CN108368059A - A kind of substituted phthalazinone compounds and its pharmaceutical composition - Google Patents
A kind of substituted phthalazinone compounds and its pharmaceutical composition Download PDFInfo
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Abstract
The invention discloses such as formulas（I）Shown in the phthalazinone compounds that replace and the medical composition and its use containing the compound or its crystal form, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, isotopic variations, hydrate or solvate.Phthalazinone compounds disclosed by the invention and composition comprising the compound have excellent inhibition to polyadenylic acid diphosphonic acid ribosyl polymerase, there is better pharmacokinetic parameter characteristic simultaneously, the drug concentration of compound in animal body can be improved, to improve curative effect of medication and safety.
Description
The invention belongs to pharmaceutical technology field more particularly to a kind of phthalazinone compounds and the composition comprising the compound and application thereof.
Polyadenylic acid diphosphonic acid ribosyl polymerase (Poly (ADP-ribose) poly-merase, it PARP) is a kind of single stranded DNA repair enzyme extracted and purified from chicken gizzard karyon by Pierre Chambon Weill and Paul Mandel etc. before 40 years, it passes through base excision repair (base excision repair, BER) approach carries out excision reparation to the single-stranded damage that DNA replication dna process occurs, to participate in the duplication of DNA and transcribe and maintain Genome stability (Vyas S, Chang P., New PARP targets for cancer therapy [J] .Nat.Rev.Ca Ncer, 2014,14,502-509.).
PARP family is by 18 nucleoprotein member compositions, but research at present thinks that 6 only therein have the function of polymerizeing ADP ribose and play DNA reparation, other members only have the function of transmitting ADP ribose, wherein PARP-1 and PARP-2 is to be found to be also to study PARP family member the most mature so far earliest, has core repair function during base excision repair.
PARP-1 contains 3 structural domains: DNA binding structural domain (the DNA binding domain that N-terminal contains 2 zinc fingers, DBD), intermediate segment self-correcting structural domain (auto-modification domain,) and C-terminal catalyst structure domain (catalytic domain, CD) AMD.The single-stranded damage of DNA can induce a large amount of activation of PARP-1, and the notch site that the PARP-1 of activation is incorporated into rapidly DNAS damage forms dimer, and is further catalyzed nicotinamide adenine dinucleotide (NAD+) resolve into ADP ribose and niacinamide, the ADP ribose of generation is integrated on PARP-1 albumen and polymerize histone and some other DNA repair proteins form ADP ribose polymers ADP ribose polymer, PAR), the common completion single-stranded repair process of DNA (single strain break, SSB) such as a large amount of reparation albumen such as XRCCl for participating in BER can further be recruited by being formed by a large amount of negative electrical charges entrained by PAR complex.Although the DNA repair function of PARP-1 is most important in the physiological state, but research finds PARP-1 in tumour cell in overexpression state, in tumour cell by the pivotal player for playing DNA reparation in cell toxicity medicament DNA destructive process, this perhaps can be with partial interpretation tumour to the primary or secondary resistance of cell toxicant based chemotherapy drug.Therefore, inhibiting raising of the DNA repair function of PARP-1 to chemotherapeutical medicine curative effect during chemotherapy of tumors, there are important researching values.
The antitumor research of PARP inhibitor is mainly distributed on 2 aspects, i.e., single medicine is used for the tumour of specific gene mutation
Hypotype and combined radio chemotherapy enhanced sensitivity.Current majority PARP inhibitor has entered clinical experimental stage, and part has obtained gratifying clinical data, and prompting PARP inhibitor, there may be the clinical values having a high potential.For example, Rucaparib is researched and developed by Pfizer company, the first PARP-1 inhibitor into clinical research.Preclinical experiment in vitro shows that Rucaparib is shown to 40 plants of reliable anti-tumor effect of ovarian cancer cell, and in combined chemotherapy drug carboplatin, Doxorubicin and topotecan to the significant lethal effect of Ovarian Cancer Cells.Olaparib (Olaparib) is that be developed by AstraZeneca company can inhibit the oral inhibitor of PARP-1 and PARP-2 function simultaneously, and experiment in vitro data show its half-inhibitory concentration (IC50) it is respectively PARP-1=5nmol/L, PARP-2=1nmol/L.In December, 2014, FDA has approved rapidly olaparib as the Patients with Advanced Ovarian Carcinoma before single therapy at least through 3 chemotherapy, or suspects the advanced ovarian cancer of BRCA mutation.It is studied currently, AstraZeneca is just carrying out multiple III phases, treatment of the investigation olaparib for BRCA mutation oophoroma, gastric cancer, breast cancer.The binding mode of olaparib assigns the potentiality of its extensive tumor type that defect is repaired with DNA.
Therefore, there is still a need for the PARP inhibitor that exploitation has inhibitory activity or more preferable pharmacodynamics performance to polyadenylic acid diphosphonic acid ribosyl polymerase for this field.
Summary of the invention
Against the above technical problems, the invention discloses a kind of phthalazinone compounds and the composition comprising the compound and application thereof, with PARP inhibitory activity, and have better pharmacodynamics/pharmacokinetics performance compound.
In this regard, the technical solution adopted by the present invention are as follows:
A kind of phthalazinone compounds, the phthalazinone compounds as shown in formula (I) or its crystal form, pharmaceutically acceptable salt, prodrug, metabolin, tautomer, stereoisomer, isotopic variations, hydrate or solvated compounds,
In formula (1),
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21And R22It is each independently hydrogen, deuterium, halogen or trifluoromethyl；
Additional conditions are that the phthalazinone compounds at least contain a D-atom.
It adopts this technical solution, shape and volume of the deuterium in drug molecule are substantially the same with hydrogen, if hydrogen is optionally replaced with deuterium in drug molecule, deuterated drug generally can also retain original bioactivity and selectivity.Inventor passes through it is experimentally confirmed that the combination of carbon deuterium key is more more stable than the combination of C-H bond simultaneously, the attributes such as absorption, distribution, metabolism and the excretion of some drugs can be directly affected, to improve the curative effect of drug, safety and tolerance.
