CN105085483A - Kinase inhibitor and application thereof - Google Patents
Kinase inhibitor and application thereof Download PDFInfo
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- CN105085483A CN105085483A CN201510304709.5A CN201510304709A CN105085483A CN 105085483 A CN105085483 A CN 105085483A CN 201510304709 A CN201510304709 A CN 201510304709A CN 105085483 A CN105085483 A CN 105085483A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides a kinase inhibitor and application thereof. The compound is a compound shown in a formula I or pharmaceutical salt, a hydrate, a solvate, a metabolite or a prodrug of the compound shown in the formula I, wherein R1 and R2 are defined in the description. The compound and a pharmaceutical composition can be used for preparing an ALK inhibitor and drugs for treating or preventing cancers and inhibiting the proliferative effect of cancer cells. The formula I is shown in the description.
Description
Technical field
The invention belongs to field of medicaments, relate to the compounds as kinase inhibitor, concrete, the present invention relates to the compound as ALK inhibitor, and the application of these compounds in the medicine for the preparation for the treatment of and preventing cancer.
Background technology
Nonsmall-cell lung cancer (Non-small-cellcarcinoma, NSCLC) and " non-small cell carcinoma " synonym.Non-small cell type lung cancer, comprises squama cancer, gland cancer, large cell carcinoma, and the division of its growth of cancer cells is comparatively slow compared with small cell carcinoma, and diffusion transfer is relatively late.Nonsmall-cell lung cancer accounts for the 80-85% of lung cancer sum.Data presentation, current China lung cancer morbidity rate increases by 26.9% every year, and between 2000 to 2005, the number of the infected of lung cancer in China estimates increase by 120,000 people.Wherein, male lung cancer patient is increased to 330,000 people of 2005 from 260,000 people of 2000, and the same period, female lung cancer patient was increased to 170,000 people from 120,000 people.In addition, lung cancer also becomes " first of many cancers " in many areas, the whole nation.Beijing's lung cancer morbidity rate increases by 56% from calendar year 2001 to 2010 year.During the decade, 1/5th be patients with lung cancer in Beijing new cancer patient; In the Zhejiang Province in 2011 " cancer spectrum " that Zhejiang Prov. Tumor Hospital issues, lung cancer is still the cancer ranked the first; In Guangzhou Area is compared with before 30 years, and lung cancer morbidity rate increases 7 times.
Along with molecular medicine progress and the continuing to bring out of targeted drug, the treatment of advanced NSCLC has entered into the epoch of individualized treatment.The individuation targeted therapy of current clinical application is mainly for EGFR saltant type and ALK (Anaplasticlymphomakinase, Nucleophosmin-anaplastic lymphoma kinase) fusion gene type lung cancer, these two kinds of genovariation type lung cancer all have the targeted drug of clear and definite molecular target, target spot detection technique and listing, and clinical efficacy is improved significantly.In lung cancer, ALK variation is mainly ALK gene generation rearrangement and other gene fusion.It is reported that the gene unconventionality on ALK gene site is relevant with kinds cancer.Echinoderms microtubule related protein sample 4 (the EML4)-ALK fusion caused due to chromosome rearrangement has been reported in nonsmall-cell lung cancer (NSCLC) patient group.
Although people have studied a large amount of compounds protein kinase being had to inhibit activities, and some kinases inhibitors have gone on the market for the treatment of NSCLC as gram azoles for Buddhist nun etc., can produce resistance, there is defect to a certain degree.Treat effective patient as gram azoles for Buddhist nun and usually resistance will occur in medication after 6 months to 1 year.And, two grams of azoles for Buddhist nun's clinical research observation to modal untoward reaction be visual disorder, feel sick, diarrhoea, vomiting, oedema and constipation, adverse reaction rate >=25%.Thus, the new A LK inhibitor medicaments developing safer, efficient Therapeutic cancer has huge social value and economic benefit, is also the study hotspot of current each large medicine enterprise.
Therefore, current ALK inhibitor still haves much room for improvement.
Summary of the invention
The present invention one of is intended to solve the problems of the technologies described above at least to a certain extent or at least provides a kind of useful business to select.For this reason, one object of the present invention is to propose a kind of compound as kinase inhibitor that can be used in preparing the medicine of Therapeutic cancer.
According to an aspect of the present invention, the present invention proposes a kind of compound.According to embodiments of the invention, the pharmacologically acceptable salt that described compound is compound shown in compound shown in formula I or formula I, hydrate, solvate, meta-bolites or prodrug,
Wherein,
R
1for halogen or
in some embodiments of the invention, R
1can be fluorine, chlorine or
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, according to embodiments of the invention, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2.
In some embodiments of the invention, R
2for one of following:
According to embodiments of the invention, R
1for fluorine or chlorine, and R
2for one of following:
According to embodiments of the invention, R
1for
and R
2for one of following:
It will be understood by those skilled in the art that according to convention used in the art, in the structural formula of the application,
for describing chemical bond, described chemical bond is the point that part or substituting group are connected with core texture or skeleton structure.In addition, in the structural formula of the application,
for two positions adjacent with substituting group chemical bond that the substituting group position described on phenyl ring is in structural formula, the position of the annulus mark namely in this chemical formula
can occur monosubstituted.
Thus, this specification sheets in the whole text in, those skilled in the art can to R described in compound shown in formula I
1~ R
4group and substituting group select, to provide compound or pharmaceutically acceptable salt thereof, hydrate, solvate, meta-bolites or prodrug shown in described in embodiments of the invention, stable formula I.
