CN109810100A - The bis- target spot inhibitor of PARP-1 and PI3K containing benzofuran - Google Patents

The bis- target spot inhibitor of PARP-1 and PI3K containing benzofuran Download PDF

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CN109810100A
CN109810100A CN201711162890.6A CN201711162890A CN109810100A CN 109810100 A CN109810100 A CN 109810100A CN 201711162890 A CN201711162890 A CN 201711162890A CN 109810100 A CN109810100 A CN 109810100A
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acid
compound
arh
added
parp
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CN109810100B (en
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徐云根
朱启华
王均伟
储昭兴
李慧
葛亦然
何广卫
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HEFEI YIGONG MEDICINE CO Ltd
China Pharmaceutical University
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HEFEI YIGONG MEDICINE CO Ltd
China Pharmaceutical University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The present invention relates to field of medicinal chemistry, and in particular to the bis- target spot inhibitor (I) of one kind PARP-1 containing benzofuran structure and PI3K, their preparation method, and the pharmaceutical composition containing these compounds.Pharmacodynamics test proves that the compound of the present invention has antitumor effect.

Description

The bis- target spot inhibitor of PARP-1 and PI3K containing benzofuran
Technical field
The present invention relates to field of medicinal chemistry, and in particular to one kind bis- targets of the PARP-1 containing benzofuran structure and PI3K Point inhibitor, their preparation method, and the pharmaceutical composition containing these compounds and its purposes in anti-tumor aspect.
Background technique
Poly adenosine diphosphate-ribose polymerase-1 (PARP) is a multifunctional protein being present in most eukaryocytes Posttranslational modification enzyme, the family is it has been found that hypotype totally 18 at present, and wherein PARP-1 proportion is maximum, is related to centering The treatment of the diseases such as wind, neurodegenerative disease, myocardial ischemia, cancer, inflammation and diabetes plays master in DNA damage reparation Lead effect.PARP-1 inhibitor is a kind of anti-tumor drug that cytotoxicity is played by adjusting DNA damage reparation, is 21 generation One of most breathtaking achievement in just oncotherapy research field of recording.It is applied to face there are three PARP inhibitor at present Bed, they be respectively 2014 listing olaparib (Olaparib), 2016 listing Lu Kapani (Rucaparib) and The Ni Lapani (Niraparib) of listing in 2017, is mainly used for the treatment of the tumours such as breast cancer, oophoroma and peritoneal cancer.But With deep and clinical test results the publication successively of research, the limitation of PARP-1 inhibitor is also further presented.One Aspect, when current PARP-1 inhibitor is used alone, just for the triple negative breast cancer or oophoroma lacked there are BRCA1/2 Effective in cure, which results in the indication of PARP-1 inhibitor is relatively narrow；On the other hand, same face is used for a long time in PARP-1 inhibitor The problem of facing drug resistance, these problems will all have an adverse effect to the clinical application of PARP-1 inhibitor.
Phosphatidyl-inositol 3-kinase (phosphatidylinositol-3-kinase, PI3K) is PI3K/Akt/mTOR letter Molecules upstream in number Signal Transduction Pathways, as the key node albumen in the access, PI3K can with phosphorylation phosphatidylinositols 4, 3 hydroxyls of 5- diphosphonic acid (PIP2) generate phosphatidylinositols 3,4,5- triphosphoric acid (PIP3).PIP3 is as second messenger, thin It plays an important role in the fundamental reactions such as survival, growth, proliferation and the metabolism of born of the same parents.PTEN Tumor Suppressor Gene can make PIP3 Dephosphorylation generates PIP2, is the antagonist of PI3K catalytic action.The abnormal activation of PI3K will lead to the disorder of the access, cause A series of diseases, including cancer, nervous system lesion, autoimmune disease and hemopoietic diseases.PI3K has become tumour One of important target spot of Therapy study is to list for 2014 respectively there are two the PI3K inhibitor of clinical application at present is main PI3K δ inhibitor Chinese mugwort is main for Larry this (Idelalisib) and the PI3K α/PI3K δ inhibitor C opanlisib listed in 2017 It is used for the treatment of various lymthomas；In addition, still there are multiple PI3K inhibitor to be in clinical investigation phase, but there is no at present The report of the bis- target spot inhibitor of PARP-1/PI3K.
Summary of the invention
The invention discloses the compound of a kind of logical formula (I), results of pharmacodynamic test is shown, the compound of the present invention or its Pharmaceutically acceptable salt can act on two target spots of PARP-1 and PI3K simultaneously, can be used as the single therapy agent of tumour；Or Person and other anti-tumor drugs are combined, to have the function that improve existing anti-tumor drug curative effect and reduce dosage and toxicity.
Wherein X represents CH or N；
R1It represents R1It is excellent Choosing represents
R2It represents R3Represent H, F, Br, Cl, CF3、CN、CH3Or OCH3, Y represents CH or N, Z represent O, NH、NCH3Or CH2, m=1 or 2；R2It is preferred that representing
Currently preferred part of compounds is as follows:
Work as R2It does not representWhen, the compound that the present invention leads to formula (I) can be prepared with following method:
Above-mentioned reaction is preferably added to carry out under the conditions of catalyst, alkali and reaction dissolvent, wherein catalyst preferably be selected from palladium chloride, Acid chloride, bis- (triphenylphosphine) palladium chlorides, tetrakis triphenylphosphine palladium, [bis- (diphenylphosphino) ferrocene of 1,1'-] dichloride Palladium or [bis- (diphenylphosphino) ferrocene of 1,1'-] Nickel Chloride；Alkali preferably be selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, Sodium carbonate or potassium carbonate；Reaction dissolvent preferably be selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, glycol dimethyl ether, Tetrahydrofuran, dioxane, toluene, ethyl alcohol, water or in which any two or three of solvent mixed solvent；Reaction temperature is preferred It is 70 DEG C~115 DEG C.
Catalyst is more preferably tetrakis triphenylphosphine palladium；Alkali is more preferably potassium carbonate；Solvent is further preferred For dioxane/water mixed solvent；Reaction temperature is more preferably 95 DEG C~110 DEG C.
In more detail, if being prepared from starting material (1), then include:
Process by compound 1 through cyanogen generation reaction prepare compound 2:
Cyanide used preferably is selected from zinc cyanide, copper cyanider or cuprous cyanide.More preferable cuprous cyanide.
Catalyst preferably is selected from palladium chloride, acid chloride, bis- (triphenylphosphine) palladium chlorides, tetrakis triphenylphosphine palladium, [1,1'- Bis- (diphenylphosphino) ferrocene] palladium chloride or [bis- (diphenylphosphino) ferrocene of 1,1'-] Nickel Chloride.More preferable four (triphenylphosphine) palladium.
Reaction dissolvent preferably is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.More preferable N, N- Dimethylformamide.
Reaction temperature preferably is selected from 30 DEG C~90 DEG C.More preferable 70 DEG C~80 DEG C.
Process by compound 2 through hydrolysis prepare compound 3:
Alkali used preferably is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate.More preferable hydroxide Sodium.