As a further improvement of the present invention, deuterium isotopic content of the deuterium in deuterated position is at least greater than natural deuterium isotopic content 0.015%, is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 99%.
In another preferred example, deuterium isotopic content of the deuterium in each deuterated position is at least greater than natural deuterium isotopic content (0.015%), is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 99%.
Specifically, R in the present invention1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21And R22Deuterium isotopic content is at least 5% in each deuterated position, it is preferably greater than 10%, even more preferably greater than 15%, even more preferably greater than 20%, even more preferably greater than 25%, even more preferably greater than 30%, even more preferably greater than 35%, even more preferably greater than 40%, even more preferably greater than 45%, even more preferably greater than 50%, even more preferably greater than 55%, even more preferably greater than 60%, even more preferably greater than 65%, even more preferably greater than 70%, even more preferably greater than 75%, even more preferably greater than 80%, even more preferably greater than 85%, even more preferably greater than 90%, even more preferably greater than 95%, even more preferably greater than 99%.
It is selected in example another, the R of compound in formula (I)1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21And R22, at least one of which R contains deuterium, more preferably two R contain deuterium, more preferably three R contain deuterium, more preferably four R contain deuterium, more preferably five R contain deuterium, more preferably six R contain deuterium, more preferably seven R contain deuterium, more preferably eight R contain deuterium, more preferably nine R contain deuterium, more preferably ten R contain deuterium, more preferably 11 R contain deuterium, more preferably 12 R contain deuterium, more preferably 13 R contain deuterium, more preferably 14 R contain deuterium, more preferably 15 R contain deuterium, more preferably 16 R contain deuterium, more preferably 17 R contain deuterium, more preferably 18 R contain deuterium, more preferably 19 R contain deuterium, more preferably 20 R contain deuterium, more preferably 21 R contain deuterium, more preferably 22 R contain deuterium.
As a further improvement of the present invention, R1、R2、R3And R4It is each independently deuterium or hydrogen.
As a further improvement of the present invention, R5And R6It is each independently deuterium or hydrogen.
As a further improvement of the present invention, R7、R8And R9It is each independently deuterium or hydrogen.
As a further improvement of the present invention, R10、R11、R12、R13、R14、R15、R16And R17It is each independently deuterium or hydrogen.
As a further improvement of the present invention, R18、R19、R20、R21And R22It is each independently deuterium or hydrogen.
As a further improvement of the present invention, the phthalazinone compounds can be selected from following any structure or its pharmaceutically acceptable salt:
The invention also discloses a kind of pharmaceutical compositions, contain pharmaceutically acceptable carrier and phthalazines as described above
Ketone compound or its crystal form, pharmaceutically acceptable salt, prodrug, metabolin, tautomer, stereoisomer, isotopic variations, hydrate or solvated compounds.
Formula (I) compound or its crystal form, pharmaceutically acceptable salt, hydrate or solvate of the present invention.It can be used for alkylating agent and together with topoisomerase-I inhibitor anticancer combination therapy (or as adjuvant), the alkylating agent such as methyl mesylate, Temozolomide and Dacarbazine, the topoisomerase-I inhibitor such as Hycamtin, Irinotecan, rubitecan, exatecan, Lurtotecan, gefitinib, Diflomotecan (hCPT class)；And the Fei Silan that 7- replaces replaces health class；7- silyl camptothecins BNP 1350；With non-camptothecin topoisomerase-I inhibitor, such as indolocarbazole class and topoisomerase-I and II double inhibitor such as phenonaphthazine class, XR 11576/MLN 576 and benzo pyridine diindyl class.
It is selected in example another, the pharmaceutical composition is injection, wafer, tablet, pill, powder or granule.
The invention also includes the compounds of isotope labelling, are equal to original chemical and are disclosed.The example that the compound of the present invention isotope can be classified as includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively such as2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F and36Cl.Compound or enantiomer in the present invention, diastereomer, isomers or pharmaceutically acceptable salt or solvate, wherein being within the scope of the present invention containing the isotope of above compound or other other isotope atoms.Certain compound isotopically labelleds in the present invention, such as3H and14The radioactive isotope of C is also useful in the experiment of the Tissue distribution of drug and substrate wherein.Tritium, i.e.,3H and carbon-14, i.e.,14C, their preparation and detection are easier, and are the first choices in isotope.In addition, higher isotope replaces such as deuterium, i.e.,2H, since its good metabolic stability is advantageous in certain therapies, such as in vivo, therefore increase half-life period or reduction dosage can be paid the utmost attention in some cases.The compound of isotope labelling can use general method that can be prepared by replacing with non isotopic reagent with the isotope labeling reagent being easy to get with the scheme in example.
The treatment of disease by inhibiting PARP to alleviate is provided in terms of another aspect of the present invention, including applying formula (I) compound or its crystal form defined in the first aspect of therapeutically effective amount to subject in need for the treatment of, pharmaceutically acceptable salt, hydrate or solvate, it is preferred that being applied in the form of pharmaceutical composition, and provide the treatment of cancer, formula (I) compound and radiotherapy (ionising radiation) or chemotherapeutant including therapeutically effective amount is administered in combination to subject in need for the treatment of, compound defined in the first aspect is preferably in the form of pharmaceutical composition, it is applied simultaneously or successively with radiotherapy or chemotherapeutant.
It is selected in example another, the pharmaceutical composition is for treating and preventing following disease: vascular diseases；Septic shock；Ischemia injury；Neurotoxicity；Haemorrhagic shock；Virus infection；Or in cancer treatment as auxiliary
Agent uses or for enhancing the therapeutic effect of ionizing radiation or chemotherapeutant to tumour cell.