According to embodiments of the invention, compound shown in formula I of the present invention can for being selected from following at least one:
Term used in the present invention, the non-toxic salt of the routine that " pharmacologically acceptable salt " is formed for compound shown in general formula I and mineral acid or organic acid reaction.Such as, the non-toxic salt of described routine obtains by compound shown in general formula I and mineral acid or organic acid reaction.Wherein, mineral acid can be hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and organic acid can for comprising citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid, naphthene sulfonic acid, ethyl sulfonic acid, naphthalene disulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, fumaric acid, succsinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutterring acid, hydroxymaleic acid, toluylic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, xitix, para-anilinesulfonic acid, Aspirin and isethionic acid etc.Or " pharmacologically acceptable salt " of compound shown in general formula I also can form sodium salt, sylvite, calcium salt, aluminium salt or ammonium salt with mineral alkali again after making compound shown in formula I and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, aspartic acid or L-glutamic acid form ester in advance.Or compound shown in general formula I and organic bases form methylamine salt, ethylamine salt or ethanolamine salt.Or compound shown in general formula I and Methionin, arginine, ornithine form corresponding inorganic acid salt again or form corresponding organic acid salt with formic acid, acetic acid, picric acid, methylsulfonic acid and ethyl sulfonic acid with hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid after forming ester.
Term used in the present invention, " prodrug " represents once give experimenter by described compound, and described compound just carries out chemical conversion by metabolic process or chemical process, thus obtains compound shown in formula I and/or its salt and/or solvate.Any compound that can transform to provide biologically active substance (i.e. compound shown in formula I) is in vivo the prodrug in the scope and spirit of the present invention.Such as, the compound containing carboxyl can hydrolyzable ester on physiology, and it is by being hydrolyzed obtain compound shown in formula I itself and serve as prodrug in vivo.The administration of described prodrug preferred oral, occurs under the impact of digestive ferment this is because hydrolysis is main in many cases.When ester itself has activity or hydrolysis occurs in blood, administered parenterally can be used.
Should also be understood that the hydrate of compound shown in formula I, solvate (such as methylate, ethylate, DMSO compound) also within the scope of the invention.The method of solvation is well known in the art.
According to a second aspect of the invention, the present invention proposes the method for compound shown in a kind of preparation formula Ι.According to embodiments of the invention, the method for compound shown in preparation formula Ι comprises:
(1) compound shown in compound with formula 2 shown in formula 1 is made to contact, to obtain compound shown in formula 3;
(2) compound shown in compound with formula 4 shown in formula 3 is made to contact, to obtain compound shown in formula 5;
(3) compound shown in formula 5 is made to contact with hydrochloric acid dioxane, to obtain compound shown in formula I,
According to embodiments of the invention, the R in compound shown in compound, formula I shown in compound, formula 5 shown in compound, formula 3 shown in compound shown in formula 1, formula 2
1and R
2for what define in description above.
Contriver finds, utilize the method for the above embodiment of the present invention can fast and effeciently compound shown in preparation formula I, and synthetic route is short, the yield of environmental friendliness, target product and purity higher, raw material is easy to get, operate and aftertreatment is simple, be applicable to suitability for industrialized production.
In one embodiment of the invention, the synthetic route of compound shown in formula I is:
Below the general method of compound shown in preparation formula I adopted in an embodiment of the present invention is described:
Step (1): the preparation of compound shown in formula 3 (intermediate)
According to a particular embodiment of the invention, in step (1), in the first organic solvent, when there is NaH, compound shown in compound with formula 2 shown in formula 1 is contacted.According to concrete example of the present invention, the first organic solvent can for being selected from least one in N-Methyl pyrrolidone, DMF (DMF), dimethyl sulfoxide (DMSO), N,N-DIMETHYLACETAMIDE, N,N-dimethylacetamide.In a concrete example of the present invention, the first organic solvent is DMF.Thus, good reaction environment can be provided for compound shown in compound and formula 2 shown in formula 1, and then improve the yield of compound shown in formula 3.
According to concrete example of the present invention, in step (1), 0 degree Celsius time, compound shown in compound with formula 2 shown in formula 1 is contacted.By selecting the temperature of reaction be suitable for, the yield of compound shown in preparation formula 3 can be improved further.According to another concrete example of the present invention, in step (1), the mol ratio of compound shown in compound and formula 2 shown in formula 1 can be (25-30): (15-30).According to a preferred embodiment of the invention, the mol ratio of compound shown in compound and formula 2 shown in formula 1 can be (27-28): (20-26).And then while compound productive rate shown in formula 3 can be improved, conservation cost.
According to a specific embodiment of the present invention, the preparation of compound shown in formula 3 (intermediate), specifically can carry out according to the following step: compound shown in formula 2 is dissolved in DMF, at 0 DEG C, add NaH in batches, add rear reaction solution and continue to stir half an hour at 0 DEG C, then by 2,5,6-trichloropyrimidine (shown in formula 1 compound) instills reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Drip frozen water cancellation after completion of the reaction, and be extracted with ethyl acetate, merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains product through column chromatography, is compound shown in formula 3.
Step (2): the preparation of compound shown in formula 5 (intermediate)
According to a particular embodiment of the invention, in step (2), in Virahol, there is tosic acid condition under, compound shown in compound with formula 4 shown in formula 3 is contacted, and is warming up to 60 ~ 80 DEG C and carries out stirring reaction.Thus, good reaction environment can be provided for compound shown in compound and formula 4 shown in formula 3, and then improve the yield of compound shown in formula 5.
Step (3): the preparation of compound shown in formula I
According to a particular embodiment of the invention, in step (3), shown in formula 5, compound contacts with hydrochloric acid dioxane, contacts stirring and react for 1.5 ~ 5 hours under 15-25 degrees celsius.Thus, the productive rate of compound shown in formula I can be improved.
According to a third aspect of the invention we, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, described intermediate is the compound shown in formula 5, shown in this formula 5, compound is the intermediate preparing compound shown in formula I, utilize compound shown in formula 5, can be used for being prepared into compound shown in formula I.
Wherein, R
1for halogen or
according to a preferred embodiment of the invention, R
1for fluorine, chlorine or
R
2for one of following:
According to embodiments of the invention, R
1for fluorine or chlorine, and R
2for one of following:
According to embodiments of the invention, R
1for
and R
2for one of following:
According to a forth aspect of the invention, the present invention proposes a kind of pharmaceutical composition.According to a particular embodiment of the invention, this pharmaceutical composition contains foregoing compound.According to concrete example of the present invention, pharmaceutical composition comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.