Reaction dissolvent preferably is selected from methanol/water, ethanol/water or tetrahydrofuran/water mixed solvent, and more preferable methanol/water is mixed Bonding solvent.
Reaction temperature preferably is selected from 20 DEG C~70 DEG C, more preferable 30 DEG C~40 DEG C.
By compound 3 and process of the compound II through acylation reaction prepare compound III:
Condensing agent preferably is selected from hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP), 1- hydroxy benzo Triazole (HOBt)/1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N'- carbonyl dimidazoles (CDI), more preferably PyBOP.
Acid binding agent preferably is selected from triethylamine, N, N- diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, Sodium acetate, sodium carbonate or potassium carbonate, more preferable DIEA.
Reaction dissolvent preferably is selected from n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide, more preferable N, N- Dimethylformamide.
Reaction temperature preferably is selected from 10 DEG C~80 DEG C, more preferable 20 DEG C~40 DEG C.
React the process of prepare compound I through Suzuki with borate IV by compound III:
Catalyst used preferably be selected from palladium chloride, acid chloride, bis- (triphenylphosphine) palladium chlorides, tetrakis triphenylphosphine palladium, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride or [bis- (diphenylphosphino) ferrocene of 1,1'-] Nickel Chloride.It is more excellent Select tetrakis triphenylphosphine palladium.
Alkali preferably is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate, more preferable potassium carbonate.
Reaction dissolvent preferably is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, glycol dimethyl ether, tetrahydro furan It mutters, the mixed solvent of dioxane, toluene, ethyl alcohol, water or in which any two or three of solvent, more preferable dioxane/water Mixed solvent.
Reaction temperature preferably is selected from 70 DEG C~115 DEG C, more preferable 95 DEG C~110 DEG C.
Work as R2It representsWhen, the compound that the present invention leads to formula (I) can be prepared with following method:
Above-mentioned reaction is preferably added to carry out under the conditions of condensing agent, acid binding agent, alkali and reaction dissolvent, and wherein condensing agent preferably is selected from PyBOP, HOBt/EDCI, DCC or CDI；Acid binding agent preferably is selected from triethylamine, DIEA, DMAP, pyridine, sodium acetate, sodium carbonate or carbon Sour potassium；Reaction dissolvent preferably is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide；Reaction temperature preferably is selected from 10 DEG C~80 DEG C.
Condensing agent is more preferably PyBOP；Acid binding agent is more preferably DIEA；Reaction dissolvent is more preferably N, Dinethylformamide；Reaction temperature is more preferably 20 DEG C~40 DEG C.
By compound (I) through the process at salt prepare compound IA, reactant A is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphorus Acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, to first Benzene sulfonic acid or ferulic acid；Solvent is methanol, ethyl alcohol, methylene chloride, acetone, ethyl acetate, toluene, tetrahydrofuran or in which any The mixed solvent of two or three of solvent.
The invention also discloses a kind of pharmaceutical compositions comprising the compound of the present invention (I) of medicine effective dose or Its salt and pharmaceutically acceptable carrier.
Compound of the present invention can add pharmaceutically acceptable carrier and common pharmaceutical formulation, such as piece is made Agent, capsule, pulvis, syrup, liquor, suspending agent, freeze-dried powder, injection can be added fragrance, sweetener, liquid or solid and fill out The common medicinal supplementary materials such as material or diluent.
The administration mode of compound of the present invention clinically can be using modes such as oral, injections.
Generally, the compound of the present invention is for when treating, people to be 1mg~1000mg/ days with dosage range.It can also basis The difference and disease severity of dosage form, dosage exceed the range.
The pharmacological experiment and result of part of compounds of the present invention are as follows:
(1) detection compound is in enzyme level to the inhibitory activity of PARP-1 and PI3K
Experimental method
Kinase activity test method employed in this experiment is essentially identical, only according to different kinases and it is corresponding not Same substrate takes different concentration to reach optimal detection range.
PARP-1 inhibitory activity experimental method: taking out in 96 orifice plates of pre-coated histone, and following enzyme is added in every hole The inhibitor of reaction system and various concentration, comprising: the reaction buffer (Tris*HCl, pH 8.0) of 50 μ L, NAD+, biotin The activated dna of label, PARP-1 enzyme and inhibitor；After reacting 1 hour at room temperature, 50 μ L Avidin marks are added in every hole The HRP of note reacts 30 minutes；The HRP substrate for adding 100 μ L detects values of chemiluminescence on SpectraMax M instrument.Under Column formula calculates enzymatic activity percentage:
Enzymatic activity percentage (%)=(OD value dosing holes-OD is worth background)/(OD value control wells-OD is worth background) × 100%
PI3K α inhibitory activity experimental method: 40mM Tris, pH 7.4,10mM MgCl2,0.1mg/ml BSA,1mM DTT, 10 μM of ATP, PI3K alpha kinase, kinase substrate；The compound to be sieved of various concentration is added simultaneously, forms the reactant of 50 μ L System, react 40 minutes at 30 DEG C, afterwards use luciferase method detection architecture in ADP content, then react after five minutes, Chemiluminescence signal, chemiluminescence signal value intensity and inhibition of enzyme activity are detected on MD-SpectraMax M5 multi-function microplate reader It is directly proportional.The chemiluminescence signal value detected, substitutes into following formula:
Enzymatic activity percentage (%)=(OD value dosing holes-OD is worth background)/(OD value control wells-OD is worth background) × 100%
Experimental result is shown in Table 1.
Drug concentration is diluted according to three times concentration gradient, and each concentration detects two multiple holes.Using drug concentration as cross Coordinate, the corresponding enzymatic activity percentage of each concentration is ordinate, does nonlinear regression using Graphpad Prism5, calculates To the IC of each test compound50Value.Experimental result is shown in Table 2.
Inhibitory activity of 1. test-compound of table to PARP-1 and PI3K α
Table 1 is the results show that the compounds of this invention is to PARP-1 inhibitory activity with higher, and majority of compounds is in 10nM 50% is greater than to the inhibiting rate of PARP-1 under concentration；Compound exists to PI3K α also inhibitory activity with higher, part of compounds 70% or more is greater than to the inhibiting rate of PI3K α under 100nM concentration.The above results show that the compounds of this invention to PARP-1 and PI3K has dual restraining activities.
Selected section compound measures its IC to PARP-1 and PI3K α respectively50Value, the results are shown in Table 2.
IC of the 2. part test-compound of table to PARP-1 and PI3K α50Value
Table 2 is the results show that the compounds of this invention has higher inhibitory activity, majority of compounds to PARP-1 and PI3K Inhibitory activity to PI3K α is better than to the inhibitory activity of PARP-1, wherein IC of the compound I-1 to PARP-150It is right for 6.3nM The IC of PI3K α50For 5.8nM, almost the same inhibitory activity is shown to two target spots.
