CN113549044B - 8-azacyclo-substituted chromone derivative and preparation method and pharmaceutical application thereof - Google Patents

8-azacyclo-substituted chromone derivative and preparation method and pharmaceutical application thereof Download PDF

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CN113549044B
CN113549044B CN202110836499.XA CN202110836499A CN113549044B CN 113549044 B CN113549044 B CN 113549044B CN 202110836499 A CN202110836499 A CN 202110836499A CN 113549044 B CN113549044 B CN 113549044B
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汪豪
龙桓
胡晓龙
熊非
叶文才
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Abstract

The invention discloses an 8-nitrogen heterocycle substituted chromone derivative, a preparation method and pharmaceutical application thereof, and belongs to the field of pharmaceutical chemistry. The invention provides an 8-azacyclo-substituted chromone compound with selective PARP1/2 inhibition activity, which can be used for preparing a medicament for preventing or treating PARP1/2 defective tumors, and has wide market application and development prospects.

Description

8-azacyclo-substituted chromone derivative and preparation method and pharmaceutical application thereof
Technical Field
The invention relates to a pharmaceutical chemistry technology, in particular to an 8-nitrogen heterocycle substituted chromone derivative, a preparation method and pharmaceutical application thereof.
Background
Poly (adenosine diphosphate) ribose polymerase-1 (PARP-1) is a nuclear enzyme that catalyzes polymorphonuclear saccharification in eukaryotic cells, playing an important role in mediating the base excision repair pathways, repairing intracellular abnormal DNA damage, and maintaining genome integrity. The repair mechanism of the PARP-1 on DNA single-strand damage is thoroughly studied at present: when DNA is broken and damaged, PARP-1 can rapidly identify and bind to damaged gaps, activate a poly (adenosine diphosphate) (PAR) synthesis pathway and repair damaged DNA. (Science 2016,353,45-50) several studies have shown that inhibition of PARP-1 can reduce DNA repair function and enhance chemotherapeutic effect on various tumors. Meanwhile, the system for repairing abnormal DNA in the cell is not the only system, and the activity of the cellular PARP-1 is normally eliminated or inhibited, and although the accumulation of single-stranded DNA breaks in the cell can be caused to a certain extent, another repair system in the cell, namely a breast cancer susceptibility gene BRCA-1 and BRCA-2 mediated Homologous Recombination (HR) pathway, can repair double-stranded DNA damage and maintain the stability of a chromosome. (Nature reviews. Molecular biology 2017,18,610-621) breast cancer is the most common cancer among female patients, the mortality rate of the patients is extremely high, and the BRCA-1 gene-related breast cancer patients are found to account for about 60% -80% of the etiology of breast malignant tumors. In cells repairing abnormal DNA, breast cancer and ovarian cancer cells defective or mutated in the oncogene BRCA-1/2 are 1000 times more sensitive to PARP-1 inhibitors than normal cells, inhibiting PARP-1 activity can target killing tumor cells, (Nature 2005,434,917-21;European journal of medicinal chemistry 2018,145,389-403) leading to synthetic death, and this synthetic lethal effect between PARP-1 and BRCA-1/2 is verified by clinical trials. In summary, PARP-1 inhibitors are key points in the treatment of tumor-related diseases, especially for BRCA-1 deficient tumors.
The PARP-1 inhibitors Olaparib (Olaparib) and rucabaresylate (Rucaparib), which are currently marketed, have good results both in combination with chemotherapy and alone in BRCA-deficient breast and ovarian cancers. Despite the great significance of PARP-1 inhibitors in tumor therapy and chemosensitization, there are still some disadvantages (Precision clinical medicine 2020,3,187-201) such as: 1) The selectivity is poor, most PARP-1 inhibitors have a certain inhibition effect on PARP-2, and after PARP-2 is defective or inhibited, the risks of cerebral apoplexy, embryo malformation and anemia are increased; 2) The half-life is very short, frequent administration is needed, and the compliance of patients is poor; 3) Side effects such as blood and lymphatic system disorder and gastrointestinal tract reaction, and pneumonia and embryotoxicity after drug withdrawal are rare; 4) The administration dosage is large, and whether the hidden toxicity exists or not needs to be further examined. Therefore, novel PARP-1 inhibitors with novel structure, better effect, less toxicity and better pharmacokinetic properties are still expected.
Disclosure of Invention
The invention aims to: aiming at the prior art, the invention provides an 8-nitrogen heterocycle substituted chromone derivative with selective PARP-1 inhibitory activity, and a preparation method and pharmaceutical application thereof.
The technical scheme is as follows: the 8-nitrogen heterocycle substituted chromone derivative or pharmaceutically acceptable salt, ester or solvate thereof has a structure shown in a formula I:
wherein R is 1 Selected from: H. OH, N 3 、F、C 1 -C 8 Alkyl, carboxyl, C 1 -C 8 Alkoxy, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 1 -C 8 Alkylcarbonyl, C 1 -C 8 Alkoxycarbonyl group, C 1 -C 8 Alkylsulfonyl, C 1 -C 8 Alkylsulfinyl, C 1 -C 8 Alkylthio, C 1 -C 5 Alkylcarbonylamino, C 1 -C 8 Alkylaminocarbonyl, di (C) 1 -C 3 ) Alkylaminocarbonyl, C 3 -C 8 Cycloalkyl, C 3 -C 8 Cycloalkyl oxy, C 3 -C 8 Heterocycloalkyl, C 3 -C 8 Heterocycloalkyloxy, phenyl, phenyloxy, phenyl (C) 1 -C 2 ) Alkyl, phenyl (C) 1 -C 2 ) Alkoxy, phenylsulfonyl, phenylsulfinyl, C 5 -C 6 Heteroaryl, C 5 -C 6 Heteroaryloxy, C 5 -C 6 Heteroaryl (C) 1 -C 3 ) Alkyl, C 5 -C 6 Heteroaryl (C) 1 -C 3 ) Alkoxy, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkyl, C 3 -C 8 Cycloalkyl (C) 1 -C 2 ) Alkoxy, C 3 -C 8 Heterocycloalkyl (C) 1 -C 2 ) Alkyl, heterocycloalkyl (C) 1 -C 2 ) An alkyloxy group, a condensed ring aryl group, or a substituted condensed ring aryl group, wherein R 1 Each of which may be unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C 1 -C 8 Alkyl and unsubstituted or halogenated C 1 -C 8 An alkoxy group;
R 2 selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、N 3 C of open chain 2 -C 8 Saturated or unsaturated alkyl, substituted C 3 -C 8 Cycloalkyl, substituted C 3 -C 8 Heterocycloalkyl, C 1 -C 9 Alkenyl, C 1 -C 9 Alkyl, wherein R is 2 Each of which may be unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, cyano, unsubstituted or halogenated C 1 -C 8 Alkyl and unsubstituted or halogenated C 1 -C 8 An alkoxy group;
R 3 、R 4 、R 5 independently selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、N 3 、Me、C 1 -C 8 Alkoxy, C 1 -C 8 Alkylthio, C 1 -C 5 Alkylcarbonylamino, C 1 -C 8 An alkoxycarbonyl group;
R 6 selected from: open chain C 2 -C 8 Saturated or unsaturated alkyl, substituted C 3 -C 8 Cycloalkyl, substituted C 3 -C 8 A heterocycloalkyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may be independently substituted with 1 to 3 substituents: H. f, cl, br, I, CN, NO 2 、NH 2 、N 3 、OH、-S(O) 2 NH 2 、-S(O) 2 NHCOCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, 1H-tetrazol-5-yl, 3H- [1,3,4]Oxadiazol-2-one-5-yl, 3H- [1,3,4]Oxadiazol-2-thione-5-yl, 4H- [1,2,4]Oxadiazol-5-one-3-yl, 4H- [1,2,4]Oxadiazol-5-thione-3-yl, 3H- [1,2,3,5]Oxathiadiazol-2-oxide-4-yl, wherein each alkyl or alkoxy group may be unsubstituted or substituted with one or more substituents selected from halogen and unsubstituted or fluorinated C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group;
a is selected from: furan, thiophene, piperidine, pyridine, pyrrole, imidazole, thiazole, oxazole, piperazine, tetrahydrofuran, tetrahydrothiophenePyridine, imidazoline, thiazoline, oxazoline, C 1 -C 6 Diazole, C 1 -C 6 Triazole, pyrazine and pyridazine, the heterocyclic rings can be independently substituted by 2-4C 1 -C 3 Alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, hydroxyalkyl or alkoxyalkyl substitution;
x is selected from: s (O) 2 -, -C (O) -or- (CH) 2 ) n-; n=0, 1 or 2;
y is selected from: 0 to 1N or C;
wherein m=0 or 1.
