CN104140426A - Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof - Google Patents

Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof Download PDF

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CN104140426A
CN104140426A CN201310165742.5A CN201310165742A CN104140426A CN 104140426 A CN104140426 A CN 104140426A CN 201310165742 A CN201310165742 A CN 201310165742A CN 104140426 A CN104140426 A CN 104140426A
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hydrogen
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CN104140426B (en
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樊兴
秦继红
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Shanghai Yidian Medical Science and Technology Development Co., Ltd.
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SHANGHAI HUILUN TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention relates to a pyrimidoimidazole derivative, a preparation method and medical use thereof, and particularly relates to a new pyrimidoimidazole derivative as shown in a general formula (I) or formula (II), a preparation method thereof, a pharmaceutical composition containing the new pyrimidoimidazole derivative, and use thereof as a therapeutic agent in particular as a poly (ADP(adenosine diphosphate)-ribose) polymerase (PARP) inhibitor.

Description

Kui Linpyrimido quinoline glyoxaline compound, its pharmaceutical composition and its production and use
Technical field
The present invention relates to Kui Linpyrimido quinoline imidazole derivative, its preparation method and the pharmaceutical composition that contains this derivative, using and as therapeutical agent with as the purposes of poly-(ADP-ribose) polysaccharase (PARP) inhibitor.
Background technology
Chemotherapeutics and ionizing radiation treatment are two kinds of common methods for the treatment of cancer.These two kinds of methods for the treatment of all can induce dna strand and/or double-strand break and then produce cytotoxic effect, thereby target tumor is because chromosome damage is dead.An important results as response DNA damage signal is that cell cycle regulating site signal is activated, thereby its object is that Cell protection does not carry out mitotic division and avoids cell injury in the situation that of DNA damage.In most of the cases, tumour cell has very high appreciation rate in damaged showing cell cycle regulating site signal.Therefore can infer, in tumour cell, have specific DNA repair mechanism, can respond fast and repair the chromosome damage relevant to breeding adjusting, thereby make himself to survive cytotoxic effect the maintenance survival of some medicines.
In clinical application, the effective concentration of chemotherapeutics or treatment yield of radiation can be resisted these DNA repair mechanisms, ensure the fragmentation effect to target tumor.But tumour cell can produce tolerance effect to treatment by strengthening its DNA damage repair mechanism, makes it to survive from fatal DNA damage.In order to overcome the tolerance of generation, conventionally need to increase the dosage of medicine or improve yield of radiation, this way will have a negative impact near healthy tissues focus, thereby makes in therapeutic process with serious untoward reaction, and then has strengthened Operative risk.Meanwhile, ever-increasing tolerance will reduce result for the treatment of, therefore can infer, by the adjusting to DNA damage signal repair mechanism, can realize the Cytotoxic raising to DNA damage medicament in the mode of tumor cell specific.
To gather the PARPs(Poly(ADP-ribose of adenosine diphosphate (ADP)-ribosylation activity as feature) polymerases), formed the superfamily of 18 kinds of cell ribozyme karyocyte matter enzymes.This poly-adenosine diphosphate (ADP)-ribosylation can regulate catalytic activity and the protein-protein interaction of target protein, and many basic bioprocesss are regulated and controled, and comprises that DNA repairs, necrocytosis, and genome stability is also associated.
PARP-1 activity accounts for 80% of total cell PARP activity, and it and the PARP-2 the most close with it become the member who possesses DNA plerosis damage ability in PARP family jointly.As inductor block and the signal protein of DNA damage, PARP-1 can rapid detection also directly be bonded to DNA damage site, and induction is afterwards assembled DNA and repaired required multiple protein, and then makes DNA damage repaired.In the time that PARP-1 in cell lacks, PARP-2 can substitute PARP-1 realizes the reparation of DNA damage.Research shows, compared with normal cell, the expression of PARPs albumen in solid tumor generally strengthens.In addition, for the tumour (as breast tumor and ovarian cancer) of DNA Related to repair gene disappearance (as BRCA-1 or BRCA-2), show the extreme sensitivity to PARP-1 inhibitor, this show PARP inhibitor as single dose in this potential use being known as aspect three negative breast cancer for the treatment of.Meanwhile, because DNA damage repair mechanism is that tumour cell reply chemotherapeutics and ionizing radiation treatment produce the main mechanism of tolerance effect, therefore PARP-1 is considered to explore an Effective target site of new cancer treatment method.
The PARP inhibitor of early development design be niacinamide using the NAD as PARP catalytic substrate as template, develop its analogue.These inhibitor, as the competitive inhibitor of NAD, with the catalytic site of NAD competition PARP, and then stop the synthetic of poly-(ADP-ribose) chain.Do not have the PARP under poly-(ADP-ribosylation) modification to disintegrate down from DNA damage site, will cause other protein that participate in repairing cannot enter injury site, and then can not carry out repair process.Therefore,, under the effect of cytotoxic drug or radiation, the existence of PARP inhibitor makes the impaired tumour cell of DNA finally dead.
In addition, the NAD being consumed as PARP catalytic substrate, is requisite in the synthetic ATP process of cell, and therefore, under high PARP activity level, intracellular NAD level can significantly decline, and then affects the ATP level in born of the same parents.Because intracellular ATP is containing quantity not sufficient, cell cannot be realized the programmed cell death process that ATP relies on, and can only turn to downright bad this special apoptotic process.In downright bad process, a large amount of inflammatory factors can be released, thereby other Organ and tissues are produced to toxic action.Therefore, PARP inhibitor also can be used for the treatment of and the relevant various diseases of this mechanism, comprise nerve degenerative diseases (as senile dementia, Huntington chorea, Parkinson's disease), diabetes, the complication in ischemic or Ischemia-Reperfusion Injury, as myocardial infarction and acute renal failure, circulation system disease, as septic shock, and diseases associated with inflammation, as chronic rheumatism etc.
Summary of the invention
One of object of the present invention is to provide a kind of new Kui Linpyrimido quinoline glyoxaline compound and derivative thereof, and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and meta-bolites precursor or prodrug.
Two of object of the present invention is to provide the pharmaceutical composition using described Kui Linpyrimido quinoline glyoxaline compound as activeconstituents.
Three of object of the present invention is to provide the preparation method of above-mentioned Kui Linpyrimido quinoline glyoxaline compound.
Four of object of the present invention is to provide the application of above-mentioned Kui Linpyrimido quinoline glyoxaline compound in medicine.
As the Kui Linpyrimido quinoline glyoxaline compound of first aspect present invention, it is the compound shown in general formula (I) or logical formula II:
Wherein: in logical formula I or logical formula II, R is hydrogen or halogen;
One of them is nitrogen for X, Y, Z, all the other are hydrocarbon or X, Y, Z one of them for hydrocarbon, all the other are nitrogen;
M is nitrogen or CR1;
R1 is hydrogen, oxygen, C 1-C 6alkyl, methoxyl group, trifluoromethyl and NR 2r 3;
R2 is hydrogen or C 1-C 4alkyl;
R3 is hydrogen or C 1-C 4alkyl.
Further preferably, the compound of structure provided by the invention as shown in logical formula I or logical formula II, wherein:
R is hydrogen or fluorine;
One of them is nitrogen for X, Y, Z, and all the other are hydrocarbon;
M is nitrogen or CR1;
R1 is hydrogen, oxygen, C 1-C 4alkyl, methoxyl group, trifluoromethyl and NR 2r 3;
R2 is hydrogen or C 1-C 4alkyl;
R3 is hydrogen or C 1-C 4alkyl.