(2) inhibitory activity of the detection compound to tumor cell proliferation
Experimental method
By the cell (HCT116, HCC1937, MDA-MB-231 and MDA-MB-468) in logarithmic growth phase with a fixed number Amount is inoculated in 96 orifice plates (200 hole μ L/), dosing after culture is allowed to adherent for 24 hours.Each drug concentration sets 3 multiple holes, and sets Corresponding zeroing hole and blank control.After drug effect 72 hours, 50%TCA (50 hole μ L/) is added in attached cell, and 4 DEG C are fixed 1 Hour, fixer is outwelled, with distillation washing 5 times, is spontaneously dried.100 μ L 4mg/mL SRB are added in every hole, and room temperature dyes 15 points Clock abandons it, is washed 5 times with 1% glacial acetic acid, spontaneously dries.150 μ L 10mM Tris solution are added in last every hole, shake up, use is adjustable Wavelength type microwell plate microplate reader measures OD value under 565nm wavelength.Inhibitory rate of cell growth is calculated with above formula, the results are shown in Table 3。
The anti tumor activity in vitro test result of 3. compound of table
It is thin can to significantly inhibit tumour the results show that the compounds of this invention all has stronger anti tumor activity in vitro for table 3 The proliferation of born of the same parents.Not only there is significant inhibitory activity to HCC1937 the and HCT116 cell of BRCA deficiency, but also to the open country BRCA MDA-MB-231 the and MDA-MB-468 cell of raw type also has stronger inhibitory activity.Wherein compound I-1 is to tumour cell The inhibitory activity of HCT116 and HCC1937 is most strong, IC50Respectively 0.094 μM and 0.061 μM；Compound I-10 is to tumour cell The inhibitory activity of MDA-MB-231 and MDA-MB-468 is most strong, IC500.244 μM and 1.402 μM are respectively reached.
(3) inhibitory activity that detection compound grows human breast carcinoma MDA-MB-468 cell Nude Mice
Test grouping situation is shown in Table 4.
The test of table 4. grouping situation and drug concentration selection
Experimental method
The MDA-MB-468 cell strain of logarithmic growth phase, is aseptically prepared into 2 × 10 afterwards7/ mL cell suspension, It is subcutaneous that armpit on the right side of nude mouse is inoculated in 0.1mL.Nude Mice vernier caliper measurement transplantable tumor diameter, it is raw to tumour It grows to 100mm3Animal is grouped at random behind left and right.Use the method for measurement knurl footpath, the antitumor effect of dynamic observation subject. The pendulous frequency of diameter of tumor is every 6 days primary.Administered volume is 0.4mL/20g.After 34 days, mouse is put to death, and operation strips tumor Block weighing.The calculation formula of gross tumor volume (TV) are as follows:
TV=1/2 × a × b2, wherein a, b respectively indicate length and width.
As a result as shown in Table 5 and 6, to dosage under, compound I-1, I-10 and olaparib/BKM120 are combined equal energy The growth of MDA-MB-468 Nude Mice is enough significantly inhibited, tumor-inhibiting action is better than positive drug olaparib and BKM120, Middle compound I-I and I-10 function and effect are better than olaparib (50mg/kg)/BKM120 (27.5mg/kg) combination group.
Influence of 5. compound of table to human breast carcinoma MDA-MB-468 cell Nude Mice volume
Influence of 6. compound of table to human breast carcinoma MDA-MB-468 cell Nude Mice knurl weight
Specific embodiment
Embodiment 1
2- (4- (4- (the close pyridine -5- base of 2- amino) -6- morpholinyl -1,3,5- triazine -2- base) piperazine -1- formoxyl) benzo The synthesis of furans -7- formamide (I-1)
7- cyano coumarilic acid methyl esters (2)
By 7- bromobenzofuran -2- methyl formate (1) (9.3g, 36.46mmol), Zn (CN)2(8.56g, 72.92mmol), tetrakis triphenylphosphine palladium (2.10g, 1.82mmol) is added in 250mL three-necked bottle, and 100mL DMF stirring is added Dissolution, white milkiness shape, nitrogen protection are heated to 80 DEG C and react 6~8 hours.TLC (petroleum ether: ethyl acetate=10:1) Detection raw material 1 has reacted, and is cooled to room temperature, and filters, and filter cake is washed with 20mL DMF, filtrate is poured into 300mL water, is precipitated big White solid is measured, is stirred 15 minutes, is filtered, filter cake 100mL water washing, it is dry, obtain crude product.Column chromatographic purifying (petroleum ether: second Acetoacetic ester=50:1~20:1 gradient elution, product are the biggish point of polarity), obtain white solid 4.7g, yield 64.0%, m.p.130-132℃.1H-NMR(300MHz,CDCl3) δ (ppm): 7.97 (1H, dd, J=8.0,1.0Hz, ArH), 7.79 (1H, Dd, J=7.6,1.0Hz, ArH), 7.62 (1H, s, ArH), 7.43 (1H, t, J=7.8Hz, ArH), 4.02 (3H, s, CH3).
7- carbamoyl coumarilic acid (3)
Compound 2 (4.7g, 23.36mmol) is dissolved in 50mL methanol, 30%H is added2O2(16mL), 1mol/L NaOH (47mL) is heated to 40 DEG C and reacts 1 hour, and TLC (methylene chloride: methanol=20:1) detection raw material 2 has reacted, and stops heating, It is cooled to room temperature, 2mol/L dilute hydrochloric acid is added and adjusts pH=1~2, a large amount of white solids are precipitated, are stirred at room temperature 15 minutes, filters, It is dry, obtain white solid 4.5g, yield 93.8%, m.p.178-180 DEG C of1H-NMR(300MHz,DMSO-d6)δ(ppm): 13.77 (1H, s, COOH), 7.92 (1H, d, J=7.5Hz, ArH), 7.85 (1H, s, 1/2CONH2), 7.83 (1H, d, J= 7.6Hz,ArH),7.74(1H,s,ArH),7.66(1H,s,1/2CONH2), 7.42 (1H, t, J=7.4Hz, ArH)
(the chloro- 4- morpholinyl of 2,6- bis-) -1,3,5- triazine (5)
Three polychlorostyrene piperazines (4) (10.00g, 54.23mmol) are taken to be dissolved in 100mL methylene chloride, addition DIEA (9.92mL, 56.94mmol), -78 DEG C are cooled to, the solution that morpholine (4.73mL, 54.23mmol) is dissolved in 10mL methylene chloride is added dropwise to It in reaction solution, finishes, a large amount of white solids is precipitated, TLC (petroleum ether: ethyl acetate=6:1) detection raw material 4 has reacted, stopped Reaction filters, and filter cake is washed with water, dry, obtains white solid 7.18g, yield 56.4%.1H NMR(300MHz,DMSO-d6)δ (ppm):3.80-3.76(4H,CH2O),3.69(4H,CH2).
4- (the chloro- 6- morpholinyl -1,3,5- triazine -2- base of 4-) piperazine -1- t-butyl formate (6)
By compound 5 (7.00g, 29.78mmol), N- tert-butoxycarbonyl-piperazine (5.55g, 29.80mmol) and K2CO3 (4.12g, 29.81mmol) is added in 250mL three-necked bottle, and 100mL DMF stirring and dissolving is added, and reacts 5 hours in 25 DEG C, TLC (petroleum ether: ethyl acetate=6:1) detection raw material 5 has reacted, and stops reaction, pours into 300mL water, a large amount of solids are precipitated, stir It mixes 30 minutes, filters, filter cake is washed with water, and it is dry, obtain white solid 10.5g, yield 91.6%.m.p.169-172℃.1H- NMR(300MHz,CDCl3)δ(ppm):3.83-3.75(12H,m,6CH2),3.52-3.49(4H,m,2CH2),1.53(9H,s, 3CH3).
