CN105777759B - A kind of bruton's tyrosine kinase inhibitor - Google Patents
A kind of bruton's tyrosine kinase inhibitor Download PDFInfo
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- CN105777759B CN105777759B CN201610286399.3A CN201610286399A CN105777759B CN 105777759 B CN105777759 B CN 105777759B CN 201610286399 A CN201610286399 A CN 201610286399A CN 105777759 B CN105777759 B CN 105777759B
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- piperidine
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- tyrosine kinase
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- 0 CCC(CC*)N(C(C12)=*C=*C1NI)N=C2C(CC=C1)=CNC1Oc1ccccc1 Chemical compound CCC(CC*)N(C(C12)=*C=*C1NI)N=C2C(CC=C1)=CNC1Oc1ccccc1 0.000 description 6
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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
Abstract
The invention provides a kind of bruton's tyrosine kinase inhibitor, the pharmaceutical composition containing it and its application in antineoplastic is prepared.The compounds of this invention has antiproliferative inhibitory action to tumor cell lines such as A549, SGC7901, MCF 7, HL 60, PC9 IR, can be applied to treat in the related solid tumor of human or animal's cell proliferative or the medicine of leukemia；The compounds of this invention has preferable pharmacokinetic property, can be applied to the related solid tumor of oral medication human or animal cell proliferative or leukemia or suffering from autoimmune disease；The compounds of this invention has the response characteristic of double site.
Description
Technical field
The invention belongs to field of medicaments, specifically a kind of bruton's tyrosine kinase inhibitor, the pharmaceutical composition containing it
And its application in antineoplastic is prepared.
Background technology
Small molecule covalency inhibitor (covalent inhibitors), also referred to as irreversible inhibitor (irreversible
Inhibitors), it is that Irreversible binding is occurred by covalent bond and target protein residue, so as to play one kind of its biological function
Inhibitor.Covalency inhibitor medicine in the past few decades in significant contribution is made that to human health.Relative to non-covalent suppression
Preparation, for covalency inhibitor by enhancing compatibility with target with target protein with Covalent bonding together, this is covalency inhibitor table
The basic reason of its existing high bioactivity.In recent years, because non-covalent anti-tumor drugs targeting is particularly largely for kinases
For the generation of Buddhist nun's class Drug-resistant, people are made to increasingly focus on covalency inhibitor medicine again.In recent years, many big drug firms
Carry out the research and development of the covalency inhibitor for certain enzyme target spot, had some covalent inhibitor at present and enter clinical test,
Including Afatinib, Cl 1033, HKI-272 etc..Wherein, Afatinib is formal by U.S. FDA on July 12nd, 2013
Ratify to be used for the Metastatic Nsclc for treating EGF-R ELISA (EGFR) gene mutation, turn into first by FDA
The irreversible inhibitor new drug of the treatment lung cancer of approval.In addition, antiviral covalent drug is also study hotspot in recent years, and
And made great progress, such as, the two anti-hepatitis c virus covalency inhibitor medicines of FDA approveds in 2011,
That is telaprevir and boceprevir.These researchs demonstrate the treatment that irreversible inhibitor can be effectively used for disease.
Bruton's tyrosine kinase (Bruton's tyrosine kinase, Btk), a kind of nonreceptor tyrosine kinase
The member of Tec families, it is the pass expressed in all hematopoetic cell types in addition to T lymphocytes and NK
Key signals enzyme.Btk is stimulated to response in downstream cellular in connection cell surface B-cell receptor (B-cell receptor, BCR)
B cell signal transduction path in play the part of vital role.Btk is B cell development, activation, signal transduction and survival
Key regulators.In addition, Bkt works in other numerous hematopoietic cell signal transduction paths, such as in macrophage
Toll-like receptor (Toll like receptor, TLR) and the TNF-α of cytokine receptor mediation produce, in mast cell
Immunoglobulin E acceptor (Fc ε R1) signal transduction, suppress Fas/APO-1 Apoptosis in B- pedigree lymphoid cells
The platelet aggregation of signal transduction and collagen stimulation.See, for example, 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 that Btk believes
Number path is current NHL (NHL), particularly chronic lymphocytic leukemia (CLL), B cell lymphoma and from
New focus in the research of body immunological diseases clinical treatment.Small molecule Btk inhibitor is tied by acting on BCR signal paths with Btk
Close and suppress Btk autophosphorylations, prevent Btk activation, so as to block cell conductance and inducing cell apoptosis.Btk inhibitor
Selectivity is strong, and toxic side effect is low, and particularly her cloth replaces the listing of Buddhist nun, is set to " breakthrough " new drug by FDA, and it researchs and develops prospect
It is wide.Yi Bu reacts for Buddhist nun and the sulfydryl of Btk enzymes cysteine (Cys481) residue, and forms covalent bond, loses Btk enzymes
Live and play curative effect.However, her cloth replaces Buddhist nun in administration process, to be easily metabolized for Buddhist nun and (be metabolized oxydasis and be metabolized to dihydroxylated
Product is inactivated by attacks such as other enzyme containing sulfydryl, cysteine, glutathione) and drug effect (seeing below formula) is influenceed, its
Clinical administration dosage has reached 560mg/ days, and makes patient's burden, therefore still needs to a kind of highly efficient BTK of development and suppress
Agent is used for the treatment of relevant disease.
A kind of double site BTK irreversible inhibitors and its optical isomer or its medicine are reported in the present inventor's patent early stage
Acceptable salt or solvate (number of patent application on：201510242552.8), using the HZ-003 in following formula as representative
Compound.For such compound compared with her cloth is for Buddhist nun, 2 in acryloyl group introduce halogens substitution, improve medicine and move property, BTK
Inhibitory activity, and it is notable to part entity knurl inhibition, but its water solubility is have impact on due to the introducing of halogen atom.Cause
This is directed to its this characteristic, while its high activity is ensured, it is found that a kind of water-soluble improved double site BTK can not retroactive inhibition
Agent has great importance.