It is selected in example another, the cancer includes but is not limited to: oophoroma, breast cancer, prostate cancer, lung cancer, head and neck cancer, cancer of the esophagus, the carcinoma of the rectum, colon cancer, nasopharyngeal carcinoma, uterine cancer, cancer of pancreas, lymthoma, leukemia, osteosarcoma, melanoma, kidney, gastric cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
The invention also discloses a kind of purposes of phthalazinone compounds as described above, it is used to prepare the pharmaceutical composition for inhibiting polyadenylic acid diphosphonic acid ribosyl polymerase.Preferably, the drug for the disease for inhibiting PARP enzyme to mediate, such as oophoroma, breast cancer, prostate cancer are used to prepare.
In other aspects of the present invention, the compound can be used for preparing the drug of the cancer for the treatment of homologous recombination (HR) dependent DNA double-strand break (DSB) repairing activity missing or for treating the cancer patient for suffering from HR dependent DNA DSB repairing activity missing, the compound including applying therapeutically effective amount to the patient.
The cancer that HR dependent DNA DSB repairs missing may include one or more cancer cells or be made of one or more cancer cells, relative to normal cell, they are reduced or losed by the ability of approach DNA plerosis DSB, i.e., the activity that HR dependent DNA DSB repairs approach in one or more cancer cells may be decreased or lose.In one or more cancer cells of the individual for the cancer for repairing missing with HR dependent DNA DSB, the activity that HR dependent DNA DSB repairs one or more components of approach may be lost.Sufficiently characterization (see, for example, Wood, etc. Science, 291,2001,1284-1289) has been carried out in the component that HR dependent DNA DSB repairs approach in the art, and including component listed above.
In some preferred embodiments, the cancer cell may have BRCA1 and/or BRCA2 missing phenotype, i.e., BRCA and/BRCA2 activity reduce or lose in cancer cell.Cancer cell with the phenotype may be what BRCA1 and/or BRCA2 was lacked, the expression of BRCA1 and/or BRCA2 and/or activity may be decreased or lose i.e. in cancer cell, such as the mutation or polymorphism for passing through code nucleic acid, or the gene by encoding regulatory factor for example encodes amplification, mutation or the polymorphism (Hughes-Davies, etc. Cell of the EMSY gene of BRCA2 regulatory factor, 115, such as gene promoter methylation 523-535), or by epigenetic mechanism,.The carrier of BRCA1 and/or BRCA2 mutation, which is also at, to have ovarian cancer, in the high risk of prostate cancer and cancer of pancreas.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and it can be combined with each other between each technical characteristic specifically described in below (e.g. embodiment), to form a new or preferred technical solution.Due to space limitations, I will not repeat them here.
Herein, unless otherwise instructed, " halogen " refers to F, Cl, Br and I.More preferably, halogen atom is selected from F, Cl and Br.
Herein, unless otherwise instructed, " deuterated " refers to one or more hydrogen in compound or group replaced deuterium；It is deuterated to can be a substitution, two replace, polysubstituted or full substitution.Term " one or more deuterated " is used interchangeably with " one or many deuterated ".
Herein, unless otherwise instructed, " non-deuterated compound " refers to that ratio containing D-atom is not higher than the compound of natural deuterium isotopic content (0.015%).
Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the salt that the compounds of this invention and acid are formed.The acid for suitably forming salt includes but is not limited to: the inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid；The organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids；And the amino acid such as proline, phenylalanine, aspartic acid, glutamic acid.Another kind of preferred salt is the salt that the compounds of this invention and alkali are formed, such as alkali metal salt (such as sodium salt or sylvite), alkali salt (such as magnesium salts or calcium salt), ammonium salt (such as rudimentary alkanol ammonium salt and other pharmaceutically acceptable amine salt), such as methylamine salt, ethylamine salt, propylamine salt, dimethyl amine salt, trismethylamine salt, diethyl amine salt, triethyl amine salt, tert-butylamine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three oxyethylamine salt, and the amine salt formed respectively by morpholine, piperazine, lysine.
Term " solvate " refers to that the compounds of this invention and solvent molecule are coordinated the complex to form special ratios." hydrate " refers to that the compounds of this invention and water carry out the complex of coordination formation.
The present invention also provides the pharmaceutical compositions of the compound comprising formula (I) or the pharmaceutically acceptable salt and pharmaceutically acceptable carrier of its pharmaceutically acceptable salt or the compound.The carrier is " acceptable " in the sense that will not be to its recipient nocuousness under for the amount in drug compatible with the other compositions of preparation and pharmaceutically in the case where acceptable carrier.
Compared with prior art, the invention has the benefit that
First, using the phthalazinone compounds of technical solution of the present invention, there is excellent inhibition to polyadenylic acid diphosphonic acid ribosyl polymerase.Second, metabolism of the compound in organism is changed by this deuterated technology, makes compound that there is better pharmacokinetic parameter characteristic.In such a case, it is possible to change dosage and form durative action preparation, improve applicability.Third can be improved the drug concentration of compound in animal body, due to its deuterium isotope effect with the hydrogen atom in deuterium substituted compound to improve curative effect of medication.4th, with the hydrogen atom in deuterium substituted compound, certain metabolites can be inhibited, improve the safety of compound.
Preferably embodiment of the invention is described in further detail below.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages are parts by weight and weight percent.
Embodiment 1 prepares 4- [3- (4- cyclopropane carbonyl -2,2,3,3,5,5,6,6-d8- piperazine -1- carbonyl) the fluoro- benzyl of -4-] -2H-
Phthalazines -1- ketone (compound 5)
Specific synthesis step is as follows:
Step 1: the synthesis of compound 3.
By n,N-diisopropylethylamine (compound 1, DIPEA, 0.3g, 2.34mmol) it is added to 2,2 continuously stirred, 3,3,5,5,6, in methylene chloride (20mL) solution of 6-d8- piperazine (200mg.2.12mmol), it is cooled to 0 DEG C under ice-water bath, Cyclopropyl carbonyl chloride (compound 2 is slowly added dropwise, 200mg, 1.91mmol), after stirring 30 minutes at room temperature, 10mL water quenching reaction is added, separation organic phase is simultaneously extracted with dichloromethane twice, after collecting organic phase drying, white solid product 190mg, yield 47% are obtained.
