CN108727400A - A kind of compound for treating tumour - Google Patents
A kind of compound for treating tumour Download PDFInfo
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- CN108727400A CN108727400A CN201810506449.3A CN201810506449A CN108727400A CN 108727400 A CN108727400 A CN 108727400A CN 201810506449 A CN201810506449 A CN 201810506449A CN 108727400 A CN108727400 A CN 108727400A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
Formula (I) compound represented or its pharmaceutically acceptable salt or its solvate：Wherein, R1It is selected fromR2、R3Separately be selected from H, halogen, alkyl,Or R2And R3Coupled carbon atom composition is containing 1~2 heteroatomic 1 substitution or polysubstituted hexa-atomic aromatic heterocycle；R4、R5、R60~3 substitution on phenyl ring, R are indicated respectively4、R5、R6It is respectively and independently selected from H, halogen atom, C1~6Alkyl, C1~6Alkoxy, hydroxyl, amino, carboxyl, nitro, CH3O(CH2)nCH2O-,The integer that wherein n is 1~6.The present invention provides purposes of the compound in the drug for preparing treatment tumour.The compounds of this invention drug effect is clear.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of compound for treating tumour.
Background technology
In recent years, with the quickening pace of modern life, people pressure further increases.Schizophrenia and cancer at
For the disease that today's society cannot be ignored, the normal development of society and normal public order are seriously affected.From 20th century,
The number of infection cancer increasingly increases.The patient for dying of cancer every year in the world is millions of, and most of cancer patient is
Low income and medium income group.The treatment of cancer at present can pass through Chinese medicine treatment, operation excision, chemotherapy, radiation treatment,
Immunization therapy and mab treatment or other treatment method, but few cases thoroughly cured.How most
The pain of the reduction cancer patient of big degree, the prevention and treatment effect reached are that there is an urgent need to solve by current many researchers
Certainly the problem of.
Invention content
The purpose of the present invention is to provide a kind of noval chemical compounds for treating tumour.
The present invention provides such as formula (I) compound represented or its pharmaceutically acceptable salts or its solvate：
Wherein, R1It is selected from
R2、R3Separately be selected from H, halogen, alkyl,Or R2And R3Coupled carbon atom
Composition is containing 1~2 heteroatomic 1 substitution or polysubstituted hexa-atomic aromatic heterocycle；
R4、R5、R60~3 substitution on phenyl ring, R are indicated respectively4、R5、R6It is respectively and independently selected from H, halogen atom, C1~6Alkane
Base, C1~6Alkoxy, hydroxyl, amino, carboxyl, nitro, CH3O(CH2)nCH2O-,Wherein n is 1~6
Integer.
Further, the R4、R5、R6It is respectively and independently selected from H, halogen atom, C1~6Alkyl, C1~6Alkoxy, CH3O
(CH2)nCH2O-,The integer that wherein n is 1~6.
Further, the R4、R5、R6It is respectively and independently selected from H, F, methyl, methoxyl group, CH3OCH2CH2O-,
Further, the R4、R5、R6Indicate the unsubstituted or substitution on phenyl ring.Further, the R1It is selected from：
Further, the hexa-atomic aromatic heterocycle isWherein R7It is selected from
Further, above-mentioned compound is one of following compounds：
Preparation method the present invention also provides above compound is：It includes the following steps：
(1) synthesis of compound 1~14：
(1) synthesis of intermediate h：
The synthesis of (2A) compound 1~7：
The synthesis of (2B) compound 8~14：
(2) synthesis of compound 15-21：
(3) synthesis of compound 22-43：
The present invention provides purposes of the above-mentioned compound in the drug for preparing treatment tumour.
The drug is the drug for treating colon cancer, fibrosarcoma, epidermal carcinoma, breast cancer.
The present invention provides above-mentioned compounds to prepare in the drug of receptor tyrosine kinase (EGFR) inhibitory activity
Purposes.
The present invention provides purposes of the above compound in the drug for preparing treatment tumour.
Wherein, the drug is the drug for treating colon cancer, fibrosarcoma, epidermal carcinoma, breast cancer.
The present invention also provides the compounds to prepare the drug to receptor tyrosine kinase (EGFR) inhibitory activity
In purposes.
The present invention also provides purposes of the compound in preparing the drug for inhibiting new vessels.
The present invention designs by pharmaceutical chemistry basic principle, has synthesized 5 series totally 43 compounds.By MTT methods,
Preliminary test compound cpd1-cpd21 inhibits under 10 μM of concentration the activity of colon cancer HT-29 and epidermal carcinoma A431.Wherein,
Compound cpd9 and other 5 lead compounds show good inhibitory activity, and wherein compound cpd9 is to HT-29 and table
The inhibiting rate of skin cancer is respectively up to 89.4% and 84.2%.
Activity and mechanism study further have been carried out to compound cpd9.Using mtt assay, cpd9 is determined different dense
It spends under (0.3125,0.625,1.25,2.5,5.0,12.5 and 25 μM) to colon cancer HT-29 and epidermal carcinoma A431 cell Proliferations
Inhibiting rate, and calculate its IC50, respectively 2.9 μM and 6.8 μM.Colon cancer cell HT-29 is through 2.5 μM of cpd9 processing
16 hours, apparent phenomena of apoptosis has occurred.
The present invention determines inhibition of the compound cpd1-cpd43 to receptor tyrosine kinase (EGFR) under 10 μM of concentration
Activity, wherein compound cpd9 and cpd37 are respectively 92.9% and 91.3% to the inhibiting rate of EGFR.Continue to determine cpd9
With cpd37 under various concentration (0.3125,0.625,1.25,2.5,5.0,12.5 and 25 μM) to the inhibitory activity of EGFR, and
Calculate its IC50, respectively 3.3 μM and 3.9 μM.
Cpd9 is determined under 1 μM, 10 μM and 20 μM concentration using zebrafish embryo, inhibits the ability of new vessels.
To sum up, the compounds of this invention has excellent antitumor activity and inhibits the ability of new vessels, application prospect excellent
It is good.
The definition using term about the present invention：Unless otherwise indicated, what group or term herein provided is initial
The group or term of definition suitable for entire description；For the term being not specifically defined herein, it should according to open
Content and context, their meaning can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix (Ca~Cb) alkyl
Show any alkyl containing " a " to " b " a carbon atom.Thus, for example, (C1~C4) alkyl refer to include 1~4 carbon atom
Alkyl.
The C1~C6Alkyl refers to C1、C2、C3、C4、C5、C6Alkyl, i.e., with 1~6 carbon atom linear chain or branched chain
Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, hexyl etc..C1-C6
Alkoxy also have meaning corresponding with its group.
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 " salt " and " pharmaceutical salt " refer to above compound or its stereoisomer, with inorganic and/or organic acid
The acid and/or basic salt formed with alkali also includes amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.This
A little salt can be directly obtained in being finally separating and purify of compound.Can also be by by above compound or it is vertical
Body isomers is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be in the solution
It forms precipitation and is collected with filter method, or recycle obtain after the solvent evaporates, or be freeze-dried after being reacted in aqueous medium
It is made.