In certain preferred embodiments, the compounds of formula I of the present invention, pharmaceutically acceptable salts or esters or solvates thereof:
R 1 preferably selected from: H. c (C) 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, wherein the substituted phenyl or substituted heteroaryl may be substituted independently with 1 to 3 substituents: F. cl, br, I, CN, NO 2 、NH 2 、OH、C 1 -C 3 An alkyl group.
R 2 Preferably selected from: H. f, cl, br, I, CN, NO 2 、NH 2 、OH、N 3 Substituted C 3 -C 8 A heterocycloalkyl group.
R 3 、R 4 、R 5 Independently preferably from: H. c (C) 1 -C 8 Alkoxy, C 1 -C 8 Alkylthio, C 1 -C 5 Alkylcarbonylamino, C 1 -C 8 An alkoxycarbonyl group.
R 6 Preferably selected from: open chain C 2 -C 8 Saturated or unsaturated alkyl, substituted C 3 -C 8 Cycloalkyl, substituted C 3 -C 8 A heterocycloalkyl, substituted phenyl, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, wherein said substituted phenyl, substituted heteroaryl, or substituted fused ring aryl may be independently substituted with 1 to 3 substituents:H、F、Cl、Br、I、CN、NO 2 、NH 2 、N 3 。
a is preferably selected from: piperidine, pyridine, pyrrole, imidazole, thiazole, oxazole, piperazine, tetrahydropyridine, imidazoline, thiazoline, oxazoline, can be independently substituted with 2-4C 1 -C 3 Alkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, hydroxyalkyl or alkoxyalkyl substitution.
X is-C (O) -or- (CH) 2 ) n-; n=1; y is selected from: 0 to 1N or C; wherein m=0 or 1.
Further preferred, the derivatives of the invention are selected from the following compounds 1-90:
the compounds of the present invention may also be used as pharmaceutically acceptable salts. The salt may be an acid salt of at least one of the following acids: galactose, D-glucuronic acid, glycerophosphate, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1, 5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharin acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, camphoric acid, dichloroacetic acid, ethanesulfonic acid. Alternatively, the salts may be salts of the compounds of the present invention with metal (including but not limited to sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including but not limited to ethylenediamine, tromethamine, etc.), ammonium ions or choline.
The compounds of the present invention may also be formulated in the form of esters, prodrugs, N-oxides or solvates thereof as the active ingredient in a pharmaceutical composition. The pharmaceutical composition is in the form of capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, cream, ointment, suppository or patch.
The use of the compound of formula I or a pharmaceutically acceptable salt or ester or solvate thereof in the manufacture of a medicament for the prevention or treatment of PARP1/2 mediated BRCA1 deficient neoplasms is also within the scope of the invention.
The compounds of formula I or pharmaceutically acceptable salts or esters or solvates thereof are novel PARP1/2 inhibitors and are therefore useful in the preparation of a medicament for the prevention or treatment of PARP1/2 mediated BRCA1 deficient tumors. The PARP related disease is cancer, apoplexy, myocardial infarction, inflammation, hypertension, atherosclerosis or diabetes. The PARP1/2 mediated BRCA-1 deficient tumor is ovarian cancer, breast cancer, fallopian tube cancer, malignant peritoneal tumor, metastatic breast cancer, ovarian epithelial cancer, primary peritoneal cancer, advanced epithelial ovarian cancer of advanced harmful germ line or somatic BRCA-variant, advanced harmful germ line or somatic BRCA-mutated fallopian tube cancer, advanced harmful germ line or somatic BRCA mutated peritoneal cancer refractory advanced ovarian cancer.
Preferred compounds are combined with at least one of the following compounds: platinum-based antitumor agents (including cisplatin, carboplatin, dicycloplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin), nucleoside analogs and antimetabolites (including arabinoside, fludarabine, gemcitabine, 5 FU), DNA intercalators (including daunorubicin, doxorubicin, epirubicin and idarubicin, camptothecin), alkylated oncological agents (including cyclophosphamide, melphalan, bendamustine, carmustine, lomustine, ifosfamide), topoisomerase inhibitors (including etoposide, topotecan), PARP inhibitors (including orapanoramide, nilapatinib, lu Kapa), microtubule dynamics-interfering substances (including combretastatin, eribulin, docetaxel, taxane, vincaline, vincristine), substances that block interactions between p53 and MDM2 or MDM4 (including noolin, darunamide, HDM-3032 b, mdg 232, mTOR-rn), rapamitrazine (including fluvalproic acid, 35 f) and the group of inhibitors (including fludarabine), rapamitrazine, including fluvalproic acid, fludarabine (including fludarabine), the group (including fludarabine, 35 f) and the inhibitors (including fludarabine), the group (including fludarabine, 35, fludarabine, and the inhibitors (including gstrobin, including fluparvozole), the inhibitors (including fluparafine, 35, fluparafat, 35, vispride, and the group (including fluparvozole) or the inhibitors) Benzamide (including entinostat, moetinostat), proteasome inhibitors (including bortezomib, ritonavir, carfilzomib), anti-vascular or anti-angiogenic agents (including 2aG4, bevacizumab), tyrosine kinase inhibitors (including lapatinib), EGFR inhibitors (including gefitinib), CDK inhibitors, PLK inhibitors, MEK inhibitors (including pimatib), immune checkpoint inhibitors (including antibodies to PD-1 (including nivolumab, pembrolizumab), PD-L1 (avermectin, atuzumab), PDL2, CTLA-4 (including ipilimumab, trimethoprim), GITR, IL-40, CD-40, LAG3/CD-223 (including BMS-986016, REGN 3767), gin inhibitors (including nivolumab, bevacizumab), and/or anti-angiogenic agents (including bevacizumab) OX-40 (including borrelizumab, PF-04518600)), antibody binding protein tyrosine kinase receptor, NFE2L2 inhibitors (including ML385, brucella, trigonelline, luteolin, ascorbic acid, ATRA), autologous T cells genetically engineered to express Chimeric Antigen Receptors (CARs) that recognize extracellular cancer targets (including CD19, PSMA, or mesothelin), glucocorticoid receptor agonists (including dexamethasone), sulfoxylamine, folic acid, metformin, sorafenib, sulfasalazine, bleomycin, erlotinib, tunicamycin, wortmannin, pilocarb, dewaruzumab, GSK3174998, tavoriximab, deazapine a, or piperlongamide.
Preferably the compound is administered alone or in combination with other active pharmaceutical ingredients, and wherein the administration is also optionally in combination with: external beam radiation by gamma radiation or neutron radiation; or targeted therapy with antibodies labeled with beta or alpha emitting radionuclides including I-131, Y-90, lu-177, bi-213, ac-225, th-227; or radiation therapy with Ra-223.
The auxiliary materials which can be arbitrarily mixed in the pharmaceutical composition of the present invention may vary depending on the dosage form, administration form, etc. The auxiliary materials comprise excipient, adhesive, disintegrating agent, lubricant, flavoring agent, colorant, sweetener, etc. The route of administration of the pharmaceutical composition may be oral, sublingual, transdermal, intramuscular or subcutaneous, cutaneous mucosal or intravenous etc. The pharmaceutical composition can be in the form of conventional preparations such as capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, cream, ointment, suppository or patch.
The preparation of the compounds of the present invention may be carried out with reference to the following synthetic routes or modified methods.
