		I-18	A
I-36	C (79%@200nM)
		I-38	D (3%@200nM)

Wherein: A represents IC₅₀Less than 8nM

B represents IC₅₀Less than 40nM

C represents IC₅₀Less than 200nM

D represents IC₅₀More than 200nM

Embodiment 64

The compound impact on acute marrow source leukemia cell line KG1 cell proliferation

Test method

Compound is to acute marrow source leukemia cell line KG1 cell (FGFR1OP2-FGFR1 kinases district fusion protein in cell Stable expressing in endochylema, FGFR1 sustained activation, for FGFR1 dependent cell strain) growth inhibited detection CCK-8 thin Born of the same parents' counting reagent kit (Dojindo) detects.Specifically comprise the following steps that the KG1 cell being in exponential phase is connect by proper density Plant to 96 well culture plates, every hole 90 μ L, after overnight incubation, add compound effects 72hr of variable concentrations, and Setting solvent matched group (negative control).After compound effects cell 72h, the impact of compound on intracellular propagation uses CCK-8 Cell counting Kit (Dojindo) detects, and every hole adds 10 μ L CCK-8 reagent, is placed in 37 DEG C of incubators After placing 2-4 hour, declining orifice plate microplate reader SpectraMax 190 reading by all-wave length, mensuration wavelength is 450nm. Use with the following equation computerized compound suppression ratio (%) to growth of tumour cell: suppression ratio (%)=(OD negative control hole -OD dosing holes)/OD negative control hole × 100%.IC₅₀Value uses the random bundled software of microplate reader to return with four parametric methods and tries to achieve.

Experimental result

By table 4 result it can be seen that the indazole compounds of the present invention when concentration is nM level to acute marrow source leukemia Cell strain KG1 cell has good proliferation inhibiting effect, overwhelming majority compound to exist the half-inhibition concentration of KG1 cell Below 10nM.

Wherein pyridine ring compound I-36 is when concentration is 40nM, is 59.7% to KG1 cell proliferation inhibition rate, and benzene The half-inhibition concentration of cycle compound I-38 is more than 200nM.

The impact on KG1 cell proliferation of table 4. compound

Compound in embodiment	Activity
		I-21	D
I-22	A
		I-23	A
I-24	A
		I-25	B
I-26	A
		I-27	D
I-28	B
		I-29	A
I-30	A
		I-31	A
I-32	A
		I-33	A
I-34	B
		I-37	B (59.7%@40nM)
I-39	D
		I-40	D
I-41	C
		I-42	D
I-43	C
		I-44	A
I-45	A
		I-46	A
I-47	A

Wherein: A represents IC₅₀Less than 8nM

B represents IC₅₀Less than 40nM

C represents IC₅₀Less than 200nM

D represents IC₅₀More than 200nM

Embodiment 65

The compound impact on stomach cancer cell line KATOIII cell proliferation

Test method

To stomach cancer cell line KATOIII cell, (stomach cancer cell line, FGFR2 gene amplification causes FGFR2 to continue to compound Activation, for FGFR2 dependent cell strain) growth inhibited detection CCK-8 Cell counting Kit (Dojindo) detection. Specifically comprise the following steps that the KATOIII cell being in exponential phase is seeded in 96 well culture plates by proper density, every hole 90 μ L, after overnight incubation, add compound effects 72hr of variable concentrations, and setting solvent matched group (negative control). After compound effects cell 72h, the impact of compound on intracellular propagation uses CCK-8 Cell counting Kit (Dojindo) Detection, every hole adds 10 μ L CCK-8 reagent, after being placed in 37 DEG C of incubators placement 2-4 hour, declines by all-wave length Orifice plate microplate reader SpectraMax 190 reading, mensuration wavelength is 450nm.Use with following equation computerized compound swollen The suppression ratio (%) of tumor cell growth: suppression ratio (%)=(OD negative control hole-OD dosing holes)/OD negative control hole × 100%.IC₅₀Value uses the random bundled software of microplate reader to return with four parametric methods and tries to achieve.

Experimental result

By table 5 result it can be seen that the indazole compounds of the present invention when concentration is nM level to stomach cancer cell line KATOIII cell has good proliferation inhibiting effect.

