CN104844609A - Double-site irreversible Brutons tyrosine kinase inhibitor - Google Patents
Double-site irreversible Brutons tyrosine kinase inhibitor Download PDFInfo
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- CN104844609A CN104844609A CN201510242552.8A CN201510242552A CN104844609A CN 104844609 A CN104844609 A CN 104844609A CN 201510242552 A CN201510242552 A CN 201510242552A CN 104844609 A CN104844609 A CN 104844609A
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- piperidine
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- tyrosine kinase
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- 0 CC*c1c(C)c(Oc(cc2)ccc2C(c2c(N)ncnc2[N+]C(CCC2)CN2C(C(*)=C)=O)=N)c(CC=*)c(*)c1*1CC1 Chemical compound CC*c1c(C)c(Oc(cc2)ccc2C(c2c(N)ncnc2[N+]C(CCC2)CN2C(C(*)=C)=O)=N)c(CC=*)c(*)c1*1CC1 0.000 description 2
- IDVZMGKRRLOIJV-UHFFFAOYSA-N Nc1ncnc2c1c(-c(cc1)ccc1Oc(cc1)ccc1Cl)n[n]2C1CNCCC1 Chemical compound Nc1ncnc2c1c(-c(cc1)ccc1Oc(cc1)ccc1Cl)n[n]2C1CNCCC1 IDVZMGKRRLOIJV-UHFFFAOYSA-N 0.000 description 1
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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
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Abstract
The invention provides a double-site irreversible Brutons tyrosine kinase inhibitor, a drug combination containing the same and application thereof to the anti-tumor field. The compound provided by the invention has an anti-proliferation inhibiting effect to tumor cell stains such as A549, SGC7901, MCF-7, PC-9 and HL-60, and can be applied to drugs for treating solid tumors or blood cancers related to human or animal cell proliferation; the compound provided by the invention has a better pharmacokinetic property and can be applied to treating solid tumors or blood cancers related to human or animal cell proliferation or autoimmune diseases through oral taking; the compound provided by the invention has a double-site response characteristic.
Description
Technical field
The invention belongs to field of medicaments, specifically a kind of dibit point irreversible bruton's tyrosine kinase inhibitor, containing its pharmaceutical composition and the application in antitumor thereof.
Background technology
Small molecules covalency inhibitor (covalent inhibitors), also irreversible inhibitor (irreversible inhibitors) is claimed, be by covalent linkage and target protein residue generation irreversible fixation, thus play a class inhibitor of its biological function.Covalency inhibitor medicaments in the past few decades in significant contribution has been made to human health.Relative to non-covalent inhibitor, covalency inhibitor is by enhancing the affinity with target with target protein with covalent bonds, and this is the basic reason that covalency inhibitor shows its high biological activity.In recent years, because non-covalent anti-tumor drugs targeting is particularly a large amount of for the kinase whose generation for Buddhist nun's class Drug-resistant, people are made to pay close attention to covalency inhibitor medicaments more again.In recent years, many big drug firms have all carried out the research and development of the covalency inhibitor for certain enzyme target spot, and existing some covalent inhibitor enters clinical trial at present, comprise Ah method for Buddhist nun, Cl 1033, HKI-272 etc.Wherein, Ah method to be used for the treatment of the Metastatic Nsclc of EGF-R ELISA (EGFR) transgenation by U.S. FDA official approval on July 12nd, 2013 for Buddhist nun, become the irreversible inhibitor new drug of the first treatment lung cancer ratified by FDA.In addition, antiviral covalent drug is also study hotspot in recent years, and makes great progress, such as, and FDA approved in 2011 two anti-hepatitis c virus covalency inhibitor medicaments, i.e. telaprevir and boceprevir.These researchs demonstrate the treatment that irreversible inhibitor can be effective to disease.
Bruton's tyrosine kinase (Bruton ' s tyrosine kinase, Btk), a member for nonreceptor tyrosine kinase Tec family is the key signal enzyme of expressing in all hematopoetic cell types except T lymphocyte and natural killer cell.Btk stimulates in the B cell signal transduction path of replying to downstream cellular play the part of vital role in connection cell surface B-cell receptor (B-cell receptor, BCR).Btk is that B cell is grown, activated, the key regulators of intracellular signaling and survival.In addition, Bkt works in other hematopoietic cell signal transduction paths numerous, the TNF-α of the Toll-like receptor (Toll like receptor, TLR) such as in scavenger cell and cytokine receptor mediation produces, immunoglobulin E acceptor (Fc ε R1) intracellular signaling in mastocyte, in B-pedigree lymphoidocyte, suppress the platelet aggregation of the apoptotic intracellular signaling of Fas/APO-1 and collagen stimulation.See such as C.A.Jeffries etc., J.Bio.Chem. (2003) 278:26258-26264, N.J.Horwood etc., J.Exp.Med. (2003) 197:1603-1611.Recent study shows, and Btk signal path is the new focus in current non-Hodgkin lymphoma (NHL), particularly chronic lymphocytic leukemia (CLL), B cell lymphoma and the research of autoimmune disease clinical treatment.Small molecules Btk inhibitor, by acting on BCR signal path, is combined with Btk and suppresses Btk autophosphorylation, stops the activation of Btk, thus blocks cell conductance and cell death inducing.Btk inhibitor selectivity is strong, and toxic side effect is low, and particularly her cloth replaces the listing of Buddhist nun, and be decided to be " breakthrough " new drug by FDA, its research and development have a extensive future.Yi Bu reacts for the sulfydryl of Buddhist nun and Btk enzyme halfcystine (Cys481) residue, and forms covalent linkage, makes Btk enzyme deactivation and plays curative effect.But, Yi Bu replaces Buddhist nun in administration process for Buddhist nun, easily affected drug effect (see following formula) by metabolism (being become dihydroxylation product or the inactivation by other attacks such as enzyme, halfcystine, gsh containing sulfydryl by metabolic enzyme oxidative metabolism), its clinical administration dosage reaches 560mg/ days, and make patient's burden, therefore still need the more efficient BTK inhibitor of development one class for the treatment of relative disease.
Summary of the invention
The object of the present invention is to provide dibit point BTK irreversible inhibitor that is novel, that have no bibliographical information and optical isomer thereof or its pharmacy acceptable salt or solvate.
