CN110452176A - Indazole analog derivative and its preparation method and application - Google Patents
Indazole analog derivative and its preparation method and application Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to indazole analog derivatives and its preparation method and application, belong to chemical medicine.The present invention provides I compounds represented of formula.The results show, the compounds of this invention can inhibit the kinds of tumor cells such as lung carcinoma cell, breast cancer cell, liver cancer cells, colorectal cancer cell to be proliferated significantly, provide a kind of new medication selection for clinical anticancer.
Description
Technical field
The present invention relates to indazole analog derivatives and its preparation method and application, belong to chemical medicine.
Background technique
The treatment and prevention of cancer are a public health problems outstanding in China.It is counted according to the cancer of newest publication
Data, China's cancer new cases are the 20% of 4,290,000, Zhan Quanqiu new cases within 2015, and death is up to 2,810,000.Its
In, the morbidity and mortality of lung cancer top the list, gastric cancer, liver cancer, breast cancer, prostate cancer morbidity and dead burden, first
Shape gland cancer disease incidence has obvious ascendant trend.Rural area cancer morbidity and the death rate are higher than Urban population, the cancer of women
Disease incidence dramatically increases.Cancer not only seriously threatens the life and health generation of the mankind, also poses a huge burden on society, solves
Prevention and control of cancer problem is very urgent.
Currently, the main method for the treatment of cancer has: the traditional remedies such as operation, radiotherapy, chemotherapy and targeted therapies, including
The immunotherapies such as PD1/PD-L1, CAR-T therapy, small molecule targeted drug, monoclonal antibody and antibody coupling drug etc..Tradition
Cancer treatment method effect is limited, is easy to appear Preventive or toxic side effect, and have larger impact to patients ' life quality.
Small molecule targeted drug is the important component of cancer target therapy, mainly with kinases, nuclear receptor, ion channel etc. for target
The effects of point, performance inhibition, excitement and antagonism.Small molecule targeted drug influences the increasing of tumour cell by adjusting target active
It grows, break up, invade, migrate, to reach antitumous effect.Small molecule targeted drug plays important work in clinical treatment
With, therefore its research and development is always the popular research direction of therapeutic field of tumor.
Summary of the invention
The purpose of the present invention is to provide indazole analog derivatives and its preparation method and application.
The present invention provides I compounds represented of formula:
R1For aryl or substituted aryl；
L isOr
X, Y, Z are independently selected from N or CH；
R2For5~8 yuan of aryl or 5~8 yuan of substituted aryl；Wherein, W is-CH2-、Or
It is not present；R21、R22Independently selected from-H or alkyl, alternatively, R21With R22It is connected to form at least containing a heteroatomic alicyclic ring.
Further, R1For 5~10 yuan of aryl or 5~10 yuan of substituted aryl.
Preferably, R1For 6 yuan of aryl or 6 yuan of substituted aryl.
It is further preferred that R1ForWherein, R11~R15Independently selected from-H, halogen or alcoxyl
Base.
Further, R11~R15Independently selected from-H, halogen or C1~C6 alkoxy.
Preferably, R11~R15Independently selected from-H ,-F ,-Cl or methoxyl group.
Further, R1For Or
Further, R21、R22Independently selected from-H or C1~C6 alkyl, alternatively, R21With R22It is connected to form at least containing one
Heteroatomic 5~8 yuan of alicyclic rings.
Preferably, R21、R22Independently selected from-H or C1~C6 alkyl, alternatively, R21With R22It is connected to form at least miscellaneous containing one
6 yuan of alicyclic rings of atom.
Further, R21、R22Independently selected from-H or methyl；Alternatively, R21With R22It is connected to formOrWherein, R4、R5Independently selected from-H, alkyl or alkane
Oxygen carbonyl, the hydrogen on alicyclic ring are optionally replaced by alkyl.
Further, R4、R5Independently selected from-H, C1~C6 alkyl or C1~C6 alkoxy carbonyl group, the hydrogen on alicyclic ring is optionally
Replaced by C1~C6 alkyl.
Preferably, R4、R5Independently selected from-H, methyl, ethyl or tertbutyloxycarbonyl, the hydrogen on alicyclic ring is optionally by methyl
Replace.
Further, R21With R22It is connected to form Or
Further, describedSpatial configuration be
Further, W is-CH2When, the compound is selected from:
Further, W isWhen, the compound is selected from:
Further, in the absence of W, the compound is selected from:
The present invention provides the stereoisomer of the compound, isotopic body, pharmaceutically acceptable salt, prodrug or crystalline substances
Body.
The present invention provides the compound, its stereoisomer, its isotopic body, its pharmaceutically acceptable salt, its
The preparation method of prodrug or its crystal, includes the following steps:
A, compound I-1 obtains compound I-2 through iodo:
B, raw material SM-1 and SM-2 passes through the coupling reaction of palladium chtalyst, obtains compound I-3:
Wherein, Ha is-Br or-I；
C, compound I-2 and compound I-3 passes through the coupling reaction of palladium chtalyst, obtains compound I-4:
D, compound I-4 and compound I-5 passes through the coupling reaction of palladium chtalyst, obtains product I-6:
Further, the preparation method further includes following steps:
E, product I-6 passes through catalytic hydrogenation, obtains product I-7:
Further, the preparation method meets at least one of following:
Compound I-1 is dissolved in DMF by step a, alkali is added, by I2It is dissolved in DMF and is added dropwise to reaction solution, reaction end is
Obtain compound I-2；
Step b is by raw material SM-1, and raw material SM-2, palladium catalyst, alkali and ligand are dissolved in solvent, under inert atmosphere protection
It is reacted to get compound I-3；
Compound I-2 and compound I-3 are dissolved in solvent by step c, addition alkali, palladium catalyst, under inert atmosphere protection
It is reacted to get compound I-4；
Compound I-4 and compound I-5 are dissolved in the in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water by step d, wherein Isosorbide-5-Nitrae-
Dioxane: water volume ratio is (8:1)~(4:1), and alkali is added, and palladium catalyst is reacted to get production under inert atmosphere protection
Object I-6；
Product I-6 is dissolved in solvent by step e, and palladium carbon is added, is reacted in hydrogen to get product I-7.
