CN106146482A - Bruton's tyrosine kinase inhibitor - Google Patents

Bruton's tyrosine kinase inhibitor Download PDF

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CN106146482A
CN106146482A CN201510175762.XA CN201510175762A CN106146482A CN 106146482 A CN106146482 A CN 106146482A CN 201510175762 A CN201510175762 A CN 201510175762A CN 106146482 A CN106146482 A CN 106146482A
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alkyl
aryl
cycloalkyl
thiazolinyl
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CN106146482B (en
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王能辉
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Zhejiang Wenda Pharmaceutical Technology Co., Ltd.
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Ningbo Wonder Pharmaceutical Technology Co Ltd
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases

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Abstract

The invention provides Bu Ludun (Burton ' s) tyrosine kinase inhibitor, specifically, by extensively in-depth study in the present invention, it is thus achieved that a class can be as the compound of Btk inhibitor, test result indicate that, described compound has good inhibition to Btk.Present invention also offers the preparation method of above-claimed cpd, and the purposes in preparing medicine.

Description

Bruton's tyrosine kinase inhibitor
Technical field
The invention belongs to field of medicine and chemical technology, specifically, the present invention relates to Bu Ludun (Burton ' s) junket Histidine kinase inhibitor.
Background technology
One of maximum family of protein kinase composition people's fermentoid, and by adding phosphate group to protein Regulate many different signal transduction process (T Hunter, Cell, 198750:823-829).Especially, EGFR-TK phosphorylated protein is at the phenol moieties of tyrosine residue.Family tyrosine kinase includes that control cell is raw Member that is long, that migrate and break up.The own human diseases through relating to many of abnormal kinase activity, including cancer, Autoimmune disease and inflammatory disease.
There is good card with regard to key effect in the pathogenesis of autoimmunity and/or inflammatory disease for the B cell According to.For the therapeutic agent based on protein of B cell, the inflammatory disease causing for autoantibody such as Rituxan If rheumatoid arthritis is effective (Rastetter etc., Annu.Rev.Med.200455:477). Therefore, the inhibitor of the protein kinase playing a role in B cell activation should be the disease for B cell mediation Sick pathology such as autoantibody generates useful smelting and treats agent.
By a series of cell response of signal transmission control of B-cell receptor (BCR), including propagation and differentiation are arrived Ripe antibody-producting cell.BCR is the crucial point of adjustment of B cell activity, and the signal conduction of exception is permissible Cause B cell proliferation and the formation of pathogenic autoantibodies of imbalance, its cause various autoimmune disease and/or Inflammatory disease.Bu Ludun (Burton ' s) LCK (Btk) is the film near-end and immediately at BCR The related kinases of the non-BCR in downstream.The shortage of Btk oneself block the conduction of BCR signal, therefore the pressing down of Btk through display System can be the effective treatment method of the lysis blocking B cell mediation.
The present invention is to develop the medicine with excellent antitumor action and treating autoimmune diseases effect It for target, is found that high selective Btk inhibitor.
Content of the invention
It is an object of the invention to provide a kind of bruton's tyrosine kinase inhibitor and application thereof.
A first aspect of the present invention, provides and has the compound of structure shown in formula I or it is pharmaceutically acceptable Salt, deuterated derivative, or prodrug:
In formula,
R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R2Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R3Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
Or R2And R3Can be formed together and comprise 0-3 the heteroatomic 4-8 ring selected from N, O and S, Described 4-8 ring is saturated or unsaturated；
R4Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2、C(O)R5, R5Selected from C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, aryl, heteroaryl；
Described alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl are substituted or non-taking Generation.
In another preference, the structure of described compound is as shown in Formulas I a:
In formula,
R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R2Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R3Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
Or R2And R3Can be formed together and comprise 0-3 the heteroatomic 4-8 ring selected from N, O and S, Described 4-8 ring is saturated or unsaturated；
Described alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl are substituted or non-taking Generation.
In another preference, described 4-8 ring is saturated.
In another preference, described 4-8 ring is undersaturated.
In another preference, described 4-8 ring is substituted or non-substituted.
In another preference, described undersaturated 4-8 ring includes aromatic rings or non-aromatic ring.
In another preference, described R2And R3Can be formed together and comprise miscellaneous selected from N, O and S of 0-3 The 5-6 ring of atom, described 5-6 ring is saturated or unsaturated.
In another preference, described R1Selected from hydrogen, halogen, C1-4Alkyl.
In another preference, described R1Selected from hydrogen, F, Cl, methyl.
In another preference, described R2For methyl.
In another preference, described R3For methyl.
In another preference, described R2And R3Formed together and comprise miscellaneous former selected from N, O and S of 0-3 The 4-8 ring of son.
In another preference, described R2And R3Forming 6 rings together, described 6 rings are saturated or not Saturated.
In another preference, described R2And R3Form aromatic rings together.