Replace the passway of metabolism analysis of Buddhist nun based on her cloth, if replace the α of Buddhist nun at her cloth, the near-end of β-unsaturated double-bond introduces halogen atom, makes its metabolism site be occupied and block double bond by metabolic enzyme institute dihydroxylation, and then improves the metabolic stability in its body.What is more important, due to the introducing of halogen atom, recruit is made to be provided with two reaction site, after (or in cell) is contained the enzyme, halfcystine, gsh etc. of sulfydryl by other in vivo, still there is a site that can react with the sulfydryl of Btk enzyme halfcystine (Cys481) residue---the amide group (see following formula) of α halo, and then play the effect of increased activity.
The present invention adopts following technical scheme:
BTK inhibitor provided by the present invention has general formula (I) structure:
And optical isomer or its pharmacy acceptable salt or solvate, wherein:
Ra, Rb, Rc are independently selected from H, halogen ,-CF
3,-CN ,-NO
2, OH, NH
2,-L-C
1-C
6alkyl ,-L-C
1-C
6the substituted or non-substituted heteroaryl of thiazolinyl ,-L-or the substituted or non-substituted aryl of-L-,
Wherein L is key, O, S ,-S (=O) ,-S (=O)
2, NH, C (O), CH
2,-NHC (O) O ,-NHC (O) or-C (O) NH.
X is selected from halogen, is preferably fluorine, chlorine and bromine.
Further, the preferred compound of the present invention has general formula (II) structure:
And optical isomer or its pharmacy acceptable salt or solvate, wherein:
Each Rd is H, halogen ,-CF independently
3,-CN ,-NO
2,-OH, C
1-C
3alkoxyl group ,-NH
2.
X is selected from halogen, is preferably fluorine, chlorine and bromine.
Further, the preferred compound of the present invention has general formula (III) structure:
And optical isomer or its pharmacy acceptable salt or solvate, wherein:
X is selected from halogen, is preferably fluorine, chlorine and bromine.
Term illustrates: term used herein " aryl " refers to full carbon monocycle or the fused polycycle group of 5 to 12 carbon atoms, has the π-electron system of total conjugated.The limiting examples of aromatic ring has: phenyl ring, naphthalene nucleus and anthracene nucleus.Aromatic ring can be without replacing or replacing.The substituting group of aromatic ring is selected from halogen, nitro, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group, C
3-C
6cycloalkyl, halo C
3-C
6cycloalkyl;
Term used herein " heteroaryl " refers to the undersaturated carbocyclic ring of 5 to 12 annular atomses, and wherein one or more carbon are by displacements such as heteroatoms such as oxygen, nitrogen, sulphur.Hetero-aromatic ring can be monocycle, also can be dicyclo, is namely condensed by two rings and forms.Concrete heterocyclic aryl can be: pyridyl, pyrimidyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl and imidazolyl etc.Heterocyclic aryl can be without replacing or replacing.The substituting group of heterocyclic aryl is selected from halogen, nitro, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group, C
3-C
6cycloalkyl, halo C
3-C
6cycloalkyl;
Term used herein " heterocycle " refers to monocycle or fused ring group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is selected from N, O or S (O)
mthe heteroatoms of (wherein m is the integer of 0 to 2), all the other annular atomses are C.These rings can have one or more double bond, but these rings do not have the π-electron system of total conjugated.Without the Heterocyclylalkyl replaced can be that pyrrolidyl, piperidyl, piperazinyl, morpholino base, thiomorpholine are for base, homopiperazine base etc.Heterocycle can be without replacing or replacing.The substituting group of heterocycle is selected from halogen, nitro, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl, halo C
1-C
6alkoxyl group, C
3-C
6cycloalkyl, halo C
3-C
6cycloalkyl.
Term used herein " alkoxyl group " refers to-O-alkyl group, and wherein alkyl as defined above.The example of " alkoxyl group " used herein includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and tert.-butoxy." alkoxyl group " also comprises substituted alkoxy.Alkoxyl group optionally can be optionally substituted by halogen one or many.
Term " thiazolinyl " refers to a class alkyl, and wherein two initial atoms of alkyl form double bond, and this double bond is not the integral part of aromatic base.That is, thiazolinyl starts from atom-C (R)=C (R)-R, and wherein R refers to the rest part of thiazolinyl, and each R can be identical or different.Alkenyl part can be side chain, straight chain or ring-type (in the case, it also can be called as " cycloalkenyl group ").According to structure, thiazolinyl can be monoradical or twoly add group (i.e. alkenylene).Thiazolinyl can be optional replacement.The limiting examples of thiazolinyl comprises-CH=CH
2,-C (CH
3)=CH
2,-CH=CHCH
3,-C (CH
3)=CHCH
3.Alkenylene includes but not limited to-CH=CH-,-C (CH
3)=CH-,-CH=CHCH
2-,-CH=CHCH
2cH
2-and-C (CH
3)=CHCH
2-.Thiazolinyl can have 2-10 carbon atom.Thiazolinyl alternatively has " low-grade alkenyl " of 2-6 carbon atom.
Term used herein " halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine, chlorine and bromine.
Term " pharmacy can accept derivative " refers to salt and the solvate of selected compounds.
Term used herein " solvate " refers to the mixture of the varying chemical metering formed by solute (such as: general formula of the present invention (I) ~ general formula (III) compound) and solvent.For the purposes of the present invention, described solvent can not disturb the biologic activity of solute.The example of suitable solvent includes but not limited to water, methyl alcohol, ethanol and acetic acid.The solvent of preferred use is pharmaceutical acceptable solvents.Suitable pharmaceutical acceptable solvents includes but not limited to water, ethanol and acetic acid.More preferably, solvent for use is water.
The present invention adopts method well-known to those skilled in the art can prepare the salt of compound of the present invention.Described salt can be organic acid salt, inorganic acid salt etc., and described organic acid salt comprises citrate, fumarate, oxalate, malate, lactic acid salt, camsilate, tosilate, mesylate etc.; Described inorganic acid salt comprises halogen acid salt, vitriol, phosphoric acid salt, nitrate etc.Such as, with lower alkanesulfonic acid, as methylsulfonic acid, trifluoromethanesulfonic acid etc. can form mesylate, fluoroform sulphonate; With aryl sulfonic acid, as Phenylsulfonic acid or tosic acid etc. can form tosilate, benzene sulfonate; With organic carboxyl acid, as acetic acid, fumaric acid, tartrate, oxalic acid, toxilic acid, oxysuccinic acid, succsinic acid or citric acid etc. can form corresponding salt; With amino acid, as L-glutamic acid or aspartic acid can form glutaminate or aspartate.With mineral acid, as haloid acid (as hydrofluoric acid, Hydrogen bromide, hydroiodic acid HI, spirit of salt), nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc. also can form corresponding salt.