Further, the preparation method meets at least one of following:
Alkali described in step a be sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, in potassium hydroxide one or two with
On；
Compound I-1 in step a: the molar ratio of alkali is 1:(1.8~3.0)；
Compound I-1:I in step a2Molar ratio be 1:(1.5~2.0)；
Step a is by I2Being dissolved in DMF to concentration is 5~10mL/g；
Step a reaction temperature is 25~80 DEG C；
The step a reaction time is 2~10h；
Solvent described in step b is toluene；
Alkali described in step b is DIEA；
Palladium catalyst described in step b is three (dibenzylidene indenes acetone) two palladiums；
Ligand described in step b is P (t-Bu)3·HBF4；
Raw material SM-1 in step b: the molar ratio of alkali is 1:(1.5~2.0)；
Raw material SM-1 in step b: the molar ratio of palladium catalyst is 1:(5~10%)；
Raw material SM-1:P (t-Bu) in step b3·HBF4Molar ratio be 1:10%；
Inert atmosphere described in step b is N2；
Reaction temperature is 95 DEG C in step b；
The reaction time is 5~8h in step b；
Solvent described in step c is dioxane, water, toluene, DMF, n-butanol, isopropanol, one or two kinds of in sec-butyl alcohol
More than；
Alkali described in step c is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, one or more kinds of in cesium carbonate；
Palladium catalyst described in step c is palladium acetate, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, [1,1'-
Bis- (diphenylphosphine) ferrocene] it is palladium chloride dichloromethane complex, one or two kinds of in three (dibenzylidene indenes acetone) two palladiums
More than；
Compound I-2 in step c: the molar ratio of alkali is 1:(2.0~3.0)；
Compound I-2 in step c: the molar ratio of palladium catalyst is 1:(3%~10%)；
Inert atmosphere described in step c is N2；
Reaction temperature is 90~110 DEG C in step c；
The reaction time is 5~12h in step c；
Alkali described in step d is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, one or more kinds of in cesium carbonate；
Catalyst described in step d is palladium acetate, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, [1,1'- is bis-
(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, in three (dibenzylidene indenes acetone) two palladiums one or two with
On；
Compound I-5 in step d: the molar ratio of alkali is 1:(2.0~3.0)；
Compound I-5 in step d: the molar ratio of palladium catalyst is 1:(3%~10%)；
Inert atmosphere described in step d is N2；
Reaction temperature is 90~110 DEG C in step d；
The reaction time is 5~12h in step d.
The present invention provides the compound, its stereoisomer, its isotopic body, its pharmaceutically acceptable salt, its
The purposes of prodrug or its crystal in the drug of preparation treatment and/or pre- preventing tumor.
Further, the drug is the drug for the treatment of and/or prevention lung cancer, breast cancer, liver cancer, colorectal cancer.
The present invention provides treatment and/or the pharmaceutical compositions of pre- preventing tumor, it is with the compound, its alloisomerism
Body, its isotopic body, its pharmaceutically acceptable salt, its prodrug or its crystal are active constituent, are added pharmaceutically acceptable
Auxiliary material or complementary ingredient, the preparation being prepared.
Term definition:
Compound and derivative provided in the present invention can according to IUPAC (International Union of Pure and Applied Chemistry) or
The name of CAS (chemical abstracts service, Columbus, OH) naming system.
Term " alkyl " is the group of linear or branched saturated hydrocarbon base.C1~C6The example of alkyl includes but is not limited to first
Base (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), normal-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl group
(C4), n-pentyl (C5), 3- amyl (C5), amyl (C5), neopentyl (C5), 3- methyl -2- butyl (C5), tertiary pentyl (C5) and just
Hexyl (C6).Unless otherwise specified, each case of alkyl independently optionally be substituted, i.e., it is unsubstituted or by one or
Multiple substituent groups replace." substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.In some realities
It applies in scheme, the C1~C6Alkyl is the C replaced by halogen (fluorine, chlorine, bromine, iodine)1~C6Alkyl.In C1~C6Alkyl is substituted
In the case where base replaces, the carbon atom number of substituent group is not counted.
Term " alkoxy " refers to group-OR, and wherein R is substituted or unsubstituted alkyl.C1~C6The reality of alkoxy
Example includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, positive penta
Oxygroup, positive hexyloxy and 1,2- dimethyl butyrate oxygroup.In some embodiments, R is replaced by halogen (fluorine, chlorine, bromine, iodine)
Alkyl.The C1~C6Alkoxy does not count the carbon atom number of substituent group in the case where R is substituted with a substituent.
Term " aryl " refers to includes or the group not comprising heteroatomic 4n+2 aromatics ring system in aromatics ring system,
In, hetero atom is independently selected from nitrogen, oxygen and sulphur.Unless otherwise specified, each case of aryl is independently optionally substituted,
It is i.e. unsubstituted or be substituted by one or more substituents.
Term " alicyclic ring " refers to the unsaturated cyclic hydrocarbon group of saturation or part.
Term " alkoxy carbonyl group " refers to group R-O-C (O)-, and wherein R is alkyl defined above, and preferably R is C1~C6
Alkyl (C1~C6 alkoxy carbonyl group i.e. of the present invention).Its example includes but is not limited to methoxycarbonyl group, carbethoxyl group, the third oxygen carbonyl
Base, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual
In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " pharmaceutically acceptable salt " refers to the acid that the compounds of this invention and inorganic and/or organic bronsted lowry acids and bases bronsted lowry are formed
And/or basic salt, also include amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.These salt, which can be, to be changed
Close being finally separating and directly obtaining in purifying for object.It is also possible to by the way that above compound and a certain number of acid or alkali is appropriate
(such as equivalent) is obtained by mixing.These salt may be formed precipitating in the solution and be collected with filter method, or molten
It recycles and obtains after agent evaporation, or be freeze-dried and be made after reacting in an aqueous medium.Heretofore described salt can be compound
Hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, acetate, propionate, fourth two
Hydrochlorate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
Term " stereoisomer " includes cis-trans-isomer, optical isomer.