Most preferably, the compound shown in the logical formula I of the present invention or logical formula II is included as one of following compound (1)～(16):
Described logical formula I or logical formula II compound are any one or both or three's the mixture arbitrarily in enantiomer, diastereomer, conformer.
Described logical formula I or logical formula II compound are pharmacy acceptable derivates.
Logical formula I of the present invention or logical formula II compound can exist with the form of pharmacy acceptable salt.
Pharmacy acceptable salt of the present invention is hydrochloride, vitriol, phosphoric acid salt, acetate, trifluoroacetate, mesylate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or the malate of logical formula I or logical formula II compound.
In a preferred embodiment of the invention, the Kui Linpyrimido quinoline glyoxaline compound of described logical formula I or logical formula II be 2-(piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide compounds with and pharmacologically acceptable salt.
As the preparation method of the compound shown in the logical formula I of second aspect present invention, its reaction formula is as follows:
Wherein, the definition of R, X, Y, Z and M is described above; Concrete steps are as follows:
Step 1): 2 of replacement, 3-diamines yl benzoic acid methyl esters and carbonyl dimidazoles ring-closure reaction, obtain replace 2-oxo-2,3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III);
Step 2): 2-oxo-2 of the replacement that step 1) obtains, 3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III) carries out chlorination reaction with phosphorus oxychloride, obtains the 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) replacing;
Step 3): under alkali exists, by step 2) 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) and the piperazine of the replacement that obtains carry out nucleophilic substitution reaction, obtains 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) replacing;
Step 4): 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) of the replacement that step 3) is obtained and polysubstituted pyrimidine compound generation nucleophilic substitution reaction, obtain intermediate (VI);
Step 5): catalytic hydrogenation reduction nitro occurs the intermediate (VI) that step 4) is obtained, and obtains intermediate (VII);
Step 6): the intermediate (VII) that step 5) is obtained by with acetic anhydride, trifluoro-acetic anhydride, trimethyl orthoformate or sodiumazide generation ring-closure reaction, obtain intermediate (VIII);
Step 7): the intermediate (VIII) that step 6) is obtained, by the aminolysis reaction of ester group occurs in methanolic ammonia solution, generates the compound shown in logical formula I.
As the preparation method of the compound shown in the logical formula II of second aspect present invention, its reaction formula is as follows:
Wherein, the definition of R, X, Y, Z and M is described above; Concrete steps are as follows
Step (1): 2 of replacement, 3-diamines yl benzoic acid methyl esters and carbonyl dimidazoles ring-closure reaction, obtain replace 2-oxo-2,3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III);
Step (2): 2-oxo-2 of the replacement that step (1) obtains, 3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III) carries out chlorination reaction with phosphorus oxychloride, obtains the 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) replacing;
Step (3): under alkali exists, 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) of the replacement that step (2) is obtained carries out nucleophilic substitution reaction with piperazine, obtains 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) replacing;
Step (4): 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) of the replacement that step (3) is obtained and polysubstituted pyrimidine compound generation nucleophilic substitution reaction, obtain intermediate (IX);
Step (5): catalytic hydrogenation reduction nitro occurs the intermediate (IX) that step (4) is obtained, and obtains intermediate (X);
Step (6): the intermediate (X) that step (5) is obtained by with acetic anhydride, trifluoro-acetic anhydride, trimethyl orthoformate or sodiumazide generation ring-closure reaction, obtain intermediate (XI);
Step (7): the intermediate (XI) that step (6) is obtained, by the aminolysis reaction of ester group occurs in methanolic ammonia solution, generates the compound shown in logical formula II.
As the medicinal compositions of third aspect present invention, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or logical formula II compound and one or more medicinal carrier substances and/or thinner.Or the logical formula I that comprises the treatment significant quantity that forms activeconstituents or logical formula II compound and pharmaceutically acceptable carrier, vehicle or thinner.
As the medicinal compositions of third aspect present invention, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable derivates of logical formula II compound and one or more medicinal carrier substances and/or thinner.Or the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable derivates of logical formula II compound and pharmaceutically acceptable carrier, vehicle or thinner.
As the medicinal compositions of third aspect present invention, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable salt of logical formula II compound and one or more medicinal carrier substances and/or thinner.Or the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable salt of logical formula II compound and pharmaceutically acceptable carrier, vehicle or thinner.
Described pharmaceutical composition is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
In described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
As the application of fourth aspect present invention, be wherein that described logical formula I or logical formula II compound are treated the application in the disease medicament that suppresses to improve because PARP is active in preparation.
As the application of fourth aspect present invention, be wherein that the pharmacy acceptable derivates of described logical formula I or logical formula II compound is treated the application in the disease medicament that suppresses to improve because PARP is active in preparation.
As the application of fourth aspect present invention, be wherein that the pharmaceutically useful salt of described logical formula I or logical formula II compound is treated the application in the disease medicament that suppresses to improve because PARP is active in preparation.
As the application of fourth aspect present invention, be wherein that described pharmaceutical composition is treated the application in the disease medicament that suppresses to improve because PARP is active in preparation.
The described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
As the application of fourth aspect present invention, be wherein described logical formula I or the application of logical formula II compound in the ancillary drug for the preparation of oncotherapy.
As the application of fourth aspect present invention, it is wherein the application in the ancillary drug for the preparation of oncotherapy of the pharmacy acceptable derivates of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, it is wherein the application in the ancillary drug for the preparation of oncotherapy of the pharmaceutically useful salt of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, be wherein the application of described pharmaceutical composition in the ancillary drug for the preparation of oncotherapy.
As the application of fourth aspect present invention, it is wherein the application in the medicine for the preparation of tumour strengthening radiotherapy of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, it is wherein the application in the medicine for the preparation of tumour strengthening radiotherapy of the pharmacy acceptable derivates of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, it is wherein the application in the medicine for the preparation of tumour strengthening radiotherapy of the pharmaceutically useful salt of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, be wherein the application of described pharmaceutical composition in the medicine for the preparation of tumour strengthening radiotherapy.
As the application of fourth aspect present invention, be wherein described logical formula I or the application of logical formula II compound in the medicine for the preparation of chemotherapy of tumors.
As the application of fourth aspect present invention, it is wherein the application in the medicine for the preparation of chemotherapy of tumors of the pharmacy acceptable derivates of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, it is wherein the application in the medicine for the preparation of chemotherapy of tumors of the pharmaceutically useful salt of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, be wherein the application of described pharmaceutical composition in the medicine for the preparation of chemotherapy of tumors.
As the application of fourth aspect present invention, it is wherein the application in the medicine of the individuation cancer therapy of preparation shortage homologous recombination (HR) dependent DNA double splitting of chain (DSB) reparation of described logical formula I or logical formula II compound.
As the application of fourth aspect present invention, be wherein that the pharmacy acceptable derivates of described logical formula I or logical formula II compound lacks the application in the medicine of individuation cancer therapy that homologous recombination (HR) dependent DNA double splitting of chain (DSB) repairs in preparation.
As the application of fourth aspect present invention, be wherein that the pharmaceutically useful salt of described logical formula I or logical formula II compound lacks the application in the medicine of individuation cancer therapy that homologous recombination (HR) dependent DNA double splitting of chain (DSB) repairs in preparation.
As the application of fourth aspect present invention, be wherein the application of described pharmaceutical composition in the medicine of the individuation cancer therapy of preparation shortage homologous recombination (HR) dependent DNA double splitting of chain (DSB) reparation.
As preferably, described cancer is to contain that one or more abilities by the DSB of HR DNA plerosis lower with respect to normal cell or the cancer of the cancer cells lost.
As preferably, described cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
As preferably, described cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer.
In order to check the exposure level of compound provided by the invention for PARP enzyme, adopt biochemistry level enzymic activity to test and determine the activity of various compound of the present invention to PARP enzyme.