In another preference, described compound is selected from:
A second aspect of the present invention, provides the preparation side of a kind of compound as described in the first aspect of the invention Method, described method includes step:
Formula II compound reacts production I with formula III compound and formula IV compound,
In another preference, described method further comprises the steps of:
In atent solvent, compound shown in formula III-3 is reacted with duplex pinacol borate, prepare formula Compound shown in III；
A third aspect of the present invention, provide compound as described in the first aspect of the invention or its pharmaceutically Acceptable salt or the purposes of solvate, (1) is used for preparing protein kinase inhibitors；And/or (2) use Medicine in preparation treatment protein kinase related disorder.
In another preference, described protein kinase is Bu Ludun (Burton ' s) LCK (Btk)。
In another preference, described protein kinase related disorder includes tumour, autoimmune disease, disease Rationality mast cell reacts.
In another preference, described tumour includes but is not limited to: chronic lymphocytic leukemia, primary lymphedema are thin Born of the same parents' lymthoma, Huppert's disease, liver cancer, lung cancer (including mediastinum cancer), oral epithelium cancer, nasopharyngeal carcinoma, Thyroid cancer, cancer of the esophagus, lymph cancer, thoracic cavity cancer, digestive system cancer, cancer of pancreas, intestinal cancer, breast cancer, ovum Nest cancer, the cancer of the uterus, kidney, carcinoma of gallbladder, cholangiocarcinoma, nervous centralis cancer, carcinoma of testis, carcinoma of urinary bladder, prostatitis Gland cancer, cutaneum carcinoma, melanoma, meat cancer, the cancer of the brain, leukemia (leukaemia), cervical carcinoma, glioma, Cancer of the stomach or ascites tumor.
In another preference, described autoimmune disease includes that systemic loupus erythematosus, rheumatoid close Joint inflammation.
A fourth aspect of the present invention, provides a kind of pharmaceutical composition, and the present invention containing safe and effective amount the Compound described in Yi Fangmian or its pharmaceutically acceptable salt or solvate；And, pharmaceutically can connect The carrier being subject to.
A fifth aspect of the present invention, provides the method for the suppression protein kinase of a kind of external non-therapeutic, Described method includes step: contact the compound described in first aspect present invention with described protein kinase, Thus suppress the activity of described protein kinase.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and below (as implemented Example) in can be combined with each other between each technical characteristic of specifically describing, thus constitute new or preferred skill Art scheme.As space is limited, at this no longer one by one tire out state.
Detailed description of the invention
The present inventor is by extensively in-depth study, it is thus achieved that a class can as the compound of Btk inhibitor, Test result indicate that, described compound has good inhibition to Btk.Present invention also offers above-mentioned The preparation method of compound, and the purposes in preparing medicine.
Term
Herein, in place of except special instruction, term " replacement " refers to the one or more hydrogen atom quilts on group The substituent being selected from the group replaces: C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, C1-8Alkoxyl, Halogen, hydroxyl, carboxyl (-COOH), C1-8Aldehyde radical, C2-10Acyl group, C2-10Ester group, amino, phenyl；Described Phenyl include unsubstituted phenyl or there is the substituted-phenyl of 1-3 substituent, described substituent is selected from: halogen, C1-10Alkyl, cyano group, OH, nitro, C3-10Cycloalkyl, C1-8Alkoxyl, amino.
In place of special instruction, among all compounds of the present invention, each asymmetric carbon atom (chiral centre) is permissible It is optionally R configuration or S configuration, or the mixture of R configuration and S configuration.
As used herein, term " C1-8Alkyl " refers to the straight or branched alkyl with 1-8 carbon atom, for example Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
As used herein, term " C2-8Thiazolinyl " refers to the straight or branched thiazolinyl with 2-8 carbon atom, example Such as vinyl, acrylic, 1,2-cyclobutenyl, 2,3-cyclobutenyl, butadienyl or similar group.
As used herein, term " C2-8Alkynyl " refers to the straight or branched alkynyl with 2-8 carbon atom, for example Acetenyl, propinyl, isopropynyl, butynyl, butynyl, secondary butynyl, tertiary butynyl or similar base Group.
As used herein, term " C3-10Cycloalkyl " refers to the cycloalkyl with 3-10 carbon atom, such as ring third Base, cyclobutyl, cyclopenta, suberyl or similar group.
As used herein, term " C1-8Alkoxyl " refers to the straight or branched alkoxyl with 1-8 carbon atom, Such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tertiary fourth oxygen Base or similar group.
As used herein, term " halogen " refers to F, Cl, Br and I.
As used herein, term " C1-4Alkoxy carbonyl " refers to have " C1-4Alkoxyl-The group of C=O " structure, Such as methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, or similar group.Wherein, C1-4Alkoxyl Defined as described above.
As used herein, term " aryl ", is preferably " C6-12Aryl ", refers to have 6-12 in ring part Monocyclic or the Bicycloaromaticity group of individual carbon atom, for example: phenyl, xenyl, naphthyl or similar group, Each carbon atom therein all can arbitrarily be replaced.
As used herein, term " heteroaryl " includes azepine aryl, oxa-aryl, thia aryl etc..
