CN106032359B - Indazole compounds and its preparation method and application - Google Patents
Indazole compounds and its preparation method and application Download PDFInfo
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- CN106032359B CN106032359B CN201510102633.8A CN201510102633A CN106032359B CN 106032359 B CN106032359 B CN 106032359B CN 201510102633 A CN201510102633 A CN 201510102633A CN 106032359 B CN106032359 B CN 106032359B
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to pharmaceutical synthesis fields, it is related to novel indazole class compound, preparation method and application, and contain pharmaceutical composition of the compound as active constituent, as well as drug is preparing treatment and the relevant diseases of tyrosine kinase FGFR, the purposes in the drug of the relevant cancers of especially FGFR.Shown in the following general formula I of indazole compounds chemical formula of the present invention, substituent group such as claims are defined in formula；Said compound shows through bioassay results, there is good inhibitory activity to fibroblast growth factor acceptor (FGFR), the drug that can be used as preparing prevention and the relevant diseases of FGFR, especially prepares the drug for the treatment of and the relevant cancers of FGFR.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to novel indazole class compound, preparation method and application, and containing
Compound is stated as the pharmaceutical composition as well as drug of active constituent preparing treatment and tyrosine kinase FGFR phases
Purposes in the drug of the relevant cancer of the disease of pass, especially FGFR.
Technical background
It is reported that cancer is the current number one killer for threatening human life and health.According to incompletely statistics, the whole world is every year about
There are 20,000,000 new cases；The annual new cases in China are about 160-200 ten thousand, and dead 1,300,000.Since tumour early stage has
The ability of transfer, about 50% patient has generated amphi position transfer in clinical diagnosis primary tumo(u)r.Studies have shown that is due to tumour cell
Increase fast, easily variation, to generate multidrug resistance, chemotherapy is caused to fail.According to the relevent statistics, 90% or more chemotherapy fails and swells
The multidrug resistance of oncocyte is related, and therefore, the antitumor drug clinically applied at present is far from the requirement for meeting treatment.
In recent years, the development of the subjects such as molecular weight tumor, molecular pharmacology makes the essence of tumour gradually be elucidated with, people
Gradually recognize that the essence of cell carcinogenesis is cell infinite multiplication caused by intracellular signal transduction pathway imbalance.Studies have shown that
As participate in cellular signal transduction mostly important member, protein tyrosine kinase (protein tyrosine kinases,
PTKs, abbreviation tyrosine kinase) it is most common growth factor receptors, it is closely related with the occurrence and development of tumour；Tyrosine
The hyperactivity of kinases leads to signal pathway activation downstream, so as to cause cell transformation, proliferation, confrontation natural death of cerebral cells, promotes
Cells survival eventually leads to the formation of tumour；Therefore, the Development Trend of antitumor drug starts from traditional cell toxicant in recent years
Drug diversion is directed to the drug of intracellular improper signal conduction, and has related drugs to be applied to clinic successively.With traditional cell
Malicious series antineoplastic medicament is compared, and this kind of therapeutic effects of molecular targeted agents is strong, toxic side effect is small, is increasingly becoming current antineoplastic drug and is ground
The hot spot of hair.
Research shows that receptor tyrosine kinase in tumor development, is invaded due to the activation of its unconventionality expression or gene mutation
It attacks the links such as transfer, drug resistance and plays key effect, it has also become the important target spot of antitumor drug research and development, wherein
Fibroblast growth factor receptor (fibroblast growth factor receptors, FGFRs) is receptor tyrosine kinase
The important member of family includes mainly tetra- kinds of hypotypes of FGFR1, FGFR2, FGFR3 and FGFR4.(Fibroblast Growth
Factors,FGFs)。(Turner N.,Grose R.,Fibroblast growthfactor signalling:from
development to cancer,NatureReviews Cancer.(2010)10:116-129.Dieci M.V.,
Arnedos M.,Andre F.,Soria J.C.,Fibroblast Growth Factor Receptor Inhibitors
as a Cancer Treatment:From a Biologic Rationale to Medical Perspectives,
CancerDiscovery.(2013)3:264-279.) due to gene magnification, mutation, fusion or ligand induction etc., FGFR
Each member's sustained activation, induction tumor cell proliferation, invasion, migration, promotes angiogenesis, promotes the occurrence and development of tumour；
FGFRs high expression and abnormal activation in kinds of tumors, such as non-small cell lung cancer, breast cancer, gastric cancer, carcinoma of urinary bladder, endometrium
Cancer, prostate cancer, cervical carcinoma, colon cancer, the cancer of the esophagus, cutin blastoma, myeloma, rhabdomyosarcoma etc. (Dieci MV,
Arnedos M,Andre F,Soria JC:Fibroblast growth factor receptor inhibitors as a
cancer treatment:from abiologic rationale to medicalperspectives.Cancer
discovery,2013,3,264-79；TurnerN,GroseR:Fibroblast growthfactor signalling:
From development to cancer.Nat.Rev.Cancer, 2010,10,116-29.), there is studies have shown that FGFR1 expansions
Increasing accounts for the 20% of non-small cell lung cancer squamous carcinoma, and lung cancer cell line in-vitro multiplication, signal path etc. by being expanded to FGFR1 are ground
Studying carefully display FGFR selective depressants highly effective can inhibit the proliferation of activation and cell of FGFR1 signal paths
(FrequentandFocalFGFR1Amplification Associates with Therapeutically Tractable
FGFR1Dependency in Squamous Cell Lung Cancer(vol 3,66er5,2011),Sci TranslMed.