According to a particular embodiment of the invention, pharmaceutical composition is tablet, capsule, injection, powder injection, pulvis, syrup, solution shape, suspension or aerosol.The suitability of this pharmaceutical composition can be significantly improved thus.And the pharmaceutical composition of the above embodiment of the present invention may reside in in the carrier of suitable solid or liquid or diluent and the suitable disinfector for injecting or instil.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the customary preparation methods of pharmaceutical field.Compound of the present invention and pharmaceutical composition to Mammals Clinical practice, can comprise humans and animals, can pass through the administration of mouth, nose, skin, lung or gi tract etc.No matter adopt which kind of instructions of taking, the optimal dose of individual should be determined according to concrete treatment plan.Increase dosage until find optimal dosage gradually under normal circumstances from low dose.Most preferred route of administration is oral.
According to a fifth aspect of the invention, the present invention proposes foregoing compound, compound that foregoing method prepares or foregoing pharmaceutical composition preparing the purposes in medicine, described medicine is used as ALK inhibitor.
According to embodiments of the invention, the compounds of this invention is having purposes in the medicine of the disease of response for the preparation for the treatment of or prevention to suppressing Nucleophosmin-anaplastic lymphoma kinase, wherein use the compounds of this invention or its pharmacologically acceptable salts of significant quantity, can be used for treating the disease to suppressing Nucleophosmin-anaplastic lymphoma kinase to have response, described have the disease of response to be selected from least one in primary cutaneous type, non-Hodgkin lymphoma, inflammatory myofibroblastic tumor, neuroblastoma and tumor disease to suppression Nucleophosmin-anaplastic lymphoma kinase.
According to a particular embodiment of the invention, described medicine be used for following one of at least: as kinase inhibitor, suppress the propagation of ALK kinase activity, treatment or preventing cancer and anticancer.According to concrete example of the present invention, the present invention is to the ALK kinase inhibiting activity determination experiment result display in vitro of described compound, compound shown in formula I of the present invention all has good ALK kinase inhibiting activity, compound of the present invention can be used as ALK inhibitor, has the antineoplaston medicine of the disease of response for the preparation of suppressing Nucleophosmin-anaplastic lymphoma kinase in pairs.
According to concrete example of the present invention, compound shown in formula I of the present invention all has significant curative effect to the restraining effect that typeⅡ pneumocyte transplanted tumor in nude mice grows, and curative effect is better than existing ALK inhibitor medicaments gram azoles for Buddhist nun.The preferred lung cancer of cancer that medicine of the present invention can treat or prevent; The propagation of anticancer preferably suppresses lung carcinoma cell.
Therefore, medicine of the present invention can effectively as ALK inhibitor, and be used for the treatment of one or more relevant tumor diseases active in ALK, described tumor disease includes but not limited to lung cancer.Kinase inhibitor of the present invention and application thereof, it has good clinical application and medicinal use as ALK inhibitor.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Embodiment
Embodiments of the invention are described below in detail.Embodiment described below is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.Unreceipted concrete technology or condition in embodiment, according to the technology described by the document in this area or condition or carry out according to product description.
In specific embodiment described below, compound structure is or/and LC-MS chromatogram (LC-MS) is determined by nucleus magnetic resonance (NMR).Wherein, NMR displacement (δ) provides with the unit of 1,000,000/(ppm), and the mensuration of NMR uses BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d
6), deuterochloroform (CDCl
3), deuterated methanol (CD3OD), is inside designated as tetramethylsilane (TMS); The mensuration Agilent1200InfinitySeries mass spectrograph of LC-MS chromatogram LC-MS.The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (SunfireC18150 × 4.6mm chromatographic column).
The monitoring of the reaction process below in embodiment adopts tlc (TLC), the system of reacting the developping agent used has: methylene dichloride and methanol system, normal hexane/sherwood oil and ethyl acetate system, the volume ratio of solvent regulates according to the polarity difference of compound.Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
The system of eluent of column chromatography that in embodiment, purifying compounds adopts below and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane/sherwood oil and ethyl acetate system, the volume ratio of solvent is different and regulate according to the polarity of compound, also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent regulates.
The starting raw material used in embodiment below can adopt or synthesize according to methods known in the art, maybe can buy from ABCRGmbH & Co.KG, AcrosOrganics, AldrichChemicalCompany, splendid far away chemistry science and technology (AccelaChemBioInc), reach the companies such as auspicious chemical.
The embodiment provides compound or pharmaceutically acceptable salt thereof shown in formula I, hydrate, solvate, metabolite or prodrug, the method for compound or pharmaceutically acceptable salt thereof shown in preparation formula Ι, hydrate, solvate or prodrug and intermediate, pharmaceutical composition and compound of the present invention and pharmaceutical composition are preparing the purposes in medicine.
Embodiment 1: compound shown in preparation formula 2-a (intermediate)
By (the 15g of compound shown in formula a, 106.31mmol), salt of wormwood (29.38g, 212.61mmol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.5g, 111.62mmol), mixture is heated with stirring to 80 DEG C, reacts 5 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula c (19.5g must be measured, productive rate 95%) is obtained through column chromatography.
By (the 19.5g of compound shown in formula c, 98.86mmol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (60.2g, 348.84mmol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, with the cancellation of the saturated sodium sulfite aqueous solution, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula e (must 20.4g be measured, productive rate 90%) through column chromatography.
By (the 20.4g of compound shown in formula e, 88.98mmol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-a (must measure 15.95g, productive rate 90%).
Embodiment 2: compound shown in preparation formula 2-b (intermediate)
By (the 14.2g of compound shown in formula f, 0.1mol), salt of wormwood (27.6g, 0.2mol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.0g, 0.105mol), mixture is heated with stirring to 75 DEG C, reacts 6 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula g (17.9g must be measured, productive rate 92.5%) is obtained through column chromatography.