Pharmaceutically acceptable salt of the present invention can be the anion group positively charged with in compound of formula I The salt being formed.Suitable anion include chlorion, bromide ion, iodide ion, sulfate radical, nitrate anion, phosphate radical, Citrate, pyrovinic acid root, trifluoroacetic acid root, acetate, malate, tosylate, tartrate anion, Fumaric acid radical, glutamate, glucuronic acid root, lactate, glutarate and maleate.It is likewise possible to Cation is formed salt with the electronegative group (such as carboxylate radical) in compound of formula I.Suitable cation bag Include sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion, such as tetramethyl ammonium.At another preference In, " pharmaceutically acceptable salt " refer to selected from following acid formed salt: hydrofluoric acid, hydrochloric acid, hydrobromic acid, Phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, TFMS, naphthalene sulfonic acids, maleic acid, lemon Acid, acetic acid, tartaric acid, butanedioic acid, creeping oxalis acid, malic acid, glutamic acid.
The present invention relates to a series of indole derivatives, its alternatively property bruton's tyrosine kinase The irreversible inhibitor of (Burton ' s tyrosine kinase, BTK), can be used alone or and other Medicine is used in combination to treat inflammation, to the aberrant B cell related autoimmune disease of propagation (as Rheumathritis) and cancer etc..The invention still further relates to comprise the pharmaceutical composition of compound shown in formula (I) and Preparation method, purposes in pharmacy for the described compound and the compounds of this invention prevention or treatment mammal The method of (particularly people) and excessive Btk activity relevant disease.
Active component and pharmaceutically acceptable salt thereof
The compound with structure shown in formula I that the present invention provides or its pharmaceutically acceptable salt, deuterated spread out Biology, or prodrug:
In formula,
R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R2Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R3Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
Or R2And R3Can be formed together and comprise 0-3 the heteroatomic 4-8 ring selected from N, O and S, Described 4-8 ring is saturated or unsaturated；
R4Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2、C(O)R5, R5Selected from C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, aryl, heteroaryl；
Described alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl are substituted or non-taking Generation.
In being preferably carried out mode, the compound structure of the present invention is as shown in Formulas I a:
In formula,
R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R2Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R3Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
Or R2And R3Can be formed together and comprise 0-3 the heteroatomic 4-8 ring selected from N, O and S, Described 4-8 ring is saturated or unsaturated.
Preparation method
Compound shown in formula I preparation method, including step:
Formula II compound reacts production I with formula III compound and formula IV compound,
In another preference, described method further comprises the steps of:
In atent solvent, compound shown in formula III-3 is reacted with duplex pinacol borate, prepare formula Compound shown in III；
Pharmaceutical composition and application process
The compound of the present invention can serve as kinase inhibitor, and especially as the inhibitor of Btk, therefore it is right The related disease of Btk has good result for the treatment of.
On the one hand, the invention provides a kind of pharmaceutical composition, it contains the chemical combination of the present invention of (a) safe and effective amount Thing or its pharmaceutically acceptable salt；And (b) pharmaceutically acceptable carrier or excipient.The compounds of this invention Quantity be usually 10 microgram-100 milligrams/agent, preferably 100-1000 microgram/agent.
For the purposes of the present invention, effective dosage for give individuality about 0.01 mg/kg to 1000 milligrams/ Kilogram, the preferably the compounds of this invention of 0.1 mg/kg to 500 mg/kg body weight.Additionally, the present invention Compound can be alone, it is possible to be used together (being such as formulated in same pharmaceutical composition) with other therapeutic agents.
Pharmaceutical composition also can contain pharmaceutically acceptable carrier.Term " pharmaceutically acceptable carrier " refers to Carrier for Therapeutic Administration.This term refers to some medicament carriers such: themselves do not induce generation to acceptance The harmful antibody of the individuality of said composition, and there is no undue toxicity after administration.These carriers are the common skills in this area Known to art personnel.At Remington's Pharmaceutical Sciences (Mack Pub.Co., N.J. 1991) discussing fully with regard to pharmaceutically acceptable excipient can be found in.This kind of carrier includes (but not limiting In): salt solution, buffer solution, glucose, water, glycerine, ethanol, adjuvant and combinations thereof.
In therapeutic composition Chinese pharmacology, acceptable carrier can contain liquid, such as water, salt solution, glycerine and ethanol. In addition, these carriers there is likely to be complementary material, such as wetting agent or emulsifying agent, pH buffer substance etc..
Generally, therapeutic composition can be made injectable agent, such as liquid solution or suspension；May also be fabricated which Be suitable for before injection allocating in solution or suspension, the solid form of liquid-carrier.
It is once made into the composition of the present invention, it can be administered by conventional route, including (but not It is limited to): intramuscular, intravenous, subcutaneous, intracutaneous or topical.Wait that the object preventing or treating can be animal； Especially people.
When the pharmaceutical composition of the present invention is used for actual therapeutic, various difference can be used according to service condition The pharmaceutical composition of formulation.Preferably injection.