(2010).Inhibitor-Sensitive FGFR1Amplification inHumanNon-Small Cell
LungCancer,PLoSONE.(2011)6:e20351.)；In breast cancer, area chromosome (8p11-12) where FGFR1
The amplification in domain accounts for the 10% of ER positive patients, and itself and the high expression of FGFR1mRNA and the prognosis mala phase of patient
Close (Dieci MV, Arnedos M, Andre F, Soria JC:Fibroblast growthfactor receptor
inhibitors as a cancer treatment:from abiologic rationale to
medicalperspectives.Cancer discovery,2013,3,264-79)；FGFR2 gene magnifications or mutation cause
The abnormal activation of FGFR2 signal paths is mainly related to gastric cancer, triple negative breast cancer, carcinoma of endometrium etc.；In stomach organization
The amplification rate of FGFR2 is 5%-10% (Matsumoto K, Arao T, Hamaguchi T, Shimada Y, Kato K, Oda
I,Taniguchi H,Koizumi F,Yanagihara K,Sasaki H,Nishio K,Yamada Y:FGFR2gene
amplification and clinicopathologicalfeatures in gastric cancer.Br.J.Cancer,
2012,106,727-32.), have research to 313 stomach organizations analysis shows that, the amplification of FGFR2 is soaked with tumor size, part
The generation of profit degree, lymphatic metastasis situation and far-end transfer is significantly correlated, and the gastric cancer with FGFR2 amplifications is generally
Evolving tumor, have poor prognosis, patient's overall survival rate it is relatively low (JungEJ, JungEJ, Min SY, Kim MA,
Kim WH:Fibroblast growth factor receptor 2gene amplification status and its
clinicopathologic significance in gastric carcinoma.Humanpathology,2012,43,
1559-66.)；FGFR2 amplifications account for 4% in intractable triple negative breast cancer；Carcinoma of endometrium is common gynaecology's reproduction
The mutation of road tumour, FGFR2 about accounts for the 12% of carcinoma of endometrium；FGFR3 mutation account in non-invasive bladder cancer
50%-60%, in aggressive carcinoma of urinary bladder FGFR3 mutation account for 10%-15%；(4 FGFR3t in Huppert's disease；14)
(p16.3；Q32) gene rearrangement accounts for 15-20% (Dieci MV, Arnedos M, Andre F, Soria JC:Fibroblast
growthfactor receptor inhibitors as a cancer treatment:from abiologic
Rationale to medicalperspectives.Cancer discovery, 2013,3,264-279), in addition, in liver cancer
In the FGFR and its ligand FGFs of a variety of hypotypes there is abnormal expression and activation, as FGFR2, FGFR3, FGFR4, FGF19,
FGF2, FGF5, FGF8, FGF9 etc.；Multinomial preclinical and clinical research shows FGF/FGFR axis abnormal activations in liver cancer
Importance (ChengAL, Shen YC, Zhu AX:Targeting Fibroblast Growth Factor Receptor
Signaling in Hepatocellular Carcinoma.Oncology-Basel,2011,81,372-80.)；Do not allow to neglect
Depending on, FGF/FGFR axis abnormal activation and EGFR inhibitor, neovascularization inhibitor and endocrine therapy etc. it is resistance to
Closely related (Nicholas T, the Richard G of medicine:Fibroblast growth factor signalingfrom
development to cancer.NatureReviews,2010,10,116-129.).Therefore, grinding for FGFR inhibitor is targeted
Hair has become the forward position focus of antitumor drug research.
Based on the present situation of molecular targeted antitumor drug research and development, present inventor is quasi- to provide new indazole compounds
And its in the application for preparing antitumor drug, especially prepare in treatment and the relevant disease medicaments of tyrosine kinase FGFR
Using.
Invention content
The purpose of the present invention is to provide new indazole compounds and its in the application for preparing antitumor drug, especially
Prepare treatment and the application in the relevant disease medicaments of tyrosine kinase FGFR.
The present invention provides with the indazole compounds of general formula I or its pharmaceutically acceptable salt, and in particular to
A kind of indazole compounds containing piperidines or piperazine, such compound can effectively inhibit the activity of FGFR, anti-to play
The effect of curing oncoma.
The second object of the present invention is, provides the preparation method of compound shown in general formula I.
The third object of the present invention is, provides comprising the medicine of compound or its pharmaceutically acceptable salt shown in general formula I
Compositions.
The present invention provides with compound or its pharmaceutically acceptable salt shown in following general formula I：
In formula, A rings represent five yuan or hexa-atomic of aromatic ring and the hetero-aromatic ring of nitrogenous, oxygen, sulphur atom；
B rings represent five yuan or hexa-atomic of aromatic ring and the hetero-aromatic ring of nitrogenous, oxygen, sulphur atom；
R1Represent hydrogen, halogen, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, isobutoxy, cyano, C1-C20
Straight chain or alkyl containing branch；
R2Represent hydrogen,
The present invention's has compound or its pharmaceutically acceptable salt shown in following general formula I, wherein describedGroup selected from following structural formula：
The present invention's has compound or its pharmaceutically acceptable salt shown in following general formula I, wherein describedGroup selected from following structural formula：
The pharmaceutically acceptable salt of compound of Formula I provided by the invention comprising：With hydrochloric acid, sulfuric acid, hydrobromic acid,
Phosphoric acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid etc. or asparagus fern
The acidic amino acids such as propylhomoserin, glutamic acid form the salt formed again with inorganic base after ester, such as sodium, potassium, calcium, aluminium salt and ammonium salt；Or with
The salt that organic base is formed, with methylamine salt, ethylamine salt, ethanolamine salt etc.；Or with the basic amine groups such as lysine, arginine, ornithine
Acid forms the salt of the inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid after ester, or with formic acid, acetic acid, picric acid, methanesulfonic acid, second
The salt of the organic acids such as sulfonic acid.
The preparation method of compound of Formula I of the present invention general formula as described below,
(1) segment C is prepared using the gradually method of condensation or fragment condensation；
(2) intermediate F is made in segment C and D condensations；
Method of condensing used can be chloride method, acyl fluorides method, mixed anhydride method or the following condensing agent of use：Bis- hexamethylene of N, N-
Base imines, 1- [3- dimethylaminos]-propyl -3- ethylcarbodiimides hydrochloride or 7- azepine benzothiazole -1- bases-oxygen (three -
(dimethylamino) phosphine) hexafluorophosphate；
(3) segment F removes tert-butyl ester protecting group, and agents useful for same is concentrated hydrochloric acid, Hydrochloride/ethyl acetate, hydrogen chloride two
Six ring solution of oxygen, hydrogen bromide ethyl acetate solution, hydrogen bromide dioxane solution, hydrogen bromide acetic acid solution, hydrogen fluoride, trifluoro second
Acid or combinations thereof；
(4) the segment F of removal tert-butyl ester protecting group obtains compound shown in general formula I with E coupling reactions；
Coupling method used is coupled for suzuki, or uses following palladium catalyst：Tetrakis triphenylphosphine palladium, 1,1'- bis- (two
Phosphenyl) ferrocene palladium chloride, the sour palladium of acid.
In the present invention, preferred compound has the following structure：
By taking compound 1-1 as an example, the preparation process of the compound of the present invention is as follows：
The present invention provides a kind of pharmaceutical composition, which contains the change of the above-mentioned general formula I of therapeutically effective amount
Object or its pharmaceutically acceptable salt are closed, and contains one or more pharmaceutically acceptable carriers；The Pharmaceutical composition is also
Odorant agent, flavouring agent, excipient or dilution etc. can be further included.
Invention further provides compounds shown in general formula I or its pharmaceutically-acceptable salts in the medicine for preparing anti-curing oncoma
Application in object.
The present invention has carried out external FGFR1 inhibitory activity test, the results show that the compound of the present invention is shown preferably
The inhibitory activity IC of FGFR1 inhibitory activity, wherein compound 1-8,1-13,1-15,1-16,1-17 for FGFR150Value is less than
10nM；
The compound of the present invention has carried out the in-vitro multiplication inhibiting effect test of gastric carcinoma cells SNU16, the results show that institute
The compound stated shows the inhibited proliferation preferably to gastric carcinoma cells SNU16.
In the present invention, used pharmacodynamics test method is method well-known to those skilled in the art；
In the present invention, FGFR1 kinases used utilizes insect baculovirus expression system expression and purification egg by this laboratory
White kinases area recombinant protein is obtained.
The compound of the present invention can further develop novel FGFR inhibitor and antitumor drug.