LC-MS (APCI): m/z=163.1 (M+1)+。
Step 2: the synthesis of compound 5.
Under nitrogen protection; successively by O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU, 644mg, 1.7mmol), N; N- diisopropylethylamine (compound 1; DIPEA, 0.52mL, 3.0mmol) it is added to 5- [(3; 4- dihydro -4- oxo -1- phthalazinyl) methyl] -2- fluobenzoic acid (compound 4; 357mg, 1.2mmol) dimethyl acetamide (DMA, 2mL)
In solution, at 15-25 DEG C, after dimethyl acetamide (DMA, the 1mL) solution of compound 3 (0.16g, 1.0mmol) is added, stir 4 hours at room temperature.It is vigorously stirred down and adds water 10mL, obtain white solid product 100mg, yield 22% with column chromatography separating purification after filtering.
LC-MS (APCI): m/z=443.2 (M+1)+。
1H NMR(300MHz,CDCl3) (δ/ppm): 10.80 (brs, 1H), 8.51-8.47 (m, 1H), 7.81-7.72 (m, 3H), 7.39-7.32 (m, 2H), 7.06 (t, J=9.0Hz, 1H), 4.32 (s, 4H), 1.78-1.71 (m, 1H), 1.05-1.00 (m, 2H), 0.84-0.81 (m, 2H).
It is prepared by embodiment 24- [[3- (4- cyclopropane carbonyl piperazine -1- carbonyl) -4- fluoro-phenyl]-d2- methyl] -2H- phthalazines -1- ketone (compound 10)
Specific synthesis step is as follows:
Step 1: the synthesis of compound 7.
Under nitrogen protection; successively by O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU; 5.7g; 15mmol), N; N- diisopropylethylamine (compound 1; DIPEA, 5.3mL, 30mmol) it is added to 5- [(3; 4- dihydro -4- oxo -1- phthalazinyl) methyl] -2- fluobenzoic acid (compound 4; 3.0g, 10mmol) dimethyl acetamide (DMA, 15mL) solution in; continuously add 6 (2.3g of compound; after dimethyl acetamide (DMA, 5mL) solution 12mmol), stir 2 hours at room temperature.Add water quenching reaction, be extracted with dichloromethane three times, is obtained after dry with column chromatography separating purification white
Solid 3.5g, yield 75%.
LC-MS (APCI): m/z=467.2 (m+1)+。
Step 2: the synthesis of compound 9.
Under nitrogen protection; by 7 (300mg of compound; it 0.64mmol) is dissolved in 10mL methylene chloride; 0 DEG C is cooled to after reaction solution clarification; trifluoroacetic acid 2mL is added dropwise, is stirred at room temperature 1 hour, after 50mL methylene chloride is added; reaction system is placed in ice salt bath; 5mL triethylamine is added dropwise, after being cooled further to -10 DEG C, Cyclopropyl carbonyl chloride (80mg is added; 0.77mmol); stirring 5 minutes adds water quenching reaction, separates organic phase; it is dried after washing and white solid product 240mg, yield 86% is obtained by column chromatography separating purification.
LC-MS (APCI): m/z=433.2 (M-1)+。
1H NMR(300MHz,CDCl3) (δ/ppm) 10.20 (br s, 1H), 8.50-8.47 (m, 1H), 7.81-7.72 (m, 3H), 7.38-7.33 (m, 2H), 7.07 (t, J=9.0Hz, 1H), 4.30 (s, 2H), 3.86-3.80 (m, 4H), 3.65-3.60 (m, 2H), 3.41-3.34 (m, 2H), 1.27 (s, 1H), 1.05-1.00 (m, 2H), 0.85-0.81 (m, 2H).
Step 3: the synthesis of compound 10.
Compound 9 (100mg, 0.23mmol) and 11 carbon -7- alkene (DBU, 76mg, 0.5mmol) of 1,8- diazabicyclo [5.4.0] are added to one, 5mL D is housed2In single neck round-bottom flask of O and 10mL DMSO-d6,70 DEG C and at such a temperature after reaction overnight are heated to, is cooled to room temperature, decompression is spin-dried for D2O and DMSO-d6 is added 20mL methylene chloride, obtains white solid product 56mg, yield 56% by column chromatography separating purification after drying.
LC-MS (APCI): m/z=435.2 (M-1)+。
1H NMR(300MHz,CDCl3) (δ/ppm): 10.80 (br s, 1H), 8.51-8.47 (m, 1H), 7.81-7.72 (m, 3H), 7.39-7.32 (m, 2H), 7.06 (t, J=9.0Hz, 1H), 3.88-3.81 (m, 4H), 3.66-3.60 (m, 2H), 3.41-3.34 (m, 2H), 1.78-1.71 (m, 1H), 1.05-1.00 (m, 2H), 0.84-0.81 (m, 2H).
It is prepared by embodiment 34- [[3- (4- cyclopropane carbonyl -2,2,3,3,5,5,6,6-d8- piperazine -1- carbonyl) -4- fluoro-phenyl]-d2- Methyl] -2H- phthalazines -1- ketone (compound 11)
Specific synthesis step is as follows:
Compound 5 (100mg, 0.23mmol) and 11 carbon -7- alkene (DBU, 76mg, 0.5mmol) of 1,8- diazabicyclo [5.4.0] are added to one, 5mL D is housed2In single neck round-bottom flask of O and 10mL DMSO-d6,70 DEG C and at such a temperature after reaction overnight are heated to, is cooled to room temperature, decompression is spin-dried for D2O and DMSO-d6 is added 20mL methylene chloride, obtains white solid product 56mg, yield 56% by column chromatography separating purification after drying.
LC-MS (APCI): m/z=445.2 (M+1)+。
1H NMR(400MHz,CDCl3) (δ/ppm): 10.80 (br s, 1H), 8.51-8.47 (m, 1H), 7.81-7.72 (m, 3H), 7.39-7.32 (m, 2H), 7.06 (t, J=9.0Hz, 1H), 1.78-1.71 (m, 1H), 1.05-1.00 (m, 2H), 0.84-0.81 (m, 2H).