PARP is a kind of post transcriptional modificaiton enzyme, DNA damage can activate this enzyme, PARP catalytic process is in vivo mainly the poly(ADP-ribose that a kind of NAD relies on) process, its substrate is mainly some nucleoprotein including PARP, histone is for wherein a kind of, the present invention by measure PARP under NAD effect to being coated in Histone poly(ADP-ribose in 96 orifice plates) degree, measure PARP activity, correspondingly measure PARP activity after the effect of PARP inhibitor, thereby evaluate the inhibition degree of this compounds to PARP activity.
Embodiment
Unless there is phase counter-statement, the following term being used in specification sheets and claim has following implication.
In the present invention, term " C 1-C 6alkyl " refer to the saturated monovalence alkyl that there is straight or branched part and contain 1 to 6 carbon atom.The example of this type of group includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.
Term " halogen " and " halo " refer to F, Cl, Br, I.
" pharmacy acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of character.This class salt comprises:
(1) with sour salify, free alkali by parent compound reacts and obtains with mineral acid or organic acid, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetic acid, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.
(2) salt that is present in that acid proton in parent compound is replaced by metal ion or is generated with organic bases ligand compound, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, and organic bases is thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc. such as.
" pharmaceutical composition " refers to one or more or its pharmacy acceptable salt, solvate, hydrate or prodrug and other chemical composition in the compound in the present invention, and for example pharmaceutically acceptable carrier mixes.The object of pharmaceutical composition is to promote the process of administration to animal.
" pharmaceutical carrier " refer to organism do not cause obvious pungency and do not disturb the biological activity of given compound and the pharmaceutical composition of character in non-active ingredient, such as, such as but not limited to calcium carbonate, calcium phosphate, various sugar (lactose, N.F,USP MANNITOL etc.), starch, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer or methacrylate polymer, gel, water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C or hydrogenated castor oil or many oxyethyl groups hydrogenated castor oil, sesame oil, Semen Maydis oil, peanut wet goods.
In aforesaid pharmaceutical composition, except comprising pharmaceutically acceptable carrier, can also be included in conventional assistant agent in medicine (agent), for example: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMIN, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
The invention discloses the application as poly-(ADP-ribose) AG14361 of a kind of compound and this compound, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention:
Preparation Example
Embodiment 1
The preparation of compound (1): 2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
Step 1:2-oxo-2, the preparation of 3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with 2 at one, 3-diamines yl benzoic acid methyl esters (0.8g, in anhydrous tetrahydrofuran solution (20mL) 4.8mmol), add carbonyl dimidazoles (1.56g, 9.6mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (sherwood oil: ethyl acetate=5:1) through rapid column chromatography and obtains faint yellow solid compound a: 2-oxo-2,3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (0.3g, yield 33%).MS(ESI)m/z:[M+H]+=193。
The preparation of step 2:2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
By compound a (1.1g, 5.7mmol) add phosphorus oxychloride (8mL), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (sherwood oil: ethyl acetate=5:1) through rapid column chromatography and obtains white solid compound b:2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (1.5g, yield 100%).MS(ESI)m/z:[M+H] +=211。
The preparation of step 3:2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
To be dissolved with compound b(59mg, in dimethyl formamide (5mL) 0.28mmol), add piperazine (110mg, 1.12mmol), be warming up to 100 DEG C, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=10:1) through rapid column chromatography and obtains white solid compound c:2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (100mg, yield 100%).MS(ESI)m/z:[M+H] +=261。
The preparation of step 4:2-(4-(2-amino-3-nitropyridine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
To be dissolved with compound c(100mg, in dimethyl formamide (5mL) 0.41mmol), add the chloro-3 nitros-PA (102mg of 4-, 0.59mmol) and diisopropyl ethyl amine (95mg, 0.74mmol), room temperature reaction is removal of solvent under reduced pressure after 8 hours, resistates separates (methylene dichloride: methyl alcohol=10:1) through rapid column chromatography and obtains white solid compound d:2-(4-(2-amino-3-nitropyridine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (100mg, yield 54%).MS(ESI)m/z:[M+H] +=398。
The preparation of step 5:2-(4-(2,3 diamino pyridine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
10% palladium carbon (20mg) is added and is dissolved with compound d(100mg, in methyl alcohol (10mL) solution 0.26mmol), hydrogenation 7 hours under normal temperature, filter, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains yellow solid Verbindung: 2-(4-(2,3-diamino-pyridine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (88mg, yield 96%).MS(ESI)m/z:[M+H] +=353。
The preparation of step 6:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with Verbindung (88mg at one, in anhydrous tetrahydrofuran solution (10mL) 0.25mmol), add carbonyl dimidazoles (162mg, 1mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains faint yellow solid compound f:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (72mg, yield 74%).MS(ESI)m/z:[M+H] +=394。
The preparation of step 7:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
To be dissolved with compound f(72mg, in tetrahydrofuran solution (5mL) 0.18mmol), add ammoniacal liquor (5mL), be warming up to 70 DEG C, tube sealing reaction is cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=10:1) through rapid column chromatography and obtains white solid compound (1): 2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (7mg, yield 11%).LC-MS(ESI):m/z379(M+1) +. 1H?NMR(300MHz,DMSO-d6):δ11.25(br,1H),10.94(br,1H),7.93(s,1H),7.76-7.74(m,1H),7.65-7.57(m,3H),7.40-7.37(m,1H),7.12-7.06(m,1H),6.64-6.60(m,1H),3.78(br,8H)。
Embodiment 2
The preparation of compound (2): 2-(4-(8-oxo-8,9-dihydro-7 hydrogen-purine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(6-amino-5-nitro-pyrimidine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound g:2-(4-(6-amino-5-nitro-pyrimidine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (150mg, yield 93%) by compound c and the chloro-5-nitro-4-of 6-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=399。
The preparation of step 2:2-(4-(5,6-di-amino-pyrimidine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound h:2-(4-(5 by compound g and palladium carbon generation catalytic hydrogenation, 6-di-amino-pyrimidine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (126mg, yield 69%).MS(ESI)m/z:[M+H]+=354。
The preparation of step 3:2-(4-(8-oxo-8,9-dihydro-7 hydrogen-purine-6-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make compound i:2-(4-(8-oxo-8 by compound h and carbonyl dimidazoles generation ring-closure reaction, 9-dihydro-7 hydrogen-purine-6-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (72mg, yield 63%).MS(ESI)m/z:[M+H]+=395。
The preparation of step 4:2-(4-(8-oxo-8,9-dihydro-7 hydrogen-purine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (2): 2-(4-(8-oxo-8 by the ammonolysis reaction of compound i and ammoniacal liquor generation ester, 9-dihydro-7 hydrogen-purine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (44mg, yield 33%).LC-MS(ESI):m/z380(M+1)+.1H?NMR(300MHz,DMSO-d6):δ11.85(br,1H),11.54(br,1H),10.90(br,1H),9.14(br,1H),8.13(s,1H),7.61(d,1H,J=7.8Hz),7.54(br,1H),7.33(d,1H,J=7.8Hz),6.99(t,1H,J=7.8Hz),3.68(br,8H)。
Embodiment 3
The preparation of compound (3): 2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(6-amino-5-nitropyridine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound j:2-(4-(6-amino-5-nitropyridine-4-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (150mg, yield 92%) by compound c and the chloro-3-nitro-4-of 2-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=398。