The novel indazole class compound containing piperazine or piperidines of the present invention can especially prepare FGFR inhibitor and antineoplastic
Object.In view of abnormal activation FGFR signal transductions, breast cancer, oophoroma, carcinoma of urinary bladder, melanoma, gastric cancer, endometrium will be caused
The generation of the kinds of tumors such as cancer, therefore, malignant tumour of the present invention includes the phase caused by FGFR signal path abnormal activations
Close the kinds of tumors such as tumour, including breast cancer, oophoroma, carcinoma of urinary bladder, melanoma, gastric cancer, carcinoma of endometrium.
Specific implementation mode
Embodiment 1：Synthesize compound 1-1,4- (4- ethyl piperazidine -1- bases)-N- (6- phenyl -1H- indazole -3- bases) benzene first
Amide
Step 1. synthesizes the bromo- 1H- indazoles -3- amine of 6- by following reaction formula：
Under nitrogen protection, the fluoro- cyanophenyls of the bromo- 2- of 4- (5g, 25.13mmol) are dissolved in 20mL n-butanols, and hydrazine hydrate is added
(1.04mL, 50.26mmol), is heated to reflux 4h.After being cooled to room temperature, a large amount of solids are precipitated.Petroleum ether filter cake is filtered and uses,
White solid 4.759g, yield 85.7% are obtained after drying.1HNMR(400MHz,DMSO-d6)δ11.52(brs,1H),7.64(d,
1H, J=8.5Hz), 7.37-7.52 (m, 1H), 7.02 (dd, 1H, J=8.5,1.6Hz), 5.47 (brs, 2H) .ESI-MS (m/
z):[M+H]+=213.0 (calcd 212.05)
Step 2. synthesizes the bromo- 1H- indazoles of 1- tertbutyloxycarbonyl -3- amidos -6- by following reaction formula：
Under nitrogen protection, the bromo- 1H- indazoles -3- amine (4.759g, 22.43mmol) of 6- are dissolved in 20mL tetrahydrofurans, ice bath
Under the conditions of be added di-tert-butyl dicarbonate (5.385g, 24.67mmol), 4-dimethylaminopyridine (1.0g, 8.19mmol).Room temperature
After reacting 3h, TLC (petrol ether/ethyl acetate=1/1) shows that raw material disappears, and reaction mixture is concentrated under reduced pressure, and adds in residue
Enter 1mol/L hydrochloric acid and is adjusted to acidity, ethyl acetate extraction.Extract liquor saturated common salt water washing, anhydrous sodium sulfate drying, decompression
Concentration, residue silica gel column chromatography (petrol ether/ethyl acetate=2/1) obtain yellow solid 6.964g, yield 88.8%.1HNMR
(400MHz, DMSO-d6) δ 8.12 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.45 (dd, J=8.4,1.7Hz, 1H), 6.44
(s,2H),1.57(s,9H).ESI-MS(m/z):[M+H]+=313.0 (Calcd:312.16).
Step 3. presses following reaction formula synthesizing methyl 4- (4- ethyl piperazidine -1- bases) methyl benzoate：
Under nitrogen protection, 4- fluorophenyl carbamates (3.0mL, 20.69mmol) are dissolved in 20mL DMSO, are sequentially added
K2CO3(5.718g, 41.38mmol), n-ethylpiperazine (1.93mL, 24.83mmol).Overnight, room is down in reaction for 120 DEG C of reactions
Wen Hou, is added ethyl acetate and each 50mL shakings layering of saturated salt solution, and aqueous layer with ethyl acetate (50mL × 3) extraction merges
Organic layer, saturated sodium-chloride washing, anhydrous sodium sulfate drying depressurize and boil off solvent, residue silica gel column chromatography (dichloromethane/
Methanol=10/1) obtain white solid 4.405g, yield 85.8%.ESI-MS(m/z):[M+H]+=249.2 (Calcd:
248.15).
Step 4. presses following reaction formula synthesizing methyl 4- (4- ethyl piperazidine -1- bases) benzoic acid：
Under nitrogen protection, methyl 4- (4- ethyl piperazidine -1- bases) methyl benzoate (4.405g, 17.75mmol) is dissolved in
In 15mL methanol, 15mL water, NaOH solids (1.420g, 35.5mmol) are added.After being heated to reflux 2h, room temperature is down in reaction, instead
It answers mixture to be concentrated under reduced pressure, 1mol/L hydrochloric acid is added in residue and is adjusted to acidity, ethyl acetate extraction.Extract liquor saturated common salt
Water washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, and it is solid that residue silica gel column chromatography (methylene chloride/methanol=10/1) obtains yellow
Body 3.009g, yield 72.4%.ESI-MS(m/z):[M+H]-=233.5 (Calcd:234.14).
Step 5. synthesizes 1- tertbutyloxycarbonyls -6- bromo- 3- (4- ethyl piperazidine -1- bases)-benzoyl by following reaction formula
Amine) -1H- indazolyls：
Under nitrogen protection, methyl 4- (4- ethyl piperazidine -1- bases) benzoic acid (3.009g, 12.85mmol) is dissolved in 15mL bis-
In chloromethanes, oxalyl chloride (2.2mL, 25.70mmol) is added under condition of ice bath.After reaction reflux 2h, reaction mixture decompression is dense
Contracting is added 20mL dichloromethane and concentrates repeatedly twice.1- tertbutyloxycarbonyl -3- amidos -6- is added in residue under condition of ice bath
In the pyridine solution (20mL) of bromo- 1H- indazoles (4.011g, 12.85mmol), room temperature reaction is overnight.TLC (methylene chloride/methanols
=5/1) display raw material disappears, and reaction mixture is concentrated under reduced pressure, and 1mol/L hydrochloric acid is added in residue and is adjusted to acidity, ethyl acetate
Extraction.Extract liquor saturated common salt water washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, residue silica gel column chromatography (dichloromethane
Alkane/methanol=2/1) obtain yellow solid 3.136g, yield 46.3%.1HNMR(400MHz,DMSO-d6):δ12.86(brs,
1H), 10.56 (brs, 1H), 7.94 (d, J=8.7Hz, 2H), 7.61-7.70 (m, 1H), 7.17 (d, J=9.9Hz, 1H),
6.99 (d, J=9.0Hz, 2H), 3.29 (t, J=7.4Hz, 4H), 2.51-2.56 (m, 4H), 2.36 (q, J=7.1Hz, 2H),
1.52 (s, 9H), 1.02 (t, J=7.2Hz, 3H) .ESI-MS (m/z):[M+H]+=528.2 (Calcd:527.10).
Step 6. is by following reaction formula synthesis 1- tertbutyloxycarbonyls -3- (4- (4- ethyl piperazidine -1- bases)-benzamide) -
6- phenyl -1H- indazolyls：
Under nitrogen protection, the bromo- 3- of 1- tertbutyloxycarbonyls -6- (4- ethyl piperazidine -1- bases)-benzamide) -1H- indazolyls
(100mg, 0.190mmol) is dissolved in 2mL dioxane, sequentially adds phenyl boric acid (46.3mg, 0.380mmol), cesium carbonate
(185.7mg, 0.570mmol), Pd (dppf) Cl2(20mg).After 120 DEG C of reaction 2h, room temperature is down in reaction, and reaction mixture subtracts
Pressure concentration, is added ethyl acetate and each 50ml extracting and demixings of saturated salt solution, aqueous layer with ethyl acetate 50mL continue to extract, and merges
Organic layer, saturated sodium-chloride are washed, and anhydrous sodium sulfate drying, decompression boils off solvent, residue silica gel column chromatography (dichloromethane/first
Alcohol=10/1) obtain white solid 47.4mg, yield 47.5%.ESI-MS(m/z):[M+H]+=526.5 (Calcd:526.22).