Embodiment 4 prepares 4- [3- (4- (2,2-d2)-cyclopropane carbonyl piperazine -1- carbonyl) the fluoro- benzyl of -4-] -2H- phthalazines -1- ketone
(compound 16)
Specific synthesis step is as follows:
Step 1: the synthesis of compound 13.
Under ice-water bath, 2,2- dichloro cyclopropyl-phenyl (compound 12,3g is added in 100mL three-necked flask, 16mmol), anhydrous ether (30mL), it is slowly added to biscuit metal sodium (4g, 173.9mmol), is added within 1 hour, at the same time, it is vigorously stirred down the mixed solution (1.5mL heavy water and 9mL MeOD) for being added dropwise to deuterated methanol and heavy water, drips off within 70 minutes, is stirred overnight at room temperature.A large amount of white solids of generation are filtered, filtrate decompression evaporates organic solvent, methylene chloride extraction, and anhydrous sodium sulfate dries, filters, and is spin-dried for obtaining colorless oil 1.5g, yield 78%.
1H NMR(400MHz,CDCl3) (δ/ppm): 7.26-7.23 (m, 2H), 7.15-7.11 (m, 1H), 7.08-7.06 (m, 2H), 1.87 (t, J=6.8Hz, 1H), 0.93 (t, J=5.6Hz, 1H), 0.67 (t, J=4.8Hz, 1H)
Step 2: the synthesis of compound 14.
Water (36mL), acetonitrile (23mL), carbon tetrachloride (23mL), 13 (0.7g of compound is added under magnetic agitation into 250mL single-necked flask, 5.83mmol), potassium metaperiodate (18.6g, 81mmol) and a hydrate ruthenium trichloride (29mg, 0.127mmol), it is stirred to react overnight for lower 40 DEG C of reaction mixture nitrogen atmosphere.It is cooled to room temperature, is added dropwise to saturation Na2CO3Aqueous solution adjusts pH~9, the solid filtering of generation, filter cake washes (50mL), and methylene chloride washs (50mL), and filtrate separates water phase, methylene chloride (20mL) washing, concentrated hydrochloric acid tune pH~4, ether (40mL*4) extraction, anhydrous sodium sulfate are dry, filtering, concentration crosses silicagel column and obtains colourless liquid 300mg, yield 58.4%.
1H NMR(400MHz,DMSO-d6)(δ/ppm):12.04(s,1H),1.50-1.46(m,1H),0.81-0.76(m,2H).
Step 3: the synthesis of compound 16
Compound 14 (60mg, 0.68mmol), anhydrous methylene chloride (3mL), N is added under magnetic agitation in 25mL twoport flask2Ice-water bath is cooling under atmosphere, and the methylene chloride being slowly added dropwise into oxalyl chloride (104mg, 0.82mmol) is molten
Liquid (1mL) and a drop anhydrous DMF, are stirred to react 2h at room temperature.Compound 8 (248mg, 0.68mmol), anhydrous methylene chloride (4mL) and triethylamine (103mg, 1.02mmol), N are added in another flask2Ice-water bath is cooling under atmosphere, and solution of acid chloride is slowly added dropwise in the solution of compound 8 by syringe, ice-water bath is removed after being added dropwise to complete, is stirred to react 1h at room temperature.Add water (10mL) quenching reaction, separate organic layer, water phase methylene chloride extracts (10mL x 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated, and crosses silicagel column and obtains white solid 260mg, yield 87.7%.
LC-MS (APCI): m/z=437.2 (M+1)+.
1H NMR (400MHz, DMSO-d6) (δ/ppm): 12.57 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.81 (t, J=6.8Hz, 1H), 7.44-7.40 (m, 1H), 7.35-7.33 (m, 1H), 7.22 (t, J=8.8Hz, 1H), 4.31 (s, 2H), 3.73-3.36 (m, 6H), 3.21-3.11 (m, 2H), 1.99-1.85 (m, 1H), 0.72-0.67 (m, 2H)
Embodiment 5 prepares 4- [3- (4- (2,2-d2)-cyclopropane carbonyl -2,2,3,3,5,5,6,6-d8- piperazine -1- carbonyl) fluoro- benzyl of -4-
Base] -2H- phthalazines -1- ketone (compound 20)
Specific synthesis step is as follows:
Step 1: the synthesis of compound 17
1 (1g of compound is added in 100mL single-necked flask, 10.6mmol) and methanol (20mL), it is added dropwise to trifluoracetic acid (1.21g, 10.6mmol), stirs 10 minutes under magnetic agitation, add water (20mL), 10min is stirred, is slowly added dropwise into di-tert-butyl dicarbonate (2.3g, 10.6mmol) and iodine (0.27g, methanol solution (40mL) 1.06mmol), is stirred to react 3h at room temperature.NaOH aqueous solution (20%) is added dropwise under ice-water bath, adjust pH~11, the solid of generation filters, ethyl acetate washs filter cake (20mL), filtrate ethyl acetate extracts (60mL x 3), washing (40mL), saturated common salt washing (20mL), and anhydrous sodium sulfate is dry, it is spin-dried for obtaining colourless liquid 1.5g, yield 72.2%.
Step 2: being raw material with compound 17, the synthetic method as the synthesis of compound 7 in case study on implementation 2 obtains compound 18.LC-MS (APCI): m/z=475.2 (M+1)+.
Step 3: being raw material with compound 18, the synthetic method as the synthesis of compound 8 in case study on implementation 2 obtains compound 19.
LC-MS (APCI): m/z=375.2 (M+1)+.
Step 4: being raw material with compound 19, the synthetic method as the synthesis of compound 16 in case study on implementation 4 obtains compound 20.
LC-MS (APCI): m/z=445.2 (M+1)+.