Obviously, the above according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific implementation mode of form by the following examples remakes further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
Description of the drawings
Fig. 1：Growth inhibition ratios of the compound cpd1-cpd21 to HT-29 cell lines
Fig. 2：Growth inhibition ratios of the compound cpd1-cpd21 to A431 cell lines
Fig. 3：Cpd9 is to HT-29 and A431 cell growth inhibition curves
Fig. 4：Cpd9 induces HT-29 Apoptosis
Fig. 5：Influences of the cpd9 to zebrafish embryo body intersegmental blood vessel, A are that negative (blank) compares；B is 10 μM of cpd9 of administration
Zebrafish embryo new vessels developmental state；C is the zebrafish embryo new vessels developmental state that 20 μM of cpd9 is administered；D is sun
Property control, that is, be administered 10 μM of Gefitinib zebrafish embryo new vessels developmental state.
Specific implementation mode
The raw material and instrument that the present invention uses can be commercially available by market.
The synthesis of embodiment 1, compound 1
Synthetic route：
Preparation method：
(1) compound a (10g, 1.0eq) and dichloromethane (100ml) are added in there-necked flask, under nitrogen protection, cooling
To -78 DEG C, the dichloromethane solution (1g/3ml) of Boron tribromide (10eq) is added.It finishes, insulation reaction 1h, is warming up to 25 DEG C of bodies
System reaction 4-6h is washed with 10ml after reaction, anhydrous sodium sulfate drying, and to doing, excessively quick column obtains concentration organic phase
6.97g compound b, yield：80.5%.
(2) compound b (5g, 1.0eq) and pyridine (50ml) are added in there-necked flask, under nitrogen protection, control temperature is small
Acetic anhydride (2.5eq) is added in 20 DEG C.It finishes, insulation reaction 1h, being warming up to 25 DEG C of system reaction 4-6h after reaction will
Reaction solution is poured into ice water, and 3N hydrochloric acid tune PH 6-7 are extracted with DCM, anhydrous sodium sulfate drying, and concentration organic phase is too fast to dry
Fast column obtains 6.14g compound c, yield：83.4%.
(3) compound c (6g, 1.0eq) and phosphorus oxychloride (50ml) are added in there-necked flask, under nitrogen protection, N are added,
Accelerine (2.5eq).It finishes, is warming up to back flow reaction 4-6h, reaction terminates, will after evaporating excessive phosphorus oxychloride
Reaction solution is poured into ice water, is extracted with DCM, anhydrous sodium sulfate drying, and for concentration organic phase to doing, excessively quick column obtains 4.19gization
Close object d, yield：65.3%.
(4) compound d (4g, 1.0eq), triethylamine (1.2eq) and dichloromethane (50ml) are added in there-necked flask, ice bath
It is cooled to 0 DEG C, the dichloromethane solution (1g/2mL) of compound e (1eq) is added.It finishes, is warming up to 25 DEG C of reaction 4-6h, reaction
Terminate, washed with 10ml, anhydrous sodium sulfate drying, for concentration organic phase to doing, excessively quick column obtains 4.50g compound f, receives
Rate：81%.
(5) compound f (4g, 1.0eq), lithium hydroxide (2.0eq), ethyl alcohol (20ml) and water (30ml) are added to there-necked flask
In, ice bath is cooled to 0 DEG C, and Boc is added2O(1.2eq).It finishes, is warming up to 25 DEG C of reaction 4-6h, reaction terminates, then adds hydrogen-oxygen
Change sodium (3eq), be warming up to 50 DEG C of reaction 5-6h, reaction finishes, reaction solution is poured into ice water, and 2N hydrochloric acid water tune PH 6-7 are used
DCM is extracted, anhydrous sodium sulfate drying, and for concentration organic phase to doing, excessively quick column obtains 3.75g compound g, yield：90%.
(6) by compound g (3g, 1.0eq), p-methyl benzenesulfonic acid (0.01eq), 4- piperidones (1.2eq) and toluene (50ml)
It is added in there-necked flask, is warming up to reflux water-dividing.Reaction terminates, and 50 DEG C of decompressions remove solvent, and excessively quick column obtains 3.21g chemical combination
Object h, yield：89%.
(7) compound h (3g, 1.0eq), triethylamine (1.2eq) and dichloromethane (50ml) are added in there-necked flask, ice bath
It is cooled to 0 DEG C, the dichloromethane solution (1g/2mL) of chlorobenzoyl chloride (1eq) is added.It finishes, is warming up to 25 DEG C of reaction 4-6h, instead
It should terminate, be washed with 10ml, anhydrous sodium sulfate drying, concentration organic phase is to doing, after adding ethyl acetate (20ml) dissolving completely,
0 DEG C is cooled to hereinafter, being passed through dry hydrogen chloride gas to after being saturated, insulated and stirred 1-2h there are a large amount of solids to be precipitated, filters out
Solid adds in 50ml water, saturated sodium carbonate tune PH8-9, DCM extractions, after anhydrous sodium sulfate drying, concentration organic phase to dry,
Quick column is crossed, target compound 3.13g, yield are obtained：75%.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m, 4H, CH2),3.29-3.39(m, 4H,
CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41
(s,1H,CH),7.63(s,2H,CH),7.70(s,1H,CH).8.03(s,2H,CH),8.49(s,1H,CH)。
Molecular formula：C26H20ClFN4O3, relative molecular mass：490.91.
The synthesis of embodiment 2, compound 2
Chlorobenzoyl chloride in 1 step of embodiment (7) is replaced with into 2- fluorobenzoyl chlorides, using system same as Example 1
Preparation Method, you can compound 2 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m, 4H,
CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s, 1H,
CH)7.29(s,1H,CH),7.40(s,1H,CH).7.41(s,1H,CH)7.42(s,1H,CH),8.00(s,1H, CH),8.01
(s,1H,CH)8.49(s,1H,CH).Molecular formula：C26H19ClF2N4O3, relative molecular mass：508.9.
The synthesis of embodiment 3, compound 3
Chlorobenzoyl chloride in 1 step of embodiment (7) is replaced to fluorobenzoyl chloride, using preparation same as Example 1
Method, you can compound 3 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m, 4H, CH2),
3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s, 1H,CH),
7.29(s,1H,CH),7.41(s,1H,CH),7.42(s,2H,CH),.8.12(s,2H,CH),8.49(s,1H, CH).Molecule
Formula：C26H19ClF2N4O3, relative molecular mass：508.9.
The synthesis of embodiment 4, compound 4
Chlorobenzoyl chloride in 1 step of embodiment (7) is replaced with into 4- methyl benzoyl chlorides, using same as Example 1
Preparation method, you can compound 4 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.34 (m, 3H, CH3)
2.13-2.38 (m, 4H, CH2), 3.29-3.39 (m, 4H, CH2), 4.0 (s, 1H, NH) 6.79 (s, 1H, CH), 7.16 (s, 1H,
CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.41(s,2H,CH),.7.91(s, 2H,CH),
8.49(s,1H,CH).Molecular formula：C27H22ClFN4O3, relative molecular mass：504.94.