Scheme 1.
Wherein R is 1 ，R 2 ，R 3 ，R 4 ,R 5 And R is 6 The definition is the same as before.
Firstly, taking substituted alpha-chloroacetophenone (II) as a raw material, carrying out addition cyclization reaction with aldehyde under alkaline condition to obtain corresponding chromone intermediates IV of various substituted types, and then carrying out Mannich reaction with formaldehyde and substituted secondary alcohol V to obtain corresponding Mannich base VI. Wherein IV is prepared by reacting compound II with III, and the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride, preferably sodium hydroxide. The reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol and perfluoroisopropanol, preferably methanol; the reaction temperature is 10 to 60℃and preferably 30 to 50 ℃.
The compound VI is prepared from the compound IV by using formaldehyde which is selected from 10-50% aqueous solution, preferably 37% -40% aqueous formaldehyde solution, and the solvent which is selected from methanol, ethanol, isopropanol, diethyl ether, methyl tert-butyl ether, tetrahydrofuran and acetonitrile, preferably tetrahydrofuran.
Scheme 2.
Wherein R is 1 ，R 3 ，R 4 ，R 5 And R is 6 The definition is the same as before.
Firstly, taking substituted acetophenone (VI) as a raw material, carrying out a Claisen condensation reaction with aldehyde under alkaline condition, closing a ring of a crude product under the condition that iodine simple substance is taken as a catalyst to generate VII, and the rest steps are similar to the scheme I.
Compound VII is prepared from compound VI using a base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium hydride, preferably potassium hydroxide. The reaction solvent is selected from methanol, ethanol, isopropanol and tert-butanol, preferably ethanol; the reaction temperature is 10-50 ℃, preferably 10-30 ℃; the solvent used in the ring closing step is selected from the group consisting of: dimethyl sulfoxide, N-dimethylformamide, toluene, preferably dimethyl sulfoxide. The reaction temperature is 60 to 120℃and preferably 80 to 110 ℃.
In the medicament for preventing or treating PARP1/2 mediated diseases of the present invention, the amount of the compound of formula I or a pharmaceutically acceptable salt or ester or solvate thereof may be appropriately changed according to the age, weight, symptoms, administration route, etc. of the patient. When administered orally to an adult (about 60 kg), the compound of formula I or a pharmaceutically acceptable salt or ester or solvate thereof is preferably administered in an amount of 1 to 500 mg/time, more preferably 5 to 60 mg/time, 1 to 3 times per day. This dosage range may also vary depending on the degree of disease and the dosage form.
The beneficial effects are that: the invention provides an 8-azacyclo-substituted chromone compound with selective PARP1/2 inhibition activity, which can be used for preparing a medicament for preventing or treating PARP1/2 defective tumors, and has wide market application and development prospects.
Drawings
FIG. 1 is the results of an anti-SK-OV-3 cell proliferation assay for the compounds;
FIG. 2 is the results of antitumor effect in vivo of the compounds;
FIG. 3 is a graph showing the results of chemosensitization in compounds;
FIG. 4 shows the results of anti-tumor and chemosensitization in vivo.
Detailed Description
The following is a detailed description of the present invention by way of examples.
Example 1 8- ((4- (cyclopropanecarbonyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 1)
The II-1 powder (1.01 g,5 mmol) was dissolved in methanol (20 mL) to prepare a solution, and potassium hydroxide (2.52 g,15 mmol) of parahydroxybenzaldehyde (0.62 g,5.05 mmol) was added to the solution. The mixture was left at room temperature and stirred for 18h. After monitoring complete disappearance of II-1 by thin layer chromatography, the mixture was diluted with ice-cooled water (50 mL) and acidified to ph=5 with 2M hydrochloric acid. Excess methanol was removed by rotary evaporator. The residue was extracted three times with dichloromethane and water. Taking the combined organic layers, passing through Na 2 SO 4 Drying and removing the solvent by a rotary evaporator. The residue was purified by silica gel column chromatography (dichloromethane and methanol, from 99:1 to 93:7) to give pure compound IV (0.82 g, 61%).
A solution of 1-cyclopropylpiperazine (142. Mu.L, 1 mmol) in acetonitrile (10 ml) was added dropwise at room temperature to a solution of compound IV-1 (0.27 g,1.0 mmol) in acetonitrile (5 ml) containing paraformaldehyde (94.6 mg,1.05 mmol). The reaction mixture was stirred until compound IV-1 had completely disappeared. Followed by rotary evaporationThe reaction solvent was removed by an instrument. The residue was purified by flash column chromatography using DCM and MeOH as eluent and silica gel as column to give compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.04(bs,1H),7.95(d,J＝8.8Hz,2H),6.95(d,J＝8.8Hz,2H),6.80(s,1H),6.25(s,1H),3.85(bs,2H),3.68(bs,2H),3.48(s,2H),2.63–2.50(m,4H),2.04–1.85(m,1H),0.94–0.52(m,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.3,171.3,164.2,163.9,161.6,160.7,155.6,128.8(C×2),121.7,116.4(C×2),103.9,103.0,101.5,99.0,54.5(C×2),52.6(C×2),50.7,10.6,7.3(C×2).
example 2 8- ((4- (Cyclobutanecarbonyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 2)
Compound 2 is prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.03(s,1H),10.33(bs,1H),7.94(d,J＝8.7Hz,2H),6.94(d,J＝8.7Hz,2H),6.80(s,1H),6.24(s,1H),3.83(s,2H),3.50(bs,2H),3.39–3.25(m,3H),2.51(bs,4H),2.24–1.98(m,4H),1.97–1.81(m,1H),1.81–1.65(m,1H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.4,172.3,164.1,164.0,161.6,160.8,155.6,128.8(C×2),121.8,116.4(C×2),104.0,103.1,101.4,99.0,52.9,52.5,50.9,44.7,40.8,36.6,24.9(C×2),17.8.
example 3 8- ((4- (Cyclohexanecarbonyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 3)
Compound 3 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(bs,1H),7.92(d,J＝8.7Hz,2H),6.94(d,J＝8.8Hz,2H),6.77(s,1H),6.23(s,1H),3.83(bs,2H),3.47(bs,4H),2.65–2.38(m,5H),1.75–1.52(m,5H),1.40–1.12(m,5H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.0,173.3,163.7,163.5,161.2,160.4,155.2,128.4(C×2),121.4,116.0(C×2),103.6,102.7,101.0,98.6,52.8,52.2,50.4(C×2),44.7,40.9,29.1(C×2),25.6,25.1(C×2).
example 4 8- ((4-Acetylpiperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 4)
Reference compound 1 formulaPreparing a compound 4; 1 H NMR(300MHz,DMSO–d 6 )δ13.04(s,1H),10.34(bs,1H),7.95(d,J＝8.8Hz,2H),6.95(d,J＝8.8Hz,2H),6.81(s,1H),6.25(s,1H),3.84(s,2H),3.44(bs,4H),2.53(bs,4H),1.98(s,3H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,168.0,163.6,163.5,161.1,160.3,155.1,128.4(C×2),121.4,115.9(C×2),103.6,102.6,101.0,98.5,52.3,51.9,50.3,45.5,40.7,21.0.
example 5 8- ((4-Benzoylpiperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 5)
Compound 5 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.03(bs,1H),7.94(d,J＝7.9Hz,2H),7.66–7.22(m,5H),6.95(d,J＝8.0Hz,2H),6.79(s,1H),6.24(s,1H),3.84(s,2H),3.72–3.26(m,4H),2.57(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.0,168.9,163.6,163.5,161.2,160.4,155.2,135.8,129.5,128.4(C×2),128.4(C×2),126.9(C×2),121.4,116.0(C×2),103.6,102.6,101.1,98.5,52.2(C×2),50.3,47.3,41.5.