These pharmaceutical compositions can be prepared by mixing, dilution or dissolving according to conventional methods, and even You add suitable medicated premix, as excipient, disintegrant, adhesive, lubricant, diluent, buffer, Isotonic agent (isotonicities), preservative, wetting agent, emulsifying agent, dispersant, stabilizer and cosolvent, And this process for preparation can be carried out according to formulation usual way.The pharmaceutical composition of the present invention can also be sustained dosage form Formula is administered.
When the pharmaceutical composition of the present invention is used for prevention or treatment, as the chemical combination of the present invention of active component Thing or the dosage of its pharmaceutically acceptable salt, can according to the body weight of each object (patient) waiting to prevent or treat, Age, sex, symptom degree and reasonably determined.
Compound according to the present invention and pharmaceutical composition may be used for treating the disease such as cancer, autoimmune disease Sick.
Term " cancer " refers to include all types of growth of cancer cells or oncogenic process, metastatic tissue or evil Property conversion cell, tissue or organ, no matter histological type or the stage infected.The embodiment of Cancerous disease is non- Restrictively include: solid tumor, soft-tissue tumor, and metastasis (metastases).The embodiment of solid tumor includes: no With the malignant tumour of tract, such as sarcoma, lung squamous cancer and cancer.For example: the prostate of infection, lung, Breast, lymph, stomach (for example: colon), and genitourinary tract (for example: kidney, epithelial cell), Pharynx.Lung squamous cancer includes malignant tumour, for example, most colon cancers, the carcinoma of the rectum, clear-cell carcinoma, liver cancer, The non-small cell carcinoma of lung, carcinoma of small intestine and cancer of the esophagus.Above-mentioned cancer metastasis venereal disease becomes can use the present invention equally Method and composition treat and prevent.
Said method is particularly useful in terms for the treatment of Different Organs System Malignant Tumor, this different organ example As: the lung of infection, breast, lymph, stomach (for example: colon), bladder, genitourinary tract (example As: prostate), pharynx, and lung squamous cancer, these diseases include malignant tumour, for example most cancer Disease, clear-cell carcinoma, prostate cancer and/or tumour, lung's non-small cell carcinoma, carcinoma of small intestine and cancer of the esophagus.
Bu Ludun (Burton ' s) LCK (Btk)
Evidence with regard to effect in autoimmune disease and inflammatory disease for the Btk is own via Btk-deficient mice Model provides.In the preclinical mouse model of systemic loupus erythematosus (SLE), Btk deficient mice shows disease Significantly improving of disease progression.Additionally, the arthritis that collagen is induced by Btk mono-deficient mice has resistance (Jasson and Holmdahl, Clin.Exp.Immunol.1993,94:459).Own channel syndrome Dose dependent effect in arthritis mouse model of bright selective Btk inhibitor (Pan etc., Chem.Med.Chem.20072:58-61).
Btk is also expressed by the cell that may relate to lysis in addition to B cell.For example, Btk is thin by hypertrophy The mast cell of cellular expression and Btk deficiency derived from bone marrow shows the particle (Iwaki of impaired antigen induction Deng J.Biol.Chem.2005280:40261).This display Btk can be effective to treat pathologic hypertrophy Cell effect, such as allergy and asthma.Additionally, the monokaryon from the XLA patient wherein lacking Btk activity is thin Born of the same parents show that the TNFa reducing after stimulation generates (Horwood etc., J.Exp.Med.2003197:1603). Therefore the inflammation of TNFa mediation can be suppressed by the micromolecular inhibitor of Btk.Additionally, oneself is through reporting that Btk exists Play a role in Apoptosis (Islam and Smith, Immunol.Rev.2000178:49), therefore Btk inhibitor will be effective (Feldhahn etc., J.Exp. for some B cell lymphoma for the treatment of and leukaemia Med.2005201:1837)。
Btk inhibitor, it is applied to treat chronic lymphocytic leukemia, small lymphocyte lymthoma, also exists simultaneously Test clinically all achieves good effect for treating Huppert's disease, its outstanding clinical effectiveness and wide Application prospect declare publicly that the high selective micromolecular inhibitor of Btk kinases is new drug development field, the whole world Focus.
Main advantages of the present invention are:
(1) obtain first a class formation novel can be as the compound of Btk inhibitor, experimental result table Bright, described compound has good inhibition to Btk；
(2) compound of the present invention has significant result for the treatment of to autoimmune disease and inflammatory disease.
Below in conjunction with specific embodiment, the further detailed old present invention.Should be understood that these embodiments are only used for The bright present invention rather than restriction the scope of the present invention.The experiment side of unreceipted detailed conditions in the following example Method, generally according to normal condition.Unless otherwise indicated, otherwise percentage and number are calculated by weight.Below Experiment material used in embodiment and reagent all can obtain from commercially available channel if no special instructions.