The preparation of step 2:2-(4-(3,4-diamino-pyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound k:2-(4-(3 by compound j and palladium carbon generation catalytic hydrogenation, 4-diamino-pyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (94mg, yield 100%).MS(ESI)m/z:[M+H]+=353。
The preparation of step 3:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make compound l:2-(4-(2-oxo-2 by compound k and carbonyl dimidazoles generation ring-closure reaction, 3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (82mg, yield 83%).MS(ESI)m/z:[M+H]+=394。
The preparation of step 4:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (3): 2-(4-(2-oxo-2 by the ammonolysis reaction of compound l and ammoniacal liquor generation ester, 3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (72mg, yield 53%).LC-MS(ESI):m/z379(M+1)+.1H?NMR(300MHz,DMSO-d6):δ11.86(br,1H),11.04(br,1H),10.93(br,1H),9.17(br,1H),7.79(d,1H,J=5.7Hz),7.65-7.52(m,2H),7.32(d,1H,J=8.7Hz),7.01-6.98(m,1H),6.66(d,1H,J=5.7Hz),3.72(br,8H)。
Embodiment 4
The preparation of compound (4): 2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound m:2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (690mg, yield 91%) by compound c and the chloro-3-nitro-2-of 6-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=398。
The preparation of step 2:2-(4-(5,6-diamino-pyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound n:2-(4-(5 by compound m and palladium carbon generation catalytic hydrogenation, 6-diamino-pyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (290mg, yield 69%).MS(ESI)m/z:[M+H]+=353。
The preparation of step 3:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make compound o:2-(4-(2-oxo-2 by compound n and carbonyl dimidazoles generation ring-closure reaction, 3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (73mg, yield 69%).MS(ESI)m/z:[M+H]+=394。
The preparation of step 4:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (4): 2-(4-(2-oxo-2 by the ammonolysis reaction of compound o and ammoniacal liquor generation ester, 3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (15mg, yield 22%).LC-MS(ESI):m/z379(M+1)+.1H?NMR(300MHz,DMSO-d6):δ11.85(br,1H),10.99(br,1H),10.40(br,1H),9.15(br,1H),7.60(d,1H,J=7.5Hz),7.51(br,1H),7.33(d,1H,J=7.5Hz),7.12(d,1H,J=8.1Hz),6.99(t,1H,J=7.5Hz),6.45(d,1H,J=8.1Hz),3.67(br,4H),3.48(br,4H)。
Embodiment 5
The preparation of compound (5): 2-(4-(1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with compound n(200mg at one, in trimethyl orthoformate solution (645mg) 0.55mmol), add tosic acid (10mg, 0.05mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains faint yellow solid compound p:2-(4-(1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (97mg, yield 48%).MS(ESI)m/z:[M+H]+=378。
The preparation of step 2:2-(4-(1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (5): 2-(4-(1 hydrogen-imidazo [4 by the ammonolysis reaction of compound p and ammoniacal liquor generation ester, 5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (32mg, yield 34%).LC-MS(ESI):m/z363(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.54(br,1H),9.17(br,1H),8.04(br,1H),7.85-7.60(m,2H),7.61-7.59(m,1H),7.52(br,1H),7.39-7.32(m,1H),7.01-6.96(m,1H),6.89-6.85(m,1H),3.70-3.68(m,1H)。
Embodiment 6
The preparation of compound (6): 2-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with compound n(200mg at one, in acetic acid solution (3mL) 0.55mmol), add diacetyl oxide (61mg, 0.6mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains faint yellow solid compound q:2-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (95mg, yield 32%).MS(ESI)m/z:[M+H]+=392。
The preparation of step 2:2-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (6): 2-(4-(2-methyl isophthalic acid hydrogen-imidazo [4 by the ammonolysis reaction of compound q and ammoniacal liquor generation ester, 5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (20mg, yield 23%).LC-MS(ESI):m/z377(M+1)+.1H?NMR(300MHz,DMSO-d6):δ11.87(br,1H),9.13(br,1H),7.70(d,1H,J=9.3Hz),7.60(d,1H,J=7.5Hz),7.52(br,1H),7.33(d,1H,J=7.5Hz),6.99(t,1H,J=7.5Hz),6.79(d,1H,J=9.3Hz),3.69(br,4H),3.62(br,4H),2.42(s,3H)。Embodiment 7
The preparation of compound (7): 2-(4-(1 hydrogen-[1,2,3] triazolos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(1 hydrogen-[1,2,3] triazolos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with compound n(250mg at one, in acetic acid solution (3mL) 0.68mmol), add Sodium Nitrite (47mg, 0.68mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains faint yellow solid compound r:2-(4-(1 hydrogen-[1,2,3] triazolo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (230mg, yield 90%).MS(ESI)m/z:[M+H]+=379。
The preparation of step 2:2-(4-(1 hydrogen-[1,2,3] triazolos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (7): 2-(4-(1 hydrogen-[1 by the ammonolysis reaction of compound r and ammoniacal liquor generation ester, 2,3] triazolo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (10mg, yield 5%).LC-MS(ESI):m/z364(M+1)+.1H?NMR(300MHz,DMSO-d6):δ11.86(br,1H),9.14(br,1H),8.17(d,1H,J=9.0Hz),7.62-7.53(m,3H),7.33(d,1H,J=7.8Hz),7.13(d,1H,J=9.0Hz),6.99(t,1H,J=7.8Hz),3.83(br,4H),3.71(br,4H)。
Embodiment 8
The preparation of compound (8): 2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound s:2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (140mg, yield 90%) by compound c and the chloro-5-nitro-4-of 2-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=398。
The preparation of step 2:2-(4-(4,5-diamino-pyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound t:2-(4-(4 by compound s and palladium carbon generation catalytic hydrogenation, 5-diamino-pyridine-2-yl) piperazine-1-yl)-1-hydrogen-benzoglyoxaline-4-methyl-formiate (100mg, yield 100%).MS(ESI)m/z:[M+H]+=353。
The preparation of step 3:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make compound u:2-(4-(2-oxo-2 by compound t and carbonyl dimidazoles generation ring-closure reaction, 3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (68mg, yield 62%).MS(ESI)m/z:[M+H]+=394。
The preparation of step 4:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (8): 2-(4-(2-oxo-2 by the ammonolysis reaction of compound u and ammoniacal liquor generation ester, 3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (32mg, yield 33%).LC-MS(ESI):m/z379(M+1)+.1H?NMR(300MHz,DMSO-d6):δ11.85(br,1H),10.88(br,1H),10.48(br,1H),9.15(br,1H),7.73(s,1H),7.61-7.59(m,1H),7.51(br,1H),7.33-7.30(m,1H),7.03-6.95(m,1H),6.46(s,1H),3.67-3.65(m,4H),3.52-3.49(m,4H)。
Embodiment 9
The preparation of compound (9): 2-(4-(2-trifluoromethyl-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with compound n(180mg at one, in trifluoroacetic acid solution (5mL) 0.49mmol), add trifluoroacetic anhydride (103mg, 0.49mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains faint yellow solid compound v:2-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (80mg, yield 37%).MS(ESI)m/z:[M+H]+=446。
The preparation of step 2:2-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (9): 2-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4 by the ammonolysis reaction of compound v and ammoniacal liquor generation ester, 5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (18mg, yield 24%).LC-MS(ESI):m/z431(M+1)+.1H?NMR(300MHz,DMSO-d6):δ13.99(br,1H),11.87(br,1H),9.16(br,1H),7.99-7.96(m,1H),7.63-7.60(m,1H),7.55(br,1H),7.33(d,1H,J=9.0Hz),7.09-6.96(m,2H),3.74-3.72(m,8H)。
Embodiment 10
Compound (10): the preparation of the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The benzoic preparation of the fluoro-3-nitro-2-of step 1:5-(2,2,2-trifluoroacetamide)
Under ice bath, by fluoro-2-trifluoroacetamide-5-phenylformic acid (2.5g, 10mmol) add slowly in nitrosonitric acid (14mL), reaction continues to stir after 1 hour to pour in frozen water under ice bath, filtration obtains the fluoro-3-nitro-2-(2 of white solid compound w:5-, 2,2-trifluoroacetamide) phenylformic acid (1.9g, yield 65%).MS(ESI)m/z:[M-H]-=295。
The preparation of the fluoro-3-nitrobenzoic acid of step 2:2-amido-5-
10% aqueous sodium hydroxide solution (20mL) is added and is dissolved with compound w(1.18g, 4mmol) ethanolic soln (20mL) in, reaction be warming up to 80 DEG C stir 3 hours.Ethanol is removed in decompression, and salt acid for adjusting pH to 4 for resistates filters, and obtains the fluoro-3-nitrobenzoic acid of yellow solid compound x:2-amido-5-(0.72g, yield 90%) MS (ESI) m/z:[M-H]-=199.