example 6 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (4-methoxybenzoyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 6)
Compound 6 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.01(s,1H),7.90(d,J＝8.4Hz,2H),7.33(d,J＝8.2Hz,2H),7.02–6.89(m,4H),6.69(s,1H),6.20(s,1H),3.81(s,2H),3.75(s,3H),3.49(bs,4H),2.55(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,168.9,165.3,163.4,161.7,160.4,160.2,155.5,129.0(C×2),128.3(C×2),127.8,121.2,116.2(C×2),113.6(C×2),103.1,102.4,101.4,98.9,55.2,52.4,50.3(C×2),47.0,41.6.
example 7, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 7)
Compound 7 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.04(s,1H),10.34(s,1H),7.93(d,J＝8.6Hz,2H),7.81(d,J＝6.7Hz,1H),7.77–7.63(m,3H),6.95(d,J＝8.6Hz,2H),6.78(s,1H),6.24(s,1H),3.86(s,2H),3.72–3.55(m,2H),3.46–3.27(m,2H),2.61(s,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.0,167.4,163.6(C×2),161.2,160.4,155.3,136.9,130.9,130.0(q,J CF ＝31.7Hz),129.6,128.4(C×2),129.2(q,J CF ＝271.0Hz),126.2(q,J CF ＝3.6Hz),123.7(q,J CF ＝3.5Hz),121.4,116.0(C×2),103.7,102.7,101.0,98.5,52.0,50.2(C×2),47.0,41.4； 19 F NMR(376MHz,DMSO–d 6 )δ-62.7.
example 8 8- ((4- (4-chlorobenzoyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl-yl) -4H-benzopyran-4-one (Compound 8)
Compound 8 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ7.91(d,J＝8.6Hz,2H),7.61–7.34(m,4H),6.95(d,J＝8.6Hz,2H),6.73(s,1H),6.23(s,1H),3.83(s,2H),3.74–3.19(m,4H),2.58(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,167.9,163.6,163.6,161.20 160.5,155.3,134.6,134.3,128.9(C×2),128.5(C×2),128.4(C×2),121.5,116.1(C×2),103.7,102.7,101.0,98.6,52.2(C×2),50.3,46.6,41.4.
example 9 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4-nicotinoylpiperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 9)
Compound 9 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.02(s,1H),8.70–8.55(m,2H),7.92(d,J＝8.6Hz,2H),7.81(d,J＝7.8Hz,1H),7.45(dd,J＝7.6,4.8Hz,1H),6.93(t,J＝8.2Hz,2H),6.76(s,1H),6.23(s,1H),3.83(s,2H),3.68(bs,2H),3.36(bs,2H),2.57(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,166.7,164.1,163.6,161.1,160.4,155.2,150.4,147.6,134.7,131.6,128.4(C×2),123.4,121.4,116.0(C×2),103.6,102.6,101.1,98.5,52.1(C×2),50.2,47.1,41.6.
example 10 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4-isonicotinylpiperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 10)
Compound 10 was prepared by the reference compound 1 method; 1 H NMR(300MHz,DMSO–d 6 )δ8.65(s,2H),7.91(s,2H),7.37(s,2H),6.94(s,2H),6.76(s,1H),6.24(s,1H),3.83(s,2H),3.65(bs,2H),3.28(bs,2H),2.62(bs,2H),2.51(bs,2H)； 13 C NMR(300MHz,DMSO–d 6 )δ182.3,167.0,163.9,161.5,161.1,160.7,155.6,150.4(C×2),143.7,128.8(C×2),121.5,121.4(C×2),116.4(C×2),104.0,103.0,101.5,98.9,52.2,50.5,47.3,47.2,41.6.
example 11 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4-pyridylpiperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 11)
Compound 11 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.03(bs,1H),10.28(bs,1H),8.56(d,J＝3.9Hz,1H),8.03–7.82(m,3H),7.55(d,J＝7.6Hz,1H),7.51–7.39(m,1H),6.94(d,J＝8.3Hz,2H),6.77(s,1H),6.23(s,1H),3.84(s,2H),3.66(bs,2H),3.41(bs,2H),2.63(bs,2H),2.54(bs,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.3,167.0,165.0,164.1,161.6,160.8,155.6,154.4,148.7,137.6,128.8(C×2),124.9,123.5,121.9,116.4(C×2),104.1,103.1,101.5,99.0,52.9,52.4,50.7,46.8,41.9.
example 12 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- (((4- (thiophene-2-carbonyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 12)
Compound 12 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ7.92(d,J＝8.7Hz,2H),7.71(dd,J＝4.9,0.6Hz,1H),7.42–7.32(m,1H),7.09(dd,J＝4.8,3.8Hz,1H),6.94(d,J＝8.7Hz,2H),6.75(s,1H),6.23(s,1H),3.84(s,2H),3.65(bs,4H),2.59(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.0,163.7,163.6,162.3,161.2,160.4,155.2,137.1,129.4,129.1,128.4(C×2),127.1,121.4,116.1(C×2),103.7,102.7,101.1,98.6,52.6(C×2),50.6,46.8,41.9.
example 13 8- (((4- (furan-2-carbonyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 13)
Compound 13 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ7.96(d,J＝8.0Hz,2H),7.82(s,1H),7.06–6.90(m,3H),6.80(s,1H),6.62(s,1H),6.27(s,1H),3.88(s,2H),3.70(bs,4H),2.62(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,163.5,163.4,162.1,161.0,160.3,155.1,136.9,129.0,128.8,128.2(C×2),126.8,121.3,115.9(C×2),103.6,102.6,100.9,98.4,52.1(C×2),50.2,44.6,40.3.
example 14 benzyl 4- (((5, 7-dihydroxy-2- (4-hydroxyphenyl) -4-oxo-4H-benzopyran-8-yl) methyl) piperazine-1-carboxylate (Compound 14)
Compound 14 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.04(bs,1H),10.04(bs,1H),7.93(d,J＝8.4Hz,2H),7.34(bs,5H),6.95(d,J＝8.5Hz,2H),6.78(s,1H),6.24(s,1H),5.07(s,2H),3.82(s,2H),3.42(s,4H),2.53(s,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,163.6,163.5,161.1,160.3,155.1,154.3,136.8,128.3(C×2),128.3(C×2),127.7,127.4(C×2),121.3,115.9(C×2),103.6,102.6,100.9,98.5,66.1,51.9(C×2),50.4,43.4(C×2).
example 15 3, 5-dimethylbenzyl 4- ((5, 7-dihydroxy-2- (4-hydroxyphenyl) -4-oxo-4H-benzopyran-8-yl) methyl) piperazine-1-carboxylic acid (Compound 15)
Compound 15 was prepared by the reference compound 1 method; 1 H NMR(500MHz,DMSO–d 6 )δ13.03(bs,1H),9.80(bs,1H),7.99–7.85(m,2H),6.94(d,J＝8.7Hz,2H),6.77(s,1H),6.48(s,2H),6.42(s,1H),6.23(s,1H),4.99(s,2H),3.82(s,2H),3.71(s,6H),3.42(bs,4H),2.53(bs,4H)； 13 C NMR(125MHz,DMSO–d 6 )δ181.9,163.6,163.5,161.1,160.5(C×2),160.4,155.2,154.2,139.2,128.4(C×2),121.4,116.0(C×2),105.1(C×2),103.6,102.6,100.9,99.4,98.5,65.9,55.1(C×2),51.9(C×2),50.4,43.4(C×2).
example 16 8- (((4- (cyclopropylmethyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 16)
Compound 16 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ12.99(bs,1H),7.91(bs,2H),6.94(d,J＝8.3Hz,2H),6.75(s,1H),6.16(s,1H),3.90(s,2H),2.61(bs,4H),2.51(bs,4H),2.17(d,J＝6.1Hz,2H),0.79(s,1H),0.51–0.34(m,2H),0.12–0.01(m,2H)； 13 C NMR(300MHz,DMSO–d 6 )δ181.9,164.8,163.4,161.2,160.4,154.8,128.4(C×2),121.4,116.0(C×2),103.4,102.6,100.2,98.8,62.5,52.4(C×2),52.0(C×2),51.4,8.1,3.6(C×2)
example 17- ((4- (cyclohexylmethyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 17)
Compound 17 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ12.98(bs,1H),7.93(d,J＝8.4Hz,2H),6.93(d,J＝8.4Hz,2H),6.76(s,1H),6.16(s,1H),3.91(s,2H),2.60(bs,4H),2.36(bs,4H),2.06(d,J＝6.8Hz,2H),1.78–1.52(m,5H),1.44(bs,1H),1.23–1.07(m,3H),0.89–0.69(m,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.7,163.3,161.1,160.3,154.7,128.4(C×2),121.3,115.9(C×2),103.3,102.6,100.1,98.7,64.5,52.9(C×2),52.1(C×2),51.4,34.3,31.1(C×2),26.3,25.4(C×2).