Step 7. synthesizes 4- (4- ethyl piperazidine -1- bases)-N- (6- phenyl -1H- indazole -3- bases) benzene first by following reaction formula
Amide：
Under nitrogen protection, 1- tertbutyloxycarbonyls -3- (4- (4- ethyl piperazidine -1- bases)-benzamide) -6- phenyl -1H- Yin
Oxazolyl (47.4mg, 0.090mmol) is dissolved in 2mL dichloromethane, is added in 1mL trifluoroacetic acids under condition of ice bath.Condition of ice bath is anti-
After answering 2h, reaction mixture is concentrated under reduced pressure, and 10mL dichloromethane is added and concentrates repeatedly twice.1mol/L sodium hydroxide water is added
Solution tune pH is extracted with ethyl acetate to alkalinity, and organic layer is washed with saturated sodium-chloride, and anhydrous sodium sulfate drying, decompression is steamed
Solvent, residue silica gel column chromatography (methylene chloride/methanol=10/1) is gone to obtain white solid 36.5mg, yield 95.4%.1HNMR
(400MHz,DMSO-d6) δ 12.81 (brs, 1H), 10.54 (brs, 1H), 8.00 (d, J=8.9Hz, 2H), 7.80 (d, J=
8.5Hz, 1H), 7.75 (d, J=7.3Hz, 2H), 7.66 (s, 1H), 7.51 (t, J=7.6Hz, 2H), 7.35-7.44 (m, 2H),
7.03 (d, J=8.9Hz, 2H), 3.37 (s, 4H), 2.49-2.59 (m, 4H), 2.41 (s, 2H), 1.06 (t, J=7.1Hz,
3H)。ESI-MS(m/z):[M+H]+=426.6 (Calcd:426.22)..
Embodiment 2：Synthesize compound 1-2,4- (4- ethyl piperazidine -1- bases)-N- (6- pyridyl group -1H- indazole -3- bases) benzene
Formamide
Step 1. synthesizes N- (the bromo- 1H- indazoles -3- bases of 6-) -4- (4- ethyl piperazidine -1- bases) benzoyl by following reaction formula
Amine：
Under nitrogen protection, the bromo- 3- of 1- tertbutyloxycarbonyls -6- (4- ethyl piperazidine -1- bases)-benzamide) -1H- indazolyls
(300mg, 0.569mmol) is dissolved in 15mL dichloromethane, is added in 5mL trifluoroacetic acids under condition of ice bath.Condition of ice bath reacts 2h
Afterwards, reaction mixture is concentrated under reduced pressure, and 10mL dichloromethane is added and concentrates repeatedly twice.1mol/L sodium hydrate aqueous solutions are added
It adjusts pH to alkalinity, and is extracted with ethyl acetate, organic layer is washed with saturated sodium-chloride, and anhydrous sodium sulfate drying, decompression boils off molten
Agent, residue silica gel column chromatography (methylene chloride/methanol=10/1) obtain white solid 220.9mg, yield 90.9%.1HNMR
(400MHz,DMSO-d6):δ 12.86 (brs, 1H), 10.56 (brs, 1H), 7.94 (d, J=8.7Hz, 2H), 7.61-7.70
(m, 1H), 7.17 (d, J=9.9Hz, 1H), 6.99 (d, J=9.0Hz, 2H), 3.29 (t, J=7.4Hz, 4H), 2.51-2.56
(m, 4H), 2.36 (q, J=7.1Hz, 2H), 1.02 (t, J=7.2Hz, 3H) .ESI-MS (m/z):[M+H]+=428.2
(Calcd:427.10).
Step 2. synthesizes 4- (4- ethyl piperazidine -1- bases)-N- (6- pyridyl group -1H- indazole -3- bases) benzene by following reaction formula
Formamide：
Under nitrogen protection, N- (the bromo- 1H- indazoles -3- bases of 6-) -4- (4- ethyl piperazidine -1- bases) benzamide (100mg,
It 0.234mmol) is dissolved in 2mL dioxane, sequentially adds 4- pyridine boronic acids (57.5mg, 0.468mmol), cesium carbonate
(228.7mg, 0.792mmol), Pd (dppf) Cl2(20mg).After 120 DEG C of reaction 2h, room temperature is down in reaction, and reaction mixture subtracts
Pressure concentration, is added ethyl acetate and each 50ml extracting and demixings of saturated salt solution, aqueous layer with ethyl acetate 50mL continue to extract, and merges
Organic layer, saturated sodium-chloride are washed, and anhydrous sodium sulfate drying, decompression boils off solvent, residue silica gel column chromatography (dichloromethane/first
Alcohol=10/1) obtain white solid 17.7mg, yield 17.8%.1H NMR(400MHz,DMSO-d6)δ12.85(brs,1H),
10.56 (brs, 1H), 8.00 (d, J=8.8Hz, 2H), 7.77 (d, J=8.4Hz, 1H), 7.58-7.63 (m, 1H), 7.41-
7.54 (m, 4H), 7.08-7.14 (m, 1H), 7.04 (d, J=8.9Hz, 2H), 3.34 (s, 4H), 2.51 (s, 4H), 2.41 (s,
2H), 1.06 (t, J=7.1Hz, 3H).ESI-MS(m/z):[M+H]+=427.4 (Calcd:426.22)..
Embodiment 3：Synthesize compound 1-3,4- (4- ethyl piperazidine -1- bases)-N- (6- (1- methyl-1 H- pyrazole-3-yls) -
1H- indazole -3- bases) benzoyl
The preparation method of the similar compound 1-2 of synthetic method obtains white solid 21.9mg, yield 21.8% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.67 (brs, 1H), 10.46 (brs, 1H), 8.23 (s, 1H), 7.98 (d, J=8.8Hz, 2H),
7.94 (s, 1H), 7.68 (d, J=8.5Hz, 1H), 7.57 (s, 1H), 7.30 (d, J=8.5Hz, 1H), 7.02 (d, J=
8.8Hz, 2H), 3.89 (s, 3H), 3.34 (s, 4H), 2.51 (s, 4H), 2.41 (d, J=6.7Hz, 2H), 1.06 (t, J=
7.2Hz,3H).ESI-MS(m/z):[M+H]+=430.4 (Calcd:429.23)..