The synthesis of embodiment 5, compound 5
Chlorobenzoyl chloride in 1 step of embodiment (7) is replaced with into anisoyl chloride, use is same as Example 1
Preparation method, you can compound 5 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m,
4H, CH2), 3.29-3.39 (m, 4H, CH2), 3.83 (m, 3H, CH3) 4.0 (s, 1H, NH) 6.79 (s, 1H, CH), 7.16 (s,
1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.17(s,2H,CH),.7.92(s, 2H,
CH),8.49(s,1H,CH).Molecular formula：C27H22ClFN4O4, relative molecular mass：520.94.
The synthesis of embodiment 6, compound 6
Chlorobenzoyl chloride in 1 step of embodiment (7) is replaced with into 4- (2- methoxy ethoxies) chlorobenzoyl chloride, using with reality
Apply 1 identical preparation method of example, you can compound 6 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=
2.13-2.38 (m, 4H, CH2), 3.29-3.39 (m, 4H, CH2), 3.30 (m, 3H, CH3) 3.79 (d, J=7.1,2H, CH2),
4.0 (s, 1H, NH) 4.31 (d, J=7.1,2H, CH2) 6.79 (s, 1H, CH), 7.16 (s, 1H, CH) 7.24 (s, 1H, CH),
7.29(s,1H,CH),7.41(s,1H,CH),7.17(s,2H,CH),.7.92(s,2H, CH),8.49(s,1H,CH).Molecule
Formula：C29H26ClFN4O5, relative molecular mass：564.99.
The synthesis of embodiment 7, compound 7
Chlorobenzoyl chloride in 1 step of embodiment (7) is replaced with into 4- ((4- methyl piperazine -1- alkyl) methyl) benzoyl
Chlorine, using preparation method same as Example 1, you can compound 7 is prepared,1H NMR(300MHz,CDCl3,25℃,
TMS):δ=2.13-2.38 (m, 4H, CH2), 2.26 (m, 3H, CH3) 2.35 (m, 4H, CH2) 2.48 (m, 4H, CH2) 3.29-
3.39(m,4H,CH2),)4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s, 1H,CH),7.29(s,
1H,CH),7.41(s,1H,CH),7.41(s,2H,CH),.7.91(s,2H,CH),8.49(s,1H, CH).Molecular formula：
C32H32ClFN6O3, relative molecular mass：603.09.
The synthesis of embodiment 8, compound 8
Synthetic route：
Step (1)-(6) are identical with embodiment 1；
Step (7) is as follows：Compound h (3g, 1.0eq) and dichloromethane (40ml) are added in there-necked flask, nitrogen protection
Under, ice bath is cooled to 0 DEG C, and the dichloromethane solution (1g/2mL) of phenyl isocyanate (1.0eq) is added.It finishes, insulation reaction
After 30min, 25 DEG C of reaction 2-3h are warming up to, reaction terminates, and concentration organic phase adds ethyl acetate (20ml) dissolving complete to doing
Afterwards, 0 DEG C is cooled to hereinafter, being passed through dry hydrogen chloride gas to after being saturated, insulated and stirred 1-2h there are a large amount of solids to be precipitated, mistake
Solid is filtered out, is added in 50ml water, saturated sodium carbonate tune PH8-9, DCM extraction, after anhydrous sodium sulfate drying, concentration organic phase is extremely
Dry, excessively quick column obtains target compound 2.05g, yield：66%.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m, 4H, CH2), 3.29-3.39 (m, 4H,
CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.19(s, 1H,CH)7.24(s,
1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.43(s,2H,CH),.7.61(s,2H, CH),8.49(s,1H,
CH).Molecular formula：C26H21ClFN5O3, relative molecular mass:505.93.
The synthesis of embodiment 9, compound 9
Phenyl isocyanate in 8 step of embodiment (7) is replaced with into 2- fluorine phenyl isocyanates, use is same as Example 8
Preparation method, you can compound 9 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m,
4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.01(s, 1H,
CH)7.16(s,1H,CH)7.20(s,1H,CH)7.22(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41
(s,1H,CH),7.96(s,1H,CH),8.49(s,1H,CH)。
Molecular formula：C26H20ClF2N5O3, relative molecular mass：523.92.
The synthesis of embodiment 10, compound 10
Phenyl isocyanate in 8 step of embodiment (7) is replaced with into 4- fluorine phenyl isocyanates, use is same as Example 8
Preparation method, you can compound 10 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38 (m,
4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s, 1H,CH),7.16(s,1H,
CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.22(s, 2H,CH),.7.60(s,2H,CH),
8.49(s,1H,CH)。
Molecular formula：C26H20ClF2N5O3, relative molecular mass:523.92.
The synthesis of embodiment 11, compound 11
Phenyl isocyanate in 8 step of embodiment (7) is replaced with into 4- methyl isocyanide acid phenenyl esters, using with 8 phase of embodiment
Same preparation method, you can compound 11 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38
(m, 4H, CH2), 2.34 (s, 3H CH3) 3.29-3.39 (m, 4H, CH2), 4.0 (s, 1H, NH) 6.0 (s, 1H, NH) 6.79 (s,
1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH), 7.21(s,2H,
CH),.7.56(s,2H,CH),8.49(s,1H,CH)。
Molecular formula：C27H23ClFN5O3, relative molecular mass:519.95.
The synthesis of embodiment 12, compound 12
By in 8 step of embodiment (7) phenyl isocyanate replace 4- methoxyl group phenyl isocyanates, using with 8 phase of embodiment
Same preparation method, you can compound 12 is prepared,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.13-2.38
(m, 4H, CH2), 3.29-3.39 (m, 4H, CH2), 3.38 (s, 3H CH3), 4.0 (s, 1H, NH) 6.0 (s, 1H, NH) 6.79
(s,1H,CH),6.97(s,2H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,
CH),7.51(s,2H,CH),8.49(s,1H,CH)。
Molecular formula：C27H23ClFN5O4, relative molecular mass:535.95.
The synthesis of embodiment 13, compound 13
Phenyl isocyanate in 8 step of embodiment (7) is replaced with into 4- (2- methoxy ethoxies) phenyl isocyanate, is used
Preparation method same as Example 8, you can compound 13 is prepared,1H NMR(300MHz,CDCl3,25℃, TMS):δ
=2.13-2.38 (m, 4H, CH2), 2.26 (m, 3H, CH3) 2.35 (m, 4H, CH2) 2.48 (m, 4H, CH2) 3.29-3.39 (m,
4H,CH2),)4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),6.97(s, 2H,CH),7.16(s,1H,CH)
7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),.7.51(s,2H, CH),8.49(s,1H,CH).Molecule
Formula：C29H27ClFN5O5, relative molecular mass:580.01.
The synthesis of embodiment 14, compound 13
Phenyl isocyanate in 8 step of embodiment (7) is replaced with into 4- ((4- methyl piperazine -1- alkyl) methyl) isocyanic acid
Phenyl ester, using preparation method same as Example 8, you can compound 14 is prepared,1H NMR(300MHz,CDCl3, 25
℃,TMS):δ=2.13-2.38 (m, 4H, CH2), 2.26 (m, 3H, CH3) 2.35 (m, 4H, CH2) 2.48 (m, 4H, CH2)
3.29-3.39(m,4H,CH2),)4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.16(s, 1H,CH)7.24
(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH),7.21(s,2H,CH),.7.56(s,2H, CH),8.49(s,
1H,CH),.Molecular formula：C32H33ClFN7O3, relative molecular mass:618.10.