Inert atmosphere of the present invention can be nitrogen protection atmosphere or argon atmosphere etc..
In certain embodiments of the invention, present invention comprises the compound of isotope labelling, the isotope labelling
Compound refers to identical as listed compound herein, but one or more of atoms are replaced by another atom, should
The atomic mass or mass number of atom are different from atomic mass or mass number common in nature.Chemical combination of the present invention can be introduced
Isotope in object includes hydrogen, carbon, nitrogen, oxygen, sulphur, i.e.,2H,3H、13C、14C、15N、17O、18O、35S.Containing above-mentioned isotope and/or
The compounds of this invention and its stereoisomer and the compound of other atom isotopes, stereoisomer it is pharmaceutical
Salt should be included within the scope of the invention.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
Pharmaceutically acceptable auxiliary material of the present invention refers in addition to the active ingredient (s include substance in dosage form.
Pharmaceutically acceptable complementary ingredient of the present invention, it has certain physiological activity, but the addition of the ingredient
The leading position of aforementioned pharmaceutical compositions in the course of disease treatment will not be changed, and only play auxiliary effect, these auxiliary
Effect is only the utilization to the ingredient known activity, is the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary
Ingredient is used cooperatively with pharmaceutical composition of the present invention, still should belong to the scope of protection of the invention.
The present invention provides the indazole analog derivatives of a kind of structure novel.The experimental results showed that the compounds of this invention can
The kinds of tumor cells such as lung carcinoma cell, breast cancer cell, liver cancer cells, colorectal cancer cell are inhibited to be proliferated, significantly for clinic
Treating cancer provides a kind of new medication selection.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
The present invention provides I compounds represented of formula:
R1For aryl or substituted aryl；
L isOr
X, Y, Z are independently selected from N or CH；
R2For5~8 yuan of aryl or 5~8 yuan of substituted aryl；Wherein, W is-CH2-、Or
It is not present；R21、R22Independently selected from-H or alkyl, alternatively, R21With R22It is connected to form at least containing a heteroatomic alicyclic ring.
The experimental results showed that above compound is to lung carcinoma cell, breast cancer cell, liver cancer cells, colorectal cancer cell etc.
Kinds of tumor cells proliferation can play significant inhibiting effect, and treatment tumor effect is significant.
The preparation of 1 the compounds of this invention A1~A15 of embodiment
Synthetic route 1
It takes compound 1 (3.72g, 20mmol, 1.0eq.), compound 2 (3.8mL, 22mmol, 1.1eq.), Pd2(dba)3
(1mmol, 5mol%), DIPEA (6.6mL, 40mmol, 2.0eq.) and P (t-Bu)3·HBF4(0.58g, 2mmol,
It 10mol%) is dissolved in dry toluene (60mL), is reacted 6 hours at 95 DEG C after nitrogen protection, TLC monitoring reaction.It has reacted
Concentrated solvent after complete, is added ethyl acetate and water extracts, and is concentrated after organic phase is dry, column chromatography for separation obtains compound 3, pale yellow
Color product (4.52g, 78.1%).1H NMR(400MHz,DMSO-d6) δ 7.94 (d, J=8.0Hz, 2H), 7.72 (d, J=
8.0Hz, 2H), 7.37 (d, J=18.4Hz, 1H), 6.31 (d, J=18.5Hz, 1H), 3.86 (s, 3H), 1.26 (s, 12H)
Compound 4 (1.97g, 10mmol, 1.0eq.) is dissolved in DMF (20mL), addition potassium carbonate (2.7g, 20mmol,
2.0eq.).By I2(5.0g, 20mmol, 2.0eq.), which is dissolved in DMF (8mL), is added dropwise to reaction solution, reacts 10 hours at 65 DEG C.
TLC monitoring after completion of the reaction pours into reaction solution in the aqueous solution (80mL) of sodium hydrosulfite (5.0g) and potassium carbonate (2.0g), has white
Color solid is precipitated.It is filtered after stirring 30min, obtains compound 5, white solid (2.3g, 71.2%).1H NMR(400MHz,
DMSO-d6) δ 13.62 (s, 1H), 7.82 (d, J=1.5Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.33 (dd, J=8.6,
1.6Hz,1H).
It takes compound 5 (0.65g, 2mmol, 1.0eq.), Pd (dppf) Cl2(50mg, 0.1mmol, 5mmol%), chemical combination
Object 3 (700mg, 2.4mmol, 1.2eq.) and cesium carbonate (972mg, 3mmol, 1.5eq.) are added to Isosorbide-5-Nitrae-dioxane and water
In the mixed solvent 30mL of (4:1), N2It is reacted 6 hours at 100 DEG C after displacement.TLC monitoring reaction, will reaction after fully reacting
Liquid removes under reduced pressure, and residue methylene chloride and methanol mixed solvent dissolve, and filters through diatomite, after filtrate concentration, through thin layer
Prepare chromatography (DCM:CH3OH=10:1 compound 6, light yellow solid (480.9mg, 67.5%)) are obtained.1H NMR
(400MHz,DMSO-d6) δ 13.28 (s, 1H), 8.18 (d, J=8.6Hz, 1H), 7.77 (d, J=1.6Hz, 1H), 7.63-
7.41 (m, 2H), 7.33 (dd, J=8.7,1.7Hz, 1H), 6.91 (d, J=2.3Hz, 2H), 6.44 (t, J=2.2Hz, 1H),
3.80(s,6H).