The content of the invention
It is an object of the invention to provide novel, the to have no document report double site BTK with good solubility not
Reversible inhibitor and its optical isomer or its pharmaceutically acceptable salt or solvate.
Metabolic pathway analysis and structure-activity relationship inside Buddhist nun are replaced based on her cloth, we remain the halogen of acrylamide 2
Element, continue to that there is the irreversible inhibitory activity of the BTK of good pharmacokinetics and double site.Introduced in its aromatic rings
Nitrogen-atoms, improve its solubility.
The present invention adopts the following technical scheme that：
BTK inhibitor provided by the present invention has formula (I) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：Ra, Rb, Rc be independently selected from H,
Halogen ,-CF3、-CN、-NO2、OH、NH2、-L-C1-C6Alkyl ,-L-C1-C6Alkenyl, the substituted or non-substituted heteroaryls of-L-
Base or the substituted or non-substituted aryl of-L-, wherein L is key, O, S ,-S (=O) ,-S (=O)2、NH、C(O)、CH2、-NHC(O)
O ,-NHC (O) or-C (O) NH, X are selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2At least one is selected from N.
Further, currently preferred compound has logical formula (II) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：Each Rd be independently H,
Halogen ,-CF3、-CN、-NO2、-OH、C1-C3Alkoxy or-NH2, X is selected from fluorine, chlorine and bromine, Y1,Y2Selected from C, N, Y1,Y2Extremely
Rare one is selected from N.
Further, currently preferred compound has logical formula (III) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：X is selected from fluorine, chlorine and bromine, Y1,Y2
Selected from C, N, Y1,Y2At least one is selected from N.
Term explanation：Terms used herein " aryl " refers to that the full carbon of 5 to 12 carbon atoms is monocyclic or fused polycycle group,
Pi-electron system with total conjugated.The non-limiting examples of aromatic ring have：Phenyl ring, naphthalene nucleus and anthracene nucleus.Aromatic ring can be unsubstituted
Or substitution.The substituent of aromatic ring is selected from halogen, nitro, amino, C1-C6Alkyl, C1-C6Alkoxy, halo C1-C6Alkyl, halogen
For C1-C6Alkoxy, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl；
Terms used herein " heteroaryl " refers to the undersaturated carbocyclic ring of 5 to 12 annular atoms, wherein one or more carbon quilts
Hetero atom is replaced such as oxygen, nitrogen, sulphur.Hetero-aromatic ring can be monocyclic or bicyclic, i.e., formed by two ring fusions.
Specifically heterocyclic aryl can be：Pyridine radicals, pyrimidine radicals, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, evil
Oxazolyl and imidazole radicals etc..Heterocyclic aryl can be unsubstituted or substitution.The substituent of heterocyclic aryl is selected from halogen, nitro, ammonia
Base, C1-C6Alkyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C1-C6Alkoxy, C3-C6Cycloalkyl, halo C3-C6Cycloalkanes
Base；
Terms used herein " heterocycle " refers to monocyclic or fused ring group, has 5 to 9 annular atoms in ring, one of them
Or two annular atoms are to be selected from N, O or S (O)mThe hetero atom of (wherein m is 0 to 2 integer), remaining annular atom is C.These rings
There can be one or more double bond, but these rings do not have the pi-electron system of total conjugated.Unsubstituted Heterocyclylalkyl
Can be pyrrolidinyl, piperidyl, piperazinyl, morpholino base, thiomorpholine for base, homopiperazine base etc..Heterocycle can be that nothing takes
Generation or substitution.The substituent of heterocycle is selected from halogen, nitro, amino, C1-C6Alkyl, C1-C6Alkoxy, halo C1-C6Alkyl,
Halo C1-C6Alkoxy, C3-C6Cycloalkyl, halo C3-C6Cycloalkyl.
Terms used herein " alkoxy " refers to-O- alkyl groups, wherein alkyl as defined above." alcoxyl used herein
The example of base " includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and tert-butoxy." alcoxyl
Base " also includes substituted alkoxy.Alkoxy can optionally be optionally substituted by halogen one or many.
Term " alkenyl " refers to a kind of alkyl, and wherein the two of the starting of alkyl atom forms double bond, and the double bond is not virtue
The part of perfume base.That is, alkenyl, which starts from atom-C (R)=C (R)-R, wherein R, refers to the remainder of alkenyl, each R
Can be with identical or different.Alkenyl part can be that (in the case, it can also be referred to as " cyclenes for side chain, straight chain or ring-type
Base ").According to structure, alkenyl can be monoradical or double plus group (i.e. alkenylene).Alkenyl can optionally substitute.Alkene
The non-limiting examples of base include-CH=CH2、-C(CH3)=CH2,-CH=CHCH3、-C(CH3)=CHCH3.Alkenylene includes
But it is not limited to-CH=CH- ,-C (CH3)=CH- ,-CH=CHCH2- ,-CH=CHCH2CH2- and-C (CH3)=CHCH2-.Alkenyl
There can be 2-10 carbon atom.Alkenyl alternatively has " low-grade alkenyl " of 2-6 carbon atom.
Term " pharmaceutically acceptable derivative " refers to the salt and solvate of selected compounds.
Terms used herein " solvate " refer to by solute (such as：The logical formula (I) of the present invention~logical formula (III) chemical combination
Thing) and solvent formed varying chemical metering compound.For the purposes of the present invention, the solvent can not disturb the life of solute
Thing activity.The example of suitable solvent includes but is not limited to water, methanol, ethanol and acetic acid.It is preferred that the solvent used is pharmacy
Acceptable solvent.Suitable pharmaceutical acceptable solvents include but is not limited to water, ethanol and acetic acid.It is highly preferred that solvent for use is
Water.