The synthesis of embodiment 15, compound 15
Synthetic route：
Preparation method：
(1) potassium tert-butoxide (1.0eq), Trimethylsulfoxonium Iodide (1.1eq) and DMSO (50ml) are added in there-necked flask, room
After (25 DEG C) are stirred to react 30min under temperature, compound i (10g, 1.0eq) is added.It finishes, overnight, reaction terminates for room temperature reaction
Afterwards, 200ml water and 200ml ethyl acetate is added, after being sufficiently stirred, separates organic phase, water phase uses 200ml ethyl acetate to extract again
It takes, merges organic phase, saturated common salt washing, anhydrous sodium sulfate drying, for concentration organic phase to doing, excessively quick column obtains 8.03gization
Close object j, yield：75%.
(2) compound j (8g, 1.0eq), compound k (1.5eq), lithium perchlorate (1.7eq) and acetonitrile (50ml) are added
It into there-necked flask, is heated to 80 DEG C and is stirred to react 12-18h, after reaction, be cooled to room temperature, it is dilute that 200ml ethyl acetate is added
It releases, saturated common salt washing, anhydrous sodium sulfate drying, for concentration organic phase to doing, excessively quick column obtains 9.06g compound l, receives
Rate：63%.
(3) compound l (8g, 1.0eq), cesium carbonate (1.5eq) and acetonitrile (50ml) are added in there-necked flask, are heated to 60
DEG C it is stirred to react 6-8h, after reaction, is cooled to room temperature, the dilution of 200ml ethyl acetate is added, saturated common salt washing is anhydrous
Sodium sulphate is dried, and for concentration organic phase to doing, excessively quick column obtains 6.37g compound m, yield：84%.
(4) morpholine (2.2eq) and anhydrous tetrahydro furan (10ml) are added in there-necked flask, under nitrogen protection, are cooled to -5
DEG C, DIBALH (2.0eq) is added, drop finishes, and insulation reaction 3h then will be by the tetrahydrofuran solution of compound m (6g, 1.0eq)
(1g/3ml) is added in reaction system, in adition process, is controlled interior temperature and is less than 0 DEG C, after adding, insulation reaction 30min is added
DIBALH (1.1eq), insulation reaction 1h, 1N hydrochloric acid, saturated common salt washing, water phase are stripped with ethyl acetate, are merged organic
Phase, anhydrous sodium sulfate drying, for concentration organic phase to doing, excessively quick column obtains 4.79g compound n, yield：87%.
(5) compound n (4g, 1.0eq), compound o and ethyl alcohol (50ml) are added in there-necked flask, then 10mg piperazines is added dropwise
Pyridine is warming up to reflux 4-6h, and reaction terminates, washed with 10ml, and anhydrous sodium sulfate drying, concentration organic phase adds acetic acid second to doing
After ester (20ml) dissolving completely, 0 DEG C is cooled to hereinafter, being passed through dry hydrogen chloride gas to after being saturated, insulated and stirred 1-2h has
A large amount of solids are precipitated, and filter out solid, add in 50ml water, saturated sodium carbonate tune PH8-9, DCM extraction, and anhydrous sodium sulfate is dry
After dry, for concentration organic phase to doing, excessively quick column obtains 3.65g compound p, yield：83%.
(6) compound p (3g, 1.0eq) and THF (50ml) are added in there-necked flask, under nitrogen protection, are cooled to 0 DEG C,
Sodium hydride (1.5eq) is added, finishes, insulated and stirred 30min, adds benzyl chloride (1.1eq), after insulation reaction 1h, is warming up to room
Temperature reaction 4-6h adds water quenching to go out after reaction, and water phase is stripped with ethyl acetate, merges organic phase, and anhydrous sodium sulfate is dried,
Organic phase is concentrated to doing, excessively quick column obtains 2.39g target compounds, yield：64%
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.51 (m, 4H), 3.66 (s, 2H),
4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
Molecular formula：C28H25FN2O3, relative molecular mass：456.51.
The synthesis of embodiment 16, compound 16
Benzyl chloride in 15 step of embodiment (6) is replaced with into 2- fluorine benzyl chlorides, using preparation method identical with embodiment 15,
Compound 16 can be prepared.Molecular formula：C28H24F2N2O3, relative molecular mass：474.50.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.51 (m, 4H), 3.66 (s, 2H),
4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
The synthesis of embodiment 17, compound 17
Benzyl chloride in 15 step of embodiment (6) is replaced with into 4- fluorine benzyl chlorides, using preparation method identical with embodiment 15,
Compound 17 can be prepared.Molecular formula：C28H24F2N2O3, relative molecular mass：474.50.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.51 (m, 4H), 3.66 (s, 2H),
4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
The synthesis of embodiment 18, compound 18
Benzyl chloride in 15 step of embodiment (6) is replaced with into 4- methyl benzyl chlorides, using preparation side identical with embodiment 15
Method, you can compound 18 is prepared.Molecular formula：C29H27FN2O3, relative molecular mass：470.53.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.34 (s, 3H), 2.51 (m, 4H),
3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,
NH)。
The synthesis of embodiment 19, compound 19
Benzyl chloride in 15 step of embodiment (6) is replaced with into 4- methoxyl group benzyl chlorides, using preparation identical with embodiment 15
Method, you can compound 19 is prepared.Molecular formula：C29H27FN2O4, relative molecular mass：486.53.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.51 (m, 4H), 3.66 (s, 2H),
3.83(s,3H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,
NH)。
The synthesis of embodiment 20, compound 20
Benzyl chloride in 15 step of embodiment (6) is replaced with into 4- (2- methoxy ethoxies) benzyl chloride, using with embodiment 15
Identical preparation method, you can compound 20 is prepared.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.51 (m, 4H), 3.30 (s, 3H),
3.66 (s, 2H), 3.79 (t, J=7.1Hz, 2H), 4.28 (s.2H), 4.31 (t, J=7.1Hz, 2H), 7.05 (m, 6H), 7.33
(m,4H),7.56(s,1 H),7.79(m,1H),8.0(s,1H,NH).Molecular formula：C31H31FN2O5, relative molecular mass：
530.59。
The synthesis of embodiment 21, compound 21
Benzyl chloride in 15 step of embodiment (6) is replaced with into 4- ((4- methyl piperazine -1- alkyl) methyl) benzyl chloride, using with
15 identical preparation method of embodiment, you can compound 21 is prepared.
1H NMR(300MHz,CDCl3,25℃,TMS):δ=1.97 (m, 4H), 2.26 (s, 3H), 2.35-2.48 (m,
8H), 3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,
1H,NH)。
Molecular formula：C34H37FN4O3, relative molecular mass：568.68.
The synthesis of embodiment 22, compound 22
Synthetic route：
Preparation method：
(1) compound d (10g, 1.0eq) and 6N hydrochloric acid (50ml) are added in there-necked flask, are warming up to 50 DEG C of reaction 4-
6h, reaction terminate, and are down to room temperature, are extracted with DCM, anhydrous sodium sulfate drying, and to doing, excessively quick column obtains concentration organic phase
5.95g compound q, yield：85%.