example 18 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- (((4-isopentylpiperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 18)
Compound 18 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.02(s,1H),8.11–7.76(m,2H),7.08–6.84(m,2H),6.73(s,1H),6.14(s,1H),3.88(s,2H),2.78–2.50(m,4H),2.51–2.29(m,4H),2.25(s,2H),1.69–1.42(m,1H),1.40–1.19(m,2H),1.04–0.64(m,6H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.8,163.3,161.2,160.4,154.7,128.3(C×2),121.3,115.9(C×2),103.3,102.6,100.1,98.8,55.7,52.6(C×2),52.0(C×2),51.4,35.2,25.7,22.5(C×2).
example 19 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (4-methylbenzyl) piperazin-1-yl) methyl-yl) -4H-benzopyran-4-one (Compound 19)
Compound 20 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(bs,1H),7.91(d,J＝8.7Hz,2H),7.22–7.07(m,4H),6.94(d,J＝8.6Hz,2H),6.74(s,1H),6.16(s,1H),3.90(s,2H),3.41(s,2H),2.61(bs,4H),2.40(bs,4H),2.25(s,3H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.7,163.3,161.1,160.3,154.7,135.9,134.8,128.7(C×2),128.6(C×2),128.3(C×2),121.3,115.9(C×2),103.4,102.6,100.1,98.7,61.5,52.2(C×2),52.0(C×2),51.4,20.6.
example 20- ((4- (4-chlorobenzyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 20)
Compound 20 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(bs,1H),7.93(d,J＝8.6Hz,2H),7.41–7.26(m,4H),6.94(d,J＝8.7Hz,2H),6.77(s,1H),6.17(s,1H),3.90(s,2H),3.46(s,2H),2.61(bs,4H),2.41(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.5,163.4,161.1,160.3,154.7,137.1,131.4,130.5(C×2),128.4(C×2),128.1(C×2),121.3,115.9(C×2),103.4,102.6,100.2,98.7,60.8,52.3(C×2),52.0(C×2),51.2.
example 21 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (4-methoxybenzyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 21)
Compound 21 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ12.98(bs,1H),7.91(d,J＝5.8Hz,2H),7.17(d,J＝7.6Hz,2H),6.89(dd,J＝26.2,7.9Hz,4H),6.74(s,1H),6.16(s,1H),3.89(s,2H),3.71(s,3H),3.38(s,2H),2.59(bs,4H),2.38(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.7,163.3,161.1,160.3,158.3,154.7,129.9(C×2),129.7,128.3(C×2),121.3,115.9(C×2),113.5(C×2),103.4,102.6,100.1,98.7,61.1,54.9,52.2(C×2),52.0(C×2),51.4.
example 22 8- (((4- (3, 5-dimethoxybenzyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 22)
Compound 22 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(bs,1H),7.94(d,J＝8.8Hz,2H),6.94(d,J＝8.8Hz,2H),6.77(s,1H),6.46(d,J＝2.2Hz,2H),6.36(d,J＝2.2Hz,1H),6.17(s,1H),3.92(s,2H),3.71(s,6H),3.41(s,2H),2.63(bs,4H),2.42(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.6,163.4,161.1,160.3(2C),160.3,154.7,140.5,128.4(2C),121.3,115.9(2C),106.5(2C),106.5,103.4,102.6,100.1,98.7,61.8,55.0(2C),52.3(2C),52.0(2C),51.4.
example 23 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (2, 3, 4-trimethoxybenzyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 23)
Compound 23 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(bs,1H),7.93(d,J＝8.0Hz,2H),7.02–6.87(m,3H),6.83–6.67(m,2H),6.17(s,1H),3.91(s,2H),3.77(s,6H),3.73(s,3H),3.40(s,2H),2.61(bs,4H),2.43(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.6,163.4,161.1,160.3,154.7,152.5,151.9,141.8,128.3(2C),124.6,123.4,121.3,115.9(2C),107.5,103.3,102.6,100.1,98.7,60.8,60.2,55.7,55.6,52.2(2C),52.1(2C),51.3
example 24 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 24)
Compound 24 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ12.99(s,1H),7.93(d,J＝8.3Hz,2H),7.66(d,J＝7.8Hz,2H),7.51(d,J＝7.6Hz,2H),6.94(d,J＝8.4Hz,2H),6.77(s,1H),6.17(s,1H),3.90(s,2H),3.56(s,2H),2.62(bs,4H),2.43(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.5,163.4,161.1,160.3,154.8,143.2,130.1(q,J CF ＝270.5Hz),129.2(2C),128.4(q,J CF ＝31.2Hz,2C),128.2,124.9(q,J CF ＝3.1Hz,2C),121.3,116.0(2C),103.4,102.6,100.3,98.7,61.0,52.4(2C),52.0(2C),51.2； 19 F NMR(376MHz,DMSO–d 6 )δ-62.4.
example 25 8- (4- (4-fluorobenzyl) phenylzin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl-yl) -4H-benzopyran-4-one (Compound 25)
Compound 25 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(s,1H),7.93(d,J＝8.6Hz,2H),7.37–7.23(m,2H),7.18–7.02(m,2H),6.94(d,J＝8.6Hz,2H),6.77(s,1H),6.17(s,1H),3.90(s,2H),3.45(s,2H),2.60(bs,4H),2.40(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,164.8(d,J CF ＝249.5Hz),164.5,163.4,161.1,160.3,154.7,134.2,130.6(d,J CF ＝7.7Hz,2C),128.4(2C),121.3,116.0(2C),115.0(d,J CF ＝20.8Hz,2C),103.4,102.6,100.2,98.7,60.8,52.2(2C),52.0(2C),51.3； 19 F NMR(376MHz,DMSO–d 6 )δ-115.93.
example 26 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- ((tetrahydrofuran-2-yl) methyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 26)
Compound 26 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.02(s,1H),8.20–7.70(m,2H),7.09–6.82(m,2H),6.75(s,1H),6.22(s,1H),4.00(bs,3H),3.80(s,2H),3.63(s,2H),3.37(bs,4H),2.50(bs,4H),1.70(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,163.7,161.2,160.4,155.1,154.4,128.4(2C),121.4,116.0(2C),103.6,102.6,101.0,98.6,64.1,51.9(2C),50.5,45.0,43.3,28.7,26.0；
example 27 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (thiophen-2-ylmethyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 27)
Compound 27 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO-d6)δ12.98(bs,1H),9.16(bs,2H),7.92(d,J＝8.7Hz,2H),7.47–7.31(m,1H),7.03–6.85(m,4H),6.74(s,1H),6.16(s,1H),3.90(s,2H),3.68(s,2H),2.62(bs,4H),2.46(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.5,163.4,161.1,160.3,154.7,141.4,128.4(2C),126.4,126.0,125.4,121.3,116.0(2C),103.4,102.6,100.2,98.7,56.0,52.0(2C),51.2.
example 28- (((4- (furan-2-ylmethyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 28)
Compound 28 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ12.99(bs,1H),10.00(bs,1H),7.88(d,J＝8.5Hz,2H),7.54(s,1H),6.92(d,J＝8.6Hz,2H),6.71(s,1H),6.37(d,J＝1.6Hz,1H),6.24(s,1H),6.15(s,1H),3.86(s,2H),3.48(s,2H),2.59(bs,4H),2.43(bs,4H)； 13 C NMR(300MHz,DMSO–d 6 )δ181.8,164.6,163.4,161.1,160.4,154.7,151.6,142.3,128.3(2C),121.4,116.0(2C),110.2,108.6,103.4,102.6,100.2,98.7,53.6,52.0(2C),51.9(2C),51.3.