By (the 19.8g of compound shown in formula g, 0.1mol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (60.9g, 0.35mol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, use saturated sodium bisulfite solution cancellation, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula h (must 21.1g be measured, productive rate 92%) through column chromatography.
By (the 23.0g of compound shown in formula h, 0.1mol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-b (must measure 18.6g, productive rate 93.5%).
Embodiment 3: compound shown in preparation formula 2-b (intermediate)
By (the 15.9g of compound shown in formula j, 0.1mmol), salt of wormwood (27.6g, 0.2mmol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.0g, 0.105mol), mixture is heated with stirring to 80 DEG C, reacts 5 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula g (18.1g must be measured, productive rate 93%) is obtained through column chromatography.
By (the 19.8g of compound shown in formula g, 0.1mol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (48.7g, 0.28mol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, use saturated sodium bisulfite solution cancellation, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula h (must 21.5g be measured, productive rate 93.5%) through column chromatography.
By (the 23.0g of compound shown in formula h, 0.1mol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1.5atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-b (must measure 18.4g, productive rate 92%).
Embodiment 4: compound shown in preparation formula 2-c (intermediate)
By (the 16.4g of compound shown in formula k, 0.1mol), salt of wormwood (27.6g, 0.2mol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.0g, 0.105mol), mixture is heated with stirring to 75 DEG C, reacts 6 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula m (18.3g must be measured, productive rate 92%) is obtained through column chromatography.
By (the 20.3g of compound shown in formula m, 0.1mol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (60.9g, 0.35mol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, use saturated sodium bisulfite solution cancellation, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula n (must 21.7g be measured, productive rate 92.5%) through column chromatography.
By (the 23.5g of compound shown in formula n, 0.1mol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-c (must measure 18.9g, productive rate 92%).
Embodiment 5: compound shown in preparation formula 4-a (intermediate)
By (tertbutyloxycarbonyl) glycine (shown in formula 6 compound) (1g, 5.7mmol) be dissolved in the DMF of 15mL drying, add N successively, N-diisopropylethylamine (DIPEA) (2.21g, 17mmol), (chemical name is 2-(7-azo benzotriazole)-N to HATU, N, N', N'-tetramethyl-urea phosphofluoric acid ester) (2.34g, 6.15mmol) with mphenylenediamine (shown in formula 7 compound) (616mg, 5.7mmol), stirred at ambient temperature reaction is spent the night, reaction solution is poured in 50 ml waters, and be extracted with ethyl acetate (50mL × 3), merge organic phase, wash through saturated aqueous sodium carbonate, salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains thick product, compound products (937mg shown in formula 4-a is obtained again through column chromatography analysis (PE/EA=2:1), yield 62%).
Embodiment 6: compound shown in preparation formula 4-a (intermediate)
By (tertbutyloxycarbonyl) glycine (shown in formula 6 compound) (1g, 5.7mmol) be dissolved in the DMF of 15mL drying, add N successively, N-diisopropylethylamine (DIPEA) (2.21g, 17mmol), (chemical name is 2-(7-azo benzotriazole)-N to HATU, N, N', N'-tetramethyl-urea phosphofluoric acid ester) (2.34g, 6.15mmol) with mphenylenediamine (shown in formula 7 compound) (627mg, 5.8mmol), stirred at ambient temperature reaction is spent the night, reaction solution is poured in 50 ml waters, and be extracted with ethyl acetate (50mL × 3), merge organic phase, wash through saturated aqueous sodium carbonate, salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains thick product, compound products (980mg shown in formula 4-a is obtained again through column chromatography analysis (PE/EA=6:1), yield 64.85%).
Embodiment 7: compound shown in preparation formula 4-b (intermediate)
By (tertbutyloxycarbonyl) glycine (shown in formula 6 compound) (1g, 5.7mmol) be dissolved in the DMF of 15mL drying, add N successively, N-diisopropylethylamine (DIPEA) (2.21g, 17mmol), (chemical name is 2-(7-azo benzotriazole)-N to HATU, N, N', N'-tetramethyl-urea phosphofluoric acid ester) (2.34g, 6.15mmol) with Ursol D (shown in formula 8 compound) (648mg, 6.0mmol), stirred at ambient temperature reaction is spent the night, reaction solution is poured in 50 ml waters, and be extracted with ethyl acetate (50mL × 3), merge organic phase, wash through saturated aqueous sodium carbonate, salt is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains thick product, compound products (1013mg shown in formula 4-b is obtained again through column chromatography analysis (PE/EA=4:1), yield 67%).
Embodiment 8: compound shown in preparation formula 3-a
By (the 5g of compound shown in formula 2-a, 25.09mmol) be dissolved in DMF (100mL), NaH (0.66g is slowly added at 0 DEG C, 27.6mmol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-c (5.93g, 27.6mmol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 300mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (200mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 3.41g, productive rate 36%) shown in formula 3-a through column chromatography (PE/EA=4:1).
Embodiment 9: compound shown in preparation formula 3-b
By (the 5g of compound shown in formula 2-b, 25.09mmol) be dissolved in DMF (100mL), NaH (0.66g is slowly added at 0 DEG C, 27.6mmol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-c (5.93g, 27.6mmol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 300mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (200mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 3.23g, productive rate 34%) shown in formula 3-b through column chromatography (PE/EA=4:1).
Embodiment 10: compound shown in preparation formula 3-c
By (the 20.5g of compound shown in formula 2-c, 0.1mol) be dissolved in DMF (300mL), NaH (2.64g is slowly added at 0 DEG C, 0.11mol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-c (23.65g, 0.1mol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 600mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (600mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 11.52g, productive rate 30%) shown in formula 3-c through column chromatography (PE/EA=4:1).
Embodiment 11: compound shown in preparation formula 3-d
By (the 5g of compound shown in formula 2-b, 25.09mmol) be dissolved in DMF (100mL), NaH (0.66g is slowly added at 0 DEG C, 27.6mmol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-a (5.06g, 27.6mmol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 300mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (200mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 2.70g, productive rate 31%) shown in formula 3-d through column chromatography (PE/EA=4:1).