(2) by compound q (5g, 1.0eq), p-methyl benzenesulfonic acid (0.01eq), 4- piperidones (1.2eq) and toluene (50ml)
It is added in there-necked flask, is warming up to reflux water-dividing.Reaction terminates, and 50 DEG C of decompressions remove solvent, and excessively quick column obtains 6.14g chemical combination
Object r, yield：87%.
(3) compound r (5g, 1.0eq) and THF (50ml) are added in there-necked flask, under nitrogen protection, are cooled to 0 DEG C,
Sodium hydride (1.5eq) is added, finishes, insulated and stirred 30min, adds 2- fluorobenzoyl chlorides (1.1eq), after insulation reaction 1h,
Be warming up to room temperature reaction 4-6h adds water quenching to go out after reaction, and water phase is stripped with ethyl acetate, merges organic phase, anhydrous slufuric acid
Sodium is dried, and for concentration organic phase to doing, excessively quick column obtains 5.18g compound raw20, yield：72%
(4) by compound raw20 (2g, 1.0eq), compound raw21 (1.5eq), DIPEA (1.0eq) and isopropanol
(50ml) is added in there-necked flask, is heated to 90 DEG C of reaction 4-6h and is directly thickened to do after reaction, excessively quick column obtains
To 1.45g target compounds, yield：55%.1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38 (m, 4H), 2.82
(s,3H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41 (m,3H),
7.50 (d, J=7.5Hz, 1H), 8.00 (m, 2H), 8.49 (s, 1H).
Molecular formula：C28H22FN5O3S, relative molecular mass：527.57.
The synthesis of embodiment 23, compound 23
Raw21 in embodiment 22 is replaced with into raw22, using preparation method identical with embodiment 22, you can prepare
Compound 23 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=0.90 (t, J=8.0Hz, 3H), 1.65 (m, 2H),
2.38(m,4H),2.86(m,2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,
1H), 7.41 (m, 3H), 7.50 (d, J=7.5Hz, 1H), 8.00 (m, 2H), 8.49 (s, 1H).
Molecular formula：C30H26FN5O3S, relative molecular mass：555.62.
The synthesis of embodiment 24, compound 24
Raw21 in embodiment 22 is replaced with into raw23, using preparation method identical with embodiment 22, you can prepare
Compound 24 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38 (m, 4H), 2.86 (m, 2H), 3.39 (m,
4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00
(m,4H),8.49(s,1H).Molecular formula：C33H24FN5O3S, relative molecular mass：589.64.
The synthesis of embodiment 25, compound 25
Raw21 in embodiment 22 is replaced with into raw24, using preparation method identical with embodiment 22, you can prepare
Compound 25 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.34 (s, 3H), 2.38 (m, 4H), 2.86 (m,
2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50
(m,3H),8.00(m,4H),8.49(s,1H).Molecular formula：C34H26FN5O3S, relative molecular mass：603.67.
The synthesis of embodiment 26, compound 26
Raw21 in embodiment 22 is replaced with into raw25, using preparation method identical with embodiment 22, you can prepare
Compound 26 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38 (m, 4H), 2.86 (m, 2H), 3.39 (m,
4H),4.0(s,1H,NH),5.35(s,1H,OH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),
7.50(m,3H),8.00(m,4H),8.49(s,1H).Molecular formula：C33H24FN5O4S, relative molecular mass：605.64.
The synthesis of embodiment 27, compound 27
Raw21 in embodiment 22 is replaced with into raw26, using preparation method identical with embodiment 22, you can prepare
Compound 27 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38 (m, 4H), 2.86 (m, 2H), 3.39 (m,
4H),3.83(s.3H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50
(m,3H),8.00(m,4H),8.49(s,1H).Molecular formula：C34H26FN5O4S, relative molecular mass：619.66.
The synthesis of embodiment 28, compound 28
Raw21 in embodiment 22 is replaced with into raw27, using preparation method identical with embodiment 22, you can prepare
Compound 28 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.34 (s, 3H), 2.38 (m, 4H), 2.86 (m,
2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50
(m,3H),8.00(m,4H),8.49(s,1H).Molecular formula：C34H26FN5O3S, relative molecular mass：603.67.
The synthesis of embodiment 29, compound 29
Raw21 in embodiment 22 is replaced with into raw28, using preparation method identical with embodiment 22, you can prepare
Compound 29 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.26 (t, 2H, J=7.1Hz, CH2), 2.26 (t,
2H, J=7.1, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 4.1 (s, 1H, NH),
5.35 (s, 1H, OH), 6.73 (d, 1H, J=7.5Hz, CH), 6.91 (d, 1H, J=7.5Hz, CH), 7.02 (s, 1H, J=
1.5Hz, CH), 7.24 (s, 1H, CH), 7.32 (s, 1H, CH), 7.34 (dd, 1H, J=7.5,7.5Hz, CH), 7.40 (dd,
1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (dd, 1H, J=7.5,8.0Hz, CH), 7.50 (d, 1H, J=
7.5Hz, CH), 7.59 (d, 1H, J=7.5Hz, CH), 8.00 (dd, 1H, J=7.5Hz, CH), 8.01 (d, 1H, J=5.0,
7.5Hz,CH),8.49(s,1H,CH).Molecular formula：C33H24FN5O4S, relative molecular mass：605.64.
The synthesis of embodiment 30, compound 30
Raw21 in embodiment 22 is replaced with into raw29, using preparation method identical with embodiment 22, you can prepare
Compound 30 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.40 (t, 2H, J=7.1Hz, CH2), 2.40 (t,
2H, J=7.1Hz, CH2), 3.37 (t, 2H, J=7.1Hz, CH2), 3.37 (t, 2H, J=7.1Hz, CH2), 4.1 (s, 1H,
), NH 6.70 (d, 1H, J=7.5Hz, CH), 7.02 (s, 1H, CH), 7.24 (s, 1H, CH), 7.39 (dd, 1H, CH), 7.41
(s, 1H, CH), 7.44 (d, 1H, J=7.5,8.0Hz, CH), 7.45 (d, 1H, J=7.5Hz, CH), 7.46 (dd, 1H, J=
7.5,7.5Hz, CH), 7.50 (d, 1H, J=7.5Hz, CH), 7.89 (d, 1H, J=7.5Hz, CH), 8.00 (dd, 1H, J=
7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.01 (s, 1H, CH), 8.51 (s, 1H, CH).
Molecular formula：C33H23ClFN5O3S, relative molecular mass：624.08.
The synthesis of embodiment 31, compound 31
Raw21 in embodiment 22 is replaced with into raw30, using preparation method identical with embodiment 22, you can prepare
Compound 31 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.44 (t, 2H, J=7.1Hz, CH2), 2.44 (t,
2H, J=7.1Hz, CH2), 3.34 (t, 2H, J=7.1Hz, CH2), 3.34 (t, 2H, J=7.1Hz, CH2), 4.0 (s, 1H,
), NH 6.73 (d, 1H, J=7.5Hz, CH), 7.02 (2,1H, CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,
7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.50 (d, 1H, J=7.5Hz, CH),
7.77 (dd, 1H, J=7.5,7.5Hz, CH), 8.00 (dd, 1H, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.22
(d, 1H, J=5.0,7.5,7.5Hz, CH), 8.42 (d, 1H, J=7.5Hz, CH), 8.49 (s, 1H, CH), 8.65 (s, 1H,
CH).Molecular formula：C33H23FN6O5S, relative molecular mass：634.64.