example 29 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (pyridin-4-ylmethyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 29)
Compound 29 was prepared according to the procedure of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ12.99(s,1H),8.49(d,J＝5.4Hz,2H),7.93(d,J＝8.7Hz,2H),7.30(d,J＝5.4Hz,2H),6.94(d,J＝8.7Hz,2H),6.76(s,1H),6.17(s,1H),3.90(s,2H),3.50(s,2H),2.62(bs,4H),2.43(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,164.4,163.4,161.2,160.3,154.8,149.8(2C),147.2,128.4(2C),123.6(2C),121.4,116.0(2C),103.5,102.7,100.3,98.7,60.3,52.4(2C),52.0(2C),51.2.
example 30 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (thiophen-3-ylmethyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 30)
Compound 30 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ7.87(d,J＝8.6Hz,2H),7.46–7.37(m,1H),7.24(s,1H),7.01(d,J＝4.8Hz,1H),6.94(d,J＝8.6Hz,2H),6.67(s,1H),6.15(s,1H),3.89(s,2H),3.48(s,2H),2.61(bs,4H),2.42(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.2,165.1,163.8,161.6,160.8,155.1,139.3,128.8,128.7(2C),126.1,123.2,121.8,116.4(2C),103.9,103.1,100.5,99.2,56.9,52.6(2C),52.5(2C),51.9.
example 31 8- (((4- (furan-3-ylmethyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 31)
Compound 31 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.01(bs,1H),7.91(d,J＝8.4Hz,2H),7.55(d,J＝16.6Hz,2H),6.94(d,J＝8.3Hz,2H),6.74(s,1H),6.40(s,1H),6.16(s,1H),3.89(s,2H),3.32(s,2H),2.61(bs,4H),2.41(bs,4H)； 13 C NMR(300MHz,DMSO–d 6 )δ181.8,164.7,163.4,161.1,160.4,154.7,143.2,140.8,128.3(2C),121.4,121.3,116.0(2C),111.4,103.4,102.6,100.1,98.8,52.1(2C),52.0(2C),51.8,51.3.
example 32 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4-phenylpiperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 32)
Compound 32 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.03(bs,1H),8.52(bs,2H),7.94(d,J＝8.6Hz,2H),7.28–7.12(m,2H),7.01–6.83(m,4H),6.81–6.73(m,2H),6.23(s,1H),3.90(s,2H),3.15(s,4H),2.71(s,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,164.0,163.5,161.1,160.3,155.0,150.7,128.8(2C),128.4(2C),121.4,118.9,115.9(2C),115.4(2C),103.5,102.6,100.7,98.6,52.1(2C),50.8,48.2(2C).
example 33 5, 7-dihydroxy-2- (2-hydroxyphenyl) -8- ((4- (2-hydroxyphenyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 33)
Compound 33 was prepared by the method of reference compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.02(bs,1H),7.96(d,J＝8.7Hz,2H),6.95(d,J＝8.6Hz,2H),6.93–6.86(m,1H),6.85–6.71(m,4H),6.21(s,1H),3.96(s,2H),2.98(s,4H),2.76(s,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ182.3,164.8,163.9,161.6,160.8,155.3,150.5,139.9,128.8(2C),123.3,121.8,119.7,119.1,116.4(2C),115.9,103.9,103.1,100.9,99.1,52.7(2C),51.7,50.4(2C).
example 34 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (4-hydroxyphenyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 34)
Compound 34 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.02(bs,1H),7.94(d,J＝7.5Hz,2H),6.94(d,J＝8.6Hz,2H),6.82–6.69(m,3H),6.70–6.55(m,2H),6.21(s,1H),3.91(s,2H),2.98(s,4H),2.70(s,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,164.3,163.5,161.2,160.4,154.9,151.0,143.9,128.4(2C),121.4,117.9(2C),116.0(2C),115.5(2C),103.5,102.7,100.7,98.7,52.3(2C),51.0,50.0(2C).
example 35, 7-dihydroxy-2- (4-hydroxyphenyl) -8- (((4- (p-tolyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 35)
Compound 35 was prepared by the method of reference compound 1; 1 H NMR(500MHz,DMSO–d 6 )δ13.02(bs,1H),9.83(bs,1H),8.00–7.89(m,2H),6.99(d,J＝5.2Hz,2H),6.94(d,J＝8.7Hz,2H),6.85–6.72(m,3H),6.22(s,1H),3.90(s,2H),3.08(s,4H),2.70(s,4H),2.17(s,3H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,164.1,163.5,161.1,160.4,154.9,148.7,129.3(2C),128.4(2C),127.7,121.4,115.9(2C),115.7(2C),103.5,102.6,100.7,98.6,52.1(2C),50.9,48.7(2C),19.9.
example 36 8- (((4- (4-chlorophenyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 36)
Compound 36 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.03(bs,1H),10.23(bs,1H),7.95(d,J＝8.7Hz,2H),7.21(d,J＝8.9Hz,2H),7.02–6.85(m,4H),6.79(s,1H),6.24(s,1H),3.89(s,2H),3.16(bs,4H),2.69(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,163.8,163.5,161.1,160.3,155.0,149.5,128.5(2C),128.4(2C),122.4,121.3,116.8(2C),115.9(2C),103.5,102.6,100.9,98.6,51.9(2C),50.6,48.0(2C).
example 37 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (4- (trifluoromethyl) phenyl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (Compound 37)
Compound 37 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.04(bs,1H),7.95(d,J＝8.5Hz,2H),7.47(d,J＝8.5Hz,2H),7.03(d,J＝8.5Hz,2H),6.94(d,J＝8.5Hz,2H),6.78(s,1H),6.25(s,1H),3.88(s,2H),3.29(bs,4H),2.69(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,163.8,163.5,161.1,160.4,155.1,153.0,128.4(2C),126.7(q,J＝268.0Hz),126.1(q,J＝3.1Hz,2C),121.4,118.1(q,J＝31.9Hz),116.0(2C),114.2(2C),103.6,102.6,100.9,98.6,51.8(2C),50.5,46.9(2C).
example 38- ((4- (4-fluorophenyl) piperazin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 38)
Compound 38 was prepared according to the procedure of compound 1; 1 H NMR(500MHz,DMSO–d 6 )δ13.02(s,1H),7.95(d,J＝7.4Hz,2H),7.12–6.99(m,2H),6.99–6.88(m,4H),6.79(s,1H),6.24(s,1H),3.91(s,2H),3.10(s,4H),2.71(s,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,164.0,163.1(d,J＝272.2Hz),161.1,160.3,157.6,155.0,147.7,128.4(2C),121.4,117.3,117.2,116.0(2C),115.3(d,J＝21.7Hz,2C),103.5,102.6,100.8,98.6,52.1(2C),50.7,49.0(2C)； 19 F NMR(376MHz,DMSO–d 6 )δ-124.4.
example 39 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4- (pyrimidin-5-yl) piperazin-1-yl) methyl) -4H-benzopyran-4-one (compound 39)
Compound 39 was prepared according to the method of compound 1; 1 H NMR(300MHz,DMSO–d 6 )δ13.03(bs,1H),9.99(bs,2H),8.34(d,J＝4.3Hz,2H),7.94(d,J＝8.2Hz,2H),6.93(d,J＝8.2Hz,2H),6.79(s,1H),6.69–6.50(m,1H),6.23(s,1H),3.88(s,2H),3.75(bs,4H),2.61(bs,4H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,163.9,163.5,161.1,161.1,160.4,157.8(2C),155.1,128.4(2C),121.4,116.0(2C),110.1,103.6,102.7,100.9,98.6,52.0(2C),50.8,43.2(2C).