Embodiment 4：Synthesize compound 1-4,4- (4- ethyl piperazidine -1- bases)-N- (6- (3- methoxyphenyls) -1H- Yin
Azoles -3- bases) benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains white solid 31.9mg, yield 29.9% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.79 (brs, 1H), 10.53 (brs, 1H), 7.99 (d, J=8.9Hz, 2H), 7.77 (d, J=
8.5Hz, 1H), 7.67 (s, 1H), 7.37 (d, J=8.6Hz, 1H), 7.03 (d, J=9.0Hz, 2H), 6.85 (d, J=2.2Hz,
2H), 6.54 (t, J=2.2Hz, 1H), 3.84 (s, 6H), 3.29-3.35 (m, 4H), 2.50-2.52 (m, 4H), 2.39 (q, J=
7.1Hz, 2H), 1.05 (t, J=7.2Hz, 3H) .ESI-MS (m/z):[M+H]+456.0(Calcd:455.23).。
Embodiment 5：Synthesize compound 1-5, N- (6- (4- cyano-phenyls) -1H- indazole -3- bases) -4- (4- ethyl piperazidines -
1- yls) benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains white solid 39.0mg, yield 37.0% altogether.1H
NMR(400MHz,DMSO-d6) δ 12.94 (brs, 1H), 10.52 (brs, 1H), 7.93-8.08 (m, 6H), 7.85 (d, J=
8.5Hz, 1H), 7.78 (s, 1H), 7.44 (d, J=8.6Hz, 1H), 7.03 (d, J=8.6Hz, 2H), 3.34 (s, 4H), 2.51
(s, 4H), 2.40 (q, J=6.7Hz, 2H), 1.06 (t, J=7.1Hz, 3H).ESI-MS(m/z):[M+H]+451.1(Calcd:
450.22).。
Embodiment 6：Synthesize compound 1-6,4- (4- ethyl piperazidine -1- bases)-N- (6- (4- trifluoromethyls) -1H- Yin
Azoles -3- bases) benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains white solid 45.2mg, yield 39.2% altogether.1H
NMR(400MHz,DMSO-d6) δ 12.92 (brs, 1H), 10.57 (brs, 1H), 7.95-8.05 (m, 4H), 7.85 (d, J=
8.4Hz, 3H), 7.77 (s, 1H), 7.44 (d, J=8.6Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 3.34 (s, 4H), 2.51
(s, 4H), 2.41 (q, J=7.2Hz, 2H), 1.06 (t, J=7.1Hz, 3H).ESI-MS(m/z):[M+H]+=494.2
(Calcd:493.21)。
Embodiment 7：Synthesize compound 1-7, N- (6- (3- ethoxyl phenenyls) -1H- indazole -3- bases) -4- (4- ethyl piperazines
Piperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains white solid 45.2mg, yield 39.2% altogether.1H
NMR(400MHz,DMSO-d6) δ 12.80 (brs, 1H), 10.54 (brs, 1H), 8.00 (d, J=8.9Hz, 2H), 7.78 (d, J
=8.5Hz, 1H), 7.66 (s, 1H), 7.35-7.43 (m, 2H), 7.29 (d, J=7.8Hz, 1H), 7.24 (s, 1H), 7.03 (d,
J=8.9Hz, 2H), 6.96 (dd, J=8.1,1.9Hz, 1H), 4.13 (q, J=6.9Hz, 2H), 3.33 (s, 4H), 2.46-
2.59 (m, 4H), 2.41 (s, 2H), 1.37 (t, J=8.0Hz, 3H), 1.06 (t, J=7.1Hz, 3H).ESI-MS(m/z):[M+
H]+=470.2 (Calcd:469.25).
Embodiment 8：Synthesize compound 1-8, N- (6- (3- isopropyl phenyls) -1H- indazole -3- bases) -4- (4- ethyl piperazines
Piperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains white solid 50.9mg, yield 45.0% altogether.1H
NMR(400MHz,DMSO-d6) δ 12.79 (brs, 1H), 10.54 (brs, 1H), 8.00 (d, J=8.8Hz, 2H), 7.78 (d, J
=8.5Hz, 1H), 7.65 (s, 1H), 7.35-7.41 (m, 2H), 7.27 (d, J=7.9Hz, 1H), 7.22 (s, 1H), 7.03 (d,
J=8.9Hz, 2H), 6.95 (dd, J=8.2,1.9Hz, 1H), 4.72-4.78 (m, 1H), 3.34 (s, 4H), 2.51 (s, 4H),
2.40 (s, 2H), 1.32 (d, J=6.0Hz, 6H), 1.06 (t, J=7.1Hz, 3H).ESI-MS(m/z):[M+H]+=484.2
(Calcd:483.26)。
Embodiment 9：Synthesize compound 1-9, N- (6- (3- isobutoxy phenyls) -1H- indazole -3- bases) -4- (4- ethyl piperazines
Piperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 29.4mg, yield 25.3% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.79 (brs, 1H), 10.54 (brs, 1H), 8.00 (d, J=8.9Hz, 2H), 7.78 (d, J=
8.5Hz, 1H), 7.67 (s, 1H), 7.37-7.40 (m, 2H), 7.29 (d, J=7.9Hz, 1H), 7.23-7.26 (m, 1H), 7.03
(d, J=9.0Hz, 2H), 6.96 (dd, J=8.1,1.8Hz, 1H), 3.85 (d, J=6.5Hz, 2H), 3.34 (s, 4H), 2.51
(s, 4H), 2.40 (s, 2H), 2.03-2.09 (m, 1H), 1.06 (t, J=7.2Hz, 3H), 1.02 (d, J=6.7Hz, 6H).
ESI-MS(m/z):[M+H]+=498.3 (Calcd:497.28).
Embodiment 10：Synthesize compound 1-10, N- (6- (thiophene -2- bases) -1H- indazole -3- bases) -4- (4- ethyl piperazidines -
1- yls)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 36.6mg, yield 30.3% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.78 (brs, 1H), 10.54 (brs, 1H), 7.99 (d, J=8.8Hz, 2H), 7.75 (d, J=
8.5Hz, 1H), 7.67 (s, 1H), 7.60 (dd, J=8.6,4.3Hz, 2H), 7.41 (d, J=8.5Hz, 1H), 7.18 (dd, J=
4.9,3.7Hz, 1H), 7.03 (d, J=8.9Hz, 2H), 3.34 (s, 4H), 2.51 (s, 4H), 2.41 (d, J=8.0Hz, 2H),
1.06 (t, J=7.2Hz, 3H).ESI-MS(m/z):[M+H]+=432.3 (Calcd:431.18).
Embodiment 11：Synthesize compound 1-11, N- (6- (2,6- 3,5-dimethylphenyl) -1H- indazole -3- bases) -4- (4- ethyls
Piperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 20.4mg, yield 19.2% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.75 (brs, 1H), 10.56 (brs, 1H), 8.02 (d, J=8.7Hz, 2H), 7.77 (d, J=
8.3Hz, 1H), 7.18 (d, J=8.4Hz, 2H), 7.14 (d, J=8.2Hz, 2H), 7.07 (d, J=8.6Hz, 2H), 6.82 (d,
J=8.3Hz, 1H), 3.37-3.43 (m, 4H), 2.54-2.68 (m, 4H), 2.35 (q, J=7.2Hz, 2H), 2.01 (s, 6H),
1.14 (t, J=7.0Hz, 3H).ESI-MS(m/z):[M+H]+=454.3 (Calcd:453.25).