The synthesis of embodiment 32, compound 32
Raw21 in embodiment 22 is replaced with into raw31, using preparation method identical with embodiment 22, you can prepare
Compound 32 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.33 (t, 2H, J=7.1Hz, CH2), 2.33 (t,
2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 3.9 (s, 1H,
), NH 6.73 (s, 1H, J=7.5Hz, CH), 7.02 (s, 1H, CH), 7.24 (s, 1H, CH), 7.24 (d, 1H, J=7.5,
8.0Hz, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0 Hz,
), CH 7.50 (d, 1H, J=7.5Hz, CH), 7.65 (d, 1H, J=5.0,7.5Hz, CH), 7.99 (s, 1H, CH), 8.00 (dd,
1H, J=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.51 (s, 1H, CH).
Molecular formula：C33H22ClF2N5O3S, relative molecular mass：642.07.
The synthesis of embodiment 33, compound 33
Raw21 in embodiment 22 is replaced with into raw32, using preparation method identical with embodiment 22, you can prepare
Compound 33 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.38 (t, 2H, J=7.1Hz, CH2), 2.38 (t,
2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 4.1 (s, 1H,
), NH 6.73 (d, 1H, J=7.5Hz, CH), 7.04 (s, 1H, CH), 7.24 (s, 1H, CH), 7.30 (d, 1H, J=7.5,
8.0Hz, CH), 7.30 (d, 1H, J=7.5,8.0Hz, CH), 7.41 (d, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H,
), CH 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.50 (d, 1H, J=7.5Hz, CH), 7.77 (d, 1H, J=5.0,7.5
Hz, CH), 7.77 (d, 1H, J=5.0,7.5Hz, CH), 8.01 (dd, 1H, J=5.0,7.5,7.5Hz, CH), 8.03 (d, 1H,
J=5.0,7.5Hz, CH), 8.49 (s, 1H, CH).Molecular formula：C33H23F2N5O3S, relative molecular mass：607.63.
The synthesis of embodiment 34, compound 34
Raw21 in embodiment 22 is replaced with into raw33, using preparation method identical with embodiment 22, you can prepare
Compound 34 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.24 (s, 3H, CH3), 2.37 (t, 2H, CH2),
2.38 (t, 2H, CH2), 3.09 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=
7.1Hz, CH2), 4.0 (s, 1H, NH), 4.27 (t, 2H, J=7.1Hz, CH2), 6.28 (d, 1H, J=10.9Hz, CH), 6.68
(d, 1H, J=7.5Hz, CH), 6.70 (s, 1H, CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,7.5 Hz, CH),
7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.43 (d, 1H, J=7.5Hz, CH), 8.00 (dd, 1H, J
=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.49 (s, 1H, CH), 8.82 (d, 1H, J=
10.9Hz,CH),16.55(OH).Molecular formula：C34H29ClFN5O6, relative molecular mass：658.08.
The synthesis of embodiment 35, compound 35
Raw21 in embodiment 22 is replaced with into raw34, using preparation method identical with embodiment 22, you can prepare
Compound 35 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.36 (s, 3H, CH3), 2.38 (t, 2H, J=
7.1Hz, CH2), 2.38 (t, 2H, J=7.1Hz, CH2), 3.09 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=
7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 4.0 (s, 1H, NH), 4.27 (t, 2H, J=7.1Hz, CH2), 6.28
(d, 1H, J=10.0Hz, CH), 6.46 (s, 1H, J=8.0Hz, CH), 6.72 (d, 1H, J=5.0,7.5Hz, CH), 7.24
(s, 1H, CH), 7.32 (d, 1H, J=7.5Hz, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, CH),
7.42 (d, 1H, J=7.5,8.0Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,
7.5Hz, CH), 8.49 (s, 1H, CH), 8.82 (d, 1H, J=10.0Hz, CH), 16.77 (OH).
Molecular formula：C34H29F2N5O6, relative molecular mass：641.62.
The synthesis of embodiment 36, compound 36
Raw21 in embodiment 22 is replaced with into raw35, using preparation method identical with embodiment 22, you can prepare
Compound 36 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.30 (s, 3H, CH3), 2.38 (t, 2H, J=
7.1Hz, CH2), 2.38 (t, 2H, J=7.1Hz, CH2), 3.09 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=
7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 4.1 (s, 1H, NH), 4.27 (t, 2H, J=7.1Hz, CH2), 6.28
(d, 1H, J=10.3Hz, CH), 7.00 (d, 1H, J=7.5Hz, CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,
7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.45 (s, 1H, CH), 7.94 (d, 1H, J
=7.6Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.49
(s, 1H, CH), 8.82 (d, 1H, J=10.3Hz, CH), 16.77 (OH).
Molecular formula：C34H29FN6O8, relative molecular mass：668.63.
The synthesis of embodiment 37, compound 37
Raw21 in embodiment 22 is replaced with into raw36, using preparation method identical with embodiment 22, you can prepare
Compound 37 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.27 (s, 3H, CH3), 2.38 (t, 2H, J=
7.1Hz, CH2), 2.38 (t, 2H, J=7.1Hz, CH2), 3.09 (t, 2H, J=7.1Hz, CH2), 3.40 (t, 2H, J=
7.1Hz, CH2), 3.40 (t, 2H, J=7.1Hz, CH2), 4.1 (s, 1H, NH), 4.27 (t, 2H, J=7.1Hz, CH2), 6.12
(s, 1H, CH), 6.28 (d, 1H, J=10.6Hz, CH), 7.13 (d, 1H, J=7.5Hz, CH), 7.22 (d, 1H, J=7.5 Hz,
), CH 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (d, 1H, J=
7.5,8.0Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH),
8.49 (s, 1H, CH), 8.82 (d, 1H, J=10.6Hz, CH), 16.60 (OH).
Molecular formula：C34H29ClFN5O6, relative molecular mass：658.08.
The synthesis of embodiment 38, compound 38
Raw21 in embodiment 22 is replaced with into raw37, using preparation method identical with embodiment 22, you can prepare
Compound 38 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.27 (s, 3H, CH3), 2.39 (t, 2H, J=
7.1Hz, CH2), 2.39 (t, 2H, J=7.1Hz, CH2), 3.09 (t, 2H, J=7.1Hz, CH2), 3.36 (t, 2H, J=
7.1Hz, CH2), 3.36 (t, 2H, J=7.1Hz, CH2), 4.0 (s, 1H, NH), 4.29 (t, 2H, J=7.1Hz, CH2), 6.28
(d, 1H, J=10.9Hz, CH), 6.44 (CH), 6.45 (CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,7.5Hz,
), CH 7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.72 (CH), 8.00 (dd, 1H, J=5.0,7.5,
7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.49 (s, 1H, CH), 8.82 (d, 1H, J=10.9 Hz, CH),
16.77(OH).Molecular formula：C34H29F2N5O6, relative molecular mass：641.62.