example 40- ((5, 7-dihydroxy-2- (4-hydroxyphenyl) -4-oxo-4H-chromen-8-yl) methyl) piperidine-4-carboxylic acid methyl ester (Compound 40)
VI-1 (1.6 g,0.01 mol) was dissolved in absolute ethanol and potassium hydroxide solid (2.8 g,0.05 mol) was added with vigorous stirring at room temperature, and the reaction system gradually turned red in color. After 4h, ph=5 was adjusted with 2M hydrochloric acid, a yellow solid gradually precipitated during the process, and after dilution with water (200 mL), the solid was filtered off and dried for direct use. The intermediate obtained in the previous step was dissolved in anhydrous dimethyl sulfoxide (30 mL), elemental iodine (0.13 g,0.5 mmol) was added as a catalyst, followed by reaction at 110℃for 8 hours, after the completion of the reaction, the reaction was cooled to room temperature, 10% sodium thiosulfate solution (50 mL) was added, after 10 minutes, and the mixture was extracted with ethyl acetate/water system, the organic phase was taken, dried and spin-dried, and the residue was purified by silica gel chromatography to give VII-1 (1.3 g, two-step yield 48%). And referring to scheme 1, compound 40 is prepared; 1 H NMR(300MHz,DMSO–d 6 )δ12.99(bs,1H),7.92(d,J＝8.8Hz,2H),6.94(d,J＝8.8Hz,2H),6.77(s,1H),6.16(s,1H),3.89(s,2H),3.60(s,3H),2.92(d,J＝11.7Hz,2H),2.47–2.37(m,1H),2.31(t,J＝10.5Hz,2H),1.87(d,J＝11.1Hz,2H),1.70–1.48(m,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,174.4,164.8,163.3,161.1,160.3,154.8,128.3(2C),121.4,115.9(2C),103.3,102.7,100.2,98.8,51.6,51.5(2C),51.4,51.4,27.7(2C).
example 41- (((5, 7-dihydroxy-2- (4-hydroxyphenyl) -4-oxo-4H-benzopyran-8-yl) methyl) piperidine-4-carboxylic acid ethyl ester (Compound 41)
Compound 41 was prepared by the method of reference compound 40; 1 H NMR(300MHz,DMSO–d 6 )δ13.00(bs,1H),8.96(bs,2H),7.91(d,J＝8.8Hz,2H),6.93(d,J＝8.7Hz,2H),6.75(s,1H),6.15(s,1H),4.06(q,J＝7.1Hz,2H),3.88(s,2H),2.92(d,J＝11.7Hz,2H),2.45–2.22(m,3H),1.86(d,J＝11.0Hz,2H),1.58(dd,J＝21.4,10.8Hz,2H),1.17(t,J＝7.1Hz,3H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,173.9,164.8,163.3,161.1,160.3,154.7,128.3(2C),121.4,115.9(2C),103.3,102.6,100.1,98.8,59.8,51.6,51.5(2C),39.6,27.7(2C),13.9
example 42 5, 7-dihydroxy-8- (((4- (hydroxymethyl) piperidin-1-yl) methyl) -2- (4-hydroxyphenyl) -4H-benzopyran-4-one (Compound 42)
Compound 42 was prepared by the method of reference compound 40; 1 H NMR(300MHz,DMSO–d 6 )δ12.97(bs,1H),7.91(d,J＝8.8Hz,2H),6.94(d,J＝8.7Hz,2H),6.74(s,1H),6.09(s,1H),3.97(s,2H),3.27(d,J＝6.1Hz,2H),3.02(d,J＝11.4Hz,2H),2.30(t,J＝11.0Hz,2H),1.73(d,J＝11.9Hz,2H),1.46(s,1H),1.30–1.08(m,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.6,166.1,163.1,161.1,160.4,154.5,128.3(2C),121.4,115.9(2C),102.9,102.6,99.41,99.0,65.4,52.3,52.1(2C),37.6,28.2(2C).
example 43 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4-phenylpiperidin-1-yl) methyl) -4H-benzopyran-4-one (Compound 43)
Compound 43 was prepared by the method of reference compound 40; 1 H NMR(300MHz,DMSO–d 6 )δ7.94(d,J＝8.8Hz,2H),7.36–7.12(m,5H),6.95(d,J＝8.8Hz,2H),6.77(s,1H),6.16(s,1H),3.98(s,2H),3.11(d,J＝11.4Hz,2H),2.60(t,J＝11.8Hz,1H),2.40(t,J＝11.2Hz,2H),1.83(d,J＝11.9Hz,2H),1.75–1.58(m,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.9,165.4,163.3,161.2,160.4,154.7,145.6,128.3(2C),128.2(2C),126.6(2C),126.1,121.4,116.0(2C),103.2,102.7,100.0,98.9,52.9(2C),51.9,41.1,32.6(2C).
example 44 8- (((4- (2, 3-difluorobenzoyl) piperidin-1-yl) methyl) -5, 7-dihydroxy-2- (4-hydroxyphenyl) -4H-benzopyran-4-one (compound 44)
Compound 44 was prepared by the method of reference compound 40; 1 H NMR(300MHz,DMSO–d 6 )δ13.01(bs,1H),8.11–7.78(m,3H),7.50–7.32(m,1H),7.32–7.13(m,1H),6.94(d,J＝7.7Hz,2H),6.76(s,1H),6.16(s,1H),3.92(s,2H),3.33–3.07(m,1H),3.01(d,J＝9.8Hz,2H),2.46–2.23(m,2H),1.87(d,J＝11.7Hz,2H),1.72–1.38(m,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ199.3(d,J CF ＝3.7Hz),181.8,167.7(dd,J CF ＝258.8Hz,14.2Hz),166.4(dd,J CF ＝254.2Hz,13.0Hz),164.8,163.3,162.9,161.1,160.3,132.6(m),128.4(2C),124.3(m),122.0(m),121.4,116.0(2C),112.6(dd,J CF ＝22.8Hz,3.6Hz),103.3,102.7,100.2,98.8,51.8(2C),51.5,46.2(d,J CF ＝3.8Hz),27.5(2C)； 19 F NMR(376MHz,DMSO–d 6 )δ-136.9,-137.0.
example 45 5, 7-dihydroxy-2- (4-hydroxyphenyl) -8- ((4-phenyl-3, 6-dihydropyridin-1 (2H) yl) methyl) -4H-benzopyran-4-one (Compound 45)
Compound 45 was prepared by the method of reference compound 40; 1 H NMR(300MHz,DMSO–d 6 )δ12.99(s,1H),7.91(d,J＝8.3Hz,2H),7.41(d,J＝7.3Hz,2H),7.31(t,J＝7.3Hz,2H),7.24(d,J＝7.0Hz,1H),6.92(d,J＝8.3Hz,2H),6.75(s,1H),6.17(d,J＝10.7Hz,2H),4.02(s,2H),3.31(s,2H),2.88(s,2H),2.51(d,J＝7.8Hz,2H)； 13 C NMR(75MHz,DMSO–d 6 )δ181.8,164.7,161.1,160.4,159.1,154.8,136.4,133.9,128.3(2C),128.3(2C),127.0,124.5(2C),121.3,120.9,115.9(2C),103.3,102.6,100.4,98.8,51.7,50.5,48.9,26.7.
EXAMPLE 46 detection of compounds IC that inhibit PARP-1/2 at the enzyme level 50 Value of
Experimental method
Dissolving a compound sample with anhydrous dimethyl sulfoxide to prepare 10mM mother liquor, adding the compound into a screening system, and diluting the compound with the detection concentration range of 0.5 nM-10 mu M according to a 3-fold gradient, wherein each concentration is provided with two compound wells. The experimental result is converted into the activity percentage, the drug concentration is taken as the abscissa, the enzyme activity percentage corresponding to each concentration is taken as the ordinate, and the IC of the tested compound on PARP-1/2 enzyme inhibition is calculated 50 Values. The specific operation steps are as follows: the target compounds were tested for their PARP-1/2 enzyme inhibitory activity in 96 well plates. Each well was pre-diluted with histone (20. Mu.g/mL) in 100. Mu.L PBS buffer (10 mM sodium dihydrogen phosphate, 10mM disodium hydrogen phosphate, 150mM sodium chloride, pH 7.4) and incubated overnight at 4 ℃. Thereafter, 100. Mu.M NAD+, 25. Mu.M biotinylated NAD+ and 200nM siDNA diluted in 30. Mu.L buffer (50 mM Tris,2mM magnesium chloride, pH 8.0) were added per well followed by 5. Mu.L of test compound or solvent control at different concentrations. mu.L (5 ng) of PARP-1 was added to each well at 30℃for 1h, 50. Mu.L of HRP was added thereto, and after 30min incubation, 100. Mu.L of buffer (0.1M H) 2 O 2 Citrate buffer, pH 5.4) was stopped and chemiluminescent values were detected on a SpectraMax M5 instrument.