1H NMR (400MHz, DMSO-d6) (δ/ppm): 12.57 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.81 (t, J=6.8Hz, 1H), 7.44-7.40 (m, 1H), 7.35-7.33 (m
1H), 7.22 (t, J=8.8Hz, 1H), 4.31 (s, 2H), 1.99-1.85 (m, 1H), 0.72-0.67 (m, 2H)
Case study on implementation 6:
Preparation4- [[3- (4- (2,2-d2)-cyclopropane carbonyl piperazine -1- carbonyl) -4- fluoro-phenyl]-d2- methyl] -2H- phthalazines -1- Ketone (compound 21)
Specific synthesis step is as follows:
It is raw material with compound 16, the synthetic method as the synthesis of compound 11 in case study on implementation 3 obtains compound 21.
LC-MS (APCI): m/z=439.2 (M+1)+.
1H NMR (400MHz, DMSO-d6) (δ/ppm): 12.57 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.81 (t, J=6.8Hz, 1H), 7.44-7.40 (m, 1H), 7.35-7.33 (m, 1H), 7.22 (t, J=8.8Hz, 1H), 3.73-3.36 (m, 6H), 3.21-3.11 (m, 2H), 1.99-1.85 (m, 1H), 0.72-0.67 (m, 2H)
Case study on implementation 7:
Preparation4- [[3- (4- (2,2-d2)-cyclopropane carbonyl -2,2,3,3,5,5,6,6-d8- piperazine -1- carbonyl) -4- fluoro-phenyl]-d2- Methyl] -2H- phthalazines -1- ketone (compound 22)
Specific synthesis step is as follows:
It is raw material with compound 20, the synthetic method as the synthesis of compound 11 in case study on implementation 3 obtains compound 22.
LC-MS (APCI): m/z=447.2 (M+1)+.
1H NMR (400MHz, CDCl3) (δ/ppm): 10.43 (s, 1H), 8.49-8.47 (m, 1H), 7.80-7.74 (m, 3H), 7.36-7.28 (m, 2H), 7.06 (t, J=8.8Hz, 1H), 1.79-1.75 (m, 1H), (1.01 t, J=4.0Hz, 1H), 0.90 (t, J=4.0Hz, 1H)
Case study on implementation 8:
Preparation4- [[3- (4- (1-d)-cyclopropane carbonyl piperazine -1- carbonyl) the fluoro- benzyl of -4-] -2H- phthalazines -1- ketone (compound 29)
Specific synthesis step is as follows:
Step 1: the synthesis of compound 24
Under magnetic agitation and ice-water bath are cooling, 1- bromine ethylene-acetic acid methyl esters (compound 23 is added in 100mL single-necked flask, 1.78g, 10mmol), ether (40mL), toluene (20mL) and water (90mg, 5mmol), it is added potassium tert-butoxide (1.12g, 10mmol), is stirred to react 1h at 0 DEG C of reaction mixture.Saturated sodium bicarbonate aqueous solution extracts (30mLx 4), merges water phase, and hydrochloric acid (6M) adjusts PH~3, and ether extracts (50mL x 4), and anhydrous sodium sulfate is dry, concentration, crosses column and obtains colourless liquid 1.0g, yield 61.3%.
Step 2: the synthesis of compound 27
Under magnetic agitation and ice-water bath, it is added 1- bromine ethylene-acetic acid (compound 24,1.0g, 6.1mmol) and thionyl chloride (5mL) in 25mL single-necked flask, under reaction mixture nitrogen atmosphere, it is overnight that reaction is stirred at room temperature.Excessive dichloro Asia atmosphere is distilled, and with anhydrous methylene chloride band 2 times, is dissolved in anhydrous methylene chloride (3mL), for use.
1-Cbz piperazine (compound 26 is added in another 50mL twoport flask, 1.34g, 6.1mmol), anhydrous methylene chloride (15mL) and triethylamine (0.8g, 7.93mmol), it is 0 DEG C cooling under nitrogen atmosphere, solution of acid chloride is slowly added dropwise in piperazine solution by syringe, and reaction 1h is stirred at room temperature.Water (10mL) quenching reaction is added, separates organic phase, water phase is extracted with dichloromethane (10mL x 2), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated, and crosses silicagel column and obtains white solid 1.8g, yield 80.3%.
LC-MS (APCI): m/z=367.1 (M+1)+.
1H NMR(400MHz,CDCl3)(δ/ppm):7.39-7.34(m,5H),5.17(s,2H),3.80-3.57(m,8H),1.44-1.38(m,2H),1.36-1.31(m,2H).
Step 3: the synthesis of compound 28
Under magnetic agitation, compound 28 (200mg, 0.55mmol), deuterated methanol (7mL) and Pd/C (10%, 150mg) are added in 50mL single-necked flask, reaction flask is vacuumized and replaced three times with deuterium, and the reaction of pressure deuterium ball is overnight.Pd/C is filtered, filter cake methanol washs (10mL), and filtrate is spin-dried for obtaining white solid 77mg, yield 90.9%.
LC-MS (APCI): m/z=156.1 (M+1)+.
Step 4: being raw material with compound 28 and compound 8, one quadrat method of synthesis with compound 5 in case study on implementation 1 synthesizes compound 29.
LC-MS (APCI): m/z=436.2 (M+1)+.
1H NMR (400MHz, CDCl3) (δ/ppm): 10.59 (s, 1H), 8.49-8.47 (m, 1H), 7.80-7.74 (m, 3H), 7.36-7.28 (m, 2H), 7.06 (t, J=8.8Hz, 1H), 4.31 (s, 2H), 3.84-3.32 (m, 8H), 1.04-1.01 (m, 2H), 0.87-0.82 (m, 2H)
Case study on implementation 9
Preparation4- [(change by [3- (4- (1,2,2,3,3,-d5)-cyclopropane carbonyl piperazine -1- carbonyl) the fluoro- benzyl of -4-] -2H- phthalazines -1- ketone Close object 39)
Specific synthesis step is as follows:
Step 1: the synthesis of compound 31
Under magnetic agitation, heavy water (40mL), anhydrous dioxane (40mL), acetophenone (compound 30 are sequentially added in 250mL single-necked flask, 4.8g, 40mmol) and nafoxidine (280mg, 4mmol), reaction is stirred at room temperature under mixture nitrogen atmosphere overnight.Decompression steams dioxane, and dilute hydrochloric acid (1M) adjusts pH~4, and methylene chloride extracts (40mLx3), merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated to give colourless liquid 4.5g, yield 93.7%.