The preparation of the fluoro-3-nitrobenzene methyl of step 3:2-amido-5-
Under ice bath, thionyl chloride (2.38g) is slowly added dropwise to and is dissolved with compound x(0.8g, in methanol solution (20mL) 4mmol), be heated to reflux, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (sherwood oil: ethyl acetate=5:1) through rapid column chromatography and obtains the fluoro-3-nitrobenzene methyl of yellow solid compound y:2-amido-5-(0.5g, yield 58%).MS(ESI)m/z:[M+H]+=215。
Step 4:2, the preparation of 3-bis-amidos-5-fluorophenyl carbamate
Adopt embodiment 1 to prepare the similar method of Verbindung, by compound y, catalytic hydrogenation occurs and make compound z:2,3-bis-amidos-5-fluorophenyl carbamate (812mg, yield 46%).MS(ESI)m/z:[M+H]+=185。
The fluoro-2-of step 5:6-oxo-2, the preparation of 3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound a, make compound a by compound z and carbonyl dimidazoles (CDI) cyclization ': the fluoro-2-of 6-oxo-2,3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (711mg, yield 37%).MS(ESI)m/z:[M+H]+=211。
The preparation of the chloro-6-of step 6:2-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound b, pass through compound a ' make the chloro-6-of compound b ': 2-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (681mg, yield 94%) with phosphorus oxychloride generation chlorination.MS(ESI)m/z:[M+H]+=229。
The preparation of the fluoro-2-of step 7:6-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound c, make the fluoro-2-of compound c ': 6-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (430mg, yield 65%) by compound b ' with piperazine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=279。
The preparation of step 8:2-(4-(2-amino-3-nitropyridine-4-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound d ': 2-(4-(2-amino-3-nitropyridine-4-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (310mg, yield 95%) by compound c ' with 4-chloro-3 nitros-PA generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=416。
The preparation of step 9:2-(4-(2,3 diamino pyridine-4-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, there is catalytic hydrogenation by compound d ' and make Verbindung ': 2-(4-(2,3-diamino-pyridine-4-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (120mg, yield 100%).MS(ESI)m/z:[M+H]+=386。
The preparation of the fluoro-2-of step 10:6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, pass through Verbindung ' make the fluoro-2-of compound f ': 6-(4-(2-oxo-2 with carbonyl dimidazoles (CDI) cyclization, 3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (76mg, yield 64%).MS(ESI)m/z:[M+H]+=412。
The preparation of the fluoro-2-of step 11:6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (10) by compound f ' with the ammonolysis reaction of ammoniacal liquor generation ester: the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (28mg, yield 34%).LC-MS(ESI):m/z397(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.07(br,1H),11.19(br,1H),10.92(br,1H),9.11(br,1H),7.73(d,1H,J=5.4Hz),7.33-7.29(m,1H),7.19-7.16(m,1H),7.02(br,1H),6.58(d,1H,J=5.4Hz),3.72(br,4H),3.21(br,4H)。
Embodiment 11
Compound (11): the preparation of the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound g ': 2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (100mg, yield 73%) by compound c ' with the chloro-5-nitro-4-of 2-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=416。
The preparation of step 2:2-(4-(4,5-diamino-pyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound h ': 2-(4-(4 by compound g ' with palladium carbon generation catalytic hydrogenation, 5-diamino-pyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (40mg, yield 100%).MS(ESI)m/z:[M+H]+=371。
The preparation of step 3:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make compound i ': 2-(4-(4 by compound h ' with carbonyl dimidazoles generation ring-closure reaction, 5-diamino-pyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (48mg, yield 72%).MS(ESI)m/z:[M+H]+=412。
The preparation of the fluoro-2-of step 4:6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (11) by compound i ' with the ammonolysis reaction of ammoniacal liquor generation ester: the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (9mg, yield 32%).LC-MS(ESI):m/z397(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.03(br,1H),10.89(br,1H),10.50(br,1H),9.11(br,1H),7.72(br,2H),7.32-7.28(m,1H),7.18-7.14(m,1H),6.45(s,1H),3.65(br,4H),3.50(br,4H)。
Embodiment 12
Compound (12): the preparation of the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound j ': 2-(4-(6-amino-5-nitropyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (110mg, yield 91%) by compound c ' with the chloro-3-nitro-2-of 6-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=416。
The preparation of step 2:2-(4-(5,6-diamino-pyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound k ': 2-(4-(5 by compound j ' with palladium carbon generation catalytic hydrogenation, 6-diamino-pyridine-2-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (90mg, yield 66%).MS(ESI)m/z:[M+H]+=371。
The preparation of step 3:2-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make compound l ': 2-(4-(2-oxo-2 by compound k ' with carbonyl dimidazoles generation ring-closure reaction, 3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (73mg, yield 78%).MS(ESI)m/z:[M+H]+=412。
The preparation of the fluoro-2-of step 4:6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (4) by compound l ' with the ammonolysis reaction of ammoniacal liquor generation ester: the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (10mg, yield 32%).LC-MS(ESI):m/z397(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.05(br,1H),11.00(br,1H),10.42(br,1H),9.10(br,1H),7.72(br,1H),7.32(br,1H),7.18-7.10(m,2H),6.43(d,1H,J=8.7Hz),3.66(br,4H),3.48(br,4H)。
Embodiment 13
Compound (13): the preparation of the fluoro-2-of 6-(4-(2-trifluoromethyl-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of the fluoro-2-of step 1:6-(4-(2-trifluoromethyl-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Be dissolved with compound k ' (180mg at one, in trifluoroacetic acid solution (5mL) 0.49mmol), add trifluoroacetic anhydride (103mg, 0.49mmol), be warming up to backflow, react cooling after 8 hours, removal of solvent under reduced pressure, resistates separates (methylene dichloride: methyl alcohol=5:1) through rapid column chromatography and obtains faint yellow solid compound m ': the fluoro-2-of 6-(4-(2-trifluoromethyl-3 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (65mg, yield 31%).MS(ESI)m/z:[M+H]+=464。
The preparation of the fluoro-2-of step 2:6-(4-(2-trifluoromethyl-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (13) by compound m ' with the ammonolysis reaction of ammoniacal liquor generation ester: the fluoro-2-of 6-(4-(2-trifluoromethyl-3 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (10mg, yield 16%).LC-MS(ESI):m/z449(M+1)+.1H?NMR(300MHz,DMSO-d6):δ14.07(br,1H),12.56(br,1H),9.12(br,1H),7.98(br,1H),7.73(br,1H),7.58-7.24(m,3H),3.73(br,8H)。
Embodiment 14