The present invention can prepare the salt of compound of the present invention using method well-known to those skilled in the art.It is described
Salt can be acylate, inorganic acid salt etc., described acylate includes citrate, fumarate, oxalates, apple
Hydrochlorate, lactate, camsilate, tosilate, mesylate etc.；Described inorganic acid salt includes halogen acid salt, sulphur
Hydrochlorate, phosphate, nitrate etc..For example, and lower alkanesulfonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid etc. can be formed mesylate,
Fluoroform sulphonate；With aryl sulfonic acid, such as benzene sulfonic acid or p-methyl benzenesulfonic acid can form tosilate, benzene sulfonate；With
Organic carboxyl acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, butanedioic acid or citric acid etc. can be formed accordingly
Salt；Glutamate or aspartate can be formed with amino acid, such as glutamic acid or aspartic acid.With inorganic acid, such as halogen acids (such as
Hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc. can also form corresponding salt.
Second object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition includes at least one activity
Component and one or more pharmaceutically acceptable carriers or excipient, described active component can be the BTK of the present invention
Inhibitor compound, the optical isomer of the compound, the compound or its optical isomer are pharmaceutically acceptable
In the solvate of salt, the compound or its optical isomer any one or it is any a variety of.
The carrier includes the conventional thinner of pharmaceutical field, excipient, filler, adhesive, wetting agent, disintegrant,
Sorbefacient, surfactant, absorption carrier, lubricant etc., it may also be necessary to add flavouring agent, sweetener etc..This hair
Tablet, pulvis, granula, capsule, the diversified forms such as oral liquid and injecting drug use, the medicine of above-mentioned each formulation can be made in bright medicine
It can be prepared according to the conventional method of pharmaceutical field.
On the other hand, the present invention is to provide using the compound described in formula disclosed herein (I)~logical formula (III) and
Its optical isomer or its pharmaceutically acceptable salt or solvate come suppress bruton's tyrosine kinase (Btk) activity or
Treat disease, obstacle or the illness benefited from the suppression of bruton's tyrosine kinase (Btk) activity.
In further aspect, it provided herein is a kind of containing therapeutically effective amount by giving curer in need
The composition of at least one compound, so as to suppress the bruton's tyrosine kinase of the subject activity method, wherein
The structural formula of the compound is logical formula (I)~logical formula (III).In some embodiments, subject in need suffers from
Autoimmune disease, such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriasis arthropathica, Bones and joints
Inflammation, 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 (Gren ' s syndrome), multiple sclerosis, infectiousness
Neuronitis (Guillain-Barr é syndrome), acute diseminated encephalomyelitis, Addision's disease (Addison ' s
Disease), opsoclonus-myoclonic syndrome, mandatory spondylitis, antiphospholipid antibody syndrome, aplastic are poor
Blood, oneself immunity hepatitis, chylous diarrhea (coeliac disease), goodpasture's syndrome (Goodpasture ' s
Syndrome), ITP, optic neuritis, chorionitis, PBC, Lai Teer are comprehensive
Simulator sickness (Reiter ' s syndrome), takayasu's arteritis (Takayasu ' s arteritis), temporal arteritis, warm type itself are exempted from
Epidemic disease hemolytic anemia, Wegner's granulomatosis (Wegener ' s granulomatosis), psoriasis, alopecia universalis, Bei He
Cut special disease (Disease), confirmed fatigue, familial dysautonomia, mullerianosis, chromic fibrous wing
Guang inflammation, neuromyotonia, chorionitis or Vulvodynia.
In further embodiment, subject in need suffers from cancer.In one embodiment, the cancer
Disease is B cell proliferative disease, for example, diffusivity large B cell lymphoid tumor, follicular lymphoma, chronic lymphocytic leukemia,
Chronic lymphocytic leukemia, B cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma/huge balls of Walden Si Telun
Proteinemia (Mmacroglobulinemia), splenic marginal zone lymthoma, plasma cell myeloma, thick liquid cell
Knurl, extranodal marginal zone B cell lymphoma, lymphoma nodal marginal zone B cell, mantle cell lymphoma, vertical diaphragm (thymus gland) are big
B cell lymphoma, intravascular large B cell lymphoma, lymphoma primary effusion, Burkitt lymphoma (Burkitt
Lymphoma)/leukaemia or lymphomatoid granulomatosis.
The present invention also provides application of the compound or pharmaceutically acceptable salt thereof of the present invention in BTK inhibitor is prepared, special
It is not to prepare the application in treating cell proliferative diseases.Described cell proliferative diseases include cancer.In other words, the present invention is gone back
Compound described in formula (I)~logical formula (III) and its optical isomer or its pharmaceutically acceptable salt are provided or solvent closes
Individually or with other drugs the application in treatment proliferative diseases (such as cancer) is used in combination in thing.Can and it is provided by the present invention
The antineoplastic that compound or pharmaceutically acceptable salt thereof is used in combination includes but and the non-limiting following species of at least one：Mitosis presses down
Preparation (such as vincaleukoblastinum, eldisine and Vinorelbine)；Tubulin decomposing inhibitor (such as PTX)；Alkylating reagent is (such as suitable
Platinum, carboplatin and endoxan)；Antimetabolite (such as 5 FU 5 fluorouracil, Tegafur, methotrexate (MTX), cytarabine and hydroxycarbamide)；Can
Insert antibiotic (such as A Leisu, mitomycin and bleomycin)；Enzyme (such as asparagine enzyme)；Topoisomerase inhibitors are (such as
Rely on primary glycosides and camptothecine)；BRM (such as interferon).