Embodiment 12：Synthesize compound 1-12, N- (6- (the chloro- 4- trifluoromethyls of 2-) -1H- indazole -3- bases) -4-
(4- ethyl piperazidine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 38.4mg, yield 21.1% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.94 (brs, 1H), 10.59 (brs, 1H), 7.99-8.03 (m, 3H), 7.82 (t, J=9.1Hz,
2H), 7.75 (d, J=8.0Hz, 1H), 7.55 (s, 1H), 7.15 (d, J=8.4Hz, 1H), 7.04 (d, J=8.8Hz, 2H),
3.35 (s, 4H), 2.58 (s, 4H), 2.45 (s, 2H), 1.07 (t, J=7.0Hz, 4H).ESI-MS(m/z):[M+H]+=
528.1(Calcd:527.17).。
Embodiment 13：Synthesize compound 1-13, N- (6- (the fluoro- 5- methoxyphenyls of 3-) -1H- indazole -3- bases) -4- (4-
Ethyl piperazidine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 44.1mg, yield 36.3% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.86 (brs, 1H), 10.59 (brs, 1H), 8.00 (d, J=8.9Hz, 2H), 7.80 (d, J=
8.5Hz, 1H), 7.72 (s, 1H), 7.40 (dd, J=8.6,1.3Hz, 1H), 7.12-7.21 (m, 2H), 7.03 (d, J=
9.0Hz, 2H), 6.87 (d, J=10.9Hz, 1H), 3.87 (s, 3H), 3.32 (s, 4H), 2.51 (s, 4H), 2.39 (q, J=
7.1Hz, 2H), 1.05 (t, J=7.2Hz, 3H).ESI-MS(m/z):[M+H]+=473.8 (Calcd:473.22)..
Embodiment 14：Synthesize compound 1-14, N- (6- (3- methoxyphenyls) -1H- indazole -3- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains yellow solid 71.4mg, yield 65.0% altogether.1HNMR
(400MHz, DMSO-d6) δ 12.88 (brs, 1H), 10.86 (brs, 1H), 8.11 (d, J=7.2Hz, 1H), 7.82 (d, J=
8.5Hz, 1H), 7.70 (s, 1H), 7.62 (d, J=7.3Hz, 1H), 7.54-7.56 (m, 1H), 7.40-7.42 (m, 1H), 7.31
(d, J=7.9Hz, 1H), 7.25-7.29 (m, 1H), 6.98 (dd, J=8.1,1.9Hz, 1H), 3.86 (s, 3H).ESI-MS(m/
z):[M+H]+=344.8 (Calcd:343.13)..
Embodiment 15：Synthesize compound 1-15, N- (6- (the fluoro- 5- methoxyphenyls of 3-) -1H- indazole -3- bases) -4- (4-
Methylpiperazine-1-yl)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 54.3mg, yield 16.9% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.86 (brs, 1H), 10.56 (brs, 1H), 7.99 (d, J=8.8Hz, 2H), 7.79 (d, J=
8.5Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=8.6Hz, 1H), 7.12-7.20 (m, 2H), 7.03 (d, J=9.0Hz, 2H),
6.82-6.91(m,1H),3.87(s,3H),3.37(s,4H),2.49(s,4H),2.26(s,3H)。ESI-MS(m/z):[M+H
]+=460.8 (Calcd:459.21)..
Embodiment 16：Synthesize compound 1-16, N- (6- (the fluoro- 5- methoxyphenyls of 3-) -1H- indazole -3- bases) -4- (4-
(dimethylamino) piperidin-1-yl)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 74.3mg, yield 16.0% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.87 (brs, 1H), 10.54 (brs, 1H), 7.99 (d, J=8.7Hz, 2H), 7.79 (d, J=
8.5Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=8.8Hz, 1H), 7.11-7.22 (m, 2H), 7.04 (d, J=8.8Hz, 2H),
6.87 (d, J=10.9Hz, 1H), 3.98 (d, J=12.2Hz, 2H), 3.87 (s, 3H), 2.84 (t, J=12.0Hz, 2H),
2.59 (s, 1H), 2.35 (s, 6H), 1.92 (s, 2H), 1.51 (d, J=10.8Hz, 2H).ESI-MS(m/z):[M+H]+=
488.3(Calcd:487.24).。
Embodiment 17：Synthesize compound 1-17, N- (6- (the fluoro- 5- methoxyphenyls of 3-) -1H- indazole -3- bases) -4- (4-
(3S, 5R) -3,5- dimethyl -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 66.5mg, yield 26.0% altogether.HNMR
(400MHz,DMSO-d6) δ 12.87 (brs, 1H), 10.56 (brs, 1H), 7.99 (d, J=8.8Hz, 2H), 7.79 (d, J=
8.6Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=8.5Hz, 1H), 7.14-7.18 (m, 2H), 7.04 (d, J=9.0Hz, 2H),
6.87 (d, J=10.9Hz, 1H), 4.47 (brs, 1H), 3.87 (s, 3H), 3.82 (s, 2H), 2.96 (s, 2H), 2.32-2.38
(m,2H),1.11(s,3H),1.08(s,3H)。ESI-MS(m/z):[M+H]+=473.8 (Calcd:473.22)..
Embodiment 18：Synthesize compound 1-18, N- (6- (the fluoro- 5- methoxyphenyls of 3-) -1H- indazole -3- bases) -5- (4-
Thyl-piperazin -1- bases) pyrazine -2- formamides
The preparation method of the similar compound 1-2 of synthetic method obtains solid 37.1mg, yield 37.4% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.95 (brs, 1H), 10.42 (brs, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 7.94 (d, J=
8.4Hz, 1H), 7.74 (s, 1H), 7.42 (d, J=8.3Hz, 1H), 7.05-7.25 (m, 2H), 6.87 (d, J=10.9Hz,
1H),3.87(s,7H),2.70(s,4H),2.42(s,3H)。ESI-MS(m/z):[M+H]+=462.0 (Calcd:
461.20).。
Embodiment 19：Synthesize compound 1-19, N- (6- (the fluoro- 5- methoxyphenyls of 3-) -1H- indazole -3- bases) -4- (4-
Methyl-1,4- homopiperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 30.1mg, yield 33.4% altogether.1HNMR
(400MHz,DMSO-d6) δ 12.83 (brs, 1H), 10.44 (brs, 1H), 7.97 (d, J=8.4Hz, 2H), 7.79 (d, J=
8.0Hz, 1H), 7.71 (s, 1H), 7.39 (d, J=8.1Hz, 1H), 7.14-7.18 (m, 2H), 6.85-6.89 (m, 1H), 6.80
(d, J=7.9Hz, 2H), 3.87 (s, 7H), 3.63-3.65 (m, 2H), 3.53 (t, J=6.8Hz, 2H), 2.70-2.78 (m,
2H),2.55-2.62(m,2H),2.48-2.51(m,4H),2.36(s,3H)。ESI-MS(m/z):[M+H]+=474.0
(Calcd:473.22).。
Embodiment 20：Synthesize compound 1-20, N- (6- (the fluoro- 5- methoxyphenyls of 2-) -1H- indazole -3- bases) -4- (4-
Ethyl piperazidine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 28.3mg, yield 30.8% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.96 (brs, 1H), 10.59 (brs, 1H), 8.01 (d, J=8.5Hz, 2H), 7.79 (d, J=
8.5Hz, 1H), 7.63 (s, 1H), 7.24-7.30 (m, 2H), 7.09-7.11 (m, 1H), 7.05 (d, J=8.0Hz, 2H),
6.97-7.00(m,1H),3.82(s,3H),3.39-3.50(m,4H),2.68-2.80(m,4H),2.51-2.62(m,2H),
1.11 (t, J=7.2Hz, 3H) .ESI-MS (m/z):[M+H]+=474.0 (Calcd:473.22)..