The preparation of embodiment 1 formula A compound
Step A:
Compound 7-1 (25g, 0.12mol) is dissolved in CH3CN (250ml), adds K2CO3 (42g, 0.23mol) With 2-bromoacetate (30g, 0.18mol).Mixture is stirred at reflux 2h, filters, and filtrate obtains after concentrating Crude product.Crude product is dissolved in acetic acid (250ml), adds Fe (20g, 0.36mol).Mixture is at 80 DEG C Stirring 2h, is subsequently poured in water, is extracted with ethyl acetate (3x 200ml), then uses aq.NaHCO3 (6 N) wash, silica gel column chromatography separating purification (EtOAc/PE=1:1) yellow solid compound 7-2 (22.2g, 85%).HNMR (400MHz, DMSO-d6) 10.8 (s, 1H), 7.0-7.1 (m, 2H), 6.9-7.0 (m, 1H),4.6(s,2H).MS(ESI)m/z:227.9/229.9(M+H)+。
Step B:
Compound 7-2 (22g, 0.1mol) is dissolved in oxolane (200ml), at 0 DEG C one one Drip ground and add BH3/ tetrahydrofuran solution (1.0M, 200ml).Then mixed liquor is under reflux conditions It is stirred overnight.Then react with methyl alcohol quencher lentamente at 0 DEG C.Mixture is concentrated to give a crude product and is directly used in The next step.
Step C:
The crude product of upper step is dissolved in dioxane (200ml), adds KOAc (15g, 0.15mol), Pd(dppf)2Cl2(8.2g, 0.01mol) and 4,4,4', 4', 5, the 5th, 5', 5' -Octamethyl-2,2-bi (the 1st, the 3rd, 2-dioxaborolane) (38g, 0.15mol), mixture refluxes It is stirred overnight.Being concentrated to give crude product, silica gel column chromatography separates (PE:EtOAc=1:1) and purifies to obtain oily Compound 7 (17.1g, 70%) .HNMR (400MHz, CDCl3) 7.0-7.2 (m, 2H), 6.7-6.8(m,1H),4.2-4.4(m,2H),3.3-3.5(m,2H),1.2-1.4(m,12H).MS(ESI)m /z:262.1(M+H)+。
Step D:
By compound 1 (75g, 342.5mmol) in room temperature vitriolization (500ml), add nitre lentamente Acid (103.8g, 1027mmol).After stirring 18h, pour in the ice more than 3 kilograms at leisure, stirring, Solid filters, and cleans with water, and at 45 DEG C, drying under reduced pressure obtains compound 2 (90g, 99.5%).HNMR(400 MHz, DMSO-d6) 8.4-8.6 (m, 1H), 7.8-8.0 (m, 1H) .MS (ESI) m/z:262.0/264.0.
Step E:
By compound 2 (4-bromo-5-fluoro-2-nitrobenzoic acid) (90g, 340mmol) and Hydrochloric acid (37%, 630ml) is blended in 630 milliliters of water, adds stannic chloride (II) (230.2g, 1020mmol), It is then heated to 90 DEG C of 3h.After being cooled to room temperature, form precipitation, filter, clean with water, dry compound 3 (60g, 76%).HNMR (400MHz, DMSO-d6) 7.4-7.6 (m, 1H), 7.0-7.2 (m, 1H) .MS (ESI)m/z:233.9/235.9.
Step F:
To one containing compound 3 (2-amino-4-bromo-5-fluorobenzoic acid) (50g, 214 Mmol), hydrochloric acid (240ml, 1M), water (74ml) is cooled in the mixed liquor in salt and ice-water bath one one With the addition of 79 milliliters of sodium nitrite in aqueous solution (16.5g, 236mmol) (temperature is less than 0 DEG C) with dripping.Add After completing, dirty solution stirs 20 minutes in salt and ice-water bath.Then by the stannic chloride (II) of 7M (145g, 641mmol) hydrochloric acid (37%, 92ml) solution drop by drop adds (temperature is less than 0 DEG C).Reaction is mixed Compound is stirred at room temperature 1h, mixture filtration under diminished pressure, and solid water cleans, and obtains white at 45 DEG C of drying under reduced pressure Solid chemical compound 4 (30g, 48.4%).HNMR (400MHz, DMSO-d6) 7.7-7.8(m,1H),7.5-7.7(m,1H).MS(ESI)m/z:248.9/250.9(M+H)+.
Step G:
To one stirring (4-bromo-2-hydrazinyl-5-fluorobenzoic acid) (8g, 28.1mmol) acetic acid (100 milliliters) solution adds butanone (4.6g, 63.8mmol).Then mixture quilt It is heated to 70 DEG C to stir 30 minutes, be then warmed up to 110 DEG C and be stirred overnight, become the liquid of a black. Mixture filters to get filtrate, filtrate concentrate after solid, silica gel column chromatography separating purification (EtOAc:PE: AcOH=55:40:5) faint yellow solid compound 5 (2.34g, 29.3%) .HNMR (400MHz, DMSO-d6)11.0(s,1H),7.4-7.5(m,1H),2.5(s,3H),2.4(s,3H).MS(ESI)m/z: 285.9/287.9[M+H]+.