Present invention also offers the method for preparing formula (I) and its pharmaceutically acceptable derivative, with shown in following scheme
Synthetic route synthesizes：
As it appears from the above, compound 1 (prepared by the method with reference to WO2012158795) and R1B(OH)2In potassium phosphate, palladium chtalyst
In the presence of agent and suitable solvent or mixed solvent such as dioxane/water, back flow reaction 24 hours, obtained compound 2 is three
In the presence of phenyl phosphorus, DIAD and suitable solvent such as THF, react to obtain compound 3 with the 3- hydroxy piperidines of Boc protections, then exist
Hydrolyzed under acidic conditions prepares key intermediate 4.In the presence of key intermediate DCC and suitable solvent such as DCM, with substituting propylene
Acid fragment condensation reaction, obtain logical formula (I) compound.
Inventor experiments prove that, the compounds of this invention is to A549, SGC7901, MCF-7, PC-9IR, HL-
60 grade tumor cell lines have antiproliferative inhibitory action, can be applied to treat the related solid tumor of human or animal cell proliferative or
In the medicine of leukemia.
Inventor experiments prove that, the compounds of this invention has preferable pharmacokinetic property, can apply
In the related solid tumor of oral medication human or animal cell proliferative or leukemia or suffering from autoimmune disease.
Inventor experiments prove that, the compounds of this invention has the response characteristic of double site.
Embodiment
Illustrate the exploitativeness of the present invention below by embodiment, it will be understood by those of skill in the art that according to existing
There is the teaching of technology, corresponding technical characteristic is modified or replaced, still falls within the scope of protection of present invention.
The key intermediate 4a of embodiment 1. preparation
The conjunction of step 1. 3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (compound 2a)
Into
By iodo- 1H- pyrazolos [3,4-d] pyrimidine -4- amine (compound 1) (2.61g, 10mmol) of 3-, 4- phenoxypyridines
Boric acid (3.83g, 18mmol) and potassium phosphate (5.375g, 25mmol) are sequentially added in single neck bottle, add Isosorbide-5-Nitrae-dioxane
(40mL) and water (10mL), under nitrogen protection, add triphenyl phosphorus palladium (1.76g, 1.5mmol), back flow reaction 24h.React
It is complete to be cooled to room temperature, it is stirred overnight, separates out yellow mercury oxide, filter, wash (50ml*3), yellow solid is obtained after drying 24 hours
2.25g, is 3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (compound 2a), yield 67%.
Step 2. 3- (4- amino -3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperazine
The synthesis of pyridine -1- t-butyl formates (compound 3a)
By 3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (compound 2a) (2.12g,
7mmol), 3- hydroxy piperidines -1- t-butyl formates (1.55g, 7.7mmol), triphenyl phosphorus (2.75g, 10.5mmol) and azo
Bis-isobutyronitrile (2.12g, 10.5mmol) is dissolved in THF (250ml), and (whether TLC thin-layer chromatographies monitoring reaction by room temperature reaction 12h
Completely).After completion of the reaction, solvent is recovered under reduced pressure.100 ethyl acetate are added into remaining reactant mixture, with 100ml*3 saturations
Sodium carbonate liquor extraction organic layer 3 times, merges organic phase, after saturated sodium-chloride washes 1 time, anhydrous sodium sulfate drying.It is recovered under reduced pressure
Solvent obtains brown solid 1.40g, yield 40%.Step 3.3- (6- phenoxypyridines -3- bases) -1- (piperidines -3- bases) -1H-
The synthesis of pyrazolo [3,4-d] pyrimidine -4- amine hydrochlorates (compound 4a)
By 3- (4- amino -3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -1- bases) piperidines -1- first
Tert-butyl acrylate (compound 3a) (0.97g, 2mmol) is dissolved in 15ml dioxane, and 10ml 2N HCl are added dropwise, were stirred at room temperature
Night.The crude product recrystallizing methanol that solvent obtains is recovered under reduced pressure, obtain off-white powder 4a (0.71g, yield 80%, [M+H]=
424.2)。
The key intermediate 4b of embodiment 2. preparation
Step 1. 3- (6- (2- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (compounds
Synthesis 2b)
Synthetic method of the step 1. of synthesis step reference implementation example 1 similar to compound 2a, from 4- (4- chlorophenoxies)
Pyridine boronic acid (4.46g, 18mmol) prepare compound 2h (2.31g, yield 68%).
Step 2. 3- (4- amino -3- (6- (2- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base) piperidines -1- t-butyl formates (compound 3b) synthesis
Synthetic method prepare compound 3b of the step 2. of synthesis step reference implementation example 1 similar to compound 3a
(1.40g, yield 40%).
Step 3. 3- (6- (2- fluorophenoxies) pyridin-3-yl) -1- (piperidines -3- bases) -1H- pyrazolos [3,4-d] are phonetic
The synthesis of pyridine -4- amine hydrochlorates (compound 4b)
Synthetic method prepare compound 4b of the step 3. of synthesis step reference implementation example 1 similar to compound 4a
(0.67g, yield 77%, [M+H]=442.2).
The key intermediate 4c of embodiment 3. preparation
Step 1. 3- (6- (4- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] pyrimidine -4- amine (compounds
Synthesis 2c)
Synthetic method of the step 1. of synthesis step reference implementation example 1 similar to compound 2a, from 4- (4- chlorophenoxies)
Pyridine boronic acid (4.46g, 18mmol) prepare compound 2c (2.32g, yield 68%).
Step 2. 3- (4- amino -3- (6- (4- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base) piperidines -1- t-butyl formates (compound 3c) synthesis
Synthetic method prepare compound 3i of the step 2. of synthesis step reference implementation example 1 similar to compound 3a
(1.32g, yield 38%).
Step 3. 3- (6- (4- fluorophenoxies) pyridin-3-yl) -1- (piperidines -3- bases) -1H- pyrazolos [3,4-d] are phonetic
The synthesis of pyridine -4- amine hydrochlorates (compound 4c)
Synthetic method prepare compound 4c of the step 3. of synthesis step reference implementation example 1 similar to compound 4a
(0.68g, yield 78%, [M+H]=442.2).