The synthesis of embodiment 39, compound 39
Raw21 in embodiment 22 is replaced with into raw38, using preparation method identical with embodiment 22, you can prepare
Compound 39 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.27 (s, 3H, CH3), 2.40 (t, 2H, J=
7.1Hz, CH2), 2.40 (t, 2H, J=7.1Hz, CH2), 3.09 (t, 2H, J=7.1Hz, CH), 3.41 (t, 2H, J=7.1
Hz, CH2), 3.41 (t, 2H, J=7.1Hz, CH2), 4.2 (s, 1H, NH), 4.27 (t, 2H, J=7.1Hz, CH2), 6.16 (J
=5.0Hz, CH), 6.28 (d, 1H, J=10.5Hz, CH), 6.88 (dd, 1H, J=7.5,8.0Hz, CH), 6.97 (J=5.0,
7.5Hz, CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, J=7.5,8.0Hz,
), CH 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.72 (d, 1H, J=7.5Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,
7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.49 (s, 1H, CH), 8.82 (d, 1H, J=10.5Hz, CH),
16.77(OH).Molecular formula：C34H29FN6O8, relative molecular mass：668.63.
The synthesis of embodiment 40, compound 40
Raw21 in embodiment 22 is replaced with into raw39, using preparation method identical with embodiment 22, you can prepare
Compound 40 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.26 (s, 3H, CH3), 2.40 (t, 2H, J=
7.1Hz, CH2), 2.40 (t, 2H, J=7.1Hz, CH2), 3.09 (t, 2H, J=7.1Hz, CH2), 3.39 (t, 2H, J=
7.1Hz, CH2), 3.39 (t, 2H, J=7.1Hz, CH2), 4.0 (s, 1H, NH), 4.28 (t, 2H, J=7.1Hz, CH2), 6.18
(s, 1H, CH), 6.28 (d, 1H, J=10.3Hz, CH), 6.36 (d, 1H, J=7.5Hz, CH), 7.09 (dd, 1H, J=7.5,
7.5Hz, CH), 7.19 (d, 1H, J=7.5Hz, CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH),
7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,7.5Hz, CH),
8.01 (d, 1H, J=5.0,7.5Hz, CH), 8.49 (s, 1H, CH), 8.83 (d, 1H, J=10.3Hz, CH), 16.77 (OH).Point
Minor：C34H30FN5O6, relative molecular mass：623.63.
The synthesis of embodiment 41, compound 41
Raw21 in embodiment 22 is replaced with into raw40, using preparation method identical with embodiment 22, you can prepare
Compound 41 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.17 (s, 3H, CH3), 2.28 (s, 3H, CH3),
2.39 (t, 2H, J=7.1Hz, CH2), 2.39 (t, 2H, J=7.1Hz, CH2), 3.10 (t, 2H, J=7.1Hz, CH2), 3.40
(t, 2H, J=7.1Hz, CH2), 3.40 (t, 2H, J=7.1Hz, CH2), 4.1 (s, 1H, NH), 4.25 (t, 2H, J=7.1Hz,
), CH2 6.06 (s, 1H, J=1.5Hz, CH), 6.28 (d, 1H, J=10.8Hz, CH), 6.87 (d, 1H, J=7.5Hz, CH),
6.89 (d, 1H, J=7.5Hz, CH), 7.24 (s, 1H, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH), 7.41 (CH),
7.42 (d, 1H, J=7.5,8.0Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,
7.5Hz, CH), 8.49 (s, 1H, CH), 8.82 (d, 1H, J=10.8Hz, CH), 16.77 (OH).Molecular formula： C35H32FN5O6,
Relative molecular mass：637.66.
The synthesis of embodiment 42, compound 42
Raw21 in embodiment 22 is replaced with into raw41, using preparation method identical with embodiment 22, you can prepare
Compound 42 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.28 (s, 3H, CH3), 2.39 (t, 2H, J=
7.1Hz, CH2), 2.39 (t, 2H, J=7.1Hz, CH2), 3.10 (t, 2H, J=7.1Hz, CH2), 3.40 (t, 2H, J=7.1
Hz, CH2), 3.40 (t, 2H, J=7.1Hz, CH2), 3.9 (s, 1H, NH), 4.28 (t, 2H, J=7.1Hz, CH2), 6.28 (d,
1H, J=10.5Hz, CH), 6.74 (d, J=7.5Hz, CH), 6.74 (d, J=7.5Hz, CH), 7.24 (s, 1H, CH), 7.40
(dd, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (d, 1H, J=7.5,8.0Hz, CH), 7.55 (dd, 1H,
J=7.5Hz, CH), 7.55 (dd, 1H, J=7.5Hz, CH), 8.00 (dd, J=5.0,7.5,7.5Hz, CH), 8.01 (d, J=
5.0,7.5Hz, CH), 8.50 (s, 1H, CH), 8.82 (d, 1H, J=10.4Hz, CH), 16.79 (OH) molecular formula：
C34H30FN5O6, relative molecular mass：623.63.
The synthesis of embodiment 43, compound 43
Raw21 in embodiment 22 is replaced with into raw42, using preparation method identical with embodiment 22, you can prepare
Compound 43 is obtained,1H NMR(300MHz,CDCl3,25℃,TMS):δ=2.16 (s, 3H, CH3), 2.30 (s, 3H, CH3),
2.39 (t, 2H, J=7.1Hz, CH2), 2.39 (t, 2H, J=7.1Hz, CH2), 3.10 (t, 2H, J=7.1Hz, CH2), 3.40
(t, 2H, J=7.3Hz, CH2), 3.40 (t, 2H, J=7.3Hz, CH2), 4.1 (s, 1H, NH), 4.28 (t, 2H, J=7.1Hz,
), CH2 6.30 (d, 1H, J=10.5Hz, CH), 6.45 (s, 1H, CH), 6.63 (d, 1H, J=7.5Hz, CH), 7.24 (d, 1H,
), CH 7.37 (d, 1H, J=7.5Hz, CH), 7.40 (dd, 1H, J=7.5,7.5Hz, CH), 7.41 (s, 1H, CH), 7.42 (d,
1H, J=7.5,8.0Hz, CH), 8.00 (dd, 1H, J=5.0,7.5,7.5Hz, CH), 8.01 (d, 1H, J=5.0,7.5Hz,
), CH 8.49 (s, 1H, CH), 8.82 (d, 1H, J=10.5Hz, CH), 16.77 (OH).Molecular formula： C35H32FN5O6, opposite point
Protonatomic mass：637.66.
Being tested below by way of compound activity proves beneficial effects of the present invention.
Test example 1, the compounds of this invention are to tumour cell HT-29 and A431 inhibiting effect
It is inoculated with HT-29 and A431 cells in 96 orifice plates, 3000 are inoculated with per hole, if 3 multiple holes.Dosing after inoculation 48h
(positive control is Pfizer Sutent SU-11248), compound (is dissolved in 0.1% DMSO to match by 10 μM of compound concentration
System), continue to cultivate 72h after dosing.After being disposed, the MTT20 μ l of 5mg/ml concentration are added per hole, 4h is incubated in 37 DEG C；37
Culture medium is removed after DEG C being incubated 4h, 180 μ lDMSO is added, 37 DEG C at least stand 30min, so that bluish violet first is praised particle fully molten
Solution.Microplate reader 20min is preheated, OD values are read in microplate reader, Detection wavelength 490nm finally calculates growth of tumour cell and inhibits
Rate.As a result as depicted in figs. 1 and 2.Compound 9 is taken, detects it under remaining concentration to the influence of tumor cell survival, as a result
As shown in Figure 3.