Embodiment 12: compound shown in preparation formula 3-e
By (the 20.5g of compound shown in formula 2-c, 0.1mol) be dissolved in DMF (300mL), NaH (2.64g is slowly added at 0 DEG C, 0.11mol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-a (22.04g, 0.12mol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 600mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (600mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 13.39g, productive rate 38%) shown in formula 3-e through column chromatography (PE/EA=4:1).
Embodiment 13: compound shown in preparation formula 3-f
By (the 20g of compound shown in formula 2-b, 0.1mol) be dissolved in DMF (500mL), NaH (2.64g is slowly added at 0 DEG C, 0.11mol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-b (18.4g, 0.11mol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 500mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (600mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 14.6g, productive rate 44%) shown in formula 3-f through column chromatography (PE/EA=4:1).
Embodiment 14: compound shown in preparation formula 3-g
By (the 20g of compound shown in formula 2-c, 0.1mol) be dissolved in DMF (500mL), NaH (2.64g is slowly added at 0 DEG C, 0.11mol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound shown in formula 1-b (18.4g, 0.11mol) is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 500mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (600mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound (must measure 15.11g, productive rate 45%) shown in formula 3-g through column chromatography (PE/EA=4:1).
Embodiment 15: compound shown in preparation formula 5-a
By (the 1.98g of compound shown in formula 3-a, 5.24mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 70 DEG C of temperature, stirring reaction 8 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-a (1.27g, productive rate 40%).
Embodiment 16: compound shown in preparation formula 5-b
By (the 1.98g of compound shown in formula 3-a, 5.24mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 65 DEG C of temperature, stirring reaction 8 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-b (2.01g, productive rate 63%).
Embodiment 17: compound shown in preparation formula 5-c
By (the 2.2g of compound shown in formula 3-b, 5.76mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-c (1.92g, productive rate 55%).
Embodiment 18: compound shown in preparation formula 5-d
By (the 2.2g of compound shown in formula 3-b, 5.76mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 60 DEG C of temperature, stirring reaction 10 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-d (2.45g, productive rate 70%).
Embodiment 19: compound shown in preparation formula 5-e
By (the 2g of compound shown in formula 3-c, 5.45mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 70 DEG C of temperature, stirring reaction 10 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-e (1869mg, productive rate 56%).
Embodiment 20: compound shown in preparation formula 5-f
By (the 2g of compound shown in formula 3-c, 5.45mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-f (2.504g, productive rate 75%).
Embodiment 21: compound shown in preparation formula 5-g
By (the 2g of compound shown in formula 3-d, 5.76mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-g (2.12g, productive rate 64%).
Embodiment 22: compound shown in preparation formula 5-h
By (the 2g of compound shown in formula 3-d, 5.76mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 60 DEG C of temperature, stirring reaction 6.5 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-h (2058mg, productive rate 62%).
Embodiment 23: compound shown in preparation formula 5-i
By (the 2g of compound shown in formula 3-e, 5.68mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-i (2376mg, productive rate 72%).
Embodiment 24: compound shown in preparation formula 5-j
By (the 2g of compound shown in formula 3-e, 5.68mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-j (2.310g, productive rate 70%).
Embodiment 25: compound shown in preparation formula 5-k
By (the 1.73g of compound shown in formula 3-f, 5.24mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 70 DEG C of temperature, stirring reaction 5 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-k (1760mg, productive rate 60%).
Embodiment 26: compound shown in preparation formula 5-l
By (the 1.73g of compound shown in formula 3-f, 5.24mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-l (2.58g, productive rate 88%).
Embodiment 27: compound shown in preparation formula 5-m
By (the 1.76g of compound shown in formula 3-g, 5.24mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-a wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 60 DEG C of temperature, stirring reaction 12 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-m (1479mg, productive rate 50%).
Embodiment 28: compound shown in preparation formula 5-n
By (the 1.76g of compound shown in formula 3-g, 5.24mmol) be dissolved in 60mL Virahol, add (the 1.53g of compound shown in formula 4-b wherein, 5.76mmol) with tosic acid (993mg, 5.76mmol), by mixture at 80 DEG C of temperature, stirring reaction 5 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in residual solids thing in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound shown in formula 5-n (1.625g, productive rate 55%).