The impact on KATOIII cell proliferation of table 5. compound

Compound in embodiment	Activity
		I-1	C
I-2	A
		I-3	A
I-4	A
		I-6	A
I-7	A
		I-8	A
I-9	C
		I-10	A

Wherein: A represents IC₅₀Less than 8nM

B represents IC₅₀Less than 40nM

C represents IC₅₀Less than 200nM

Embodiment 66

The impact that non-small cell lung cancer cell NCI-H1581 Nude Mice is grown by compound

1. experimental technique:

The tumor tissue taking growth animated period cuts into 1.5mm³Left and right, aseptically, is inoculated on the right side of nude mouse Axillary fossa is subcutaneous.Nude mouse subcutaneous transplantation tumor vernier caliper measurement transplanted tumor diameter, treats that tumor average volume grows to 115 mm³By animal random packet after Zuo You.I-46 10mg/kg and 2mg/kg group, once a day oral administration, give continuously Medicine 21 days；Positive control medicine AZD4547 20mg/kg group, once a day oral administration, successive administration 21 days；Molten Agent matched group is to equivalent solvent.In whole experimentation, measure transplanted tumor diameter 2 times a week, weigh Mice Body simultaneously Weight.Gross tumor volume growth inhibition rate TGI%, computing formula is as follows: TGI%=[1-(TVt-TV₀)/(CVt-CV₀)]× 100%, TVt are the tumor volume that treatment group is measured every time；TV₀Gained tumor volume when being administered for therapeutic component cage；CVt The tumor volume every time measured for matched group；CV₀For gained tumor volume during matched group sub-cage administration.Experimental result such as Fig. 1 Shown in.Result shows, the compounds of this invention I-46 TGI% under the conditions of 10mg/kg and 2mg/kg is administered is respectively 96.9% and 44.5%, the TGI% (73.9%) under the conditions of being administered higher than positive control medicine AZD4547 20mg/kg, tool There is the inhibition of excellence.

The all documents mentioned in the present invention are incorporated as reference the most in this application, just as each document coverlet Solely it is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, this area skill The present invention can be made various changes or modifications by art personnel, and these equivalent form of values fall within the application claims equally Book limited range.

Claims

1. the compound as shown in following formula (I):

Wherein:

R¹、R²、R³Be each independently selected from lower group: H, halogen；

R⁹For substituted or unsubstituted 5-7 unit heteroaryl；

M is selected from lower group: CH₂、CH、NH、N、O、S；

W is selected from O, NH；

2. compound as claimed in claim 1, it is characterised in that

R⁹Selected from substituted or unsubstituted five yuan and six membered heteroaryl, it is preferable that described R⁹Selected from unsubstituted or by 1-4 The substituted group selected from lower group of individual substituent group: pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, oxazolyl, Isoxazolyl, thiazolyl, isothiazolyl, furyl；Wherein, described substituent group selected from lower group: F, Cl, Br, first Base, methoxyl group, amino；

3. compound as claimed in claim 1, it is characterised in that R⁹For following structure:

Wherein:

4. compound as claimed in claim 3, it is characterised in that described compound has shown in formula (III) or (IV) Structure:

Wherein:

5. compound as claimed in claim 1, it is characterised in that described R⁹For substituted or unsubstituted pyridine radicals, Wherein, replace the one or more hydrogen atoms referring on group to be selected from the substituent group of lower group and replace: halogen, C1-C4 alkyl.

6. compound as claimed in claim 1, it is characterised in that described compound is selected from lower group:

7. a pharmaceutical composition, it is characterised in that including: being selected from according to claim 1～6 of (a) therapeutically effective amount According to any one of compound, or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt Or prodrug, its hydrate or solvate, or a combination thereof, and optional (b) pharmaceutically acceptable carrier.

8. the compound as described in arbitrary in claim 1-6, or its stereoisomer, geometric isomer, tautomerism Body, pharmaceutically acceptable salt or prodrug, its hydrate or solvate, or the purposes of a combination thereof, it is characterised in that use Prevent in preparation (i) and/or treat the medicine of cancer-related diseases；(ii) as protein tyrosine kinase (preferably FGFR) Inhibitor.

9. purposes as claimed in claim 8, it is characterised in that described tumor is selected from lower group: breast carcinoma, pulmonary carcinoma, Bladder cancer, gastric cancer, cancer of pancreas, carcinoma of prostate, colon cancer, multiple myeloma AML, hepatocarcinoma, melanoma, head Neck cancer, thyroid carcinoma, renal cell carcinoma, glioblast cancer and carcinoma of testis.

10. a protein tyrosine kinase is lived inhibitor, it is characterised in that containing suppression effective dose such as claim Compound described in 1-6.