The 1- of embodiment 4. (3- (4- amino -3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base) piperidin-1-yl) -2- bromopropyl -2- alkene -1- ketone preparation (compound 5-1)
4a (548mg, 1.3mmol), 2- bromopropenes acid (195mg, 1.3mmol) are dissolved in 5ml dichloromethane, and room temperature is added dropwise
DCC (267mg, 1.3mmol) dichloromethane (5ml) solution, back flow reaction 4 hours.After reaction terminates, room temperature is cooled to, is taken out
Filter, after filtrate concentration, column chromatography for separation (petroleum ether：Ethyl acetate：Triethylamine=2：1：0.1) white solid 202mg, yield are obtained
30%, [M+H]=520.1.1H-NMR(δ,CDCl3-d6):8.50 (d, 1H, J=2.0Hz, ArH), 8.35 (s, 1H, ArH),
8.03(dd,1H,J1=8.4Hz, J2=2.4Hz, ArH), 7.42 (td, 2H, J1=7.6Hz, J2=2.0Hz, ArH), 7.23
(t, 1H, J=7.6Hz, ArH), 7.18 (dd, 2H, J1=8.4Hz, J2=2.0Hz, ArH), 7.08 (d, 1H, J=8.4Hz,
ArH),6.04(s,2H,-NH2), 5.19 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.10 (d, 0.5H, J=4.0Hz ,-C=
CH2), 5.05 (d, 1H ,-C=CH2),4.91(m,1H,piperidine),4.63(m,0.5H,piperidine),4.45(m,
0.5H,piperidine),4.12(m,0.5H,piperidine),3.75(m,0.5H,piperidine),3.43(m,0.5H,
piperidine),3.17(m,0.5H,piperidine),2.85(m,0.5H,piperidine),2.77(m,0.5H,
piperidine),2.30(m,2H,piperidine),1.73(m,2H,piperidine)。
The 1- of embodiment 5. (3- (4- amino -3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base) piperidin-1-yl) -2- chloropropyl -2- alkene -1- ketone preparation (compound 5-2)
Synthetic method prepare compound 5-2 (214mg, production of the synthesis step reference implementation example 4. similar to compound 5-1
Rate 35%, [M+H]=476.2).1H-NMR(δ,CDCl3-d6):8.51 (d, 1H, J=2.0Hz, ArH), 8.36 (s, 1H,
ArH),8.05(dd,1H,J1=8.0Hz, J2=2.0Hz, ArH), 7.44 (td, 2H, J1=7.6Hz, J2=2.0Hz, ArH),
7.24 (t, 1H, J=7.6Hz, ArH), 7.20 (dd, 2H, J1=8.4Hz, J2=2.0Hz, ArH), 7.11 (d, 1H, J=
8.4Hz,ArH),5.98(s,2H,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.11 (d, 0.5H, J=
4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.92(m,1H,piperidine),4.63(m,0.5H,
piperidine),4.43(m,0.5H,piperidine),4.11(m,0.5H,piperidine),3.74(m,0.5H,
piperidine),3.42(m,0.5H,piperidine),3.17(m,0.5H,piperidine),2.82(m,0.5H,
piperidine),2.75(m,0.5H,piperidine),2.31(m,2H,piperidine),1.73(m,2H,
piperidine)。
((4- amino -3- (6- (2- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] are phonetic by 3- by the 1- of embodiment 6.
Pyridine -1- bases) piperidin-1-yl) -2- bromopropyl -2- alkene -1- ketone preparation (compound 5-3)
Synthetic method prepare compound 5-3 (227mg, production of the synthesis step reference implementation example 4. similar to compound 5-1
Rate 29%, [M+H]=538.1).1H-NMR(δ,CDCl3-d6):8.51 (d, 1H, J=2.0Hz, ArH), 8.39 (s, 1H,
ArH),8.06(dd,1H,J1=8.4Hz, J2=2.0Hz, ArH), 7.37 (dd, 2H, J1=8.4Hz, J2=7.2Hz, ArH),
7.17 (d, 1H, J=8.4Hz, ArH), 6.94 (m, 3H, ArH), 6.00 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-
C=CH2), 5.11 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.03 (d, 1H ,-C=CH2),4.92(m,1H,
piperidine),4.60(m,0.5H,piperidine),4.42(m,0.5H,piperidine),4.11(m,0.5H,
piperidine),3.72(m,0.5H,piperidine),3.43(m,0.5H,piperidine),3.13(m,0.5H,
piperidine),2.82(m,0.5H,piperidine),2.70(m,0.5H,piperidine),2.31(m,2H,
piperidine),1.75(m,2H,piperidine)。
((4- amino -3- (6- (2- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] are phonetic by 3- by the 1- of embodiment 7.
Pyridine -1- bases) piperidin-1-yl) -2- chloropropyl -2- alkene -1- ketone preparation (compound 5-4)
Synthetic method prepare compound 5-4 (201mg, production of the synthesis step reference implementation example 4. similar to compound 5-1
Rate 31%, [M+H]=494.1).1H-NMR(δ,CDCl3-d6):8.52 (d, 1H, J=2.0Hz, ArH), 8.39 (s, 1H,
ArH),8.05(dd,1H,J1=8.4Hz, J2=2.0Hz, ArH), 7.37 (dd, 2H, J1=8.4Hz, J2=7.6Hz, ArH),
7.15 (d, 1H, J=8.4Hz, ArH), 6.94 (m, 3H, ArH), 5.92 (s, 2H ,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-
C=CH2), 5.12 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.91(m,1H,
piperidine),4.63(m,0.5H,piperidine),4.41(m,0.5H,piperidine),4.11(m,0.5H,
piperidine),3.75(m,0.5H,piperidine),3.44(m,0.5H,piperidine),3.16(m,0.5H,
piperidine),2.81(m,0.5H,piperidine),2.75(m,0.5H,piperidine),2.32(m,2H,
piperidine),1.74(m,2H,piperidine)。
((4- amino -3- (6- (4- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] are phonetic by 3- by the 1- of embodiment 8.