Embodiment 29: compound shown in preparation formula I-1
By (the 400mg of compound shown in formula 5-g, 0.694mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2 hours under 20 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (281mg, productive rate 85%) of compound shown in formula I-1 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：475.9(M+H
+)
Embodiment 30: compound shown in preparation formula I-2
By (the 400mg of compound shown in formula 5-h, 0.694mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 5 hours under 15 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (231mg, productive rate 70%) of compound shown in formula I-2 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：475.9(M+H
+)
Embodiment 31: compound shown in preparation formula I-3
By (the 400mg of compound shown in formula 5-i, 0.688mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2.5 hours under 20 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (385mg, productive rate 92%) of compound shown in formula I-3 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：481.0(M+H
+)
Embodiment 32: compound shown in preparation formula I-4
By (the 400mg of compound shown in formula 5-j, 0.688mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 1.5 hours under 25 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (352mg, productive rate 84%) of compound shown in formula I-4 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：480.9(M+H
+)
Embodiment 33: compound shown in preparation formula I-5
By (the 400mg of compound shown in formula 5-k, 0.715mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 3 hours under 20 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (356mg, productive rate 85%) of compound shown in formula I-5 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：459.5(M+H
+)
Embodiment 34: compound shown in preparation formula I-6
By (the 400mg of compound shown in formula 5-l, 0.715mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2 hours under 20 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (335mg, productive rate 80%) of compound shown in formula I-6 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：459.5(M+H
+)
Embodiment 35: compound shown in preparation formula I-7
By (the 400mg of compound shown in formula 5-m, 0.709mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2.5 hours under 15 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (293mg, productive rate 70%) of compound shown in formula I-7 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：464.6(M+H
+)
Embodiment 36: compound shown in preparation formula I-8
By (the 400mg of compound shown in formula 5-n, 0.709mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 4 hours under 18 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (327mg, productive rate 78%) of compound shown in formula I-8 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：464.6(M+H
+)
Embodiment 37: compound shown in preparation formula I-9
By (the 400mg of compound shown in formula 5-c, 0.676mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2 hours under 25 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (399mg, productive rate 93%) of compound shown in formula I-9 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：507.5(M+H
+)
Embodiment 38: compound shown in preparation formula I-10
By (the 400mg of compound shown in formula 5-d, 0.676mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 5 hours under 20 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (390mg, productive rate 91%) of compound shown in formula I-10 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：507.5(M+H
+)
Embodiment 39: compound shown in preparation formula I-11
By (the 400mg of compound shown in formula 5-e, 0.670mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 1.5 hours under 25 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (343mg, productive rate 80%) of compound shown in formula I-11 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：512.6(M+H
+)
Embodiment 40: compound shown in preparation formula I-12
By (the 400mg of compound shown in formula 5-f, 0.670mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2 hours under 25 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (360mg, productive rate 84%) of compound shown in formula I-12 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：512.6(M+H
+)
Embodiment 41: compound shown in preparation formula I-13
By (the 400mg of compound shown in formula 5-a, 0.677mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 3 hours under 15 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (317mg, productive rate 74%) of compound shown in formula I-13 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：506.5(M+H
+)
Embodiment 42: compound shown in preparation formula I-14
By (the 400mg of compound shown in formula 5-b, 0.677mmol) be placed in 100mL reaction flask, add 50 milliliters of hydrochloric acid dioxane (2M), stir 2 hours under 20 DEG C of conditions, monitoring is filtered after completion of the reaction, the product (334mg, productive rate 78%) of compound shown in formula I-14 is obtained with washed with diethylether filter cake.
MSm/z(ESI)：506.5(M+H
+)
The mensuration of embodiment 43:ALK kinase inhibiting activity
Adopt following methods to measure compound of the present invention in vitro to the kinase whose inhibit activities of ALK, this inhibit activities adopts IC50 this index to represent, the concentration of compound during the kinase whose activity inhibited 50% of IC50 and ALK.
Write a Chinese character in simplified form and define
Mg milligram
ML milliliter
μ g microgram
μ l microlitre
MM mmole
EDTA ethylenediamine tetraacetic acid (EDTA)
DMSO methyl-sulphoxide
SD standard deviation
SOP Standard operation procedure SOP
Experiment material:
ALK(Carna,Cat.No08-105,Lot.No.08CBS-0112)
ALKL1196M(Carna,Cat.No08-529,Lot.No.11CBS-1134)
PeptideFAM-P22(GLBiochem,Cat.No.112393,Lot.No.P080401-XY112393)
ATP(Sigma,Cat.No.A7699-1G,CASNo.987-65-5)
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)
EDTA(Sigma,Cat.No.E5134,CASNo.60-00-4)
96 orifice plates (Corning, Cat.No.3365, Lot.No.22008026)
384 orifice plates (Corning, Cat.No.3573, Lot.No.12608008)
Staurosporine(Sigma,Cat.No.S4400-1MG,Lot.No.046K4080)
Experimental technique:
1. prepare kinase buffer liquid and the stop buffer of 1 times
1) 1 times of kinase buffer liquid
50mMHEPES,pH7.5
0.0015％Brij-35
10mMMgCl
2
2mMDTT
2) stop buffer
100mMHEPES,pH7.5
0.015％Brij-35
0.2％CoatingReagent#3
50mMEDTA
2. compound preparation
1) by the 100%DMSO solution of final for diluted chemical compound 50 times the highest required inhibition concentration.Shift this diluted chemical compound liquid of 100 μ L in 96 orifice plates.Such as, if need the highest inhibitor concentration to be 1 μM, just prepare the DMSO solution of 50 μMs in this step.
2) compound is become 10 concentration by 3 times of serial dilutions.
3) adding 100 μ l100%DMSO empty does not have compound to control with in the 96 identical orifice plates controlled without enzyme to 2.Mark source plate.
4) preparation of intermediate plate
Shift from source plate in 10 μ L compounds to new 96 orifice plates as intermediate plate.
Add 90 μ L1 times kinase buffer liquid in the hole of each intermediate plate.
To vibrate 10 minutes in mixing cpd to intermediate plate.
3. prepare test board
From 96 hole intermediate plates, in each hole, in transferase 45 μ l to 384 orifice plates, conduct repeats.Such as, the A1 in 96 orifice plates transfers to A1 and A2 in 384 orifice plates.A2 in 96 orifice plates transfers to A3 and A4 of 384 orifice plates.
4. kinase reaction
1) 2.5 times of enzyme solution are prepared
Kinases is added 1 times of kinase buffer liquid, form 2.5 times of enzyme solution.
2) substrate solution of 2.5 times is prepared
The polypeptide mark FAM and ATP add 1 times of kinase buffer liquid, form 2.5 times of substrate solutions.
3) test board has contained the DMSO solution of 10% of 5 μ l compounds.
4) transferase 12 .5 times of enzyme solution is to test board.
5) incubated at room temperature 10 minutes
6) transferase 12 .5 times of peptide solution is to test board.
7) kinase whose reaction and stopping
20 minutes are hatched at 28 DEG C.Add 25 μ l stop solution termination reactions.
5.Caliper reading of data
Caliper upper reading and converting rate data.
6. fitting of a curve
1) conversion data is copied from Caliper.
2) conversion is become inhibiting rate data.Wherein max refers to that the transformation efficiency that DMSO contrasts, min refer to the transformation efficiency without enzyme contrast alive.Percentinhibition＝(max-conversion)/(max-min)*100.
3) XLFitexceladd-inversion4.3.1 is used to carry out curve fitting data importing MSExcel.