Take compound 7 (0.5mmol, 1.0eq.) and compound 6 (0.6mmol, 1.2eq.), potassium carbonate (1.0mmol,
2.0eq.), Pd (dppf) Cl2(50mg, 5mmol%) is added into the mixed solvent 20mL of Isosorbide-5-Nitrae-dioxane and water (4:1),
Under nitrogen protection after 95 DEG C are reacted 8 hours, TLC monitoring reaction.Concentrated solvent is added ethyl acetate 15mL and dissolves residue,
Diatomite drainage obtains clear filtrate, and the extraction of 15mL water is added, is concentrated after organic phase is dry, thin layer prepares chromatography separation
Obtain compound A1, light yellow solid (24.3mg, 11.0%).HRMS(ESI-TOF)m/z Calcd for C27H27N3O3[M+
H]+:442.2131,found:442.2125；1H NMR(400MHz,DMSO-d6) δ 13.14 (s, 1H), 8.22 (d, J=
8.5Hz, 1H), 7.69-7.61 (m, 3H), 7.57 (d, J=16.7Hz, 1H), 7.50-7.43 (m, 2H), 7.09-7.02 (m,
2H), 6.92 (d, J=2.3Hz, 2H), 6.43 (t, J=2.2Hz, 1H), 3.81 (s, 6H), 3.77 (t, J=4.8Hz, 4H),
3.18 (t, J=4.9Hz, 4H)
Use the available following compound of similar approach:
Compound A2:(E) -3- (3,5- dimethoxy-styryl) -6- (6- (4- methyl piperazine base -1- base) pyridine -3-
Base) -1H- indazole
HRMS(ESI-TOF)m/z Calcd for C27H29N5O2[M+H]+:456.2400,found:456.2386；1H
NMR(400MHz,DMSO-d6) δ 13.18 (s, 1H), 8.54 (d, J=2.6Hz, 1H), 8.24 (d, J=8.5Hz, 1H), 7.95
(dd, J=8.9,2.6Hz, 1H), 7.68 (s, 1H), 7.57 (d, J=16.6Hz, 1H), 7.51-7.42 (m, 2H), 7.02-
6.86 (m, 3H), 6.44 (t, J=2.2Hz, 1H), 3.81 (s, 6H), 3.56 (dd, J=7.1,3.1Hz, 4H), 2.43 (t, J=
5.0Hz,4H),2.24(s,3H).13C NMR(101MHz,DMSO-d6)δ161.16,156.575,154.34,146.37,
142.59,139.70,136.66,129.96,125.84,125.73,121.85,116.07,107.49,104.85,55.73,
54.81,46.23,45.05.
Compound A-13: tert-butyl-(E) -4- (5- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) pyridine -
2- yl) piperazine -1- formamide
HRMS(ESI-TOF)m/z Calcd for C31H35N5O4[M+H]+:542.2768,found:542.2781；1H
NMR(400MHz,DMSO-d6) δ 13.19 (s, 1H), 8.56 (d, J=2.6Hz, 1H), 8.24 (d, J=8.5Hz, 1H), 7.98
(dd, J=8.9,2.6Hz, 1H), 7.71-7.66 (m, 1H), 7.57 (d, J=16.7Hz, 1H), 7.51-7.43 (m, 2H),
6.96 (d, J=8.9Hz, 1H), 6.92 (d, J=2.2Hz, 2H), 6.44 (t, J=2.2Hz, 1H), 3.81 (s, 6H), 3.57
(dd, J=6.9,3.7Hz, 4H), 3.46 (dd, J=6.6,3.8Hz, 4H), 1.44 (s, 9H)13C NMR(101MHz,DMSO-
d6)δ161.16,154.93,150.43,146.63,142.58,139.73,129.88,128.08,121.64,120.57,
115.98,104.83,100.57,80.07,55.73,55.02,48.28,46.26,28.64.
Compound A4:(E) -3- (3,5- dimethoxy-styryl) -6- (4- (4- methylpiperazine-1-yl) phenyl) -1H-
Indazole
HRMS(ESI-TOF)m/z Calcd for C28H30N4O2[M+H]+:455.2448,found:455.2436；1H
NMR(400MHz,DMSO-d6) δ 13.14 (s, 1H), 8.21 (d, J=8.5Hz, 1H), 7.68-7.60 (m, 3H), 7.57 (d, J
=16.7Hz, 1H), 7.51-7.42 (m, 2H), 7.04 (d, J=8.7Hz, 2H), 6.92 (d, J=2.2Hz, 2H), 6.44 (t, J
=2.2Hz, 1H), 3.81 (s, 6H), 3.21 (d, J=4.9Hz, 4H), 2.47 (t, J=5.0Hz, 4H), 2.23 (s, 3H)13C
NMR(101MHz,DMSO-d6)δ161.16,158.55,154.43,146.36,142.58,139.70,136.78,136.36,
129.98,125.81,121.86,121.66,120.27,107.66,107.11,104.86,100.58,79.51,73.99,
55.73,44.94.
Compound A-45: (E) -3- (3,5- dimethoxy-styryl) -6- (4- ((4- methylpiperazine-1-yl) methyl) benzene
Base) -1H- indazole
HRMS(ESI-TOF)m/z Calcd for C29H32N4O2[M+H]+:469.2604,found:469.2625；1HNMR(400MHz,DMSO-d6) δ 13.23 (s, 1H), 8.27 (d, J=8.5Hz, 1H), 7.77-7.67 (m, 3H), 7.58 (d, J
=16.7Hz, 1H), 7.54-7.38 (m, 4H), 6.92 (d, J=2.3Hz, 2H), 6.44 (t, J=2.3Hz, 1H), 3.81 (s,
6H), 3.51 (s, 2H), 2.38 (d, J=21.4Hz, 8H), 2.17 (s, 3H)13CNMR(101MHz,DMSO-d6)δ161.17,
139.68,139.49,138.89,138.13,130.03,129.97,128.35,127.43,121.80,121.61,120.99,
120.38,108.24,104.85,100.60,62.12,55.74,55.11,52.89,46.05.
Compound A6:(E) -4- ((4- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) phenyl) morpholine
HRMS(ESI-TOF)m/z Calcd for C28H29N3O3[M+H]+:456.2288,found:456.2291；1H
NMR(400MHz,DMSO-d6) δ 13.23 (s, 1H), 8.27 (d, J=8.5Hz, 1H), 7.72 (d, J=7.8Hz, 3H), 7.59
(d, J=16.7Hz, 1H), 7.53-7.39 (m, 4H), 6.92 (d, J=2.3Hz, 2H), 6.44 (t, J=2.2Hz, 1H), 3.81
(s, 6H), 3.60 (t, J=4.6Hz, 4H), 3.52 (s, 2H), 2.39 (t, J=4.6Hz, 4H)13C NMR(101MHz,DMSO-
d6)δ161.16,158.47,154.36,142.58,139.70,136.78,136.36,129.98,125.81,121.86,
121.66,120.27,107.66,107.11,104.86,100.58,66.70,62.49,55.75,53.63.