Pyridine -1- bases) piperidin-1-yl) -2- bromopropyl -2- alkene -1- ketone preparation (compound 5-5)
Synthetic method prepare compound 5-5 (234mg, production of the synthesis step reference implementation example 4. similar to compound 5-1
Rate 30%, [M+H]=538.1).1H-NMR(δ,CDCl3-d6):8.41 (d, 1H, J=2.0Hz, ArH), 8.28 (s, 1H,
ArH),7.96(dd,1H,J1=8.8Hz, J2=2.4Hz, ArH), 7.01 (m, 5H, ArH), 5.84 (s, 2H ,-NH2),5.29
(d, 0.5H, J=4.0Hz ,-C=CH2), 5.13 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.03 (d, 1H ,-C=CH2),
4.92(m,1H,piperidine),4.61(m,0.5H,piperidine),4.44(m,0.5H,piperidine),4.12(m,
0.5H,piperidine),3.74(m,0.5H,piperidine),3.41(m,0.5H,piperidine),3.13(m,0.5H,
piperidine),2.82(m,0.5H,piperidine),2.68(m,0.5H,piperidine),2.32(m,2H,
piperidine),1.75(m,2H,piperidine)。
((4- amino -3- (6- (4- fluorophenoxies) pyridin-3-yl) -1H- pyrazolos [3,4-d] are phonetic by 3- by the 1- of embodiment 9.
Pyridine -1- bases) piperidin-1-yl) -2- chloropropyl -2- alkene -1- ketone preparation (compound 5-6)
Synthetic method prepare compound 5-6 (205mg, production of the synthesis step reference implementation example 4. similar to compound 5-1
Rate 31%, [M+H]=494.1).1H-NMR(δ,CDCl3-d6):8.41 (d, 1H, J=2.0Hz, ArH), 8.28 (s, 1H,
ArH),7.97(dd,1H,J1=8.4Hz, J2=2.0Hz, ArH), 7.01 (m, 5H, ArH), 5.92 (s, 2H ,-NH2),5.21
(d, 0.5H, J=4.0Hz ,-C=CH2), 5.12 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),
4.99(m,1H,piperidine),4.65(m,0.5H,piperidine),4.41(m,0.5H,piperidine),4.17(m,
0.5H,piperidine),3.75(m,0.5H,piperidine),3.43(m,0.5H,piperidine),3.16(m,0.5H,
piperidine),2.83(m,0.5H,piperidine),2.71(m,0.5H,piperidine),2.33(m,2H,
piperidine),1.74(m,2H,piperidine)。
The 1- of embodiment 10. (3- (4- amino -3- (6- phenoxypyridines -3- bases) -1H- pyrazolos [3,4-d] pyrimidine -1-
Base) piperidin-1-yl) -2- fluoropropyl -2- alkene -1- ketone preparation (compound 5-7)
Synthetic method prepare compound 5-7 (195mg, production of the synthesis step reference implementation example 4. similar to compound 5-1
Rate 33%, [M+H]=460.2).1H-NMR(δ,CDCl3-d6):8.51 (d, 1H, J=2.0Hz, ArH), 8.36 (s, 1H,
ArH),8.05(dd,1H,J1=8.0Hz, J2=2.4Hz, ArH), 7.43 (td, 2H, J1=7.6Hz, J2=2.0Hz, ArH),
7.26 (t, 1H, J=8.0Hz, ArH), 7.21 (dd, 2H, J1=8.4Hz, J2=2.0Hz, ArH), 7.12 (d, 1H, J=
8.4Hz,ArH),5.99(s,2H,-NH2), 5.21 (d, 0.5H, J=4.0Hz ,-C=CH2), 5.11 (d, 0.5H, J=
4.0Hz ,-C=CH2), 5.06 (d, 1H ,-C=CH2),4.92(m,1H,piperidine),4.65(m,0.5H,
piperidine),4.39(m,0.5H,piperidine),4.12(m,0.5H,piperidine),3.72(m,0.5H,
piperidine),3.42(m,0.5H,piperidine),3.17(m,0.5H,piperidine),2.83(m,0.5H,
piperidine),2.76(m,0.5H,piperidine),2.32(m,2H,piperidine),1.77(m,2H,
piperidine)。
The external Btk kinase inhibiting activities of embodiment 11. and anti tumor activity in vitro test
The external Btk kinase inhibiting activities assay method of the compounds of this invention：
Medicine is dissolved in the storing solution that 10mM is made in DMSO, and the test concentrations decoction for being diluted to 50x is standby, test is dense
Degree is with 3 by gradient dilution, respectively 25nM, 8.33nM, 2.78nM, 0.93nM, 0.31nM, 0.10nM.Added in 96 orifice plates
10 μ L 50x medicine reserve liquids, add 90 μ L 1x kinase buffer liquids, shake 10 minutes on the oscillator.From each hole of 96 orifice plates
Take 5 μ L to be transferred to 384 orifice plates, 2 multiple holes are set in 384 orifice plates.Kinase reaction：Prepare 2.5x kinase buffer liquids：Enzyme addition 1x is swashed
In enzyme basis buffer.Prepare 2.5x small peptide solution：The small peptide of FAM marks and ATP are added in 1x kinases basis buffers.