The formula used is:
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)) following table show the compound shown in formula I-1 ~ formula I-14 in vitro ALK kinase inhibition measure in activity.Result shows, compound shown in formula I of the present invention all has good ALK kinase inhibiting activity, compound of the present invention can be used as ALK inhibitor, be used for the treatment of one or more relevant tumor diseases active in ALK, for the preparation of the antineoplaston medicine becoming to suppress Nucleophosmin-anaplastic lymphoma kinase.
| Compound number | IC50(nM) |
| I-1 | <10 |
| I-2 | <10 |
| I-3 | <10 |
| I-4 | <100 |
| I-5 | <100 |
| I-6 | <100 |
| I-7 | <10 |
| I-8 | <10 |
| I-9 | <10 |
| I-10 | <100 |
| I-11 | <100 |
| I-12 | <10 |
| I-13 | <100 |
| I-14 | <10 |
As can be seen from above-claimed cpd to ALK kinase inhibiting activity measuring experimental result, compound of the present invention has very high inhibit activities for Nucleophosmin-anaplastic lymphoma kinase.Compound I-1, I-2, I-3, I-7, I-8 of the present invention, the IC50 of I-9, I-12 and I-14 is all less than 10nM, Compound I-4, I-5, I-6 of the present invention, the IC50 of I-10, I-11, I-13 is all less than 100nM, and it is at 10nM-100nM, and the IC50 value of all compounds is all less than 100nM.These results show, compound of the present invention is excellent ALK inhibitor, effectively can treat relevant tumor disease active in ALK.
Embodiment 44: for the tablet of oral administration, prescription is in table 2
Table 2: for the tablet formulation of oral administration
| Composition | Bulk drug (gram) |
| Activeconstituents | 25 |
| Lactose | 40 |
| Microcrystalline Cellulose | 100 |
| Polyvinylpolypyrrolidone | 6 |
| Magnesium Stearate | 1.5 |
| Be prepared into | 1000 |
Preparation technology:
By the activeconstituents comminution by gas stream of compound of the present invention, pulverize pressure 0.3Mpa, D90=50 micron, recipe quantity takes, then mix in multinomial movement mixer with the Microcrystalline Cellulose of recipe quantity, then add polyvinylpolypyrrolidone, lactose, Magnesium Stearate mix, and rotary tablet machine becomes tablet with the compacting of direct compression technique, be prepared into 1000 altogether, the activeconstituents (compound of the present invention) of every sheet is 25mg.
Embodiment 45: the impact that compound of the present invention grows typeⅡ pneumocyte transplanted tumor in nude mice
(1) preparation of people's Pulmonary carcinoma nude mice Transplanted tumor model
SPF level BALB/c-nu mouse 36,6 week age, weight l6g-18g.Take the logarithm lung cancer cell types cell in vegetative period, adjusting A549 cell concn with aseptic PBS is 3 × 10
7/ mL, at BALB/c-nu mouse back subcutaneous vaccination A549 cell 0.1ml, treats that subcutaneous transplantation knurl volume reaches 75mm
3during left and right (about 10 days), model manufacturing success.
(2) grouping and administration
Be divided into following 8 groups by knurl volume and mice with tumor body weight homeostatic principle, often organize 12:
A, model control group: 1 times/day, the physiological saline of gavage equivalent, altogether administration 30 days;
B, oxaliplatin group: abdominal injection 10mg/kg oxaliplatin, the next day administration 1 time, amount to 8 times;
C, gram azoles are for Buddhist nun's group: gavage gives gram azoles for Buddhist nun's capsule (Pfizer produces, trade(brand)name: Sai Kerui) powder, and dosage is 25mg/kg, 2 times/day, and administration amounts to 8 times;
Compound group shown in D, formula I-1: gavage gives the tablet powder prepared according to embodiment 44, and dosage is 10mg/kg, 2 times/day, altogether administration 30 days;
During administration every 4 days with the most major diameter (L) of vernier caliper measurement transplanted tumor and most minor axis (w).Last administration dislocates after 48 hours and puts to death mouse, and excision transplanted tumor, takes knurl weight.Tumor-like hyperplasia (%) IR=(1-experimental group knurl weight-average value/model control group knurl weight-average value) × 100%.What weighed by knurl relatively embodies the impact of medicine on the growth of typeⅡ pneumocyte nude mice suppression knurl.Data represent with mean ± standard deviation (x ± s), adopt SPSS15.0 software to carry out variance analysis.
(3) results and analysis
Compound shown in formula I-1 on the experimental result of the impact that typeⅡ pneumocyte transplanted tumor in nude mice grows in table 4.
Table 4
| Group | Knurl heavy (mg) | Average tumour inhibiting rate (%) |
| Model control group | 402.3±76.7 | / |
| Oxaliplatin group | 216.3±51.0* | 44.05 |
| Gram azoles is for Buddhist nun's group | 195.0±47.8* | 49.33 |
| The group of compound shown in formula I-1 | 177.6±45.0** | 53.20 |
Note: compare with model control group, * P < 0.05, * * P < 0.01.
The test-results of table 4 shows: compared with model control group, each treatment group all has significant difference to the restraining effect that typeⅡ pneumocyte transplanted tumor in nude mice grows, especially compared with model control group, compound shown in formula I-1 of the present invention has pole significant difference (P < 0.01) in the restraining effect grown typeⅡ pneumocyte transplanted tumor in nude mice, with chemotherapy oxaliplatin group, ALK inhibitor gram azoles is compared for Buddhist nun's group, average tumour inhibiting rate increases, this illustrates that compound of the present invention has extremely significant curative effect in treatment nonsmall-cell lung cancer, while the remarkable drug effect of acquisition, there is the low advantage of toxic side effect, obtain unforeseeable technique effect.
In like manner, shown in applying equation I-2 of the present invention, compound shown in compound to formula I-14 is tested the impact that typeⅡ pneumocyte transplanted tumor in nude mice grows, and the results are shown in Table 5.