1H NMR(400MHz,CDCl3)(δ/ppm):7.95-7.92(m,2H),7.65-7.56(m,3H).
Step 2: the synthesis of compound 32
Under magnetic agitation, acetophenone-d3 (compound 31,4.5g, 36.6mmol) and MeOD (30mL), NaBD is added in ice-water bath in 100mL single-necked flask4(1.53g, 36.6mmol) it is slowly added in reaction solution, the reaction was continued 10 minutes after adding, and saturated sodium bicarbonate aqueous solution (40mL) quenching reaction is added, and ethyl acetate extracts (50mL x 3), ethyl acetate is spun off with methanol, (10mLx 2) is extracted with ethyl acetate in residue again, and anhydrous sodium sulfate dries, filters, it is concentrated to give anhydrous liquid 4.0g, yield 88.9%.
LC-MS (APCI): m/z=127.1 (M+1)+.
Step 3: the synthesis of compound 33
Nitrogen atmosphere under ice-water bath, sequentially adds compound 32 (4g, 31.7mmol) and three in 25mL three-necked flask
Reaction 3h is stirred at room temperature in methylsilyl bromine (5.8g, 38.04mmol), and decompression steams the hexamethyl silicon ether that reaction generates, and residue crosses silicagel column and obtains anhydrous grease 3.8g, yield 63.8%.
Step 4: the synthesis of styrene-d3 (compound 34)
Nitrogen atmosphere under ice-water bath, is added compound 33 (3.8g, 20.2mmol) in 100mL twoport flask, the tetrahydrofuran solution (1M, 24.2mL, 24.2mmol) into potassium tert-butoxide is slowly added dropwise, and reaction 3h is stirred at room temperature.It is added ether (100mL), filtering, filter cake ether washs (10mL), and ether and tetrahydrofuran is evaporated off in room temperature, water 10mL is added, ether extracts (20mL x 2), and anhydrous sodium sulfate is dry, filtering, room temperature are evaporated off ether and obtain weak yellow liquid 1.1g, yield 50.2%.
1H NMR(400MHz,CDCl3)(δ/ppm):7.42-7.40(m,2H),7.34-7.30(m,2H),7.26-7.25(m,1H).
Step 5: the synthesis of compound 35
Under ice-water bath, 34 (1.1g of compound is sequentially added in 100mL twoport flask, 10.3mmol), benzyl triethyl ammonium bromide (56mg, 0.204mmol) and bromofom (25.5g, 103mmol), it is vigorously stirred down, is slowly added dropwise into 50%KOH aqueous solution (26mL, 0.26mol), 4h is reacted.Water 50mL is added, methylene chloride extracts (40mL x 3), and anhydrous sodium sulfate dries, filters, and concentration, residue crosses silicagel column and obtains colourless liquid 0.6g, yield 21.6%.
1H NMR(400MHz,CDCl3)(δ/ppm):7.39-7.35(m,3H),7.30-7.28(m,2H).
Step 5: the synthesis of compound 36
It is raw material with compound 35, it is similar with the synthetic method of compound 13 in case study on implementation 4, obtain compound 36.
1H NMR(400MHz,CDCl3)(δ/ppm):7.26-7.23(m,2H),7.15-7.11(m,1H),7.08-7.06(m,2H).
Step 6: the synthesis of compound 37
It is raw material with compound 36, it is similar with the synthetic method of compound 14 in case study on implementation 4, obtain compound 37.
Step 7: the synthesis of compound 39
It is raw material with compound 37, it is similar with the synthetic method of compound 16 in case study on implementation 4, obtain compound 39.
LC-MS (APCI): m/z=440.2 (M+1)+.
1H NMR (400MHz, CDCl3) (δ/ppm): 10.59 (s, 1H), 8.49-8.47 (m, 1H), 7.80-7.74 (m, 3H), 7.36-7.28 (m, 2H), (7.06 t, J=8.8Hz, 1H), 4.31 (s, 2H), 3.84-3.32 (m, 8H)
Biological activity test
(1) kinase inhibitory activity
By the mammal PARP separated from Hela nucleus extraction object Z buffer [25mM Hepes (Sigma)；12.5mM MgCl2(Sigma)；50mM KCl(Sigma)；1mM DTT(Sigma)；10% glycerol (Sigma) 0.001%NP-40 (Sigma)；PH7.4] it is cultivated in 96 hole FlashPlates, and the inhibitor of various concentration is added.All compounds are diluted in DMSO, make final analytical concentration between 10 to 0.01 μM, the ultimate density of DMSO is every hole 1%.Total measurement volume in each hole is 40 μ L.
After being cultivated 1 minute at 30 DEG C, 10 μ L are added and contain NAD (5 μM), the reaction mixture initiation reaction of 3H-NAD and 30mer double-stranded DNA-oligomer.The specified positive and negative reaction hole are combined with compound well (unknown) and are handled to calculate enzymatic activity %.Then plate is shaken 2 minutes, is cultivated 45 minutes at 30 DEG C.After culture, the acetic acid that 50 μ L 30% are added into each hole terminates reaction.Then plate is shaken at room temperature 1 hour.Plate is transferred on TopCount NXT and carries out scinticounting.Record value is the counting (cpm) per minute after counting 30 seconds to each hole.
The experimental results showed that the compounds of this invention has potent inhibitory activity to polyadenylic acid diphosphonic acid ribosyl polymerase.