4- (the chloro- 6- morpholinyl -1,3,5- triazine -2- base of 4-) piperazine hydrochloride (II-1)
Compound 6 (10.0g, 25.98mmol) is dissolved in 50mL ethyl acetate, the ethyl acetate that saturation HCl is added is molten Liquid (20mL) is stirred to react 2 hours in 25 DEG C, and TLC (petroleum ether: ethyl acetate=6:1) detection raw material 6 has reacted, and is stopped anti- It answers, filters, filter cake is washed with ethyl acetate, and it is dry, obtain white solid 7.65g, yield 91.6%.1H-NMR(300MHz, MeOD) δ (ppm): 4.06 (4H, t, J=5.2Hz, 2CH2O),3.81-3.77(4H,m,2CH2),3.70-3.67(4H,m, 2CH2), 3.27 (4H, t, J=5.4Hz, 2CH2).
2- (4- (the chloro- 6- morpholinyl -1,3,5- triazine -2- base of 4-) piperazine -1- formoxyl) benzofuran -7- formamide (III-1)
By compound 3 (1.35g, 6.60mmol), II-1 (2.12g, 6.60mmol) and PyBOP (4.12g, 7.92mmol) It is added in 100mL three-necked bottle, 50mL DMF stirring and dissolving is added, adds DIEA (3.82mL, 23.10mmol), is stirred in 25 DEG C Mix reaction 4~6 hours, TLC (methylene chloride: methanol=20:1) detection raw material 3 has reacted, and stops reaction, reaction solution is poured into In 150mL water, a large amount of solids are precipitated, stir 10 minutes, filter, filter cake 50mL water washing, it is dry, crude product is obtained, column chromatography is pure Change (methylene chloride: methanol=120:1~80:1 gradient elution), obtains white solid 2.5g, yield 80.3%, m.p.142-144 ℃.1H-NMR(300MHz,DMSO-d6) δ (ppm): 7.94 (1H, d, J=7.8Hz, ArH), 7.86 (1H, d, J=7.1Hz, ArH),7.84(1H,s,1/2CONH2),7.77(1H,s,1/2CONH2), 7.58 (1H, s, ArH), 7.46 (1H, t, J= 7.7Hz,ArH),3.90-3.66(16H,m,6CH2N,2CH2O).
2- (4- (4- (the close pyridine -5- base of 2- amino) -6- morpholinyl -1,3,5- triazine -2- base) piperazine -1- formoxyl) benzo Furans -7- formamide (I-1)
By compound III-1 (2.5g, 5.30mmol), 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan Alkane -2- base) pyrimidine -2- amine (IV-1) (1.76g, 7.95mmol) be added 250mL three-necked bottle in, be added 80mL dioxane stirring Dissolution.By K2CO3(2.92g, 21.20mmol) is dissolved in 8mL water, and reaction solution is added, adds tetrakis triphenylphosphine palladium (0.62g,0.53mmol).Under nitrogen protection, heating reflux reaction 6~8h, TLC (methylene chloride: methanol=20:1) detection are former Material III-1 has reacted, and a large amount of light yellow solids are precipitated, and stops heating, is cooled to room temperature.Filter, filter cake successively use 20mL water, The washing of 20mL ethyl acetate, it is dry, crude product is obtained, 30mL ethyl acetate is added and is beaten 2h, filters, it is dry, obtain white solid 1.67g, yield 59.4%.m.p.>250℃.1H-NMR(300MHz,DMSO-d6)δ(ppm):9.06(2H,s,ArH),7.90 (1H, d, J=7.3Hz, ArH), 7.82 (1H, s, 1/2CONH2), 7.81 (1H, d, J=5.4Hz, ArH), 7.74 (1H, s, 1/ 2CONH2), 7.55 (1H, s, ArH), 7.42 (1H, t, J=7.1Hz, ArH), 7.30 (2H, s, NH2),4.00-3.64(16H,m, 6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm):170.89,169.81,168.69,165.88,163.43, 162.49,155.64,153.48,147.68,132.41,131.42,130.17,128.39,124.68,123.38,115.86, 70.73,51.14,48.02,47.48.HRMS(ESI):m/z[M+H]+.Calcd for C25H26N10O4:531.2211； Found:531.2209.
Embodiment 2
2- (4- (4- (6- aminopyridine -3- base) -6- morpholinyl -1,3,5- triazine -2- base) piperazine -1- formoxyl) benzo The synthesis of furans -7- formamide (I-2)
By compound III-1 (300mg, 0.64mmol) and 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan Alkane -2- base) pyridine -2- amine (IV-2) (154mg, 0.70mmol) be added 50mL three-necked bottle in, be added 20mL dioxane, stirring Dissolution.By K2CO3(354mg, 2.56mmol) is dissolved in 2mL water, is added in reaction solution, is added tetrakis triphenylphosphine palladium (74mg,0.06mmol).Under nitrogen protection, heating reflux reaction 4~6 hours, TLC (methylene chloride: methanol=20:1) detection Raw material II I-1 has reacted, and stops heating, is cooled to room temperature, and filters, and 40mL ethyl acetate, mixing is added in filtrate concentration, residue Liquid is successively washed with water (20mL × 1) and saturated sodium chloride solution (20mL × 2), anhydrous Na2SO4It is dry, it filters, filtrate concentration, Residue obtains light yellow solid 156mg, yield with column chromatographic purifying (methylene chloride: methanol=80:1~20:1 gradient elution) 46.0%.m.p.>250℃.1H-NMR(300MHz,DMSO-d6) δ (ppm): 8.88 (1H, s, ArH), 8.34 (1H, d, J= 7.7Hz, ArH), 7.90 (1H, d, J=7.8Hz, ArH), 7.82 (1H, s, ArH), 7.80 (1H, s, 1/2CONH2),7.75 (1H,s,1/2CONH2), 7.55 (1H, s, ArH), 7.42 (1H, t, J=7.6Hz, ArH), 7.06 (2H, s, NH2),6.62(1H, D, J=8.6Hz, ArH), 4.00-3.57 (16H, m, 6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm): 168.63,165.07,164.28,161.90,158.67,150.87,149.66,148.74,136.66,131.46,127.66, 126.66,125.43,123.64,120.11,119.92,111.08,106.90,66.01,43.22,28.94,26.51.HRMS (ESI):m/z[M+H]+.Calcd for C26H27N9O4:530.2259；Found:530.2252.