Compound A7:(E) -3- (3,5- dimethoxy-styryl) -6- (6- (piperazinyl -1- base) pyridin-3-yl) -
1H- indazole
HRMS(ESI-TOF)m/z Calcd for C26H27N5O2[M+H]+:442.2244,found:442.2252；1HNMR(400MHz,DMSO-d6) δ 13.25 (s, 1H), 8.59 (d, J=2.6Hz, 1H), 8.29 (d, J=8.5Hz, 1H),
8.05-7.95 (m, 1H), 7.73 (s, 1H), 7.62 (d, J=16.8Hz, 1H), 7.57-7.46 (m, 2H), 6.97 (d, J=
2.4Hz, 3H), 6.49 (t, J=2.3Hz, 1H), 3.87 (s, 6H), 3.54 (t, J=4.7Hz, 4H), 2.96-2.77 (m, 4H),
1.28(s,1H).13C NMR(101MHz,DMSO-d6)δ161.16,146.35,143.63,142.15,139.70,136.58,
129.96,121.84,121.62,120.25,120.00,107.31,107.03,104.85,100.58,55.73,46.24,
45.82.
Compound A-28: (E) -4- ((4- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) phenyl) sulphonyl
Base) morpholine
HRMS(ESI-TOF)m/z Calcd for C27H27N3O5S[M+H]+:506.1750,found:506.1764；1H
NMR(400MHz,DMSO-d6) δ 13.38 (s, 1H), 8.35 (d, J=8.5Hz, 1H), 8.09-8.04 (m, 2H), 7.90-7.81
(m, 3H), 7.64-7.57 (m, 2H), 7.50 (d, J=16.7Hz, 1H), 6.94 (d, J=2.2Hz, 2H), 6.45 (t, J=
2.2Hz, 1H), 3.82 (s, 6H), 3.66 (t, J=4.7Hz, 4H), 2.99-2.90 (m, 4H)13C NMR(101MHz,DMSO-
d6)δ161.17,145.56,142.73,142.29,139.63,137.08,133.69,130.24,128.84,128.60,
122.16,121.39,121.10,120.99,109.37,104.91,100.66,65.79,55.74,46.39.
Compound A9:(E) -4- (5- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) pyrimidine -2- amine
HRMS(ESI-TOF)m/z Calcd for C27H30N6O2[M+H]+:471.2509,found:471.2521；1H
NMR(400MHz,DMSO-d6) δ 13.24 (s, 1H), 8.80 (s, 2H), 8.26 (d, J=8.5Hz, 1H), 7.73 (s, 1H),
7.57 (d, J=16.7Hz, 1H), 7.51-7.43 (m, 2H), 6.92 (d, J=2.2Hz, 2H), 6.44 (d, J=2.3Hz, 1H),
3.81 (s, 10H), 2.46 (s, 4H), 2.39 (d, J=7.4Hz, 2H), 1.05 (t, J=7.1Hz, 3H)13C NMR(101MHz,
DMSO-d6)δ161.16,161.01,156.63,142.66,142.46,139.66,133.72,130.06,122.72,
122.04,121.54,120.27,119.89,107.08,104.88,100.58,55.73,52.55,52.10,43.90,
12.28.
Compound A10:(E) -4- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base)-N, N- dimethyl benzene
Sulfonamide
HRMS(ESI-TOF)m/z Calcd forC25H25N3O4S[M+H]+:464.1645,found:464.1654；1H
NMR(400MHz,DMSO-d6) δ 13.36 (s, 1H), 8.34 (d, J=8.5Hz, 1H), 8.05 (d, J=8.3Hz, 2H), 7.92-
7.81 (m, 3H), 7.66-7.56 (m, 2H), 7.50 (d, J=16.6Hz, 1H), 6.93 (d, J=2.2Hz, 2H), 6.45 (d, J
=2.2Hz, 1H), 3.82 (s, 6H), 2.68 (s, 6H)13C NMR(101MHz,DMSO-d6)δ161.17,145.20,
142.73,142.31,139.63,137.15,134.07,130.23,128.71,128.49,122.15,121.39,121.06,
120.96,109.30,104.91,100.66,55.74,38.08.
Compound A11:(E) -4- (5- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) pyridine -2- base)
Morpholine
HRMS(ESI-TOF)m/z Calcd for C26H26N4O3[M+H]+:443.2084,found:443.2069；1H
NMR(400MHz,DMSO-d6) δ 13.19 (s, 1H), 8.57 (d, J=2.6Hz, 1H), 8.24 (d, J=8.5Hz, 1H), 7.98
(dd, J=8.8,2.6Hz, 1H), 7.69 (t, J=1.0Hz, 1H), 7.57 (d, J=16.7Hz, 1H), 7.50-7.43 (m,
2H), 7.01-6.85 (m, 3H), 6.44 (t, J=2.2Hz, 1H), 3.81 (s, 6H), 3.77-3.70 (m, 4H), 3.57-3.46
(m,4H).13C NMR(101MHz,DMSO-d6)δ161.16,158.94,146.29,142.58,142.56,139.69,
136.75,136.35,129.99,126.00,121.87,121.63,120.30,120.07,107.51,107.15,104.86,
100.58,66.43,55.73,45.64.
Compound A12:(E) -5- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) pyridine -2- amine
HRMS(ESI-TOF)m/z Calcd for C22H20N4O2[M+H]+:373.1665,found:373.1674；1H
NMR(400MHz,DMSO-d6) δ 13.14 (s, 1H), 8.34 (d, J=2.4Hz, 1H), 8.22 (d, J=8.5Hz, 1H), 7.80
(dd, J=8.6,2.6Hz, 1H), 7.64-7.53 (m, 2H), 7.50-7.40 (m, 2H), 6.92 (d, J=2.3Hz, 2H), 6.58
(d, J=8.6Hz, 1H), 6.44 (d, J=2.3Hz, 1H), 6.11 (s, 2H), 3.81 (s, 6H)13C NMR(101MHz,DMSO-
d6)δ161.16,159.60,146.36,142.64,142.58,139.70,136.95,136.45,129.91,124.60,
121.76,121.69,120.15,108.63,106.65,104.83,100.58,99.98,55.73.