Second object of the present invention is to provide a kind of pharmaceutical composition, described pharmaceutical composition comprises at least one active ingredient and one or more pharmaceutically acceptable carrier or vehicle, described active ingredient can be in the solvate of BTK inhibitor compound of the present invention, the optical isomer of described compound, described compound or its optical isomer pharmaceutically acceptable salt, described compound or its optical isomer any one or multiple arbitrarily.
Described carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc., can also add flavouring agent if desired, sweeting agent etc.Medicine of the present invention can make tablet, pulvis, granula, capsule, the various ways such as oral liquid and injecting drug use, and the medicine of above-mentioned each formulation all can be prepared according to the ordinary method of pharmaceutical field.
On the other hand, the present invention is to provide the disease, obstacle or the illness that use the compound described in general formula disclosed herein (I) ~ general formula (III) and optical isomer thereof or its pharmacy acceptable salt or solvate to benefit from the active suppression of bruton's tyrosine kinase (Btk) to suppress the active or treatment of bruton's tyrosine kinase (Btk).
In in further, provided hereinly be composition by giving a kind of at least one compound containing treatment significant quantity of curer in need thus suppress the method for the bruton's tyrosine kinase activity of described curee, the structural formula of wherein said compound is general formula (I) ~ general formula (III).In some embodiments, curee's suffering from autoimmune disease in need, such as inflammatory bowel, sacroiliitis, lupus, rheumatoid arthritis, psoriasis arthropathica, osteoarthritis, Still disease (Still ' s disease), adolescent arthritis, diabetes, myasthenia gravis, Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Order thyroiditis (Ord ' s thyroiditis), Graves' disease (Graves ' disease), rheumatoid arthritis syndrome (
syndrome), multiple sclerosis, Guillain-Barre syndrome (Guillain-Barr é syndrome), acute disseminated encephalomyelitis, bronzed disease (Addison ' s disease), opsoclonus-myoclonic syndrome, mandatory spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease (coeliac disease), goodpasture's syndrome (Goodpasture ' s syndrome), idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter syndrome (Reiter ' s syndrome), aortic arch syndrome (Takayasu ' s arteritis), temporal arteritis, warm type autoimmune hemolytic anemia, Wegner granulomatosis (Wegener ' s granulomatosis), psoriatic, alopecia universalis, behcet disease (Behcet ' s disease), confirmed fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia.
In further embodiment, curee's suffers from cancer in need.In one embodiment, described cancer is B cell proliferative disease, such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, chronic lymphocytic leukemia, B cell PL, lymphoplasmacytic lymphoma/macroglobulinemia Waldenstron (
macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmoma, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, vertical diaphragm (thymus gland) large B cell lymphoid tumor, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma (Burkitt lymphoma)/leukemia or lymphomatoid granulomatosis.
The present invention also provides the application of compound or pharmaceutically acceptable salt thereof of the present invention in preparation BTK inhibitor, the application particularly in preparation treatment cell proliferative diseases.Described cell proliferative diseases comprises cancer.In other words, the present invention also provides compound described in general formula (I) ~ general formula (III) and optical isomer thereof or its pharmacy acceptable salt or solvate separately or and the application of other drug conbined usage in treatment proliferative diseases (as cancer).The antitumour drug of energy and compound or pharmaceutically acceptable salt thereof conbined usage provided by the present invention comprises but not limits the following kind of at least one: mitotic inhibitor (as vinealeucoblastine(VLB), vindesine and Vinorelbine); Tubulin decomposing inhibitor (as PTX); Alkylating reagent (as cis-platinum, carboplatin and endoxan); Metabolic antagonist (as 5 FU 5 fluorouracil, Tegafur, methotrexate, cytosine arabinoside and hydroxyurea); Microbiotic (as A Leisu, mitomycin and bleomycin) can be inserted; Enzyme (as asparagine enzyme); Topoisomerase inhibitors (as relied on uncle's glycosides and camptothecine); Biological response modifier (as Interferon, rabbit).
Present invention also offers and prepare the method that general formula (I) and pharmacy thereof can accept derivative, the synthetic route synthesis with shown in following scheme:
As shown in reaction formula, compound 1 (prepared by the method with reference to WO2012158795) and R
ib (OH)
2at potassiumphosphate, palladium catalyst and suitable solvent or mixed solvent as under dioxane/water exists; back flow reaction 24 hours; the compound 2 obtained triphenyl phosphorus, DIAD and suitable solvent as THF exist under; the 3-hydroxy piperidine protected with Boc is obtained by reacting compound 3, and key intermediate 4 is prepared in hydrolysis in acid condition subsequently.This key intermediate DCC and suitable solvent, as under DCM existence, with substitutional crylic acid fragment condensation reaction, obtain general formula (I) compound.
Inventor confirms by experiment, the compounds of this invention has antiproliferative restraining effect to tumor cell lines such as A549, SGC7901, MCF-7, PC-9, HL-60, can be applicable to treat in the medicine of solid tumor that human or animal cell proliferative is correlated with or leukemia.
Inventor confirms by experiment, and the compounds of this invention has good pharmacokinetic property, can be applicable to the relevant solid tumor of oral administration human or animal cell proliferative or leukemia or suffering from autoimmune disease.
Inventor confirms by experiment, and the compounds of this invention has the response characteristic of dibit point.
Embodiment
Below by embodiment, exploitativeness of the present invention is described, it will be understood by those of skill in the art that the instruction according to prior art, corresponding technical characteristic modified or replaces, still belonging to the scope of protection of present invention.
The preparation of embodiment 1. key intermediate 4a
The synthesis of step 1. 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2a)
By iodo-for 3-1H-pyrazolo [3; 4-d] pyrimidine-4-amine (compound 1) (2.61g; 10mmol), 4-phenoxy group phenylo boric acid (3.85g, 18mmol) and potassiumphosphate (5.375g, 25mmol) add in single neck bottle successively; add 1; 4-dioxane (40mL) and water (10mL), under nitrogen protection, add triphenyl phosphorus palladium (1.76g; 1.5mmol), back flow reaction 24h.React complete and be cooled to room temperature, stirring is spent the night, separate out yellow mercury oxide, suction filtration, washing (50ml*3), obtaining yellow solid 2.18g after dry 24 hours, is 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2a), productive rate 72%.