Step H:
By compound 5 (4-bromo-5-fluoro-2,3-dimethyl-1H-indole-7-carboxylic Acid) (2.0g, 7.0mmol), HATU (3.8g, 10.5mmol), NH4Cl (526mg, 10.5mmol) is molten In dichloromethane (85ml), stir 10 minutes at 0 DEG C, be subsequently adding DIPEA (3.9g, 30mmol), Stir 15 minutes at 0 DEG C, 2h is then stirred at room temperature again.Concentrate mixture and obtain solid, then add water and stir Mix 10 minutes to obtain dirty solution, filter, dry compound 6 (0.9g, 45%).HNMR (400MHz, DMSO-d6)11.0(s,1H),8.4-8.5(m,1H),2.5(s,3H),2.4(s,3H).MS(ESI):m /z 285.0/287.0[M+H]+。
Step I:
4-bromo-5-fluoro-2
3-dimethyl-1H-indole-7-carboxamide (800mg, 2.806mmol), compound 7 (783 Mg, 3.0mmol), and Pd (dppf) 2cl2 (230mg, 0.28mmol) is dissolved in DMA (15ml), stirring, Deaerate half an hour with N2.The sodium acid carbonate (2.8ml) of 2M adds, after the half an hour that again deaerates, N2's Under the conditions of, 120 DEG C of heating 2h.Then mixture pours 150 milliliters of water into, with dichloromethane extraction, has After machine phase washes with water, then washing with saturated brine, Na2SO4 is dried, and filters, is concentrated to give crude product.This is thick Product are dissolved in dichloromethane (40ml) and are cooled to-30 degrees Celsius, add acryloyl chloride (0.76g) at leisure. After dripping, 1h is stirred at room temperature.Reactant liquor is poured into water, with dichloromethane extraction, organic phases washed with water After, then wash with saturated brine, Na2SO4 is dried, and filters, is concentrated to give crude product.Silica gel column chromatography separates pure Change (EtOAc:PE=1:5 to 1:1) obtain crude product, then by HPLC be further purified A (200mg, 18%).HNMR (400MHz, DMSO-d6) 10.5-11(s,1H),8.0-8.1(s,1H),7.4-7.6(m,3H),7.0-7.1(m,2H),6.8-6.9(m,1 H),6.2-6.3(m,1H),5.7-5.8(m,1H),4.3-4.5(m,2H),3.9-4.2(m,2H),2.4(s,3H ),1.7(s,3H).MS(ESI):394.1。(M+H)+。
The preparation of embodiment 2 formula B compound
Step A:
To one stirring (4-bromo-2-hydrazinyl-5-fluorobenzoic acid) (8g, 28.1mmol) acetic acid (100ml) solution adds cyclohexanone (6.3g, 63.8mmol).Then mixture quilt It is heated to 70 DEG C to stir 30 minutes, is then warmed up to 110 DEG C and is stirred overnight, become the liquid of a black.Mixed Compound filters to get filtrate, and filtrate obtains solid, silica gel column chromatography separating purification (EtOAc:PE:AcOH after concentrating =55:40:5) obtain faint yellow solid compound 8 (2.54g, 25.7%) .HNMR (400MHz, DMSO-d6) 11.0(s,1H),7.4-7.6(m,1H),3.0(m,2H),2.7(m,2H),1.7(m,4H).MS(ESI)m/z: 312.0/314.0[M+H]+.
Step B:
By compound 8 (5-bromo-6-fluoro-2, the 3rd, the 4th, 9-tetrahydro-1H-carbazole-8-carboxylic acid)(2.0g,6.4mmol), HATU (3.8g, 10.5mmol), NH4Cl (526mg, 10.5mmol) are dissolved in dichloromethane (85ml), stirring It within 10 minutes, at 0 DEG C, is subsequently adding DIPEA (3.9g, 30mmol), 0 DEG C of stirring 15 minutes, so After be stirred overnight at room temperature again.Concentrate mixture and obtain solid, then add water and stir 10 minutes to obtain dirty solution. Filter, dry crude Compound, be directly used in the next step.