Embodiment 21：Synthesize compound 1-21, N- (6- (the fluoro- 3- methoxyphenyls of 2-) -1H- indazole -3- bases) -4- (4-
Ethyl piperazidine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 29.0mg, yield 31.0% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.85 (brs, 1H), 10.57 (brs, 1H), 8.00 (d, J=8.9Hz, 2H), 7.79 (d, J=
8.5Hz, 1H), 7.58 (s, 1H), 7.19-7.28 (m, 3H), 7.12-7.15 (m, 1H), 7.03 (d, J=9.0Hz, 2H), 3.90
(s, 3H), 3.25-3.41 (m, 4H), 2.54-2.66 (m, 4H), 2.41-2.48 (m, 2H), 1.08 (t, J=7.4Hz, 3H)
.ESI-MS(m/z):[M+H]+=474.0 (Calcd:473.22)..
Embodiment 22：Synthesize compound 1-22, N- (6- (the fluoro- 3- methoxyphenyls of 2-) -1H- indazole -3- bases) -4- (4-
Methyl-1,4- homopiperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 32.1mg, yield 34.3% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.86 (brs, 1H), 10.56 (brs, 1H), 7.99 (d, J=8.9Hz, 2H), 7.79 (d, J=
8.2Hz, 1H), 7.58 (s, 1H), 7.19-7.21 (m, 3H), 7.12-7.15 (m, 1H), 7.04 (d, J=7.8Hz, 2H), 3.90
(s,3H),3.82-3.85(m,2H),2.95(s,2H),2.34-2.40(m,2H),1.12(s,3H),1.10(s,3H).ESI-
MS(m/z):[M+H]+=474.0 (Calcd:473.22)..
Embodiment 23：Synthesize compound 1-23, N- (6- (the fluoro- 3- methoxyphenyls of 2-) -1H- indazole -3- bases) -4- (4-
Methyl-1,4- homopiperazine -1- bases)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 22.1mg, yield 25.8% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.84 (brs, 1H), 10.47 (brs, 1H), 7.97 (d, J=8.5Hz, 2H), 7.78 (d, J=
8.2Hz, 1H), 7.58 (s, 1H), 7.20-7.26 (m, 3H), 7.12-7.15 (m, 1H), 6.81 (d, J=7.8Hz, 2H), 3.90
(s, 3H), 3.63-3.66 (m, 2H), 3.54 (t, J=6.2Hz, 2H), 2.80 (s, 2H), 2.65 (s, 2H), 2.40 (s, 3H),
1.96-2.03(m,2H).ESI-MS(m/z):[M+H]+=474.0 (Calcd:473.22)..
Embodiment 24：Synthesize compound 1-24, N- (6- (the fluoro- 3- methoxyphenyls of 2-) -1H- indazole -3- bases) -4- (4-
Methylpiperazine-1-yl)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 19.2mg, yield 22.5% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.87 (brs, 1H), 10.57 (brs, 1H), 7.98 (d, J=8.2Hz, 2H), 7.76 (d, J=
8.2Hz, 1H), 7.56 (s, 1H), 7.19-7.24 (m, 3H), 7.10-7.13 (m, 1H), 7.02 (d, J=7.8Hz, 2H), 3.88
(s,3H),3.24-3.39(s,4H),2.44-2.52(s,4H),2.31(s,3H).ESI-MS(m/z):[M+H]+=460.0
(Calcd:459.20).。
Embodiment 25：Synthesize compound 1-25, N- (6- (the fluoro- 3- methoxyphenyls of 2-) -1H- indazole -3- bases) -5- (4-
Thyl-piperazin -1- bases) pyrazine -2- formamides
The preparation method of the similar compound 1-2 of synthetic method obtains solid 23.2mg, yield 24.8% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.93(brs,1H),10.40(brs,1H),8.78(s,1H),8.41(s,1H),7.94(d,J
=8.2Hz, 1H), 7.59 (s, 1H), 7.20-7.28 (m, 3H), 7.12-7.15 (m, 1H), 3.90 (s, 3H), 3.72-3.83
(m,4H),2.42-2.51(m,4H),2.26(s,3H).ESI-MS(m/z):[M+H]+=462.1 (Calcd:461.20)..
Embodiment 26：Synthesize compound 1-26, N- (6- (the fluoro- 3- methoxyphenyls of 2-) -1H- indazole -3- bases) -4- (4-
(dimethylamino) piperidin-1-yl)-benzamide
The preparation method of the similar compound 1-2 of synthetic method obtains solid 35.4mg, yield 33.8% altogether.1HNMR
(400MHz,DMSO-d6)δ:12.96 (brs, 1H), 10.55 (brs, 1H), 7.98 (d, J=8.0Hz, 2H), 7.78 (d, J=
7.8Hz, 1H), 7.59 (s, 1H), 7.20-7.26 (m, 3H), 7.11-7.14 (m, 1H), 7.02 (d, J=8.2Hz, 2H), 3.95
(s,2H),3.90(s,3H),2.80-2.86(m,2H),2.19(s,6H),1.82-1.86(m,2H),1.43-1.48(m,2H)
.ESI-MS(m/z):[M+H]+=488.3 (Calcd:487.24)..