Compound A13:(E) -5- (3- (3,5- dimethoxy-styryl) -1H- pyrazoles [4,3-b] pyridine -6- base) pyrrole
Pyridine -2- amine
HRMS(ESI-TOF)m/z Calcd for C21H19N5O2[M+H]+:374.1618,found:374.1604；1H
NMR(400MHz,DMSO-d6) δ 13.33 (s, 1H), 8.85 (d, J=1.9Hz, 1H), 8.41 (d, J=2.5Hz, 1H), 8.13-
8.03 (m, 2H), 7.87 (dd, J=8.6,2.6Hz, 1H), 7.54 (d, J=16.4Hz, 1H), 6.83 (d, J=2.3Hz, 2H),
6.60 (d, J=8.6Hz, 1H), 6.45 (t, J=2.2Hz, 1H), 6.22 (s, 2H), 3.82 (s, 6H)13C NMR(101MHz,
DMSO-d6)δ161.23,159.98,146.89,144.44,142.46,139.62,137.94,136.61,134.71,
132.18,131.94,121.73,120.99,114.31,108.69,104.63,100.88,55.74.
Compound A14:(E) -5- (3- (3,5- dimethoxy-styryl) -1H- pyrazoles [4,3-b] pyridine -6- base) is phonetic
Pyridine -2- amine
HRMS(ESI-TOF)m/z Calcd for C20H18N6O2[M+H]+:375.1570,found:375.1564；1H
NMR(400MHz,DMSO-d6) δ 13.42 (s, 1H), 8.88 (d, J=2.0Hz, 1H), 8.74 (s, 2H), 8.17 (d, J=
2.0Hz, 1H), 8.10 (d, J=16.4Hz, 1H), 7.55 (d, J=16.4Hz, 1H), 6.92 (s, 2H), 6.83 (d, J=
2.2Hz, 2H), 6.45 (t, J=2.2Hz, 1H), 3.82 (s, 6H)13C NMR(101MHz,DMSO-d6)δ163.61,
161.23,157.18,144.09,142.51,139.59,138.25,134.53,132.29,129.26,120.92,120.20,
114.61,104.65,100.91,55.74.
Compound A15:(E) -5- (3- (3,5- dimethoxy-styryl) -1H- indazole -6- base) pyrimidine -2- amine
HRMS(ESI-TOF)m/z Calcd for C21H19N5O2[M+H]+:374.1618,found:374.1602；1H
NMR(400MHz,DMSO-d6) δ 13.21 (s, 1H), 8.67 (s, 2H), 8.25 (d, J=8.5Hz, 1H), 7.69 (s, 1H),
7.57 (d, J=16.6Hz, 1H), 7.50-7.43 (m, 2H), 6.92 (d, J=2.2Hz, 2H), 6.80 (s, 2H), 6.43 (t, J
=2.2Hz, 1H), 3.81 (s, 6H)13C NMR(101MHz,DMSO-d6)δ163.41,161.16,156.81,153.71,
142.49,139.68,134.10,130.00,122.82,121.98,121.57,120.17,119.79,106.82,104.87,
100.60,55.73.
The preparation of 2 the compounds of this invention A16 of embodiment
Synthetic route 2
The method of compound 3 is as shown in 1 first step of synthetic route.Compound 3 (1.45g, 5mmol, 1.0eq.) is taken to be dissolved in
It in dry DMF (15mL), is added N- chlorosuccinimide (1.33g, 10mmol, 2.0eq.), in 65 DEG C under nitrogen protection
Reaction 2 hours, TLC monitoring reaction.Concentrated solvent after fully reacting, is added ethyl acetate and water extracts, dense after organic phase is dry
Contracting, column chromatography for separation obtain compound 8, pale solid (0.84g, 47.2%).1H NMR(400MHz,DMSO-d6)δ7.20
(d, J=18.8Hz, 1H), 6.89 (s, 1H), 5.98 (d, J=18.8Hz, 1H), 3.92 (s, 6H), 1.26 (s, 12H)
The synthetic method of compound 5 is as shown in 1 second step of synthetic route.Compound 5 (0.65g, 2mmol, 1.0eq.) is taken,
Pd(dppf)Cl2(50mg, 5mmol%), compound 8 (861mg, 2.4mmol, 1.2eq.) and cesium carbonate (972mg,
3mmol, 1.5eq.) it is added into the mixed solvent 50mL of Isosorbide-5-Nitrae-dioxane and water (4:1), N2It is anti-at 100 DEG C after displacement
It answers 6 hours.TLC monitoring reaction, removes reaction solution under reduced pressure after fully reacting, residue methylene chloride and methanol mixed solvent
Dissolution, is filtered through diatomite, after filtrate concentration, prepares chromatography (DCM:CH through thin layer3OH=15:1 compound 9) is obtained,
Greenish yellow solid (395.5mg, 46.2%).1H NMR(400MHz,DMSO-d6) δ 13.25 (s, 1H), 8.03 (d, J=8.6Hz,
1H), 7.82 (d, J=1.6Hz, 1H), 7.46-7.30 (m, 3H), 6.93 (s, 1H), 3.96 (s, 6H)
Method by 9 prepare compound A16 of compound is similar with A1.HRMS(ESI-TOF)m/z Calcdfor
C27H27Cl2N5O2[M+H]+:524.1621,found:524.1609；1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),
8.54 (d, J=2.6Hz, 1H), 8.10 (d, J=8.5Hz, 1H), 7.95 (dd, J=8.9,2.6Hz, 1H), 7.75-7.70 (m,
1H), 7.51 (dd, J=8.5,1.5Hz, 1H), 7.45 (d, J=16.9Hz, 1H), 7.38 (d, J=17.0Hz, 1H), 6.99-
6.90 (m, 2H), 3.96 (s, 6H), 3.56 (t, J=5.0Hz, 4H), 2.42 (t, J=5.0Hz, 4H), 2.23 (s, 3H)13C
NMR(101MHz,DMSO-d6)δ158.81,154.94,148.73,146.37,142.68,136.63,135.54,129.66,
125.35,124.22,121.31,120.81,119.83,114.25,112.98,107.50,107.19,97.86,57.18,
54.79,46.21,45.03.