The apoptosis experiment of test example 2, cpd9 induction HT-29 cells
HT-29 cells are handled 16 hours through 2.5 μM of cpd9, extract genomic DNA, are fixed through 4% paraformaldehyde thin
Born of the same parents, Hoechst dyeing, the results are shown in Figure 4.We have found that through cpd9, treated that apparent DNA occurs in cell
Ladder prompts to have occurred that apoptosis (Fig. 4 A).Meanwhile micro- sem observation find the cell after drug-treated occur shrinkage,
It is rounded, falls off, be cracked into the nucleus after discovery drug-treated after the reactive dye Hoechst dyeing of DNA specific bindings
Fragment is to generate apoptosis (Fig. 4 B).
3 compound cpd1-cpd43 of test example in vitro tests receptor tyrosine kinase inhibitory activity
Enzyme linked immunological washes kettle and measures (ELISA)
(1) the no potassium ions of enzyme reaction substrate Poly (Glu, Tyr) 4/1 PBS (10mM sodium phosphate buffers, 150
MMNaCl, pH 7.2-7.4) 20 μ g/ml are diluted to, 125 μ L/ sky coated elisa plates react 12-15 hours under 37 degrees Celsius
Afterwards, aerial liquid is discarded, with the T-PBS in 200 holes μ L/ (PBS without potassium ion containing 0.1% Tween-20) board-washing 3 times,
7 minutes every time, then ELISA Plate is about 2 hours dry under 37 degrees Celsius.
(2) per hole be added with reaction buffer (the HEPES pH 7.4 of 50mM, 50mM MgCl2,0.5mM MnCl2,
0.2mM Na3VO4,1mM DTT) diluted 49 μ L of ATP solution, per hole in 1 μ L untested compounds are added, add 50 μ L with anti-
The diluted EGFR kinase domains recombinant protein of buffer solution is answered to start reaction, experiment every time need to set no ATP control wells holes.Place 37
After degree Celsius shaking table (100rpm) reacts 1 hour, liquid in hole is discarded, T-PBS board-washings are three times.
(3) 100 holes μ L/ antibody PY99 (antibody is diluted with the T-PBS 1/500 of the 5mg/ml containing BSA) are added, sets 37 and takes the photograph
Under family name's degree after shaking table reaction half an hour, liquid in hole is discarded, three times with T-PBS board-washings.
(4) 100 holes the μ L/ (T- of antibody 5mg/ml containing BSA of sheep anti mouse secondary antibody of horseradish peroxidase-labeled is added
PBS 1/2000 dilutes), after setting 37 degrees Celsius of shaking table reaction half an hour, liquid in hole is discarded, T-PBS board-washings are three times.
(5) 100 holes μ L/ of OPD developing solutions of 2mg/ml are added (with the 0.1M citric acid-sodium citrates containing 0.03%H2O2
Buffer solution dilutes), it is protected from light 5 minutes under 25 degrees Celsius.
(6) 50 holes μ L/ 2M H2SO4 are added and terminate reaction, are read with the wet microwell plate microplate reader VERSAmax of wavelengthtunable,
Wavelength is 490nm.
Interpretation of result：The inhibiting rate (%) of sample=[1- (compound OD values-are without enzyme control wells OD values)/(negative control hole
OD values-are without enzyme control wells OD values)] * 100%.
1 compound cpd1-cpd43 of table is in vitro to receptor tyrosine kinase inhibitory activity test result
Test example 4, zebra fish experiment
(1) processing of zebrafish embryo
The previous day is screened, tgflil is selected:EGFP (+/+) dress gene zebra fish homozygotes and AB wild-type zebrafish are put in
It mates in box, morning light stimulation oviposition, the embryo collected in half an hour is put in the culture dish for filling embryo medium
In, it is placed in 28.5 degrees Celsius of incubator cultures.When embryonic development is from 10hpf, it is transferred to 24 orifice plates for filling embryo medium
In, it is spare that 10 embryos are put into each hole.Embryonic development from 12hpf when, prepared liquid is sequentially added in 24 orifice plates,
Experiment is in triplicate.
(2) embryonic development is to 48hpf, with OLYMPUS MVX10 body formula fluorescence microscopes.Selecting anti-angiogenesis has
Embryo's index of effect is as follows：1. general form development is normal compared with same time wild type AB zebrafish embryo；2. flil genes
The embryo of luciferase expression remitted its fury, missing or blood vessel fluorescence distribution disorder abnormal expression；
(3) analysis of Agiogenesis inhibition
Each group embryo is taken out, is placed in the culture solution containing anesthetic, using OLYMPUS MVX10 body formula fluorescence microscopies
Mirror is taken pictures, using FV10-ASW 1.7Viewer softwares to zebra fish body intersegmental blood vessel (10 body intersegmental blood vessels after yolk)
Carry out length measurment, engineer's scale 10mm.
(4) the anti-zebra fish embryoid body intersegmental blood vessel the selection results of cpd9
When the liquor strength of cpd9 is 10 μM and 20 μM, the degree of blood vessel is inhibited to gradually increase, but entire embryo's hair
It educates normally, 80% or more occurs different degrees of new vessels inhibiting effect, as shown in Figure 5.
To sum up, the compounds of this invention has excellent antitumor activity and inhibits the ability of new vessels, application prospect excellent
It is good.
Claims (8)
1. formula (I) compound represented or its pharmaceutically acceptable salt or its solvate：
Wherein, R1It is selected from
R2、R3Separately be selected from H, halogen, alkyl,Or R2And R3Coupled carbon atom composition contains
1~2 heteroatomic 1 substitution or polysubstituted hexa-atomic aromatic heterocycle；
R4、R5、R60~3 substitution on phenyl ring, R are indicated respectively4、R5、R6It is respectively and independently selected from H, halogen atom, C1~6Alkyl, C1~6
Alkoxy, hydroxyl, amino, carboxyl, nitro, CH3O(CH2)nCH2O-,The integer that wherein n is 1~6.
2. compound according to claim 1, which is characterized in that the R4、R5、R6It is respectively and independently selected from H, halogen atom,
C1~6Alkyl, C1~6Alkoxy, CH3O(CH2)nCH2O-,The integer that wherein n is 1~6.
3. compound according to claim 2, which is characterized in that the R4、R5、R6It is respectively and independently selected from H, F, methyl, first
Oxygroup, CH3OCH2CH2O-,
4. compound according to claim 3, which is characterized in that the R4、R5、R6Indicate phenyl ring on it is unsubstituted or one
Substitution.
5. compound according to claim 1, which is characterized in that the R1It is selected from
6. compound according to claim 1, it is characterised in that：The hexa-atomic aromatic heterocycle is
Wherein R7It is selected from
7. compound according to claim 1, it is characterised in that：The compound is one of following compounds：
8. the preparation method of compound described in claim 7, it is characterized in that：It includes the following steps：
(1) synthesis of compound 1~14：
(1) synthesis of intermediate h：
The synthesis of (2A) compound 1~7：
The synthesis of (2B) compound 8~14：
(2) synthesis of compound 15-21：
(3) synthesis of compound 22-43：
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