Compound (14): the preparation of the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(5-amino-6-nitropyridine-3-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound n ': 2-(4-(5-amino-6-nitropyridine-3-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (210mg, yield 73%) by compound c ' with the bromo-2-nitro-3-of 5-aminopyrimidine generation nucleophilic substitution reaction.MS(ESI)m/z:[M+H]+=416。
The preparation of step 2:2-(4-(5,6-diamino-pyridine-3-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate
Adopt embodiment 1 to prepare the similar method of Verbindung, make compound o ': 2-(4-(5 by compound n ' with palladium carbon generation catalytic hydrogenation, 6-diamino-pyridine-3-yl) piperazine-1-yl) the fluoro-1-hydrogen-benzoglyoxaline-4-of-6-methyl-formiate (91mg, yield 68%).MS(ESI)m/z:[M+H]+=371。
The preparation of the fluoro-2-of step 3:6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound f, make the fluoro-2-of compound p ': 6-(4-(2-oxo-2 by compound o ' with carbonyl dimidazoles generation ring-closure reaction, 3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (63mg, yield 73%).MS(ESI)m/z:[M+H]+=412。
The preparation of the fluoro-2-of step 4:6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (14) by compound p ' with the ammonolysis reaction of ammoniacal liquor generation ester: the fluoro-2-of 6-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-b] pyridine-6-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (12mg, yield 31%).LC-MS(ESI):m/z449(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.04(br,1H),10.95(br,1H),10.48(br,1H),9.10(br,1H),7.71(br,1H),7.31-7.28(m,2H),7.15(s,1H),6.44(s,1H),3.67(br,4H),3.49(br,4H)。
Embodiment 15
Compound (15): the preparation of the fluoro-2-of 6-(4-(2-methoxyl group-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(the chloro-1 hydrogen-imidazo of 2-[4,5-b] pyridine-5-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound b, make compound q ': 2-(4-(the chloro-1 hydrogen-imidazo [4 of 2-by compound l ' with phosphorus oxychloride generation chlorination, 5-b] pyridine-5-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (381mg, yield 74%).MS(ESI)m/z:[M+H]+=430。
The preparation of the fluoro-2-of step 2:6-(4-(2-methoxyl group-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare the similar method of compound d, make the fluoro-2-of compound r ': 6-(4-(2-methoxyl group-1 hydrogen-imidazo [4 by compound q ' with sodium methylate generation nucleophilic substitution reaction, 5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (132mg, yield 51%).MS(ESI)m/z:[M+H]+=426。
The preparation of the fluoro-2-of step 3:6-(4-(2-methoxyl group-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (15) by compound r ' with the ammonolysis reaction of ammoniacal liquor generation ester: the fluoro-2-of 6-(4-(2-methoxyl group-3 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide (13mg, yield 33%).LC-MS(ESI):m/z411(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.03(br,1H),9.09(br,1H),7.96(br,1H),7.72-7.61(m,2H),7.32(d,1H,J=7.5Hz),6.80(d,1H,J=7.5Hz),3.82(s,3H),3.67(br,4H),3.61(br,4H)。
Embodiment 16
The preparation of compound (16): 2-(4-(2-dimethylamino-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-fluoro-1 hydrogen-h-benzimidazole-4-carboxamide of 6-, concrete reaction formula is as follows:
The preparation of step 1:2-(4-(2-dimethylamino-1 hydrogen-imidazo [4,5-b] pyridine-5-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate
Adopt embodiment 1 to prepare the similar method of compound d, make compound s ': 2-(4-(2-dimethylamino-1 hydrogen-imidazo [4 by compound q ' with dimethylamine generation nucleophilic substitution reaction, 5-b] pyridine-5-yl) piperazine-1-yl)-6-fluoro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (72mg, yield 33%).MS(ESI)m/z:[M+H]+=439。
The preparation of step 2:2-(4-(2-dimethylamino-3 hydrogen-imidazos [4,5-b] pyridine-5-yl) piperazine-1-yl)-fluoro-1 hydrogen-h-benzimidazole-4-carboxamide of 6-
Adopt embodiment 1 to prepare similarly method of compound (1), make compound (16): 2-(4-(2-dimethylamino-3 hydrogen-imidazo [4 by compound s ' with the ammonolysis reaction of ammoniacal liquor generation ester, 5-b] pyridine-5-yl) piperazine-1-yl) the fluoro-1 hydrogen-h-benzimidazole-4-carboxamide of-6-(15mg, yield 31%).LC-MS(ESI):m/z424(M+1)+.1H?NMR(300MHz,DMSO-d6):δ12.05(br,1H),9.06(br,1H),7.95(br,1H),7.73-7.63(m,2H),7.31(d,1H,J=7.2Hz),6.82(d,1H,J=7.2Hz),3.69(br,4H),3.60(br,4H),3.14(s,6H).
Biological assessment
Experimental principle:
After the poly ADP ribose of nucleoprotein is the translation when occurring in DNA damage and replying.PARP, full name is poly-adenosine diphosphate (ADP) ribose polymerase, in the time having NAD to exist, catalysis poly (ADP-ribose) is connected on the nucleoprotein closing on, thereby causes the DNA repair mechanism via base excision repair path.The HT Universal Chemiluminescent PARP Assay Kit that Trevigen company produces can measure this by the combination level of biotin labeled ADP-ribose and histone.
Reagent and consumptive material
1.HT Universal Chemiluminescent PARP Assay Kit with Histone-coated Strip Wells, U.S. Trevigen, article No.: 4676-096-K
2. read plate instrument, U.S. Perkin Elmer, EnVision Multilabel Plate Reader
Solution and damping fluid
1. the PBS solution that washing lotion contains 0.1%Triton X-100
2.20X PARP damping fluid obtains 1X damping fluid with deionized water by 20 times of 20X PARP damping fluid dilutions, and this damping fluid is used to dilution restructuring PARP enzyme, PARP Cocktail and tested compound.
3.10X PARP Cocktail prepares 1X PARP Cocktail:10X PARP Cocktail2.5 μ l/well, 10X activated dna 2.5 μ l/well, 1X PARP damping fluid 20 μ l/well in accordance with the following methods.
4.PARP Enzyme only before use, carefully dilutes recombinase with 1X PARP damping fluid, and the enzyme solution having diluted will use as early as possible, unspent will discarding.
Only before use, by 1X Strep diluted, Strep-HRP500 doubly obtains 1X solution to 5.Strep-HRP.
6. chemical luminous substrate only before use, mixes by the PeroxyGlow A of same volume and B solution the substrate that obtains horseradish peroxidase.
Experimental technique
Compound preparation
1. with DMSO, each 10mM test compound mother liquor is diluted to 10uM, 1uM.
2. only before experiment starts, the gradient concentration solution 1X PARP damping fluid that is dissolved in the each compound in DMSO is diluted to 20 times, obtain the compound solution of 5X, can be used to detect, positive control (POSITIVE) and negative control (NEGATIVE) hole are 1X PARP damping fluid (DMSO content 5%)
Operation steps
1. every hole adds 50 μ l1X PARP damping fluids to soak histone, incubated at room orifice plate 30 minutes, then by the 1X PARP damping fluid sucking-off in hole, and on paper handkerchief, residual liquid is patted dry only.
2. according to compound (1)～(16), the 5X compound solution having diluted is added in corresponding hole, every hole 10 μ l, positive control (POSITIVE) and negative control (NEGATIVE) hole are 1X PARP damping fluid (DMSO content 5%)
3. with 1X PARP damping fluid, PARP enzyme is diluted to every 15 μ l solution and contains 0.5Unit, then add 15 μ l enzyme solution in other holes except negative control hole, negative control hole only adds 1X PARP damping fluid, incubated at room orifice plate 10 minutes.