The preparation of 3 the compounds of this invention A17 of embodiment
Synthetic route 3
It takes compound A2 (45mg, 0.1mmol, 1.0eq), palladium carbon (20mg, 0.15mmol, 1.5eq) is added to 10mL first
In alcohol, overnight, TLC monitors reaction for reaction at room temperature for several times and after protecting for hydrogen displacement.Concentrated solvent after fully reacting is added
Ethyl acetate 15mL dissolves residue, and diatomite drainage obtains clear filtrate, and the extraction of 15mL water is added, dense after organic phase is dry
Contracting, thin layer prepare the isolated compound A17 of chromatography, light yellow solid (26.1mg, 57.1%).HRMS(ESI-TOF)
m/z Calcd forC27H31N5O2[M+H]+:458.2557,found:458.2571；1H NMR(400MHz,DMSO-d6)δ
12.67 (s, 1H), 8.49 (d, J=2.6Hz, 1H), 7.90 (dd, J=8.9,2.6Hz, 1H), 7.79 (d, J=8.4Hz, 1H),
7.58 (d, J=1.3Hz, 1H), 7.32 (dd, J=8.4,1.5Hz, 1H), 6.93 (d, J=8.9Hz, 1H), 6.46 (d, J=
2.3Hz, 2H), 6.31 (t, J=2.3Hz, 1H), 3.70 (s, 6H), 3.54 (t, J=5.1Hz, 4H), 3.24-3.16 (m, 2H),
3.04-2.96 (m, 2H), 2.41 (t, J=5.1Hz, 4H), 2.23 (s, 3H)13C NMR(101MHz,DMSO-d6)δ160.81,
158.74,146.27,144.98,144.42,142.13,136.62,136.07,125.85,121.04,118.97,107.48,
106.92,106.73,98.27,55.48,54.82,46.25,45.08,35.37,28.75.
Use the available following compound of the above method:
The Structural Identification data of the part of compounds of the present invention of table 1
Influence of 4 the compounds of this invention of embodiment to tumor cell line proliferative capacity
1. test method
The cell of logarithmic growth phase, every hole is with 2.5 × 103-1×104Cell quantity be inoculated in 96 orifice plates, cell training
Support overnight incubation 24 hours (37 DEG C, 5%CO in case2), the DMSO solution of DMEM culture medium dilution untested compound is simultaneously added to
In 96 orifice plates, 8 gradients of every kind of compound (contain 3 multiple holes).Dosing group by gradient (1000,333,127,42.3,14.1,
4.7,1.56,0.53nM) culture medium solutions of 100 μ L compounds is added in every hole；It is added in the every hole of negative control group and contains 1 ‰ DMSO
100 μ L of blank cultures, totally 6 multiple holes；100 μ L culture mediums are added in each hole of blank group.96 orifice plates are placed in cell culture
3 days (37 DEG C, 5%CO are cultivated in incubator2).20 μ LMTT solution are added in drug-treated group, negative control group and the every hole of blank group
(5mg/mL) continues culture 2-4 hours, is formed to first a ceremonial jade-ladle, used in libation and terminates culture, and every hole adds 150 μ L DMSO after supernatant removes, and suspends
50 μ L SDS solution (20%) are then added in cell, shake on shaking table 15~20 minutes.Each hole cell absorbance is detected with microplate reader
(OD 570) takes its average value to record result.Cell proliferation inhibition rate=(control group OD570Experimental group OD570)/(control group
OD570Blank group OD570) × 100%, Graphpad Prism software is fitted half-inhibitory concentration.
2. test result
The bright compound in the part of the present invention of table 2 inhibits the IC of tumor cell proliferation50Value
Note: A549 is human lung carcinoma cell line；4T1 is mouse mastopathy cell strain；HepG2 is human hepatoma cell strain；MCF-7
For Breast cancer lines；HCT116 is people's colorectal cancer cell lines.
Claims (19)
1. I compound represented of formula:
R1For aryl or substituted aryl；
L is
X, Y, Z are independently selected from N or CH；
R2For5~8 yuan of aryl or 5~8 yuan of substituted aryl；Wherein, W is-CH2-、Or it does not deposit
In；R21、R22Independently selected from-H or alkyl, alternatively, R21With R22It is connected to form at least containing a heteroatomic alicyclic ring.
2. compound as described in claim 1, it is characterized in that: R1For 5~10 yuan of aryl or 5~10 yuan of substituted aryl；It is preferred that
Ground, R1For 6 yuan of aryl or 6 yuan of substituted aryl；It is further preferred that R1ForWherein, R11~R15Solely
On the spot it is selected from-H, halogen or alkoxy.
3. compound as claimed in claim 2, it is characterized in that: R11~R15Independently selected from-H, halogen or C1~C6 alkoxy；
Preferably, R11~R15Independently selected from-H ,-F ,-Cl or methoxyl group.
4. the compound as described in claims 1 to 3 any one, it is characterized in that: R1For
5. compound as described in claim 1, it is characterized in that: R21、R22Independently selected from-H or C1~C6 alkyl, alternatively, R21
With R22It is connected to form at least containing heteroatomic 5~8 yuan of alicyclic ring；Preferably, R21、R22Independently selected from-H or C1~C6 alkane
Base, alternatively, R21With R22It is connected to form at least containing heteroatomic 6 yuan of alicyclic ring.
6. compound as claimed in claim 5, it is characterized in that: R21、R22Independently selected from-H or methyl；Alternatively, R21With R22Phase
Even formedWherein, R4、R5Independently selected from-H, alkane
Base or alkoxy carbonyl group, the hydrogen on alicyclic ring are optionally replaced by alkyl.