Embodiment 3
2- (4- (4- (6- amino -4- (trifluoromethyl) pyridin-3-yl) -6- morpholinyl -1,3,5- triazine -2- base) piperazine - 1- formoxyl) benzofuran -7- formamide (I-3) synthesis
With compound III-1 (300mg, 0.64mmol) and 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan Alkane -2- base) -4- (trifluoromethyl) pyridine -2- amine (IV-3) (202mg, 0.70mmol) be raw material, operate with I-2 method, column Chromatographic purifying (methylene chloride: methanol=80:1~20:1, gradient elution), obtains off-white powder 185mg, yield 48.4%. m.p.>250℃.1H-NMR(300MHz,DMSO-d6) δ (ppm): 8.62 (1H, s, ArH), 7.92 (1H, d, J=7.8Hz, ), ArH 7.83 (1H, d, J=7.4Hz, ArH), 7.77 (1H, s, 1/2CONH2),7.71(1H,s,1/2CONH2),7.55(1H, S, ArH), 7.43 (1H, t, J=7.7Hz, ArH), 6.94 (2H, s, NH2),6.83(1H,s,ArH),3.92-3.65(16H,m, 6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm):174.24,169.82,168.83,165.92,163.46, 157.27,155.63,153.42,140.63,132.41,131.40,130.18,129.61,128.37,125.99,124.66, 123.40,115.80,109.39,70.67,59.63,47.94,47.24.HRMS(ESI):m/z[M+H]+.Calcd for C27H26F3N9O4:598.2133；Found:598.2136.
Embodiment 4
2- (4- (4- (4- amino -3- fluorophenyl) -6- morpholinyl -1,3,5- triazine -2- base) piperazine -1- formoxyl) benzo The synthesis of furans -7- formamide (I-4)
With compound III-1 (300mg, 0.64mmol) and the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxa boron Heterocycle pentane -2- base) aniline (IV-4) (166mg, 0.70mmol) be raw material, operate with I-2 method, column chromatographic purifying (two Chloromethanes: methanol=80:1~20:1, gradient elution), obtain light yellow solid 170mg, yield 48.6%.m.p.>250℃.1H- NMR(300MHz,DMSO-d6) δ (ppm): 7.96-7.91 (3H, m, ArH), 7.84 (1H, d, J=7.2Hz, ArH), 7.80 (1H,s,1/2CONH2),7.73(1H,s,1/2CONH2), 7.56 (1H, s, ArH), 7.44 (1H, t, J=7.7Hz, ArH), 6.80 (1H, t, J=8.9Hz, ArH), 5.78 (2H, s, NH2),4.02-3.62(16H,m,6CH2N,2CH2O).13C-NMR (75MHz,DMSO-d6)δ(ppm):168.77,165.39,164.38,159.01,150.82,148.16,139.69, 127.64,126.89,125.97,125.19,124.32,123.80,121.69,119.10,114.96,114.55,114.30, 111.19,72.86,65.98,43.19,42.42.HRMS(ESI):m/z[M+H]+.Calcd for C27H27FN8O4: 547.2212；Found:547.2211.
Embodiment 5
2- (4- (4- (1H- indoles -5- base) -6- morpholinyl -1,3,5- triazine -2- base) piperazine -1- formoxyl) benzo furan It mutters the synthesis of -7- formamide (I-5)
With compound III-1 (300mg, 0.64mmol) and 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan Alkane -2- base) -1H- indoles (IV-5) (170mg, 0.70mmol) be raw material, operate with I-2 method, column chromatographic purifying (dichloro Methane: methanol=100:1~30:1, gradient elution), obtain light yellow solid 160mg, yield 45.2%.m.p.164-166℃ .1H-NMR(300MHz,DMSO-d6) δ (ppm): 11.28 (1H, s, NH), 8.65 (1H, s, ArH), 8.17 (1H, d, J= 8.6Hz, ArH), 7.91 (1H, d, J=7.8Hz, ArH), 7.82 (1H, d, J=7.5Hz, ArH), 7.79 (1H, s, 1/ 2CONH2),7.72(1H,s,1/2CONH2),7.55(1H,s,ArH),7.45-7.38(3H,m,ArH),6.55(1H,s,ArH), 4.08-3.67(16H,m,6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm):177.92,170.63,165.46, 164.51,159.05,150.83,148.06,137.85,127.62,127.44,127.28,126.95,126.19,126.03, 123.81,121.48,121.13,118.95,111.21,110.82,102.37,66.00,45.70,43.19,42.50.HRMS (ESI):m/z[M+H]+.Calcd for C29H28N8O4:553.2306；Found:553.2306.
Embodiment 6
2- (4- (4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -6- morpholinyl -1,3,5- triazine -2- base) Piperazine -1- formoxyl) benzofuran -7- formamide (I-6) synthesis
4- (the chloro- 6- of 4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -1,3,5- triazine -2- base) morpholine (V- 1)
By 2- (difluoromethyl) -1H- benzo [d] imidazoles (7) (1.43g, 8.51mmol), compound 5 (2.00g, 8.51mmol) and K2CO3(1.18g, 8.51mmol) is added in 50mL three-necked bottle, and 25mL DMF stirring and dissolving is added, anti-in 25 DEG C It answers 4 hours, TLC (petroleum ether: ethyl acetate=5:1) detection raw material 5 has reacted, and stops reaction, reaction solution is poured into 80mL water In, a large amount of white solids are precipitated, stir 10 minutes, filter, filter cake is washed with water, and it is dry, obtain white solid 2.7g, yield 86.5%.m.p.244-247℃.1H-NMR(300MHz,CDCl3) δ (ppm): 8.44 (1H, d, J=7.7Hz, ArH), 7.91 (1H, d, J=7.5Hz, ArH), 7.59 (1H, CHF2),7.53-7.43(2H,m,ArH),4.02-3.95(4H,m,CH2), 3.87-3.81(4H,m,CH2).
4- (4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -6- morpholinyl -1,3,5- triazine -2- base) piperazine Piperazine -1- t-butyl formate (VI-1)
By compound V-1 (2.70g, 7.36mmol), N- tert-butoxycarbonyl-piperazine (1.44g, 7.73mmol) and K2CO3 (1.53g, 11.0 4mmol) are added in 100mL three-necked bottle, and the stirring of 50mL acetone is added in muddy shape, reacts 8 hours in 30 DEG C, TLC (petroleum ether: ethyl acetate=5:1) detection raw material V-1 has reacted, and stops reaction, and 50mL dichloro is added in evaporated under reduced pressure solvent 50mL water extracting and washing is added in methane dissolution residual substance, and water layer uses 30mL methylene chloride to extract again, merges dichloromethane layer, satisfies (50mL × 2) are washed with sodium chloride solution, anhydrous Na2SO4It is dry, it filters, filtrate is concentrated, obtains foaming solid 3.50g, yield 92.1%.m.p.184-187℃.1H-NMR(300MHz,CDCl3) δ (ppm): 8.34 (1H, d, J=7.6Hz, ArH), 7.90 (1H, d, J=6.9Hz, ArH), 7.57 (1H, t, J=53.6Hz, CHF2),7.48-7.39(2H,m,ArH),3.92-3.85 (8H,m,CH2),3.80(4H,s,CH2),3.55(4H,s,CH2),1.50(9H,s,CH3).