The crude Compound that upper step obtains, compound 7 (2.5g, 9.6mmol), and Pd (dppf) 2cl2 (1g, 1.3mmol) being dissolved in DMA (20ml), stirring N2 deaerates half an hour.The sodium acid carbonate (6ml) of 2M adds, Again deaerating after half an hour, under conditions of N2,120 DEG C are heated 12h.Then mixture is poured into water, With dichloromethane extraction, after organic phases washed with water, then washing with saturated brine, Na2SO4 is dried, and filters, dense Contract to obtain crude product, is then further purified to obtain faint yellow solid compound 9 (800mg, 34%) .HNMR by HPLC (400MHz, DMSO-d6) 10.8(s,1H),8.0(m,1H),7.4-7.5(m,2H),6.4-6.8(m,3H),5.8(s,1H),4.0-4.2( m,4H),2.7(m,2H),2.0(m,2H),1.7(m,2H),1.5(m,2H).MS(ESI)m/z:365.1。 (M+H)+。
Step C:
Compound 9 (0.8g, 2.2mmol) is dissolved in dichloromethane (10ml) and is cooled to-30 degrees Celsius, slowly Slowly add acryloyl chloride (0.25g, 2.5mmol).After dripping, 1h is stirred at room temperature.It is concentrated to give crude product. Silica gel column chromatography separating purification (EtOAc:PE=20% to 50%) obtains crude product, then pure further by HPLC Change to obtain yellow solid B.HNMR (400MHz, DMSO-d6) 10.9-11(s,1H),8.0-8.1(s,1H),7.4-7.6(m,3H),7.0-7.1(m,2H),6.8-6.9(m,1 H),6.2-6.3(m,1H),5.7-5.8(m,1H),4.3-4.5(m,2H),3.9-4.2(m,2H),2.6-2.7( m,2H),2.0-2.2(m,2H),1.5-1.7(m,4H).MS(ESI)m/z:420.1(M+H)+。
The preparation of embodiment 3 formula C compound
Step A:
Compound 8 (2.5g, 8mmol) is dissolved in methyl alcohol (30ml), adds the concentrated sulfuric acid (3ml), then Return stirring 18h.Cooling, is concentrated to give crude product, crude product acetic acid ethyl dissolution, and aq.NaHCO3 (6N) washs, After organic phases washed with water, then washing with saturated brine, Na2SO4 is dried, and filters, is concentrated to give crude product, silica gel Column chromatographic isolation and purification (EtOAc:PE=1:1) obtains compound as white solid 10 (2.4g, 93%) .HNMR (400MHz, DMSO-d6) 11(s,1H),7.4(m,1H),3.9(s,3H),2.9(m,2H),2.7(m,2H),1.8(m,4H).MS(ESI)m /z:277.9/279.9(M+H)+。
Step B:
Compound 10 (2.0g, 7.01mmol) adds DDQ (1.86g, 8.4mmol) in toluene (20ml), Then it is stirred at reflux after 48h. concentrates and obtains crude product, be re-dissolved in dichloromethane and water, after organic phases washed with water, Again with saturated brine washing, Na2SO4 is dried, and filters, is concentrated to give crude product. and then pure further by HPLC Change to obtain yellow solid 11 (0.8g, 36.2%) .HNMR (400MHz, DMSO-d6) 11.8(s,1H),8.7(m,1H),7.8-8.0(m,2H),7.6(m,1H),7.4(m,1H),4.0(s,3H).MS :m/z:321.9/323.9[M+H]+
Step C:
Compound 11 (0.8g, 2.5mmol) is dissolved in the sealing pipe containing NH4OH (10ml), after closing 130 DEG C of stirring 16h.Cooled and filtered, after solids washed with water, dry compound as white solid 12 (0.73g, 95.1%) .HNMR (400MHz, MeOD) 8.6(s,1H),7.8(m,1H),7.6(m,1H),7.5(m,1H),7.3(m,1H).MS(ESI)m/ z:306.9/308.9(M+H)+。
Step D:
Compound 12 (700mg, 2.3mmol), compound 7 (780mg, 3.0mmol), and Pd (dppf) 2 Cl2 (188mg, 0.23mmol) is dissolved in DMA (15ml), and stirring deaerates half an hour.The sodium acid carbonate of 2M (2.8ml) add, after the half an hour that again deaerates, under conditions of N2,120 DEG C of heating 2h.Then mix Thing is poured into water.With dichloromethane extraction, after organic phases washed with water, then wash with saturated brine, Na2SO4 It is dried, filter, be concentrated to give crude product.This dissolving crude product is cooled to-30 degrees Celsius at dichloromethane (40ml), Add acryloyl chloride (0.7g) at leisure, after dripping, 1h is stirred at room temperature.Reactant liquor is poured into water, uses Dichloromethane extracts, and after organic phases washed with water, then washs with saturated brine, and Na2SO4 is dried, and filters, dense Contract to obtain crude product.Silica gel column chromatography separating purification (EtOAc:PE=20% to 50%) obtains crude product, then by HPLC It is further purified to obtain C (200mg, 20%) .HNMR (400MHz, DMSO-d6) 11.5(s,1H),8.2(m,1H),8.0(m,1H),7.6-7.8(m,3H),7.1-7.4(m,4H),6.7-7.0( m,2H),6.2(m,1H),5.7(m,1H),4.4(m,2H),4.1(m,2H).MS(ESI):416.1。(M+ H)+。
Embodiment 4 biological activity test
The BA of compound
Mensuration to the external inhibitory activity (IC50 value) of BTK
In the present invention, compound is to the 503nhibiting concentration (IC50) of BTK in zymetology level and cytology level all It is determined: in enzymatic activity reaction, measure its rejection ability to BTK kinase activity, simultaneously at cytology Functional analysis determines the inhibitory action of the calcium current of BCR induction in compound on intracellular.