The synthesis of step 2. 3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3a)
By 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2a) (2.12g, 7mmol), 3-hydroxy piperidine-1-t-butyl formate (1.55g, 7.7mmol), triphenyl phosphorus (2.75g, 10.5mmol) with Diisopropyl azodicarboxylate (2.12g, 10.5mmol) be dissolved in THF (250ml), room temperature reaction 12h (whether TLC thin-layer chromatography monitoring reaction is complete).After completion of the reaction, decompression and solvent recovery.In residue reaction mixture, add 100 ethyl acetate, extract organic layer 3 times with 100ml*3 saturated sodium carbonate solution, merge organic phase, after saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying.Decompression and solvent recovery obtains brown solid 1.12g, productive rate 33%.
The synthesis of step 3. 3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4a)
By 3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3a) (0.97g, 2mmol) be dissolved in 15ml dioxane, drip 10ml 2N HCl, stirred overnight at room temperature.The crude product recrystallizing methanol that decompression and solvent recovery obtains, obtains off-white color solid 4a (0.56g, productive rate 66%, [M+H]=423.1).
The preparation of embodiment 2. key intermediate 4b
The synthesis of step 1. 3-(4-(4-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2b)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2b (2.56g, productive rate 77%) from 4-(4-methoxyphenoxy) phenylo boric acid (4.39g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(4-(4-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3b)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3b (1.26g, productive rate 35%).
The synthesis of step 3. 3-(4-(4-methoxyphenoxy) phenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4b)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4b (0.59, productive rate 65%, [M+H]=453.3).
The preparation of embodiment 3. key intermediate 4c
The synthesis of step 1. 3-(4-(3-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2c)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2c (2.49g, productive rate 75%) from 4-(3-methoxyphenoxy) phenylo boric acid (4.39g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(4-(3-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3c)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3c (1.25g, productive rate 35%).
The synthesis of step 3. 3-(4-(3-methoxyphenoxy) phenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4c)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4c (0.61g, productive rate 68%, [M+H]=453.3).
The preparation of embodiment 4. key intermediate 4d
The synthesis of step 1. 3-(4-(3,4-dimethoxy phenoxy group) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2d)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2d (2.62g, productive rate 72%) from 4-(3,4-dimethoxy phenoxy group) phenylo boric acid (4.93g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(4-(3,4-dimethoxy phenoxy group) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3d)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3d (1.04g, productive rate 30%).
The synthesis of step 3. 3-(4-(3,4-dimethoxy phenoxy group) phenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4d)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4d (0.53g, productive rate 64%, [M+H]=483.1).
The preparation of embodiment 5. key intermediate 4e
The synthesis of step 1. 3-(4-(4-fluorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2e)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2e (2.37g, productive rate 74%) from 4-(4-fluorophenoxy) phenylo boric acid (4.18g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(4-(4-fluorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3e)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3e (1.30g, productive rate 37%).
The synthesis of step 3. 3-(4-(4-fluorophenoxy) phenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4e)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4e (0.65g, productive rate 74%, [M+H]=441.1).
The preparation of embodiment 6. key intermediate 4f
The synthesis of step 1. 3-(4-(4-chlorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (compound 2f)
Synthesis step reference example 1 step 1. synthetic method being similar to compound 2a, prepares compound 2f (2.29g, productive rate 68%) from 4-(4-chlorophenoxy) phenylo boric acid (4.46g, 18mmol).
The synthesis of step 2. 3-(4-amino-3-(4-(4-chlorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-t-butyl formate (compound 3f)
Synthesis step reference example 1 step 2. synthetic method being similar to compound 3a prepares compound 3f (1.46g, productive rate 40%).
The synthesis of step 3. 3-(4-(4-chlorophenoxy) phenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine hydrochlorate (compound 4f)
Synthesis step reference example 1 step 3. synthetic method being similar to compound 4a prepares compound 4f (0.72g, productive rate 79%, [M+H]=457.2).
The preparation (compound 5-1) of embodiment 7. 1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-fluoropropyl-2-alkene-1-ketone
4a (548mg, 1.3mmol), 2-perfluoroalkyl acrylate (117mg, 1.3mmol) are dissolved in 5ml methylene dichloride, and room temperature drips methylene dichloride (5ml) solution of DCC (267mg, 1.3mmol), back flow reaction 4 hours.After reaction terminates, be cooled to room temperature, suction filtration, after filtrate is concentrated, column chromatography for separation (sherwood oil: ethyl acetate: triethylamine=2: 1: 0.1) obtain white solid 207mg, productive rate 35%, [M+H]=459.2.
1H-NMR(δ， CDCl
3-d6)：8.34(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.39(m，2H，ArH)，7.16(m，3H，ArH)，7.08(d，2H，J＝8.0Hz，ArH)，6.12(s，2H，-NH
2)，5.30(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.18(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.12(m，0.5H，piperidine)，3.76(m，0.5H，piperidine)，3.47(m，0.5H，piperidine)，3.17(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.81(m，0.5H，piperidine)，2.30(m，2H，piperidine)，1.75(m，2H，piperidine).
The preparation (compound 5-2) of embodiment 8. 1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-2 (257mg, productive rate 42%, [M+H]=475.2).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.40(m，2H，ArH)，7.17(m，3H，ArH)，7.09(d，2H，J＝8.0Hz，ArH)，5.67(s，2H，-NH
2)，5.62(m，2H，-C＝CH
2)，4.93(m，1H，piperidine)，4.68(m，0.5H，piperidine)，4.52(m，0.5H，piperidine)，4.13(m，0.5H，piperidine)，3.98(m，0.5H，piperidine)，3.80(m，0.5H，piperidine)，3.50(m，0.5H，piperidine)，3.23(m，0.5H，piperidine)，2.91(m，0.5H，piperidine)，2.30(m，2H，piperidine)，1.77(m，2H，piperidine).
The preparation (compound 5-3) of embodiment 9. 1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-base)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-3 (225mg, productive rate 33%, [M+H]=519.2).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.64(d，2H，J＝8.0Hz，ArH)，7.40(m，2H，ArH)，7.16(m，3H，ArH)，7.09(d，2H，J＝8.0Hz，ArH)，6.05(s，1H，-NH
2)，5.79(m，3H，-C＝CH
2，-NH
2)，4.93(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.51(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.97(m，0.5H，piperidine)，3.77(m，0.5H，piperidine)，3.22(m，0.5H，piperidine)，3.11(m，0.5H，piperidine)，2.91(m，0.5H，piperidine)，2.28(m，2H，piperidine)，1.71(m，2H，piperidine).