4- (4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -6- (piperazine -1- base) -1,3,5- triazine -2- Base) morpholine hydrochloride (VII-1)
Compound VI-1 (3.50g, 6.78mmol) is added in 50mL three-necked bottle, it is molten that the stirring of 20mL ethyl acetate is added The ethyl acetate solution (5mL) of saturation HCl is added dropwise in solution, and a large amount of white solids are precipitated, and 25 DEG C are stirred 4 hours, TLC (petroleum ether: Ethyl acetate=5:1) detection raw material VI-1 react, filtered, and filter cake washs with ethyl acetate, dries, obtains white solid 2.72g, yield 88.6%.m.p.230-232℃.1H NMR(300MHz,CDCl3) δ (ppm): 8.36 (1H, d, J=7.3Hz, ), ArH 7.91 (1H, d, J=7.1Hz, ArH), 7.59 (1H, CHF2),7.49-7.39(2H,m,ArH),3.98-3.87(8H, m,CH2),3.81(4H,s,CH2),3.02(4H,s,CH2).
2- (4- (4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -6- morpholinyl -1,3,5- triazine -2- base) Piperazine -1- formoxyl) benzofuran -7- formamide (I-6)
By compound 3 (180mg, 0.88mmol), compound VII-1 (400mg, 0.88mmol) and PyBOP (550mg, It 1.06mmol) is added in 50mL three-necked bottle, 20mL DMF stirring and dissolving is added, adds DIEA (0.44mL, 2.64mmol), adds Finish, reacted 8~10 hours in 25 DEG C, TLC (methylene chloride: methanol=20:1) detection raw material 3 has reacted, and stops reaction, will be anti- It answers liquid to pour into 60mL water, a large amount of white solids is precipitated, stir 10 minutes, filter, filter cake 20mL water washing, it is dry, it obtains slightly Product.Column chromatographic purifying (methylene chloride: methanol=100:1~60:1, gradient elution), obtains white solid 220mg, yield 41.4%.m.p.189-191℃.1H-NMR(300MHz,CDCl3) δ (ppm): 8.33 (1H, d, J=7.7Hz, ArH), 8.22 (1H, d, J=7.3Hz, ArH), 7.92 (1H, d, J=7.1Hz, ArH), 7.86 (1H, d, J=8.0Hz, ArH), 7.56 (1H, T, J=53.6Hz, CHF2),7.45(3H,m,ArH),7.35(1H,s,ArH),7.22(1H,s,1/2CONH2),6.02(1H,s, 1/2CONH2),4.03-3.81(16H,m,6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm):165.07, 164.33,161.28,158.81,150.92,148.61,145.83,141.30,132.88,127.68,126.68,125.90, 125.44,124.31,123.62,120.65,119.91,115.83,111.03,108.56,87.07,65.84,45.99, 43.65,43.08.HRMS(ESI):m/z[M+H]+.Calcd for C29H27F2N9O4:604.2227；Found:604.2233.
Embodiment 7
2- (4-2'- amino -2- morpholinyl-[bis- pyrimidine of 4,5'-] -6- base) piperazine -1- formoxyl) benzofuran -7- first The synthesis of amide (I-7)
4- (4,6- dichloro pyrimidine -2- base) morpholine (9)
2,4,6- trichloropyrimidines (8) (10.00g, 54.52mmol) are added in 250mL three-necked bottle, 100mL dichloro is added Methane, stirring and dissolving, be added DIEA (8.50mL, 48.70mmol), be cooled to -78 DEG C, be slowly added dropwise morpholine (4.30mL, 49.40mmol), it finishes, insulated and stirred is reacted 1~2 hour, and TLC (petroleum ether: ethyl acetate=6:1) detects raw material 8 and reacts It is complete, stop reaction, reaction solution is poured into 150mL water, extract, separate dichloromethane layer, water layer uses 50mL methylene chloride to extract again It takes, merges dichloromethane layer, saturated sodium chloride solution washes twice (80mL × 2), anhydrous Na2SO4It is dry, it filters, filtrate is concentrated Crude product is obtained, mixed solvent (petroleum ether: ethyl acetate=50:1,100mL) is added and is beaten 2 hours, filters, it is dry, it obtains white solid Body 9.4g, yield 73.7%.m.p.122-124℃.1H NMR(300MHz,CDCl3)δ(ppm):6.56(1H,s,ArH), 3.83-3.80(4H,m,2CH2O),3.76-3.72(4H,m,2CH2).
4- (the chloro- 2- morpholinyl pyrimidine-4-yl of 6-) piperazine -1- t-butyl formate (10)
100mL is added in compound 9 (2.00g, 8.54mmol) and N- tert-butoxycarbonyl-piperazine (3.98g, 21.35mmol) In three-necked bottle, 50mL acetone is added, stirring and dissolving adds triethylamine (4.00mL, 28.86mmol), heating reflux reaction 10 Hour or so, TLC (methylene chloride: methanol=20:1) detection raw material 9 has reacted, and stops reaction, is cooled to room temperature, and is precipitated a large amount of White solid filters, filter cake acetone washing, dry, obtains white solid 2.84g, yield 86.6%.m.p.215-217℃ .1H-NMR(300MHz,CDCl3)δ(ppm):5.87(1H,s,ArH),3.78-3.73(8H,m,2CH2O,2CH2NCO),3.57- 3.54(4H,m,2CH2),3.48-3.44(4H,m,2CH2).
4- (the chloro- 6- of 4- (piperazine -1- base) pyrimidine -2-base) morpholine hydrochloride (II-2)
Compound 10 (2.84g, 7.40mmol) is added in 50mL three-necked bottle, 15mL ethyl acetate stirring and dissolving is added, The ethyl acetate solution (5mL) of saturation HCl is added, 25 DEG C are stirred to react 2~3 hours, and a large amount of white solids, TLC (two is precipitated Chloromethanes: methanol=20:1) detection raw material 10 reacted, stopped reaction, filter, and filter cake washs with ethyl acetate, and it is dry, it obtains white Color solid 2.36g, yield 99.6%.1H NMR(300MHz,DMSO-d6)δ(ppm):9.53(1H,s,HCl),6.92(1H,s, ), NH 6.30 (1H, s, ArH), 3.90 (4H, t, J=4.8Hz, 2CH2O),3.67-3.58(8H,m,4CH2N),3.12(4H,s, 2CH2N).
2- (4- (the chloro- 2- morpholine pyrimidine -4- of 6- replaces) piperazine -1- formoxyl) benzofuran -7- formamide (III-2)
By compound 3 (500mg, 2.44mmol), II-2 (780mg, 2.44mmol) and PyBOP (1.52g, 2.92mmol) It is added in 50mL three-necked bottle, 25mL DMF stirring and dissolving is added, adds DIEA (1.21mL, 7.32mmo), it is anti-in 25 DEG C of stirrings It answers 3~5 hours, TLC (methylene chloride: methanol=20:1) detection raw material 3 has reacted, and stops reaction, reaction solution is poured into 80mL In water, a large amount of solids are precipitated, stir 10 minutes, filter, filter cake 20mL water washing, it is dry, white solid (VI-1) 0.9g is obtained, Yield 78.3% is directly used in single step reaction without further purification.