Use even phase time-resolved fluorescence (HTRF) method to establish the kinase activity detection platform of BTK, carry out The mensuration of compound activity.Compound is started to carry out with DMSO from 10uM the gradient dilution (totally 9 of 10 times Individual concentration), each concentration takes 4uL and joins (50mM HEPES, pH7 in the reaction buffer of 96uL.4, 10mM MgCl2,1mM EGTA, 0.01%Tween-20,0.005%BAS, 2mM DTT), take 2.5uL and add It to 384 orifice plates (potiPlate-384, PerkinElmer), is subsequently adding the BTK kinases of 5uL (Millipore), centrifuge mixing, add the ATP (final concentration of Km value) and TK peptide of 2.5uL (HTRF, Cisbio) mixture starts reaction (cumulative volume is 10uL).384 orifice plates are put in incubator In 23 DEG C react 120 minutes, be subsequently adding the Eu3+cryptate-labeled of 5uL Anti-phosphotyrosine antibody (Cisbio), 5uL's Streptavidin-XL-665 (HTRF, Cisbio) stops reaction.Hatch 1 hour in incubator after, (320nm excites Envision (PerkinElmer) upper reading fluorescent value, the transmitting of detection 665nm and 615nm Light, both ratios are enzymatic activity).Each compound measures the activity of enzyme respectively under 9 concentration, and data are used GraFit6.0 software (Erithacus Software) is calculated the IC50 of this compound.
Calcium current test uses Fluo-4DirectTM Calcium Assay Kits (Invitrogen) detection examination Agent box, the rejection ability of calcium storehouse release in mensuration compound on intracellular.Exist according to the explanation of detection kit Operate on FlexStation III (Molecular Device), comprise the following steps that.Ramos cell Add 10% hyclone (Hyclone) with RPMI-1640 (Invitrogen) to cultivate, after centrifugal elutriation, use low blood Clear culture medium is taped against (Corning) in 96 orifice plates (1X105 cell/45uL) again, is subsequently adding the glimmering of 45uL Photoinitiator dye (Invitrogen) 37C hatches 1 hour. and the gradient that compound DMSO to be detected carries out 3 times is dilute Release, then dilute 100 times with low blood serum medium, take 10uL and join 96 orifice plates completing cell (Corning), in (final concentration of the 0.1% of DMSO), 96 orifice plates are put in incubator (37 DEG C, 5%CO2) Hatch 30 minutes.The cell that compound treatment is crossed add goat-anti-human IgM antibody (10ug/ml, SouthernBiotech) (494nm excites, 516nm to read fluorescent value after stimulating on FlexStation III Detect 90 seconds).The data of each compound use GraphPad Prism5 (GraphPad Software) Process of fitting treatment, is calculated corresponding IC50.
It is analyzed according to the compound to above-mentioned preparation for the biological method as herein described.Its result is shown in Following table:
The all documents mentioned in the present invention are incorporated as reference all in this application, just as each document It is individually recited as with reference to like that.In addition, it is to be understood that after the above-mentioned instruction content having read the present invention, The present invention can be made various changes or modifications by those skilled in the art, and these equivalent form of values fall within this Shen equally Please appended claims limited range.

Claims (10)

1. there is compound or its pharmaceutically acceptable salt of structure shown in formula I, deuterated derivative, or front Medicine, it is characterised in that:
In formula,
R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R2Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R3Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
Or R2And R3Can be formed together and comprise 0-3 the heteroatomic 4-8 ring selected from N, O and S, Described 4-8 ring is saturated or unsaturated；
R4Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2、C(O)R5, R5Selected from C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, aryl, heteroaryl；
Described alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl are substituted or non-taking Generation.
2. compound as claimed in claim 1, it is characterised in that the structure of described compound such as Formulas I a Shown in:
In formula,
R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R2Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
R3Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, C3-10Cycloalkyl, heterocyclic radical, Aryl, heteroaryl, CN, NO2；
Or R2And R3Can be formed together and comprise 0-3 the heteroatomic 4-8 ring selected from N, O and S, Described 4-8 ring is saturated or unsaturated；
Described alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl are substituted or non-taking Generation.
3. compound as claimed in claim 1, it is characterised in that described R2And R3Bag can be formed together Containing 0-3 the heteroatomic 5-6 ring selected from N, O and S, described 5-6 ring is saturated or insatiable hunger Sum.
4. compound as claimed in claim 1, it is characterised in that described R1Selected from hydrogen, halogen, C1-4 Alkyl.
5. compound as claimed in claim 1, it is characterised in that described R2And R3Form 6 yuan together Ring, described 6 rings are saturated or unsaturated.
6. compound as claimed in claim 1, it is characterised in that described compound is selected from:
7. the preparation method of a compound as claimed in claim 1, it is characterised in that described method includes Step:
Formula II compound reacts production I with formula III compound and formula IV compound,
8. the purposes of compound as claimed in claim 1 or its pharmaceutically acceptable salt or solvate, It is characterized in that, (1) is used for preparing protein kinase inhibitors；And/or (2) are used for preparing treatment albumen and swash The medicine of enzyme relevant disease.
9. a pharmaceutical composition, it is characterised in that the change described in the claim 1 containing safe and effective amount Compound or its pharmaceutically acceptable salt or solvate；And, pharmaceutically acceptable carrier.
10. the method for the suppression protein kinase of an external non-therapeutic, it is characterised in that described method Including step: the compound described in claim 1 is contacted with described protein kinase, thus suppression is described The activity of protein kinase.
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