Experimental results: experimental results show that PARP-1 inhibition rate IC of compound 11-13,27,28 50 A value of less than 25nM, wherein PARP-1 inhibition IC of Compound 27 is preferred 50 The value is 15nM, and the effect is slightly weaker than that of the marketed medicine Olaparib (IC) 50 =5.1 nM). But the selectivity is 60, which is far greater than that of the commercially available medicine Olaparib (selectivity 0.2), and the clinical significance is greater.
PARP-1 IC of the compounds of Table 1 at the enzyme level 50 Value of
/>
Example 47 cell anti-proliferation assay to detect preferred Compound 27
All cells were cultured according to ATCC recommendations with Olaroparib as positive control drug. SK-OV-3 tumor cells in the logarithmic growth phase were inoculated in 96-well plates at a density of 5000 cells/well, treated with compounds of different concentrations (0.1, 1, 10. Mu.M) after 24h, a blank group was set, and 3 multiplex wells were arranged in parallel. After 48h, MTT solution (5 mg. ML) was added to each well -1 ) 20. Mu.L. At 37 ℃,5% CO 2 After the culture was continued in the incubator for 4 hours, the supernatant was aspirated, 150. Mu.L of DMSO was added to each well, and the formazan crystals were completely dissolved by shaking on a shaker for 10 minutes, and the absorbance was measured at 490nm to calculate the cell viability.
The experimental results are shown in figure 1, * p<0.05, ** p<0.01 or *** p<Comparison of 0.001 with the blank shows that at lower concentrations, the preferred compound 27 significantly inhibits SK-OV-3 cell proliferation, with better results than the marketed drug olaparib.
EXAMPLE 48 in vivo anti-tumor assay to detect preferred Compound 27
After resuscitating SK-OV-3 cells, the cells were expanded according to conventional cell culture methods. When the cells swelled to exponential phase, the cells were collected and prepared to 5×10 8 cell suspensions of cells/mL, tumor cell suspensions were prepared under sterile conditions (in an ultra clean bench). 0.3mL of the tumor cell suspension prepared above was aspirated and inoculated subcutaneously into the right armpit of the mouse, and the inoculation was completed within 60 min. When the tumor volume reaches 100mm 3 Grouping and administration are performed.
Grouping animals: blank group, olaparib group (Olaparib, 10 mg/kg), compound 27 low dose group (25 mg/kg), compound 27 high dose group (50 mg/kg). Tumor diameter was measured once every two days, tumor body short diameter a and long diameter b (including skin thickness) were measured with vernier calipers, and tumor body volume v=a was calculated 2 X b/2, and tumor growth curves were plotted. On the last day of the experiment, tumors were dissected and recorded with photographs.
The experimental results are shown in fig. 2, and the results show that the compound 27 can obviously inhibit the growth of subcutaneous SK-OV-3 tumor cells of tumor-bearing mice at a lower dosage, and the effect is better than that of the medicine Olaparib on the market at an equal dosage.
EXAMPLE 49 in vivo chemosensitization efficacy test of Compound 27
After resuscitating the a549 cells, the cells were expanded according to conventional cell culture methods. When the cells swelled to exponential phase, the cells were collected and prepared to 5×10 8 cell suspensions of cells/mL, tumor cell suspensions were prepared under sterile conditions (in an ultra clean bench). 0.3mL of the tumor cell suspension prepared above was aspirated and inoculated subcutaneously into the right armpit of the mouse, and the inoculation was completed within 60 min. When the tumor volume reaches 100mm 3 Grouping and administration are performed.
Grouping animals: blank, carboplatin, carboplatin+Olaparib (Olaparib, 10 mg/kg), carboplatin+compound 27 low dose (25 mg/kg) and carboplatin+compound 27 high dose (50 mg/kg). Tumor diameter was measured once every two days, tumor body short diameter a and long diameter b (including skin thickness) were measured with vernier calipers, and tumor body volume v=a was calculated 2 X b/2, and tumor growth curves were plotted. On the last day of the experiment, tumors were dissected and recorded with photographs.
The experimental results are shown in fig. 3, and the result shows that the inhibition effect of carboplatin on tumors can be obviously improved by the preferable compound 27 at a lower dosage, and the effect is better than that of the medicine Olaparib on the market at an equal dosage.
Example 50 in vivo anti-tumor efficacy and chemosensitization efficacy test of Compound 25
Cell seeding and animal grouping were as in examples 48 and 49.
The results of the experiment are shown in fig. 4, and show that compound 25 can also significantly increase the inhibition of tumor growth by carboplatin at lower doses, but the effect is weaker than that of the preferred compound 27 at equal doses and stronger than that of the commercially available medicine olaparib.

Claims (10)

1. An 8-azacyclo-substituted chromone derivative represented by formula I, or a pharmaceutically acceptable salt thereof:
；
I
wherein R is 1 A substituted phenyl group, said substituted phenyl group being substituted with 1 substituent: OH, F, cl, br, I;
R 2 and R is 4 Independently selected from: H. f, cl, br, I;
R 3 、R 5 independently selected from: H. f, cl, br, I, OH;
R 6 selected from: open chain C 2 -C 8 Saturated alkyl, C 3 -C 8 Cycloalkyl, substituted phenyl, wherein the substituted phenyl is substituted with 1 to 2 substituents: H. f, cl, br, I, CN, NO 2 、OH、C 1 -C 6 Alkyl, C 1 -C 6 An alkoxy group;
a is selected from: piperidine, piperazine, tetrahydropyridine;
x is selected from: -C (O) -or- (CH) 2 ) n-; n=0, 1 or 2;
y is selected from: 0N or C;
wherein m=1;
the 8-nitrogen heterocycle substituted chromone derivative is not a compound with the following structure:
；/>。
2. the 8-azacyclo-substituted chromone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein:
R 6 selected from: open chain C 2 -C 8 Saturated alkyl, C 3 -C 8 Cycloalkyl, substituted phenyl, wherein the substituted phenyl is substituted with 1 to 2 substituents: H. f, cl, br, I, CN, NO 2 ；
X is-C (O) -or- (CH) 2 )n-；n = 1。
3. An 8-azacyclo-substituted chromone derivative or a pharmaceutically acceptable salt thereof, wherein the derivative is selected from the group consisting of:
；
；
；
；
。
4. a process for the preparation of a compound according to any one of claims 1 to 3, characterized in that the reaction route is selected from any one of the following:
the method comprises the following steps:
；
the second method is as follows:
。
5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable adjuvant.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, cream, ointment, suppository or patch.
7. Use of a derivative according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 5 for the manufacture of a medicament against PARP related diseases.
8. The use according to claim 7, wherein the PARP related disorder is a tumor, stroke, myocardial infarction, inflammation, hypertension, atherosclerosis or diabetes.
9. The use according to claim 8, wherein the tumor is a PARP-1/2 mediated BRCA1 gene deficient tumor.
10. The use according to claim 8, wherein the tumor is ovarian cancer, breast cancer and fallopian tube cancer, malignant peritoneal tumor, metastatic breast cancer, ovarian epithelial cancer, primary peritoneal cancer, advanced harmful germ line or somatic BRCA-mutated advanced epithelial ovarian cancer, advanced harmful germ line or somatic BRCA-mutated fallopian tube cancer, advanced harmful germ line or somatic BRCA mutated peritoneal cancer refractory advanced ovarian cancer.
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