2- (4-2'- amino -2- morpholinyl-[bis- pyrimidine of 4,5'-] -6- base) piperazine -1- formoxyl) benzofuran -7- first Amide (I-7)
Compound III-2 (300mg, 0.64mmol) and IV-1 (155mg, 0.70mmol) is added in 50mL three-necked bottle, 20mL dioxane, stirring and dissolving is added.By K2CO3(354mg, 2.56mmol) is dissolved in 2mL water, is added in reaction solution, then plus Enter tetrakis triphenylphosphine palladium (74mg, 0.06mmol).Under nitrogen protection, heating reflux reaction 4~6 hours, TLC (methylene chloride: Methanol=20:1) detection raw material II I-2 react, stop heating, be cooled to room temperature, filter, filtrate concentration, residue addition 40mL ethyl acetate, mixed liquor are successively washed with water (20mL × 1) and saturated sodium chloride solution (20mL × 2), anhydrous Na2SO4It is dry It is dry, it filters, filtrate concentration, residue is obtained pale yellow with column chromatographic purifying (methylene chloride: methanol=80:1~60:1 gradient elution) Color solid 160mg, yield 47.4%, m.p. > 250 DEG C1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):8.92(2H,s, ), ArH 7.93 (1H, d, J=7.7Hz, ArH), 7.83 (1H, d, J=7.2Hz, ArH), 7.53 (1H, s, ArH), 7.43 (1H, T, J=7.7Hz, ArH), 6.55 (1H, s, ArH), 3.86-3.61 (16H, m, 6CH2N,2CH2O).13C-NMR(75MHz, DMSO-d6)δ(ppm):164.99,163.94,163.34,160.75,159.39,158.73,156.90,154.93, 150.85,148.73,127.68,126.65,125.49,123.64,119.89,119.72,110.88,86.68,65.91, 44.05,43.41.HRMS(ESI):m/z[M+H]+.Calcd for C26H27N9O4:530.2259；Found:530.2250.
Embodiment 8
2- (4- (6- (6- amino -4- (trifluoromethyl) pyridin-3-yl) -2- morpholinyl pyrimidine-4-yl) piperazine -1- formyl Base) benzofuran -7- formamide (I-8) synthesis
With compound III-2 (300mg, 0.64mmol) and compound IV-3 (202mg, 0.70mmol) for raw material, operation With the method for I-7, column chromatographic purifying (methylene chloride: methanol=80:1~60:1, gradient elution) obtains light yellow solid 175mg, Yield 45.8%, m.p.208-210 DEG C of1H-NMR(300MHz,DMSO-d6)δ(ppm):8.17(1H,s,ArH),7.91(1H, D, J=8.3Hz, ArH), 7.82 (1H, d, J=7.1Hz, ArH), 7.79 (1H, s, 1/2CONH2),7.72(1H,s,1/ 2CONH2), 7.53 (1H, s, ArH), 7.42 (1H, t, J=7.6Hz, ArH), 6.82 (1H, s, ArH), 6.73 (2H, s, NH2), 6.25(1H,s,ArH),4.03-3.59(16H,m,6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm): 165.33,162.88,162.71,160.33,159.95,159.00,150.80,150.34,148.22,136.06,127.64, 126.82,125.89,124.80,123.75,121.29,119.14,110.99,104.62,92.01,65.82,49.83, 43.79,43.32.HRMS(ESI):m/z[M+H]+.Calcd for C28H27F3N8O4:597.2180；Found:597.2177.
Embodiment 9
2- (4- (6- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -2- morpholinyl pyrimidine-4-yl) piperazine -1- Formoxyl) benzofuran -7- formamide (I-9) synthesis
4- (the chloro- 6- of 4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) pyrimidine -2-base) morpholine (V-2)
With compound 7 (500mg, 2.97mmol) and compound 9 (700mg, 2.99mmol) for raw material, same compound is operated The method of V-1 obtains white solid 1.00g, yield 92.1%.m.p.197-200℃.1H-NMR(300MHz,DMSO-d6)δ (ppm): 8.31 (1H, d, J=8.1Hz, ArH), 7.86 (1H, d, J=7.7Hz, ArH), 7.69 (1H, CHF2),7.55-7.42 (2H,m,ArH),7.09(1H,s,ArH),3.74(8H,brs,2CH2O,2CH2).
4- (6- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -2- morpholinyl pyrimidine-4-yl) piperazine -1- formic acid The tert-butyl ester (VI-2)
With compound V-2 (1.00g, 2.73mmol), N- tert-butoxycarbonyl-piperazine (0.54g, 2.87mmol) for raw material, behaviour Make the method with compound VI-1, obtains white solid 1.25g, yield 88.8%.m.p.195-198℃.1H-NMR(300MHz, CDCl3) δ (ppm): 8.22 (1H, d, J=7.1Hz, ArH), 7.90 (1H, d, J=7.1Hz, ArH), 7.51 (1H, CHF2), 7.44-7.35(2H,m,ArH),5.52(1H,s,ArH),3.84-3.81(4H,m,2CH2O),3.65-3.57(12H,m, 6CH2) .4- (4- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -6- (piperazine -1- base) pyrimidine -2-base) morpholine hydrochloric acid Salt (VII-2)
With compound VI-2 (1.20g, 2.33mmol) for raw material, the method with compound VII-1 is operated, white solid is obtained 0.89g, yield 84.5%.m.p.196-198℃.1H-NMR(300MHz,DMSO-d6)δ(ppm):9.10(2H,brs,NH, ), HCl 8.20 (1H, d, J=8.1Hz, ArH), 7.82 (1H, d, J=7.7Hz, ArH), 7.68 (1H, CHF2),7.49-7.39 (2H,m,ArH),6.08(1H,s,ArH),3.88-3.65(12H,m,2CH2O,4CH2),3.18(4H,brs,2CH2).
2- (4- (6- (2- (difluoromethyl) -1H- benzo [d] imidazoles -1- base) -2- morpholinyl pyrimidine-4-yl) piperazine -1- Formoxyl) benzofuran -7- formamide (I-9)
With compound 3 (90mg, 0.44mmol) and compound VII-2 (199mg, 0.44mmol) for raw material, operation assimilation The method for closing object I-6, column chromatographic purifying (methylene chloride: methanol=100:1~50:1, gradient elution) obtain off-white powder 120mg, yield 45.4%.m.p.126-128℃.1H-NMR(300MHz,DMSO-d6) δ (ppm): 8.23 (1H, d, J= 8.1Hz, ArH), 7.91 (1H, d, J=7.8Hz, ArH), 7.84-7.80 (2H, m, ArH), 7.75 (1H, s, 1/2CONH2) 7.70 (1H, t, J=52.7Hz, CHF2),7.56(1H,s,ArH),7.49-7.36(3H,m,ArH),6.04(1H,s,ArH), 3.96-3.64(16H,m,6CH2N,2CH2O).13C-NMR(75MHz,DMSO-d6)δ(ppm):229.53,197.77,165.05, 163.81,163.32,162.48,158.79,153.78,150.93,148.66,141.22,127.69,126.65,125.45, 123.81,121.86,120.50,119.92,114.94,111.04,108.61,79.51,65.78,45.80,44.52, 25.82.HRMS(ESI):m/z[M+H]+.Calcd for C30H28F2N8O4:603.2274；Found:603.2278.