(2) metabolic stability is evaluated
Microsomal assay: people's hepatomicrosome: 0.5mg/mL, coenzyme (NADPH/NADH): 1mM, magnesium chloride: 10nM, 100mM phosphate buffer (pH 7.4)
The measurement of metabolic stability: it by the no reaction system for adding coenzyme preculture 10 minutes at 37 DEG C, then adds coenzyme and starts to react.It after adding coenzyme, cultivates 0,5,10,20,30 and 60 minute, takes out a part of reaction solution at intervals of set time, the reaction solution of taking-up is added in the acetonitrile solution containing internal standard substance, stop reaction.It after reaction stops, being centrifuged, supernatant is injected and measures remaining unchanged substance in reaction system in liquid chromatograph tandem mass spectrum.Ionization carries out electrospray ionisation according to cation detection mode, utilizes the selection reaction detection method for using the parent ion and daughter ion that have set.
Data analysis:
The residual rate of evaluation compound calculates according to the following formula.
Residual rate=(peak area/internal standard substance peak area of evaluation compound when reaction time t minute) ÷ (peak area/internal standard substance peak area of the evaluation compound at reaction time 0 minute)
Nonlinear least square method parsing is carried out to residual rate and incubation time, finds out disappearance velocity constant (0.693/t1/2), in turn, liver clearance rate (CL is found out using formula (1)int)。
CLint(μ L/min/mg)=(0.693/t1/2) ÷ 0.2 (mg/mL) × 1000 (1)
To the compounds of this invention and its not deuterated compound is test compare simultaneously, and the metabolic stability of appraiser's liver microsomes, the results are shown in Table 1.
The liver particle metabolic evaluation of 1 embodiment compound of table
Experimental result is as listed in Table 1, and compared with Olaparib, the half-life period of the compounds of this invention is longer, and clearance rate is smaller, all shows preferably metabolic stability in people's hepatomicrosome and rat liver microsomes experiment.
(3) pharmacokinetics in rats is tested
Experiment purpose: after research rat gives Olaparib, embodiment compound, the pharmacokinetics behavior of the compounds of this invention is investigated.
Experimental animal:
Type and strain: SD rat grade: SPF grades
Gender and quantity: male, 6
Weight range: 180~220g (actual weight range is 187~197g)
Source: the western Poole Bi Kai experimental animal Co., Ltd in Shanghai
Experiment and animal certificate number: SCXK (Shanghai) 2013-0016.
Experimentation:
Before blood specimen collection, the 2M Fluorinse (esterase inhibitor) of 20L is added in EDTA-K2 anticoagulant tube in advance, after 80 degree of drying in oven, is placed in 4 degree of refrigerator storages.
Rat, male, 187~197g of weight is randomly divided into 2 groups, be fasted in experiment noon before that day overnight but can free water, 4h is to food after administration.A group gives Olaparib 3mg/kg, B group gives embodiment compound 3mg/kg, 15min, 30min, 1,2,3,5,8,10h from rat orbital vein take blood 100-200L or so after administration respectively, it is placed in the Eppendorf pipe through EDTA-K2 anticoagulant 0.5mL, it mixes immediately, after anticoagulant, after being as early as possible gently mixed by inversion test tube 5-6 times, blood is placed in ice chest after taking, 30min
It is interior blood sample under the conditions of 4000rpm, 10min, 4 DEG C centrifugal separation plasma, saved immediately in -20 DEG C after collecting whole blood plasma.The blood concentration in the blood plasma of each time point is measured after all time point sample acquisitions.
According to mean blood plasma concentration-time data after above-mentioned resulting administration, using Winnonin software, seeking calculation male SD rat by non-chamber statistical moment theory, i.g gives the pharmacokinetics relevant parameter after Olaparib (3mg/kg), embodiment compound (3mg/kg) respectively.
Experiment shows that compared with Olaparib, the compounds of this invention has more preferably activity, and has excellent pharmacokinetic property, therefore is more suitable for inhibiting the compound of anaplastic lymphoma kinase, and then be suitble to the drug of preparation treating cancer.
The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, without departing from the inventive concept of the premise, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to protection scope of the present invention.
Claims (9)
- A kind of substituted phthalazinone compounds, it is characterized by: the phthalazinone compounds as shown in formula (I), or its crystal form, pharmaceutically acceptable salt, prodrug, metabolin, tautomer, stereoisomer, isotopic variations, hydrate or solvated compoundsIn formula (1), R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21And R22It is each independently hydrogen, deuterium, halogen or trifluoromethyl；Additional conditions are that the phthalazinone compounds at least contain a D-atom.
- Phthalazinone compounds according to claim 1, it is characterised in that: R1、R2、R3And R4It is each independently deuterium or hydrogen.
- Phthalazinone compounds according to claim 1, it is characterised in that: R5And R6It is each independently deuterium or hydrogen.
- Phthalazinone compounds according to claim 1, it is characterised in that: R7、R8And R9It is each independently deuterium or hydrogen.
- Phthalazinone compounds according to claim 1, it is characterised in that: R10、R11、R12、R13、R14、R15、R16And R17It is each independently deuterium or hydrogen.
- Phthalazinone compounds according to claim 1, it is characterised in that: R18、R19、R20、R21And R22It is each independently deuterium or hydrogen.
- Phthalazinone compounds described in any one according to claim 1~6, it is characterised in that: the phthalazinone compounds can be selected from following any structure or its pharmaceutically acceptable salt:
- A kind of pharmaceutical composition, it is characterized by: it contains pharmaceutically acceptable carrier and phthalazinone compounds or its crystal form, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, isotopic variations, hydrate or solvate as described in claim 1~7 any one.
- A kind of purposes of the phthalazinone compounds as described in claim 1~7 any one, it is characterised in that: be used to prepare by the drug of the polymerase-mediated disease of polyadenylic acid diphosphonic acid ribosyl, such as oophoroma.
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| GB201804924D0 (en) * | 2018-03-27 | 2018-05-09 | Univ Oxford Innovation Ltd | Radiolabelled compound |
| AU2022268464A1 (en) | 2021-05-04 | 2023-12-21 | Shanghai Zheye Biotechnology Co. Ltd. | Nitrogen-containing heterocyclic pyridine compound |
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