The preparation (compound 5-4) of embodiment 10. 1-(3-(4-amino-3-(4-(4-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-fluoropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-4 (212mg, productive rate 33%, [M+H]=489.2).
1H-NMR(δ，CDCl
3-d6)：8.35(s，1H，ArH)，7.66(d，2H，J＝8.0Hz，ArH)，7.38(d，2H，J＝8.0Hz，ArH)，7.17(d，2H，J＝8.0Hz，ArH)，7.08(d，2H，J＝8.0Hz，ArH)，6.15(s，2H，-NH
2)，5.31(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.18(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.12(m，0.5H，piperidine)，3.76(m，0.5H，piperidine)，3.62(s，3H，-OCH
3)，3.47(m，0.5H，piperidine)，3.17(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.81(m，0.5H，piperidine)，2.30(m，2H，piperidine)，1.75(m，2H，piperidine).
The preparation (compound 5-5) of embodiment 11. 1-(3-(4-amino-3-(4-(4-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-5 (212mg, productive rate 38%, [M+H]=505.1).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.38(d，2H，J＝8.0Hz，ArH)，7.17(d，2H，J＝8.0Hz，ArH)，7.09(d，2H，J＝8.0Hz，ArH)，6.03(s，2H，-NH
2)，5.24(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.07(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.01(d，1H，-C＝CH
2)，4.87(m，1H，piperidine)，4.62(m，0.5H，piperidine)，4.39(m，0.5H，piperidine)，4.22(m，0.5H，piperidine)，3.77(m，0.5H，piperidine)，3.68(s，3H，-OCH
3)，3.45(m，0.5H，piperidine)，3.14(m，0.5H，piperidine)，2.86(m，0.5H，piperidine)，2.78(m，0.5H，piperidine)，2.28(m，2H，piperidine)，1.74(m，2H，piperidine).
The preparation (compound 5-6) of embodiment 12. 1-(3-(4-amino-3-(4-(4-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-6 (234mg, productive rate 33%, [M+H]=551.1).
1H-NMR(δ，CDCl
3-d6)：8.36(s，1H，ArH)，7.66(d，2H，J＝8.0Hz，ArH)，7.39(d，2H，J＝8.0Hz，ArH)，7.17(d，2H，J＝8.0Hz，ArH)，7.09(d，2H，J＝8.0Hz，ArH)，6.18(s，2H，-NH
2)，5.33(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.19(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.12(d，1H，-C＝CH
2)，4.96(m，1H，piperidine)，4.68(m，0.5H，piperidine)，4.45(m，0.5H，piperidine)，4.16(m，0.5H，piperidine)，3.77(m，0.5H，piperidine)，3.65(s，3H，-OCH
3)，3.48(m，0.5H，piperidine)，3.18(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.81(m，0.5H，piperidine)，2.31(m，2H，piperidine)，1.75(m，2H，piperidine).
The preparation (compound 5-7) of embodiment 13. 1-(3-(4-amino-3-(4-(3-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-fluoropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-7 (205mg, productive rate 32%, [M+H]=489.2).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.63(d，2H，J＝8.0Hz，ArH)，7.12(m，1H，ArH)，7.05(d，2H，J＝8.0Hz，ArH)，6.52(m，2H，ArH)，6.39(s，1H，ArH)，6.14(s，2H，-NH
2)，5.27(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.06(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.03(d，1H，-C＝CH
2)，4.91(m，1H，piperidine)，4.62(m，0.5H，piperidine)，4.40(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.73(m，0.5H，piperidine)，3.64(s，3H，-OCH
3)，3.43(m，0.5H，piperidine)，3.13(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.80(m，0.5H，piperidine)，2.17(m，2H，piperidine)，1.77(m，2H，piperidine).
The preparation (compound 5-8) of embodiment 14. 1-(3-(4-amino-3-(4-(3-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-8 (272mg, productive rate 41%, [M+H]=505.2).
1H-NMR(δ，CDCl
3-d6)：8.36(s，1H，ArH)，7.64(d，2H，J＝8.0Hz，ArH)，7.16(m，1H，ArH)，7.05(d，2H，J＝8.0Hz，ArH)，6.53(m，2H，ArH)，6.38(s，1H，ArH)，6.14(s，2H，-NH
2)，5.32(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.16(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.63(m，0.5H，piperidine)，4.40(m，0.5H，piperidine)，4.12(m，0.5H，piperidine)，3.73(m，0.5H，piperidine)，3.66(s，3H，-OCH
3)，3.43(m，0.5H，piperidine)，3.13(m，0.5H，piperidine)，2.85(m，0.5H，piperidine)，2.83(m，0.5H， piperidine)，2.27(m，2H，piperidine)，1.76(m，2H，piperidine).
The preparation (compound 5-9) of embodiment 15. 1-(3-(4-amino-3-(4-(3-methoxyphenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-9 (222mg, productive rate 31%, [M+H]=551.1).
1H-NMR(δ，CDCl
3-d6)：8.36(s，1H，ArH)，7.64(d，2H，J＝8.0Hz，ArH)，7.13(m，1H，ArH)，7.05(d，2H，J＝8.0Hz，ArH)，6.52(m，2H，ArH)，6.38(s，1H，ArH)，6.14(s，2H，-NH
2)，5.27(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.03(d，1H，-C＝CH
2)，4.91(m，1H，piperidine)，4.62(m，0.5H，piperidine)，4.40(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.76(m，0.5H，piperidine)，3.67(s，3H，-OCH
3)，3.44(m，0.5H，piperidine)，3.13(m，0.5H，piperidine)，2.85(m，0.5H，piperidine)，2.77(m，0.5H，piperidine)，2.33(m，2H，piperidine)，1.77(m，2H，piperidine).
Embodiment 16. 1-(3-(4-amino-3-(4-(3,4-dimethoxy phenoxy group) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl) preparation (compound 5-10) of-2-fluoropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-10 (211mg, productive rate 31%, [M+H]=519.2).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.63(d，2H，J＝8.0Hz，ArH)，7.05(d，2H，J＝8.0Hz，ArH)，6.62(d，1H，J＝8.0Hz，ArH)，6.41(d，1H，J＝8.0Hz，ArH)，6.27(s，1H，ArH)，5.96(s，2H，-NH
2)，5.27(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.06(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.03(d，1H，-C＝CH
2)，4.91(m，1H，piperidine)，4.62(m，0.5H，piperidine)，4.40(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.74(m，3.5H，-OCH
3，piperidine)，3.66(s，3H，-OCH
3)，3.43(m，0.5H，piperidine)，3.12(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.85(m，0.5H，piperidine)，2.17(m，2H，piperidine)，1.75(m，2H，piperidine).