Embodiment 10
2- (4- (4- morpholinyl -6- (6- (2- morpholinyl acetylamino) -4- (trifluoromethyl) pyridin-3-yl) -1,3,5- Triazine -2- base) piperazine -1- formoxyl) benzofuran -7- formamide (I-10) synthesis
The chloro- N- of 2- (5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) -4- (trifluoromethyl) pyrrole Pyridine -2- base) acetamide (11)
Compound IV-3 (600mg, 2.08mmol) is dissolved in 15mL methylene chloride, addition DIEA (1.03mL, 6.24mmol), it is cooled to -15 DEG C, under nitrogen protection, is slowly added to chloracetyl chloride (235 μ L, 3.12mmol), finishes, heat preservation is anti- It answers 1~2 hour, TLC (methylene chloride: methanol=20:1) detection raw material IV-3 has reacted, and stops reaction, and 15mL water quenching is added and goes out Reaction.Extraction separates organic layer, and water layer uses the extraction of 15mL methylene chloride primary again, merges organic layer, and saturated sodium chloride solution is washed Wash (15mL × 2), anhydrous Na2SO4It is dry, it filters, concentration filtrate, column chromatographic purifying (petroleum ether: ethyl acetate=50:1~10: 1 gradient elution), obtain yellow oil 580mg, yield 76.5%.1H-NMR(300MHz,CDCl3)δ(ppm):9.08(1H,s, CONH),8.71(1H,s,ArH),8.53(1H,s,ArH),4.24(2H,s,COCH2Cl),1.39(12H,s,4CH3).MS(ESI (+)70V)m/z:387.1[M+Na]+.
2- morpholinyl-N- (5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base) -4- (fluoroform Base) pyridine -2- base) acetamide (IV-6)
Compound 11 (500mg, 1.37mmol) is dissolved in 15mL methylene chloride, is added triethylamine (380 μ L, 2.74mmol) With morpholine (170 μ L, 2.05mmol), heating reflux reaction 8~10 hours, TLC (methylene chloride: methanol=20:1) detected raw material 11 have reacted, and stop heating, are cooled to room temperature, and 15mL water is added, and extraction separates organic layer, and water layer uses 15mL methylene chloride to extract again Take primary, merging organic layer, saturated sodium chloride solution washing (15mL × 2), anhydrous Na2SO4It is dry, it filters, filtrate, column is concentrated Chromatographic purifying (methylene chloride: methanol=100:1~40:1 gradient elution), obtains light yellow solid (IV-6) 465mg, yield 81.7%.m.p.144-146℃.1H-NMR(300MHz,CDCl3)δ(ppm):9.75(1H,s,CONH),8.68(1H,s, ), ArH 8.57 (1H, s, ArH), 3.83 (4H, t, J=4.5Hz, 2CH2O),3.22(2H,s,COCH2), N 2.66 (4H, t, J= 4.4Hz,2CH2N),1.38(12H,s,4CH3).MS(ESI(+)70V)m/z:416.2[M+H]+.
2- (4- (4- morpholinyl -6- (6- (2- morpholinyl acetylamino) -4- (trifluoromethyl) pyridin-3-yl) -1,3,5- Triazine -2- base) piperazine -1- formoxyl) benzofuran -7- formamide (I-10)
With compound III-1 (300mg, 0.64mmol) and IV-6 (290mg, 0.70mmol) for raw material, same chemical combination is operated The method of object I-2, column chromatographic purifying (methylene chloride: methanol=100:1~50:1, gradient elution), obtains light yellow solid (I- 10) 300mg, yield 65.1%.m.p.120-122℃.1H-NMR(300MHz,DMSO-d6)δ(ppm):10.70(1H,s, ), CONH 8.90 (1H, s, ArH), 8.56 (1H, s, ArH), 7.92 (1H, d, J=7.7Hz, ArH), 7.83 (1H, d, J= 7.2Hz,ArH),7.81(1H,s,1/2CONH2),7.74(1H,s,1/2CONH2),7.56(1H,s,ArH),7.43(1H,t,J =7.6Hz, ArH), 3.94-3.63 (20H, m, 10CH2),3.29(2H,s,COCH2N),2.56(4H,s,2CH2).
Compound I-10 (250mg) is dissolved in 4mL ethyl acetate, the ethyl acetate solution of HCl saturation is added dropwise, is precipitated white Color solid is stirred at room temperature 15 minutes until pH value of solution=1~2, filters, ethyl acetate washs filter cake, is dried in vacuo to obtain I-10 Hydrochloride 235mg, HPLC:99.40%.1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):8.95(1H,s,ArH),8.51 (1H, s, ArH), 7.96 (1H, d, J=7.9Hz, ArH), 7.85 (1H, d, J=7.5Hz, ArH), 7.58 (1H, s, ArH), 7.46 (1H, t, J=7.6Hz, ArH), 4.34 (2H, s, COCH2N),4.09-3.86(12H,m,6CH2),3.75-3.31(12H, m,6CH2).13C-NMR(75MHz,DMSO-d6)δ(ppm):168.73,165.08,163.98,158.77,152.72, 151.29,150.91,148.65,146.44,137.01,127.67,126.68,125.45,123.63,120.77,120.14, 119.87,114.50,111.10,110.03,65.89,63.27,57.32,52.05,43.28,28.32,13.80.HRMS (ESI):m/z[M+H]+.Calcd for C33H36F3N10O6:725.2766；Found:725.2760.

Claims (10)

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:
Wherein X represents CH or N；
R1It represents
R2It represents R3Represent H, F, Br, Cl, CF3、CN、CH3Or OCH3；Y represents CH or N；Z represent O, NH、NCH3Or CH2；M=1 or 2.
2. the compound (I) of claim 1 or its pharmaceutically acceptable salt, wherein R1It represents R2It represents
3. a kind of method for the compound for preparing claim 1, works as R2It does not representWhen, comprising:
Wherein R1、R2Definition with claim 1.
4. method for claim 3 is carried out under the conditions of catalyst, alkali and reaction dissolvent is added, wherein catalyst is selected from double (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium or [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride；Alkali is selected from Sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate；Reaction dissolvent is selected from N,N-dimethylformamide, N, N- Dimethyl acetamide, glycol dimethyl ether, tetrahydrofuran, dioxane, toluene, ethyl alcohol, water or in which two or three any The mixed solvent of solvent；Reaction temperature is 95 DEG C~110 DEG C.
5. a kind of method for the compound for preparing claim 1, works as R2It representsWhen, comprising:
Wherein R1、R3Definition with claim 1.
6. method for claim 5 is carried out under the conditions of condensing agent, acid binding agent and reaction dissolvent is added, wherein condensing agent is Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, acid binding agent is n,N-diisopropylethylamine；Reaction dissolvent is N, Dinethylformamide.
7. the compound of claim 1 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt is logical formula (I) chemical combination The acid-addition salts of object, wherein for the acid at salt are as follows: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, wine Stone acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.
8. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used The carrier of receiving.
9. the compound of claim 1 or its pharmaceutically acceptable salt are in the preparation bis- target spot inhibitor medicaments of PARP-1 and PI3K In purposes.
10. the purposes of claim 9, wherein the bis- target spot inhibitor medicaments of PARP-1 and PI3K are anti-tumor drugs.
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