4. continue to add the 1X PARP Cocktail of 25 μ l in each hole.
Hatch orifice plate 60 minutes for 5.27 DEG C.
6. hatch after end, by the reaction solution sucking-off in hole, and on paper handkerchief, residual liquid is patted dry only.Then rinse orifice plate 4 times with the PBS solution that contains 0.1%Triton X-100,200 μ l for each every hole, and on paper handkerchief, residual liquid is patted dry only.
7. next, in every hole, add the 1X Strep-HRP solution having diluted, then hatch orifice plate 60 minutes at 27 DEG C.
8. hatch after end, by the reaction solution sucking-off in hole, and on paper handkerchief, residual liquid is patted dry only.Then rinse orifice plate 4 times with the PBS solution that contains 0.1%Triton X-100,200 μ l for each every hole, and on paper handkerchief, residual liquid is patted dry only.
9. washing and hardening after bundle, the PeroxyGlow A of same volume and B solution are mixed, every hole adds 100 μ l, puts into immediately and reads plate instrument and record chemiluminescence signal.
Data processing
Reading in every hole need to be converted into inhibiting rate.The inhibiting rate of compound can use following formula to calculate:
Note: positive control hole reading is positive hole reading, meaning is enzyme 100% activity; Negative control hole reading is negative hole reading, and meaning is enzyme 0%; Active X is the reading of each each concentration of sample.
The inhibition activity of table 1 compound to PARP-1 enzyme
Compound number The inhibiting rate (%) of 100nM concentration The inhibiting rate (%) of 30nM concentration IC 50Value
（1） 78 65 24nM
（2） 64 38 64nM
（3） 55 31 94nM
（4） 83 71 8nM
（5） 72 57 26nM
（6） 68 50 37nM
（7） 77 56 28nM
（8） 76 63 21nM
（9） 47 33 195nM
（10） 85 74 13nM
（11） 82 71 14nM
（12） 86 76 9nM
（13） 50 30 93nM
（14） 81 73 17nM
（15） 63 47 62nM
（16） 58 36 84nM
The activity data of listing in table 1 fully shows, compound of the present invention is all the inhibitor of PARP-1, wherein in embodiment, and compound (1), (2), (3), (4), (5), (6), (7), (8), (10), (11), (12), (13), (14), (15), (16) IC50 value is not more than 100nM, compound (4), and the IC50 value of (13) is not more than 10nM.

Claims (75)

1. Kui Linpyrimido quinoline glyoxaline compound, it is the compound shown in logical formula I or logical formula II:
Wherein, in logical formula I or logical formula II:
R is hydrogen or halogen;
One of them is nitrogen for X, Y, Z, all the other are hydrocarbon or X, Y, Z one of them for hydrocarbon, all the other are nitrogen;
M is nitrogen or CR1;
R1 is hydrogen, oxygen, C1-C6 alkyl, methoxyl group, trifluoromethyl and NR2R3;
R2 is hydrogen or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl.
2. Kui Linpyrimido quinoline glyoxaline compound according to claim 1, is characterized in that, the compound shown in described logical formula I or logical formula II, wherein:
R is hydrogen or fluorine;
One of them is nitrogen for X, Y, Z, and all the other are hydrocarbon;
M is nitrogen or CR1;
R1 is hydrogen, oxygen, C 1-C 4alkyl, methoxyl group, trifluoromethyl and NR2R3;
R2 is hydrogen or C 1-C 4alkyl;
R3 is hydrogen or C 1-C 4alkyl.
3. Kui Linpyrimido quinoline glyoxaline compound according to claim 1, is characterized in that, the compound shown in described logical formula I is following compound (1)～(3) and (10):
4. Kui Linpyrimido quinoline glyoxaline compound according to claim 1, is characterized in that, the compound shown in described logical formula II is following compound:
5. Kui Linpyrimido quinoline glyoxaline compound as claimed in claim 1, is characterized in that, described logical formula I or logical formula II compound are any one or both or three's the mixture arbitrarily in enantiomer, diastereomer, conformer.
6. Kui Linpyrimido quinoline glyoxaline compound as claimed in claim 1, is characterized in that, described logical formula I or logical formula II compound are pharmacy acceptable derivates.
7. Kui Linpyrimido quinoline glyoxaline compound as claimed in claim 1, is characterized in that, the logical formula I of described general formula or logical formula II compound exist with the form of pharmacy acceptable salt.
8. Kui Linpyrimido quinoline glyoxaline compound as claimed in claim 6, it is characterized in that, described pharmacy acceptable salt is hydrochloride, vitriol, phosphoric acid salt, acetate, trifluoroacetate, mesylate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or the malate of logical formula I or logical formula II compound.
9. Kui Linpyrimido quinoline glyoxaline compound as claimed in claim 1, it is characterized in that, the Kui Linpyrimido quinoline glyoxaline compound of described logical formula I or logical formula II be 2-(piperazine-1-yl)-1 hydrogen-h-benzimidazole-4-carboxamide compounds with and pharmacologically acceptable salt.
10. the preparation method of the compound shown in logical formula I described in claim 1, its reaction formula is as follows:
Wherein, the definition of R, X, Y, Z and M is described above; Concrete steps are as follows:
Step 1): 2 of replacement, 3-diamines yl benzoic acid methyl esters and carbonyl dimidazoles ring-closure reaction, obtain replace 2-oxo-2,3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III);
Step 2): 2-oxo-2 of the replacement that step 1) obtains, 3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III) carries out chlorination reaction with phosphorus oxychloride, obtains the 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) replacing;
Step 3): under alkali exists, by step 2) 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) and the piperazine of the replacement that obtains carry out nucleophilic substitution reaction, obtains 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) replacing;
Step 4): 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) of the replacement that step 3) is obtained and polysubstituted pyrimidine compound generation nucleophilic substitution reaction, obtain intermediate (VI);
Step 5): catalytic hydrogenation reduction nitro occurs the intermediate (VI) that step 4) is obtained, and obtains intermediate (VII);
Step 6): the intermediate (VII) that step 5) is obtained by with acetic anhydride, trifluoro-acetic anhydride, trimethyl orthoformate or sodiumazide generation ring-closure reaction, obtain intermediate (VIII);
Step 7): the intermediate (VIII) that step 6) is obtained, by the aminolysis reaction of ester group occurs in methanolic ammonia solution, generates the compound shown in logical formula I.
The preparation method of the compound shown in logical formula II described in 11. claims 1, its reaction formula is as follows:
Wherein, the definition of R, X, Y, Z and M is described above; Concrete steps are as follows
Step (1): 2 of replacement, 3-diamines yl benzoic acid methyl esters and carbonyl dimidazoles ring-closure reaction, obtain replace 2-oxo-2,3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III);
Step (2): 2-oxo-2 of the replacement that step (1) obtains, 3-dihydro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (III) carries out chlorination reaction with phosphorus oxychloride, obtains the 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) replacing;
Step (3): under alkali exists, 2-chloro-1 hydrogen-benzoglyoxaline-4-methyl-formiate (IV) of the replacement that step (2) is obtained carries out nucleophilic substitution reaction with piperazine, obtains 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) replacing;
Step (4): 2-(piperazine-1-yl)-1 hydrogen-benzoglyoxaline-4-methyl-formiate (V) of the replacement that step (3) is obtained and polysubstituted pyrimidine compound generation nucleophilic substitution reaction, obtain intermediate (IX);
Step (5): catalytic hydrogenation reduction nitro occurs the intermediate (IX) that step (4) is obtained, and obtains intermediate (X);
Step (6): the intermediate (X) that step (5) is obtained by with acetic anhydride, trifluoro-acetic anhydride, trimethyl orthoformate or sodiumazide generation ring-closure reaction, obtain intermediate (XI);
Step (7): the intermediate (XI) that step (6) is obtained, by the aminolysis reaction of ester group occurs in methanolic ammonia solution, generates the compound shown in logical formula II.