Table 5
| Group | Knurl heavy (mg) | Average tumour inhibiting rate (%) |
| Model control group | 402.3±76.7 | / |
| Oxaliplatin group | 216.3±51.0* | 44.05 |
| Gram azoles is for Buddhist nun's group | 195.0±47.8* | 49.33 |
| The group of compound shown in formula I-2 | 172.7±43.5** | 53.20 |
| The group of compound shown in formula I-3 | 175.3±43.2** | 52.90 |
| The group of compound shown in formula I-4 | 179.9±44.6** | 54.22 |
| The group of compound shown in formula I-5 | 184.5±50.3** | 55.01 |
| The group of compound shown in formula I-6 | 182.8±49.6** | 53.72 |
| The group of compound shown in formula I-7 | 170.3±42.5** | 50.34 |
| The group of compound shown in formula I-8 | 172.1±43.1** | 51.00 |
| The group of compound shown in formula I-9 | 174.4±45.8** | 53.21 |
| The group of compound shown in formula I-10 | 175.6±46.9** | 54.30 |
| The group of compound shown in formula I-11 | 173.9±50.2** | 52.69 |
| The group of compound shown in formula I-12 | 176.8±51.9** | 53.70 |
| The group of compound shown in formula I-13 | 185.0±42.1** | 56.12 |
| The group of compound shown in formula I-14 | 183.2±43.7** | 55.80 |
Note: compare with model control group, * P < 0.05, * * P < 0.01.
The result display of table 5, formula I, especially shown in described formula I-2, shown in compound to formula I-14, compound all has significant curative effect in the restraining effect grown typeⅡ pneumocyte transplanted tumor in nude mice, while the remarkable drug effect of acquisition, there is the low advantage of toxic side effect, all obtain unforeseeable technique effect.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (10)
1. a compound, its pharmacologically acceptable salt for compound shown in compound shown in formula I or formula I, hydrate, solvate, meta-bolites or prodrug,
Wherein,
R
1for halogen or
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace,
Wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl,
P is 0,1 or 2.
2. compound according to claim 1, is characterized in that, R
1for fluorine, chlorine or
R
2for one of following:
Optionally, R
1for fluorine or chlorine, and R
2for one of following:
Optionally, R
1for
and R
2for one of following:
3. compound according to claim 1 and 2, is characterized in that, described compound is be selected from following one or its pharmacologically acceptable salt, hydrate, solvate, meta-bolites or prodrug:
4. prepare a method for compound according to any one of claim 1-3, it is characterized in that, comprising:
(1) compound shown in compound with formula 2 shown in formula 1 is made to contact, to obtain compound shown in formula 3;
(2) compound shown in compound with formula 4 shown in described formula 3 is made to contact, to obtain compound shown in formula 5;
(3) compound and hydrochloric acid dioxane shown in described formula 5 is made to enter tactile, to obtain compound shown in formula I,
Wherein, R
1, R
2any one of claim 1-3 define.
5. method according to claim 4, is characterized in that, in step (1), in the first organic solvent, exists under NaH condition, and compound shown in compound with described formula 2 shown in described formula 1 is contacted,
Optionally, described first organic solvent is be selected from least one in N-Methyl pyrrolidone, DMF, dimethyl sulfoxide (DMSO), N,N-DIMETHYLACETAMIDE, N,N-dimethylacetamide, preferred DMF,
Optionally, in step (1), under 0 degrees celsius, compound shown in compound with described formula 2 shown in described formula 1 is contacted.
6. method according to claim 4, is characterized in that, in step (2), in Virahol, there is tosic acid condition under, shown in described formula 3, shown in compound with described formula 4, compound contacts,
Optionally, in step (2), under 60 ~ 80 degrees celsius, compound shown in compound with described formula 4 shown in described formula 3 is contacted.
7. method according to claim 4, is characterized in that, in step (3), under 15-25 degrees celsius, makes compound shown in described formula 5 contact 1.5-5 hour with hydrochloric acid dioxane.
8. an intermediate, described intermediate is the compound shown in formula 5,
Wherein,
R
1for halogen or
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace,
Wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl,
P is 0,1 or 2.
9. intermediate according to claim 8, is characterized in that, R
1for fluorine, chlorine or
R
2for one of following:
Optionally, R
1for fluorine or chlorine, and R
2for one of following:
Optionally, R
1for
and R
2for one of following:
10. the compound according to any one of claim 1-3 is preparing the purposes in medicine, and described medicine is used as ALK inhibitor.
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| CN106083670A (en) * | 2016-06-08 | 2016-11-09 | 常州安迪沃克医药科技有限公司 | The synthetic method of cancer therapy drug Ceritinib intermediate 1 amino 2 (isopropyl sulphonyl) benzene |
| WO2016192132A1 (en) * | 2015-06-04 | 2016-12-08 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative serving as alk inhibitor |
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| CN107586278A (en) * | 2016-07-08 | 2018-01-16 | 中国科学院上海药物研究所 | 2,4 2 amine pyrimidine compounds, its preparation method, pharmaceutical composition and the purposes of a kind of fragment containing phenol |
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| WO2016192132A1 (en) * | 2015-06-04 | 2016-12-08 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative serving as alk inhibitor |
| US10899710B2 (en) | 2015-08-07 | 2021-01-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Pyridines and their use in the treatment of cancer |
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| CN107586278B (en) * | 2016-07-08 | 2020-01-10 | 中国科学院上海药物研究所 | 2, 4-diamino pyrimidine compound, preparation method, pharmaceutical composition and application thereof |
| WO2018146472A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11028067B2 (en) | 2017-02-07 | 2021-06-08 | Oblique Therapeutics Ab | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11161815B2 (en) | 2017-02-07 | 2021-11-02 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11168069B2 (en) | 2017-02-07 | 2021-11-09 | Oblique Therapeutics Ab | Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11208384B2 (en) | 2017-02-07 | 2021-12-28 | Oblique Therapeutics Ab | Sulfinylpyridines and their use in the treatment of cancer |
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| CN105085483B (en) | 2019-01-01 |
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