Embodiment 17. 1-(3-(4-amino-3-(4-(3,4-dimethoxy phenoxy group) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl) preparation (compound 5-11) of-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-11 (232mg, productive rate 33%, [M+H]=535.2).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.64(d，2H，J＝8.0Hz，ArH)，7.04(d，2H，J＝8.0Hz，ArH)，6.62(d，1H，J＝8.0Hz，ArH)，6.42(d，1H，J＝8.0Hz，ArH)，6.27(s，1H，ArH)，5.96(s，2H，-NH
2)，5.27(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.06(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.06(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.61(m，0.5H，piperidine)，4.40(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.75(m，3.5H，-OCH
3，piperidine)，3.66(s，3H，-OCH
3)，3.43(m，0.5H，piperidine)，3.12(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.75(m，0.5H，piperidine)，2.31(m，2H，piperidine)，1.73(m，2H，piperidine).
Embodiment 18. 1-(3-(4-amino-3-(4-(3,4-dimethoxy phenoxy group) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl) preparation (compound 5-12) of-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-12 (197mg, productive rate 26%, [M+H]=581.1).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.63(d，2H，J＝8.0Hz，ArH)，7.05(d，2H，J＝8.0Hz，ArH)，6.62(d，1H，J＝8.0Hz，ArH)，6.40(d，1H，J＝8.0Hz，ArH)，6.27(s，1H，ArH)，6.08(s，2H，-NH
2)，5.27(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.06(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.03(d，1H，-C＝CH
2)，4.91(m，1H，piperidine)，4.62(m，0.5H，piperidine)，4.45(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.75(m，3.5H，-OCH
3，piperidine)，3.66(s，3H，-OCH
3)，3.43(m，0.5H，piperidine)，3.12(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.76(m，0.5H，piperidine)，2.27(m，2H，piperidine)，1.75(m，2H，piperidine).
The preparation (compound 5-13) of embodiment 19. 1-(3-(4-amino-3-(4-(4-fluorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-fluoropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-13 (223mg, productive rate 36%, [M+H]=477.2).
1H-NMR(δ，CDCl
3-d6)：8.35(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.47(d，2H，J＝8.0Hz，ArH)，7.25(d，2H，J＝8.0Hz，ArH)，7.02(d，2H，J＝8.0Hz，ArH)，6.12(s，2H，-NH
2)，5.31(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.18(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.12(m，0.5H，piperidine)，3.75(m，0.5H，piperidine)，3.44(m，0.5H，piperidine)，3.19(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.75(m，0.5H，piperidine)，2.30(m，2H，piperidine)，1.77(m，2H，piperidine).
The preparation (compound 5-14) of embodiment 20. 1-(3-(4-amino-3-(4-(4-fluorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-14 (254mg, productive rate 40%, [M+H]=493.1).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.47(d，2H，J＝8.0Hz，ArH)，7.25(d，2H，J＝8.0Hz，ArH)，7.02(d，2H，J＝8.0Hz，ArH)，6.12(s，2H，-NH
2)，5.32(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.19(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.65(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.12(m，0.5H，piperidine)，3.75(m，0.5H，piperidine)，3.44(m，0.5H，piperidine)，3.19(m，0.5H，piperidine)，2.89(m，0.5H，piperidine)，2.77(m，0.5H，piperidine)，2.32(m，2H，piperidine)，1.76(m，2H，piperidine).
The preparation (compound 5-15) of embodiment 21. 1-(3-(4-amino-3-(4-(4-fluorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-15 (213mg, productive rate 30%, [M+H]=538.1).
1H-NMR(δ，CDCl
3-d6)：8.36(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.47(d，2H，J＝8.0Hz，ArH)，7.24(d，2H，J＝8.0Hz，ArH)，7.06(d，2H，J＝8.0Hz，ArH)，6.09(s，2H，-NH
2)，5.31(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.18(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.63(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.12(m，0.5H，piperidine)，3.75(m，0.5H，piperidine)，3.43(m，0.5H，piperidine)，3.19(m，0.5H，piperidine)，2.87(m，0.5H，piperidine)，2.79(m，0.5H，piperidine)， 2.31(m，2H，piperidine)，1.72(m，2H，piperidine).
The preparation (compound 5-16) of embodiment 22. 1-(3-(4-amino-3-(4-(4-chlorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-fluoropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-16 (211mg, productive rate 33%, [M+H]=493.1).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.43(d，2H，J＝8.0Hz，ArH)，7.11(d，2H，J＝8.0Hz，ArH)，6.89(d，2H，J＝8.0Hz，ArH)，6.02(s，2H，-NH
2)，5.26(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.13(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.01(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.73(m，0.5H，piperidine)，3.44(m，0.5H，piperidine)，3.19(m，0.5H，piperidine)，2.86(m，0.5H，piperidine)，2.73(m，0.5H，piperidine)，2.30(m，2H，piperidine)，1.74(m，2H，piperidine).
The preparation (compound 5-17) of embodiment 23. 1-(3-(4-amino-3-(4-(4-chlorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-chloropropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-17 (245mg, productive rate 37%, [M+H]=509.1).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.43(d，2H，J＝8.0Hz，ArH)，7.11(d，2H，J＝8.0Hz，ArH)，6.89(d，2H，J＝8.0Hz，ArH)，6.02(s，2H，-NH
2)，5.19(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.10(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.00(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.44(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.73(m，0.5H，piperidine)，3.44(m，0.5H，piperidine)，3.19(m，0.5H，piperidine)，2.86(m，0.5H，piperidine)，2.77(m，0.5H，piperidine)，2.31(m，2H，piperidine)，1.74(m，2H，piperidine).
The preparation (compound 5-18) of embodiment 24. 1-(3-(4-amino-3-(4-(4-chlorophenoxy) phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-2-bromopropyl-2-alkene-1-ketone
Synthesis step reference example 7. synthetic method being similar to compound 5-1 prepares compound 5-18 (226mg, productive rate 31%, [M+H]=554.1).