12. medicinal compositionss, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or logical formula II compound and one or more medicinal carrier substances and/or thinner.
13. pharmaceutical compositions as claimed in claim 12, the pharmaceutical composition described in it is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
14. pharmaceutical compositions as claimed in claim 12, in described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
15. medicinal compositionss, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or logical formula II compound and pharmaceutically acceptable carrier, vehicle or thinner.
16. pharmaceutical compositions as claimed in claim 15, the pharmaceutical composition described in it is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
17. pharmaceutical compositions as claimed in claim 15, in described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
18. medicinal compositionss, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable derivates of logical formula II compound and one or more medicinal carrier substances and/or thinner.
19. pharmaceutical compositions as claimed in claim 18, the pharmaceutical composition described in it is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
20. pharmaceutical compositions as claimed in claim 18, in described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
21. medicinal compositionss, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable derivates of logical formula II compound and pharmaceutically acceptable carrier, vehicle or thinner.
22. pharmaceutical compositions as claimed in claim 21, the pharmaceutical composition described in it is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
23. pharmaceutical compositions as claimed in claim 21, in described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
24. medicinal compositionss, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable salt of logical formula II compound and one or more medicinal carrier substances and/or thinner.
25. pharmaceutical compositions as claimed in claim 24, the pharmaceutical composition described in it is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
26. pharmaceutical compositions as claimed in claim 18, in described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
27. medicinal compositionss, the logical formula I that comprises the treatment significant quantity that forms activeconstituents or the pharmacy acceptable salt of logical formula II compound and pharmaceutically acceptable carrier, vehicle or thinner.
28. pharmaceutical compositions as claimed in claim 27, the pharmaceutical composition described in it is made tablet, capsule, aqueous suspension, oiliness suspensoid, dispersible pulvis, granule, lozenge, emulsion, syrup, ointment, ointment, suppository or injection.
29. pharmaceutical compositions as claimed in claim 27, in described pharmaceutical composition, described logical formula I or logical formula II compound exist with free form.
Application in the disease medicament that described in 30. claim 1 to 5 any one claims, logical formula I or logical formula II compound suppress to improve because PARP is active in preparation treatment.
31. application as claimed in claim 30, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 32. claims 6, the pharmacy acceptable derivates of logical formula I or logical formula II compound suppresses to improve because PARP is active in preparation treatment.
33. application as claimed in claim 32, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 34. claims 7 or 8 or 9, the pharmaceutically useful salt of logical formula I or logical formula II compound suppresses to improve because PARP is active in preparation treatment.
35. application as claimed in claim 34, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 36. claims 12 or 13 or 14, pharmaceutical composition suppresses to improve because PARP is active in preparation treatment.
37. application as claimed in claim 36, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 38. claims 15 or 16 or 17, pharmaceutical composition suppresses to improve because PARP is active in preparation treatment.
39. application as claimed in claim 38, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 40. claims 18 or 19 or 20, pharmaceutical composition suppresses to improve because PARP is active in preparation treatment.
41. application as claimed in claim 40, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 42. claims 21 or 22 or 23, pharmaceutical composition suppresses to improve because PARP is active in preparation treatment.
43. application as claimed in claim 42, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 44. claims 24 or 25 or 26, pharmaceutical composition suppresses to improve because PARP is active in preparation treatment.
45. application as claimed in claim 44, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Application in the disease medicament that described in 46. claims 27 or 28 or 29, pharmaceutical composition suppresses to improve because PARP is active in preparation treatment.
47. application as claimed in claim 46, the described disease of improving because of the active inhibition of PARP is vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Logical formula I or the application of logical formula II compound in the ancillary drug for the preparation of oncotherapy described in 48. claim 1 to 5 any one.
The application of the pharmacy acceptable derivates of logical formula I or logical formula II compound in the ancillary drug for the preparation of oncotherapy described in 49. claims 6.
The application of the pharmaceutically useful salt of logical formula I or logical formula II compound in the ancillary drug for the preparation of oncotherapy described in 50. claims 7 or 8 or 9.
The application of pharmaceutical composition in the ancillary drug for the preparation of oncotherapy described in 51. claim 12 to 29 any one claims.
Logical formula I or the logical formula II compound application in the medicine for the preparation of tumour strengthening radiotherapy described in 52. claim 1 to 5 any one claims.
The application of the pharmacy acceptable derivates of logical formula I or logical formula II compound in the medicine for the preparation of tumour strengthening radiotherapy described in 53. claims 6.
The application of the pharmaceutically useful salt of logical formula I or logical formula II compound in the medicine for the preparation of tumour strengthening radiotherapy described in 54. claims 7 or 8 or 9.
The application of pharmaceutical composition in the medicine for the preparation of tumour strengthening radiotherapy described in 55. claim 12 to 29 any one claims.
Logical formula I or the application of logical formula II compound in the medicine for the preparation of chemotherapy of tumors described in 56. claim 1 to 5 any one claims.
The application of the pharmacy acceptable derivates of logical formula I or logical formula II compound in the medicine for the preparation of chemotherapy of tumors described in 57. claims 6.
The application of the pharmaceutically useful salt of logical formula I or logical formula II compound in the medicine for the preparation of chemotherapy of tumors described in 58. claims 7 or 8 or 9.
The application of pharmaceutical composition in the medicine for the preparation of chemotherapy of tumors described in 59. claim 12 to 29 any one claims.
Application in the medicine of the individuation cancer therapy that described in 60. claim 1 to 5 any one claims, logical formula I or logical formula II compound are repaired in preparation shortage homologous recombination (HR) dependent DNA double splitting of chain (DSB).
61. application as claimed in claim 61, wherein said cancer is to contain that one or more abilities by the DSB of HR DNA plerosis lower with respect to normal cell or the cancer of the cancer cells lost.
62. application as claimed in claim 61, wherein said cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
63. application as claimed in claim 61, described cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer.
Application in the medicine of the individuation cancer therapy that described in 64. claims 6, the pharmacy acceptable derivates of logical formula I or logical formula II compound is repaired in preparation shortage homologous recombination (HR) dependent DNA double splitting of chain (DSB).
65. application as described in claim 65, wherein said cancer is to contain that one or more abilities by the DSB of HR DNA plerosis lower with respect to normal cell or the cancer of the cancer cells lost.
66. application as described in claim 65, wherein said cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
67. application as described in claim 65, described cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer.
Application in the medicine of the individuation cancer therapy that described in 68. claims 7 or 8 or 9, the pharmaceutically useful salt of logical formula I or logical formula II compound is repaired in preparation shortage homologous recombination (HR) dependent DNA double splitting of chain (DSB).
69. application as described in claim 69, wherein said cancer is to contain that one or more abilities by the DSB of HR DNA plerosis lower with respect to normal cell or the cancer of the cancer cells lost.
70. application as described in claim 69, wherein said cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
71. application as described in claim 69, described cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer.
Application in the medicine of the individuation cancer therapy that described in 72. claim 12 to 29 any one claims, pharmaceutical composition is repaired in preparation shortage homologous recombination (HR) dependent DNA double splitting of chain (DSB).
73. application as described in claim 73, described cancer is to contain that one or more abilities by the DSB of HR DNA plerosis lower with respect to normal cell or the cancer of the cancer cells lost.
74. application as described in claim 73, described cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
75. application as described in claim 73, described cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer.
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