In added with the orifice plate of 5 μ L decoctions 384,10 μ L 2.5x kinase buffer liquids are added, are incubated at room temperature 10 minutes.Added in 384 orifice plates
10 μ L 2.5x small peptide solution, 28 DEG C are incubated 1 hour.Add 25 μ L terminate liquids and stop reaction.Reading, and compound is calculated to enzyme
Inhibiting rate, the Fitting Calculation goes out the IC of BTK kinases50。
Anti tumor activity in vitro has been carried out to synthesized compound from different solid tumor and leukemia cell line
Measure:
Cell line：Human lung carcinoma cell (A549), human breast cancer cell (MCF7), gastric carcinoma cells (SGC7901), it is acute before
Promyelocytic leukemia cell (HL60), human lung carcinoma cell Gefitinib mdr cell (PC9-IR).
Culture medium：A549:RPMI 1640+ hyclones
MCF7：DMEM+ hyclones
SGC7901：RPMI 1640+ NBCSs
HL60：RPMI 1640+ hyclones
PC9-IR：DMEM+ hyclones
Method for preparation of drug：Medicine is dissolved in the storing solution that 10mM is made in DMSO, and dilution obtains 5 by a certain percentage
Various concentrations (test concentrations 100x).
Tumour cell in vitro culture：
By selected five plants of tumour cells A549, MCF7, SGC7901, HL60, PC9-IR, in 37 DEG C, 5%CO2Cell
It is incubated in incubator, passage (attached cell is passed on after being digested with Duck ' s EDTA), uses when cell density grows to 70~90%
In needed for later experiment.
Tumour cell A549, MCF7, SGC7901, HL60, PC9-IR, planted on 96 orifice plates into 4000/200 μ L/ holes,
In 37 DEG C, 5%CO2It is incubated overnight in cell culture incubator.Add compound 2 μ L per hole, final concentration of 50 μM, 10 μM, 2 μM, 0.4
μM, 0.08 μM jointly in 37 DEG C, 5%CO2It is incubated 72 hours in cell culture incubator, with DMSO (2%) for control group.72 hours
Afterwards, 20 μ L CCK-8 solution are added, are placed in 37 DEG C, 5%CO24 hours in cell culture incubator.With having added respective amount cell culture fluid
With CCK-8 solution but without add cell hole as blank control.With ELIASA in 450nm measure absorbances (OD values), institute
Data are obtained to be used to calculate IC50。
The calculation formula of cell inhibitory rate is：Cell inhibitory rate %=[(control group OD values-blank group OD values)-(medication groups
OD values-blank group OD values)]/(control cell OD values-blank group OD values) × 100%, calculated with CalcuSyn softwares and try to achieve half
Inhibition concentration (IC50)。
The part of compounds of table 1 is to BTK kinase inhibiting activities and tumor cell in vitro proliferation inhibition activity
As can be seen from the table, majority of compounds all has obvious inhibitory activity to BTK, with HZ-003 phases
Than being declined slightly.But on a cellular level, the compound 5-1~5-6 tested shows more stronger than positive control
The tumor cell proliferation inhibition activity of effect, stronger or suitable Cytostatic to tumor cell is also shown compared with HZ-003 and is lived
Property.Compared with her cloth is for Buddhist nun, compound 5-1~5-6 solid tumor cell activity is stronger (A549, SGC-7901, MCF-7), and
It is same to blood oncocyte (HL-60).Particularly in human lung carcinoma cell (A549), compound 5-1 lives than her cloth for Buddhist nun
Property improves 10 times, and 5 times are improved than HZ-003.Meanwhile all compounds are same in PC9-IR (Gefitinib persister)
Show potent tumor cell proliferation inhibition activity.Therefore, it is involved in the present invention can be used as BTK inhibitor have it is wide
Antitumor application thereof prospect.
The solubility test of embodiment 12.
Weigh the test-compound 100mg for being ground into fine powder, respectively at 25 DEG C ± 2 DEG C a certain amount of solvent (1ml, 3ml,
10ml, 100ml) in, every strength shaking in 5 minutes 30 seconds；Dissolving situation in observation 30 minutes, such as without visible solute, depending on
To be completely dissolved.
Experimental result shows, HZ-003 still has that part is undissolved in 100ml solvents, with reference to the definition of Chinese Pharmacopoeia, category
In soluble,very slightly.And compound 5-1 is completely dissolved in 100ml solvents, there is fraction undissolved in 10ml, belong to slightly soluble,
Significantly improved than HZ-003.Illustrate that the introducing of fragrant theheterocyclic nitrogen atom significantly improves the solubility of compound.
The sign of the external double site irreversible inhibitor property of embodiment 13.：
First, after pre-processing restructuring Btk using compound 5-1, with the culture medium repeated washing without inhibitor, its activity
It will not recover (see, for example, J.B.Smaill etc., J.Med.Chem.1999,42,1803).Secondly, by mass spectrum, observed
It is 1 that main mass spectra peak, which corresponds to the ratio between molecular weight of covalent complex between compound 5-3 and Btk,:1 (compound 4:518, road
Er Dun, recombinate Btk kinases binding domain：33487；Compound predicted value is 34005, measured value 34005).
Secondly, after incubating bath altogether 3 hours using compound 5-1 and cysteine, detected through HPLC-MS, find major partization
Compound 5-1 is changed into that (predicted molecular weight is by the product of two cysteine additions：682), actual molecular weight is (682), real
Verify bright, the compound tested has by the ability of bimolecular compounds containing thiol groups addition, and this also illustrates such compound
Although her cloth of Btk kinase inhibiting activities and positive drug is suitable for Buddhist nun in vitro, Yi Bu can be substantially better than in cell aspect
For Buddhist nun.