1H-NMR(δ，CDCl
3-d6)：8.37(s，1H，ArH)，7.65(d，2H，J＝8.0Hz，ArH)，7.43(d，2H，J＝8.0Hz，ArH)，7.11(d，2H，J＝8.0Hz，ArH)，6.89(d，2H，J＝8.0Hz，ArH)，6.12(s，2H，-NH
2)，5.19(d，0.5H，J＝4.0Hz，-C＝CH2)，5.12(d，0.5H，J＝4.0Hz，-C＝CH
2)，5.00(d，1H，-C＝CH
2)，4.92(m，1H，piperidine)，4.66(m，0.5H，piperidine)，4.40(m，0.5H，piperidine)，4.11(m，0.5H，piperidine)，3.75(m，0.5H，piperidine)，3.39(m，0.5H，piperidine)，3.19(m，0.5H，piperidine)，2.89(m，0.5H，piperidine)，2.74(m，0.5H，piperidine)，2.27(m，2H，piperidine)，1.75(m，2H，piperidine).
The external Btk kinase inhibiting activity of embodiment 25. and anti tumor activity in vitro test
The external Btk kinase inhibiting activity measuring method of the compounds of this invention:
Medicine is dissolved in DMSO the storing solution making 10mM, and the test concentrations liquid being diluted to 50x is for subsequent use, test concentrations by gradient dilution, is respectively 25nM with 3,8.33nM, 2.78nM, 0.93nM, 0.31nM, 0.10nM.In 96 orifice plates, add 10 μ L 50x medicine reserve liquids, then add 90 μ L 1x kinase buffer liquid, shake 10 minutes on the oscillator.Get 5 μ L from the 96 each holes of orifice plate and be transferred to 384 orifice plates, in 384 orifice plates, establish 2 multiple holes.Kinase reaction: prepare 2.5x kinase buffer liquid: added by enzyme in 1x kinases basis buffer.Prepare 2.5x small peptide solution: the small peptide mark FAM and ATP add in 1x kinases basis buffer.Be added with in 5 μ L liquid 384 orifice plates, adding 10 μ L 2.5x kinase buffer liquid, incubated at room 10 minutes.In 384 orifice plates, add 10 μ L 2.5x small peptide solution, hatch 1 hour for 28 DEG C.Add 25 μ L stop buffer stopped reaction.Reading, and computerized compound is to the inhibiting rate of enzyme, the Fitting Calculation goes out the kinase whose IC of BTK
50.
Different solid tumors and leukemia cell line is selected to carry out the mensuration of anti tumor activity in vitro to synthesized compound:
Cell strain: human lung carcinoma cell (A549, PC9), human breast cancer cell (MCF7), gastric carcinoma cells (SGC7901), acute promyelocytic leukemia cell (HL60).
Substratum: A549:RPMI 1640+ foetal calf serum
MCF7:DMEM+ foetal calf serum
SGC7901:RPMI 1640+ new-born calf serum
HL60:RPMI 1640+ foetal calf serum
PC9:DMEM+ foetal calf serum
Method for preparation of drug: medicine is dissolved in DMSO the storing solution making 10mM, and dilution obtains 5 different concns (test concentrations 100x) by a certain percentage.
Tumour cell vitro culture:
By four selected strain tumour cell A549, MCF7, SGC7901, HL60, PC9, in 37 DEG C, 5%CO
2hatch in cell culture incubator, go down to posterity when cell density grows to 70 ~ 90% (attached cell Duck ' s EDTA goes down to posterity after digesting), for later needed for experiment.
Tumour cell A549, MCF7, SGC7901, HL60, PC9,96 orifice plates are planted into 4000/200 μ L/ holes, in 37 DEG C, 5%CO
2overnight incubation in cell culture incubator.Every hole adds compound 2 μ L, and final concentration is 50 μMs, 10 μMs, 2 μMs, 0.4 μM, and 0.08 μM common in 37 DEG C, 5%CO
272 hours are hatched, with DMSO (2%) for control group in cell culture incubator.After 72 hours, add 20 μ L CCK-8 solution, be placed in 37 DEG C, 5%CO
2in cell culture incubator 4 hours.With added respective amount cell culture fluid and CCK-8 solution but the hole not adding cell as blank.Measure absorbancy (OD value) by microplate reader at 450nm, the data obtained is for calculating IC
50.
The calculation formula of cell inhibitory rate is: cell inhibitory rate %=[(control group OD value-blank group OD value)-(medication group OD value-blank group OD value)]/(compared with control cells OD value-blank group OD value) × 100%, tries to achieve half-inhibition concentration (IC by CalcuSyn computed in software
50).
Table 1 part of compounds is to BTK kinase inhibiting activity and tumor cell in vitro proliferation inhibition activity
As can be seen from the table, all compounds all have obvious inhibit activities to BTK, activity is all less than 10nM, quite active for Buddhist nun with her cloth of positive control, illustrate that introducing halogen in the α position of acrylamide does not affect substantially on its activity, still shows potent BTK kinase inhibiting activity.But, on a cellular level, compound 5-1 ~ the 5-6 tested and 5-1 ~ 5-18 all shows the tumor cell proliferation inhibition activity more more potent than positive control, not only to solid tumor cell activity stronger (A549, SGC-7901, MCF-7, PC-9), and like this equally to blood tumor cell (HL-60).For example, compound 5-2 is active high 5 times on SGC-7901 cell.Therefore, the involved in the present invention BTK inhibitor that can be used as has wide antitumor application prospect.
The sign of embodiment 26. external dibit point irreversible inhibitor character:
First, after adopting compound 5-3 pre-treatment restructuring Btk, with the substratum repeated washing not containing inhibitor, its activity can not be recovered (see such as J.B.Smaill etc., J.Med.Chem.1999,42,1803).Secondly, by mass spectrum, the ratio that observed the molecular weight of the covalent complex between corresponding compound 5-3 and Btk of main mass spectra peak is 1: 1 (compound 4:518, dalton, restructuring Btk kinases binding domain: 33487; Mixture predictor is 34005, and measured value is 34005).
Secondly, compound 5-3 and halfcystine is adopted to incubate bath altogether after 3 hours, detect through HPLC-MS, find that majority of compounds 5-3 changes by the product of two halfcystine additions that (predicted molecular weight is: 680) into, actual molecular weight is (680), experiment proves, the compound tested has by the ability of bimolecular compounds containing thiol groups addition, although this also illustrates this compounds, her cloth of Btk kinase inhibiting activity and positive drug is suitable for Buddhist nun in vitro, cell aspect obviously can be better than her cloth and replace Buddhist nun.
The oral pharmacokinetic studies of embodiment 27.