7. compound as claimed in claim 6, it is characterized in that: R4、R5Independently selected from-H, C1~C6 alkyl or C1~C6 alkane
Oxygen carbonyl, the hydrogen on alicyclic ring are optionally replaced by C1~C6 alkyl；Preferably, R4、R5Independently selected from-H, methyl, ethyl or uncle
Butoxy carbonyl, the hydrogen on alicyclic ring are optionally replaced by methyl.
8. the compound as described in claim 1,5~7 any one, it is characterized in that: R21With R22It is connected to form Further, describedSpatial configuration be
9. the compound as described in claim 1~8 any one, it is characterized in that: W is-CH2When, the compound is selected from:
10. the compound as described in claim 1~8 any one, it is characterized in that: W isWhen, the compound choosing
From:
11. the compound as described in claim 1~8 any one, it is characterized in that: the compound is selected from the absence of W:
12. the stereoisomer of compound described in claim 1~11 any one, isotopic body, pharmaceutically acceptable salt,
Prodrug or crystal.
13. compound described in claim 1~11 any one, its stereoisomer, its isotopic body, its is pharmaceutically acceptable
Salt, its prodrug or its crystal preparation method, it is characterized in that: including the following steps:
A, compound I-1 obtains compound I-2 through iodo:
B, raw material SM-1 and SM-2 passes through the coupling reaction of palladium chtalyst, obtains compound I-3:
Wherein, Ha is-Br or-I；
C, compound I-2 and compound I-3 passes through the coupling reaction of palladium chtalyst, obtains compound I-4:
D, compound I-4 and compound I-5 passes through the coupling reaction of palladium chtalyst, obtains product I-6:
14. preparation method as claimed in claim 13, it is characterized in that: further including following steps:
E, product I-6 passes through catalytic hydrogenation, obtains product I-7:
15. preparation method according to claim 13 or 14, it is characterized in that: meeting at least one of following:
Compound I-1 is dissolved in DMF by step a, alkali is added, by I2It is dissolved in DMF and is added dropwise to reaction solution, reaction terminates to change to obtain the final product
Close object I-2；
Raw material SM-1, raw material SM-2, palladium catalyst, alkali and ligand are dissolved in solvent by step b, are carried out under inert atmosphere protection
Reaction is to get compound I-3；
Compound I-2 and compound I-3 are dissolved in solvent by step c, addition alkali, palladium catalyst, are carried out under inert atmosphere protection
Reaction is to get compound I-4；
Compound I-4 and compound I-5 are dissolved in the in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water by step d, wherein Isosorbide-5-Nitrae-dioxy
Six rings: water volume ratio is (8:1)~(4:1), and alkali is added, and palladium catalyst is reacted to get product I- under inert atmosphere protection
6；
Product I-6 is dissolved in solvent by step e, and palladium carbon is added, is reacted in hydrogen to get product I-7.
16. preparation method as claimed in claim 15, it is characterized in that: meeting at least one of following:
Alkali described in step a is sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, one or more kinds of in potassium hydroxide；
Compound I-1 in step a: the molar ratio of alkali is 1:(1.8~3.0)；
Compound I-1:I in step a2Molar ratio be 1:(1.5~2.0)；
Step a is by I2Being dissolved in DMF to concentration is 5~10mL/g；
Step a reaction temperature is 25~80 DEG C；
The step a reaction time is 2~10h；
Solvent described in step b is toluene；
Alkali described in step b is DIEA；
Palladium catalyst described in step b is three (dibenzylidene indenes acetone) two palladiums；
Ligand described in step b is P (t-Bu)3·HBF4；
Raw material SM-1 in step b: the molar ratio of alkali is 1:(1.5~2.0)；
Raw material SM-1 in step b: the molar ratio of palladium catalyst is 1:(5~10%)；
Raw material SM-1:P (t-Bu) in step b3·HBF4Molar ratio be 1:10%；
Inert atmosphere described in step b is N2；
Reaction temperature is 95 DEG C in step b；
The reaction time is 5~8h in step b；
Solvent described in step c is dioxane, water, toluene, DMF, n-butanol, isopropanol, one or more kinds of in sec-butyl alcohol；
Alkali described in step c is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, one or more kinds of in cesium carbonate；
Palladium catalyst described in step c is palladium acetate, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, [1,1'- bis- (two
Phenylphosphine) ferrocene] it is palladium chloride dichloromethane complex, one or more kinds of in three (dibenzylidene indenes acetone) two palladiums；
Compound I-2 in step c: the molar ratio of alkali is 1:(2.0~3.0)；
Compound I-2 in step c: the molar ratio of palladium catalyst is 1:(3%~10%)；
Inert atmosphere described in step c is N2；
Reaction temperature is 90~110 DEG C in step c；
The reaction time is 5~12h in step c；
Alkali described in step d is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, one or more kinds of in cesium carbonate；
Catalyst described in step d is palladium acetate, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, the [bis- (hexichol of 1,1'-
Base phosphine) ferrocene] it is palladium chloride dichloromethane complex, one or more kinds of in three (dibenzylidene indenes acetone) two palladiums；
Compound I-5 in step d: the molar ratio of alkali is 1:(2.0~3.0)；
Compound I-5 in step d: the molar ratio of palladium catalyst is 1:(3%~10%)；
Inert atmosphere described in step d is N2；
Reaction temperature is 90~110 DEG C in step d；
The reaction time is 5~12h in step d.
17. compound described in claim 1~11 any one, its stereoisomer, its isotopic body, its is pharmaceutically acceptable
Salt, its prodrug or its crystal preparation treatment and/or pre- preventing tumor drug in purposes.
18. purposes as claimed in claim 17, it is characterized in that: the drug is treatment and/or prevention lung cancer, breast cancer, liver
The drug of cancer, colorectal cancer.
19. the pharmaceutical composition for the treatment of and/or pre- preventing tumor, it is characterized in that: it is described in claim 1~11 any one
Compound, its stereoisomer, its isotopic body, its pharmaceutically acceptable salt, its prodrug or its crystal are active constituent, are added
Enter pharmaceutically acceptable auxiliary material or complementary ingredient, the preparation being prepared.
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