14. oral pharmacokinetic studies of embodiment
Buddhist nun is replaced to investigate pharmacokinetic properties of the compound 5-1 in rat body respectively as reference using her cloth, specific side
Method is as follows：Using SD rats as experimental animal, gastric infusion 20mg/kg, tail vein Bolos intravenous administration 5mg/kg.The tail of gastric infusion is quiet
It is 0.17,0.33,0.5,1,1.5,2,4,6,8,12,24 hours that arteries and veins, which takes blood time point,；It is 0.05 that intravenously administrable, which takes blood time point,
0.1,0.17,0.5,1,2,4,6,8,12,24 hour.Whole blood 0.3ml is taken, takes blood plasma 0.1ml to be divided using LC-MS after centrifugation
Analysis.As a result showing, compound 5-1 oral administration biaavailability is respectively 19%, and it is 12% that her cloth, which replaces the bioavilability of Buddhist nun,
Therefore the stability of compound 5-1 in vivo has for Buddhist nun compared with her cloth and significantly significantly improved.Its reason may is that acryloyl
After the α positions of amine introduce halogen introducing, on the premise of drug absorption is not influenceed so that the metabolic rate of double bond is by a certain extent
Suppression, and then improve blood concentration and improve bioavilability.
Embodiment 15：Divide wet arthritis using compound 5-1 treatments class
In the mouse model of rheumatoid arthritis, effect inside compound 5-1 is have rated, in Balb/c mouse
In, by give anti-collagen protein antibodies and lipopolysaccharide-induced arthritis (Nandakumar etc., Am.J.Pathol.2003,
163:1827-1837).Specific method is as follows：At the 0th day, the anti-II types of 100mg/kg are injected in female Balb/c mouse veins
The Chemico mAb mixture of collagen, at the 1st day, intraperitoneal injection 1.25mg/kg lipopolysaccharides.At the 2nd day to 12 days, press
10mg/kg compound 5-1, it is administered orally 1 time daily.As a result show, compound 5-1 has anti-class point inside obvious moist
Arthritic effect, specifically, the inflammatory cell infiltration that occurs in model group, synovial hyperplasia, inflammatory granulation tissue are formed, bad
Phenomena such as dead tissue occurs after compound 5-1 treatments be improved significantly.
Claims (8)
1. a kind of bruton's tyrosine kinase inhibitor, it is characterised in that it has formula II structure：
And its pharmaceutically acceptable salt, wherein：Each Rd is independently H, halogen ,-CF3、-CN、-NO2、-OH、C1-C3's
Alkoxy or-NH2, X is selected from fluorine, chlorine and bromine, Y1、Y2Selected from CH, N, Y1、Y2At least one is selected from N.
2. a kind of bruton's tyrosine kinase inhibitor, it is characterised in that it has the structure of general formula III：
And its pharmaceutically acceptable salt, wherein：X is selected from fluorine, chlorine and bromine, Y1、Y2Selected from CH, N, Y1、Y2At least one is selected from
N。
3. a kind of pharmaceutical composition, described pharmaceutical composition includes at least one active component and one or more pharmaceutically may be used
The carrier or excipient of receiving, the active component are that the bruton's tyrosine as described in any one in claim 1 to 2 swashs
Inhibitor compound, the compound pharmaceutically any one in acceptable salt or any a variety of.
4. bruton's tyrosine kinase inhibitor compound as described in any one in claim 1 to 2 and its pharmaceutically
Acceptable salt is preparing the medicine of disease, obstacle or illness that treatment benefits from the suppression of bruton's tyrosine kinase activity
In application.
5. bruton's tyrosine kinase inhibitor compound as described in any one in claim 1 to 2 and its pharmaceutically
Acceptable salt is preparing application independent or being used in combination with other drugs in the medicine for the treatment of cell proliferative diseases.
6. bruton's tyrosine kinase inhibitor compound as described in any one in claim 1 to 2 and its pharmaceutically
Acceptable salt is preparing application independent or being used in combination with other drugs in the medicine for the treatment of cancer.
7. bruton's tyrosine kinase inhibitor compound as described in any one in claim 1 to 2 and its pharmaceutically
Acceptable salt is preparing application independent or being used in combination with other drugs in the medicine for the treatment of autoimmune disease.
8. bruton's tyrosine kinase inhibitor compound as described in any one in claim 1 to 2 and its pharmaceutically
Acceptable salt is preparing application independent or being used in combination with other drugs in the medicine for the treatment of lupus erythematosus.
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| CN108069974B (en) * | 2016-11-15 | 2019-12-10 | 杭州和正医药有限公司 | Selective Bruton tyrosine kinase inhibitor and application thereof |
| CN109305944B (en) * | 2017-07-28 | 2022-09-02 | 深圳睿熙生物科技有限公司 | Inhibitors of bruton's tyrosine kinase |
| CN109369654A (en) * | 2018-11-20 | 2019-02-22 | 山东大学 | 1,3- bis- substituted-4-amino Pyrazolopyrimidines and its preparation method and application |
| KR20210151859A (en) * | 2019-06-27 | 2021-12-14 | 항저우 힐젠 테라퓨틱스 컴퍼니 리미티드 | Casein kinase 1ε inhibitors and pharmaceutical compositions and their applications |
| 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 |
| WO2023088477A1 (en) * | 2021-11-22 | 2023-05-25 | 杭州和正医药有限公司 | Multifunctional compound capable of degrading btk kinase, and composition and use |
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| WO2014188173A1 (en) * | 2013-05-20 | 2014-11-27 | Redx Pharma Limited | Pyrazolopyrimidine derivatives useful as inhibitors of bruton's tyrosine kinase |
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| WO2014188173A1 (en) * | 2013-05-20 | 2014-11-27 | Redx Pharma Limited | Pyrazolopyrimidine derivatives useful as inhibitors of bruton's tyrosine kinase |
| WO2014187319A1 (en) * | 2013-05-21 | 2014-11-27 | Jiangsu Medolution Ltd | Substituted pyrazolopyrimidines as kinases inhibitors |
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