Replace Buddhist nun for reference with her cloth, investigated the pharmacokinetic property of compound 5-2 and 5-3 in rat body respectively, concrete grammar is as follows: with SD rat for laboratory animal, gastric infusion 20mg/kg, tail vein Bolos intravenous administration 5mg/kg.The tail venous blood sampling time point of gastric infusion is 0.17,0.33,0.5,1,1.5,2,4,6,8,12, and 24 hours; It is 0.05,0.1 that intravenously administrable gets blood time point, 0.17,0.5,1,2,4,6,8,12, and 24 hours.Get whole blood 0.3ml, get blood plasma 0.1ml after centrifugal and adopt LC-MS to analyze.Result shows, the oral administration biaavailability of compound 5-2 and 5-3 is respectively 25% and 17%, and her cloth is 12% for the bioavailability of Buddhist nun, therefore compound 5-2 and 5-3 stability in vivo comparatively her cloth had for Buddhist nun and significantly significantly improved.After its reason may be that halogen introducing is introduced in the α position of acrylamide, under the prerequisite not affecting drug absorption, make the metabolic rate of double bond by suppression to a certain extent, and then improve Plasma Concentration and improve bioavailability.
Embodiment 28: use compound 5-2 to treat class and divide wet arthritis
In the mouse model of rheumatoid arthritis, effect in the body that have rated compound 5-2, in Balb/c mouse, by giving anti-collagen antibody and lipopolysaccharide-induced sacroiliitis (Nandakumar etc., Am.J.Pathol.2003,163:1827-1837).Concrete grammar was as follows: at the 0th day, injected the Chemico mAb mixture of the anti-II collagen type of 100mg/kg in female Balb/c mouse vein, at the 1st day, and peritoneal injection 1.25mg/kg lipopolysaccharides.At the 2nd day to 12 days, by the compound 5-2 of 10mg/kg, every day oral administration 1 time.Result shows, compound 5-2 has anti-class in obvious body and divides the effect of wet arthritis, specifically, the inflammatory cell infiltration occurred in model group, synovial hyperplasia, inflammatory granulation tissue formed, the phenomenons such as necrotic tissue appearance compound 5-2 treat after be improved significantly.
Claims (8)
1. a bruton's tyrosine kinase inhibitor, is characterized in that it has the structure of formula I:
And optical isomer or its pharmacy acceptable salt or solvate, wherein: Ra, Rb, Rc are independently selected from H, halogen ,-CF
3,-CN ,-NO
2, OH, NH
2,-L-C
1-C
6alkyl ,-L-C
1-C
6the substituted or non-substituted heteroaryl of thiazolinyl ,-L-or the substituted or non-substituted aryl of-L-, wherein L is key, O, S ,-S (=O) ,-S (=O)
2, NH, C (O), CH
2,-NHC (O) O ,-NHC (O) or-C (O) NH, X be selected from halogen, is preferably fluorine, chlorine and bromine.
2. a bruton's tyrosine kinase inhibitor, is characterized in that it has the structure of general formula I I:
And optical isomer or its pharmacy acceptable salt or solvate, wherein: each Rd is H, halogen ,-CF independently
3,-CN ,-NO
2,-OH, C
1-C
3alkoxyl group or-NH
2, X is selected from halogen, is preferably fluorine, chlorine and bromine.
3. a bruton's tyrosine kinase inhibitor, is characterized in that it has the structure of general formula III:
And optical isomer or its pharmacy acceptable salt or solvate, wherein: X is selected from halogen, be preferably fluorine, chlorine and bromine.
4. a pharmaceutical composition, described pharmaceutical composition comprises at least one active ingredient and one or more pharmaceutically acceptable carrier or vehicle, described active ingredient be as the bruton's tyrosine kinase inhibitor compound in claims 1 to 3 as described in any one, as described in compound optical isomer, as described in compound or its optical isomer pharmaceutically acceptable salt, as described in compound or its optical isomer solvate in any one or multiple arbitrarily.
5. as the bruton's tyrosine kinase inhibitor compound in claims 1 to 3 as described in any one and optical isomer thereof or its pharmacy acceptable salt or solvate are suppressing the application that bruton's tyrosine kinase is active or treat in the disease, obstacle or the illness that benefit from the suppression of bruton's tyrosine kinase activity.
6. as the bruton's tyrosine kinase inhibitor compound in claims 1 to 3 as described in any one and optical isomer thereof or its pharmacy acceptable salt or solvate separately or and other drug conbined usage treatment cell proliferative diseases as the application in cancer.
7. as the bruton's tyrosine kinase inhibitor compound in claims 1 to 3 as described in any one and optical isomer thereof or its pharmacy acceptable salt or solvate separately or and other drug conbined usage treatment autoimmune disorder as the application in lupus erythematosus.
8. prepare the method that bruton's tyrosine kinase inhibitor as claimed in claim 1 and pharmacy thereof can accept derivative, it is characterized in that comprising the steps:
Compound 1 and R
1b (OH)
2at potassiumphosphate, palladium catalyst and suitable solvent or mixed solvent as under dioxane/water exists; back flow reaction 24 hours; the compound 2 obtained triphenyl phosphorus, DIAD and suitable solvent as THF exist under; the 3-hydroxy piperidine protected with Boc is obtained by reacting compound 3; key intermediate 4 is prepared in hydrolysis in acid condition subsequently; this key intermediate as under DCM exists, with substitutional crylic acid fragment condensation reaction, obtains compound of Formula I at DCC and suitable solvent.
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| WO2016180334A1 (en) * | 2015-05-12 | 2016-11-17 | 杭州和正医药有限公司 | Dual-site irreversible bruton's tyrosine kinase inhibitor, composition and application therefof |
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| WO2016180334A1 (en) * | 2015-05-12 | 2016-11-17 | 杭州和正医药有限公司 | Dual-site irreversible bruton's tyrosine kinase inhibitor, composition and application therefof |
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| CN106146518A (en) * | 2016-06-30 | 2016-11-23 | 苏州爱玛特生物科技有限公司 | A kind of bruton's tyrosine kinase inhibitor intermediate and preparation method thereof |
| CN107383015A (en) * | 2017-07-03 | 2017-11-24 | 四川大学华西医院 | The application of amino-pyrazol simultaneously [3,4 d] pyrimidine derivatives and the anti-non-small cell lung cancer of alkane sulphur end group widow PEG modifications |
| CN110606848A (en) * | 2019-08-27 | 2019-12-24 | 药雅科技(上海)有限公司 | 5-azaindole derivative Bruton's tyrosine kinase inhibitor and preparation method and application thereof |
| CN112111558A (en) * | 2020-08-19 | 2020-12-22 | 翌圣生物科技（上海）有限公司 | Method for determining activity of capping enzyme of vaccinia virus |
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