Embodiment 27：External FGFR1 inhibitory activity test
By enzyme reaction substrate Poly (Glu, Tyr)4:1With PBS (10mM sodium phosphate buffers, the 150mM of no potassium ion
NaCl, pH7.2-7.4) 20 μ g/mL are diluted to, 125 holes μ L/ coated elisa plates are set 37 DEG C and are reacted 12-16 hours.It discards in hole
Board-washing after liquid, three times with T-PBS (PBS containing the 0.1%Tween-20) board-washing in 200 holes μ L/, 5 minutes every time.In 37 DEG C of bakings
Dry ELISA Plate 1-2 hours in case；
It is added per hole and uses reaction buffer (50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,
0.2mMNa3VO4,1mM DTT) diluted 50 μ L of ATP solution, 5 μM of final concentration.Compound is diluted to suitable concentration with DMSO, and 1
The holes μ L/ or or the DMSO (negative control hole) containing respective concentration, add with the 49 diluted FGFR1 kinases of μ L reaction buffers
Domain recombinant protein starts reaction, and experiment every time need to set no ATP control wells holes.37 DEG C of shaking tables (100rpm) are set to react 1 hour.T-
PBS board-washings are three times.100 holes μ L/ of primary antibody PY99 dilutions are added, 37 DEG C of shaking tables react 0.5 hour.T-PBS board-washings are three times.It is added
100 holes μ L/ of IgG dilutions of secondary antibody horseradish peroxidase-labeled sheep anti mouse, 37 DEG C of shaking tables react 0.5 hour.T-PBS board-washings
Three times.100 holes μ L/ of OPD developing solutions of 2mg/ml are added (with containing 0.03%H2O20.1M citric acid-sodium citrates buffering
Liquid (pH=5.4) dilutes), 25 DEG C are protected from light 1-10 minutes.(ultrasound, developing solution need to be used to need now with the current when OPD dissolves).Add
Enter 2M H2SO450 holes μ L/ stopped reactions are read with the wavelengthtunable orifice plate microplate reader SPECTRAMAX 190 that declines, and wavelength is
490nm；
The inhibiting rate of sample is acquired by following equation：
Inhibiting rate (%)=[1- (the OD values-of compound are without ATP control wells OD values)/(negative control OD value-is compareed without ATP
Hole OD values)] × 100%
IC50Value uses the random bundled software of microplate reader to be acquired with the recurrence of four parametric methods；
The result shows that (as shown in table 1), the compound of the present invention shows preferable FGFR1 inhibitory activity, wherein chemical combination
The inhibitory activity IC of object 1-8,1-13,1-15,1-16,1-17 for FGFR150Value is less than 10nM.
Table 1 is the external inhibitory activity result of the FGFR1 of the compounds of this invention.
Table 1
Embodiment 28：Influence experiment of the compound to the FGFR2 tumor cell proliferation abilities mediated
The compound of the present invention is detected using CCK-8 Cell counting Kits (Dojindo) to press down the proliferation of SNU16 cells
It makes and uses, specific steps include：SNU16 cells in exponential phase are seeded to by proper density in 96 well culture plates, often
90 μ L of hole after overnight incubation, are added the compound effects 72hr of various concentration, and setting solvent control group (negative control), wait for
After compound effects cell 72h, the influence of compound on intracellular proliferation is examined using CCK-8 Cell counting Kits (Dojindo)
It surveys, 10 μ L CCK-8 reagents is added per hole, are placed in 37 DEG C of incubators after placing 2-4 hours, declined orifice plate enzyme mark with all-wave length
Instrument SpectraMax 190 is read, and measurement wavelength is 450nm；
Use the inhibiting rate (%) that compound on tumor cell growth is calculated with following equation：
Inhibiting rate (%)=[(OD control wells-OD dosing holes)/OD control wells] × 100%
IC50Value uses the random bundled software of microplate reader to be acquired with the recurrence of four parametric methods.
The result shows that (as shown in table 2), in-vitro multiplication inhibiting effect of the compound of the present invention to gastric carcinoma cells SNU16
Test, the results show that the compound shows the inhibited proliferation preferably to gastric carcinoma cells SNU16.
Table 2 is in-vitro multiplication inhibiting effect of the compounds of this invention to gastric carcinoma cells SNU16.
Table 2
Claims (8)
1. a kind of indazole compounds or its pharmaceutically acceptable salt, the compound is one kind in following compounds：
2. compound according to claim 1 or its pharmaceutically acceptable salt, the compound is in following compounds
One kind：
3. a kind of method preparing claim 1~2 any one of them compound or its pharmaceutically acceptable salt, feature
It is, by general formula I, to include the following steps：
(1) segment C is prepared using the gradually method of condensation or fragment condensation；
(2) intermediate F is made in segment C and D condensations,
The method of condensing is chloride method, acyl fluorides method or mixed anhydride method, or uses condensing agent：N, N- dicyclohexyl imines,
1- [3- dimethylaminos]-propyl -3- ethylcarbodiimides hydrochloride or 7- azepine benzothiazole -1- bases-oxygen (three-(dimethylamine
Base) phosphine) hexafluorophosphate；
(3) segment F removes tert-butyl ester protecting group, and agents useful for same is concentrated hydrochloric acid, Hydrochloride/ethyl acetate, hydrogen chloride dioxy six
Ring solution, hydrogen bromide ethyl acetate solution, hydrogen bromide dioxane solution, hydrogen bromide acetic acid solution, hydrogen fluoride, trifluoroacetic acid or
A combination thereof；
(4) the segment F of removing tert-butyl ester protecting group obtains compound shown in claim 1~2 with E coupling reactions；Coupling side used
Method is coupled for suzuki, or uses following catalyst：Tetrakis triphenylphosphine palladium, 1,1'- bis- (diphenyl phosphine) ferrocene dichloride
Palladium or the sour palladium of acid；
Wherein R1,R2, A rings, B rings are claim 1, the substituent group of the corresponding position of compound shown in 2.
4. a kind of pharmaceutical composition, characterized in that the composition contains described in any one of claim 1~2 of therapeutically effective amount
Compound or its pharmaceutically acceptable salt.
5. pharmaceutical composition according to claim 4, characterized in that the compound or its pharmaceutically acceptable salt
Account for the 20%~99% of the pharmaceutical composition total weight.
6. pharmaceutical composition according to claim 4 or 5, characterized in that the composition further includes one or more
Pharmaceutically acceptable carrier, odorant agent, flavouring agent, excipient or dilution.
7. claim 1~2 any one of them compound or its pharmaceutically acceptable salt are in preparing prevention tumour medicine
Purposes, wherein the tumour is and the relevant tumours of tyrosine kinase FGFR.
8. purposes according to claim 7, characterized in that the tumour is breast cancer, oophoroma, carcinoma of urinary bladder, black
Plain tumor, gastric cancer or carcinoma of endometrium.
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| WO2003097610A1 (en) * | 2002-05-17 | 2003-11-27 | Pharmacia Italia S.P.A. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| WO2005085227A1 (en) * | 2004-03-02 | 2005-09-15 | Smithkline Beecham Corporation | Inhibitors of akt activity |
| WO2006003276A1 (en) * | 2004-06-04 | 2006-01-12 | Aventis Pharma S.A. | Substituted indazoles, compositions containing same, preparation and use |
| CN102595899A (en) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | Indazoles as WNT/B-catenin signaling pathway inhibitors and therapeutic uses thereof |
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| WO2003097610A1 (en) * | 2002-05-17 | 2003-11-27 | Pharmacia Italia S.P.A. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| WO2005085227A1 (en) * | 2004-03-02 | 2005-09-15 | Smithkline Beecham Corporation | Inhibitors of akt activity |
| WO2006003276A1 (en) * | 2004-06-04 | 2006-01-12 | Aventis Pharma S.A. | Substituted indazoles, compositions containing same, preparation and use |
| CN102595899A (en) * | 2009-08-10 | 2012-07-18 | 埃皮瑟瑞克斯有限公司 | Indazoles as WNT/B-catenin signaling pathway inhibitors and therapeutic uses thereof |
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| AZD4547: An orally bioavailable, potent and selective inhibitor of the Fibroblast Growth Factor Receptor tyrosine kinase family.;Paul R.Gavine，等;《Cancer Research》;20120227;第72卷(第8期);第2045-2056页 * |
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