CN110283171A - Compound of the one kind containing Pyridopyrimidine -4- amine structure, pharmaceutical composition and its application - Google Patents

Abstract

Compound, pharmaceutical composition and its application the present invention relates to one kind containing Pyridopyrimidine -4- amine structure, with formula (I) structure.Structure of the invention such as formula (I) compound represented has good inhibiting effect to Bu Ludun kinase activity, and half-inhibitory concentration is generally 10^‑7mol.L^‑1Below.Meanwhile the compound with formula (I) structure prepared in the embodiment of the present invention shows specific anti-inflammatory activity on different animal models.

Description

Compound of the one kind containing Pyridopyrimidine -4- amine structure, pharmaceutical composition and It is applied

Technical field

Compound, pharmaceutical composition and its application the present invention relates to one kind containing Pyridopyrimidine -4- amine structure. The isoquinolinol class compound can be used for inhibiting Bu Ludun (Bruton ' s) kinases (Btk), and can be used for treat by Autoimmune disease caused by aberrant B cell activates and inflammatory disease.

Background technique

Protein kinase forms one of maximum family of mankind's enzyme and by adjusting on addition phosphate group to protein Save many different signal transduction processes (1987 50:823-829 of T.Hunter, Cell).Particularly, tyrosine kinase phosphoric acid Change protein in the phenol moieties of tyrosine residue.Family tyrosine kinase includes the member for controlling cell growth, migration and differentiation. Abnormal kinase activity oneself be related to many human diseases, including cancer, autoimmune disease and inflammatory disease.Due to protein Kinases belongs to the key regulator of cellular signal transduction, their offers adjust the mesh of cell function with small molecule kinase inhibitors Mark, and therefore, it has become good drug design targets.In addition to the treatment of kinase mediated lysis, the choosing of kinase activity Selecting property and effective inhibitor can also be used to study cell signaling processes and identify other cell targets with therapeutic potential.

About key effect of the B cell in the pathogenesis of autoimmunity and/or inflammatory disease, there are good evidences. Consume closing based on the therapeutic agent of protein such as Rituxan for such as rheumatoid of inflammatory disease caused by autoantibody for B cell Section inflammation is effective (2004 55:477 of Rastetter etc., Annu Rev Med).Therefore, it plays a role in B cell activation Protein kinase inhibitor should be for B cell mediate disease pathology such as autoantibody generate useful therapeutic agent.

A series of B cell responses are controlled by the signal transduction of B-cell receptor (BCR), including are proliferated and break up maturation Antibody-producting cell.BCR is the active crucial point of adjustment of B cell and abnormal signal transduction can cause the B of imbalance thin The formation of born of the same parents proliferation and pathogenic autoantibodies, leads to various autoimmune disease and/or inflammatory disease.Bu Ludun (Bruton ' s) tyrosine pka acid (Btk) is the film proximal end and the immediately relevant kinases of non-BCR in downstream in BCR.Btk Shortage oneself through display block BCR signal transduction, and therefore inhibitions of Btk can be block B cell mediation lysis Effective treatment method.

Btk is the member of tyrosine kinase Tec family, and shows it is that early stage B cell is formed and mature B cell activates With key regulator (1995 3:283 of Khan etc., Immuni ty of survival；Ellmeier etc., J.Exp.Med.2000 192: 1611).The Btk mutation of people causes the chain gamma-globulin of illness X to lack mass formed by blood stasis (XLA) (in New such as Rosen It is summarized in the Immunol.Rev.2005 203:200 such as Eng.J.Med.1995 333:431 and Li ndvall).These patients are Immunocompromised host, and show that impaired B cell is mature, reduced immunoglobulin and external application b cell level, reduction are disobeyed Rely the immune response of T cell and the calciokinesis of the decrease after BCR is irritated.

About effect of the Btk in autoimmune disease and inflammatory disease evidence oneself via Btk deficient mice model It provides.In the preclinical mouse model of systemic loupus erythematosus (SLE), Btk deficient mice shows significantly changing for progression of disease It is kind.In addition, Btk- deficient mice (Jansson and Holmdahl resistant to Collagen-Induced Arthritis Clin.Exp.Immunol.1993 94:459).Oneself dosage of the verified selectivity Btk inhibitor in arthritis mouse model Dependence effect (z.Pan etc., Chem.Med Chem.2007 2:58-61).

Btk is also expressed by the cell that may relate to lysis other than B cell.For example, Btk is by mast cell-expressed And the mast cell of Btk deficiency derived from bone marrow shows threshing (Iwaki etc. of impaired antigen induction J.Biol.Chem.2005 280:40261).This display Btk can be used for treating pathologic mast cells reaction such as allergy And asthma.In addition, the TNF α that the monocyte from XLA patient for wherein lacking Btk activity is shown in reduction after irritating generates (the J Exp Med such as Horwood 197:1603,2003).Therefore, the inflammation that TNF α mediates can be by small molecule Btk inhibitor tune Section.In addition, oneself is reported that Btk plays a role Oslam and Smith Immunol.Rev.2000178:49 in Apoptosis), And therefore Btk inhibitor B cells leaching the sixth of the twelve Earthly Branches tumors certain for treatment and leukaemia will be effective (Feldhahn etc. J.Exp.Med.2005 201:183 7).

Although a series of Bu Ludun kinase inhibitor has been disclosed at present, there is still a need for development structure type is richer, New possibility is active with high, the better compound of patent medicine property.By being continually striving to, present invention design has logical formula (I) Shown in structure compound, and the compound for being found to have this class formation shows excellent effect and effect.

Summary of the invention

The application provides structure Btk inhibitor compound as shown in formula (I), its application method, such as institute herein below It states:

Structure such as formula (I) compound represented or its pharmaceutically acceptable salt:

Wherein,

X, Y is independently selected from CH or N；

L is-O- ,-NHC (O)-,-C (O) NH-；

Ring A is substituted C₆-C₁₀Aryl, C₅-C₁₀Heteroaryl, the substituent group are selected from hydrogen, halogen, C₁-C₄Alkyl, C₃- C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl；

Ring B is substituted C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl, C₆-C₁₀Aryl, C₅-C₁₀Heteroaryl, the substitution Base is selected from hydrogen, halogen, C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl；

R₁Selected from H, halogen, cyano, C₁-C₄Alkyl, C₁-C₃Alkoxy, C₃-C₆Naphthenic base, C₃-C₆Heterocyclylalkyl, the alkane Base, alkoxy, naphthenic base, Heterocyclylalkyl are optionally by one or more halogens, C₁-C₆Alkyl, C_i-C₆Alkoxy, halogenated C₁-C₆Alkane Base, C₃-C₆Naphthenic base, C₃-C₆Heterocyclylalkyl replaces；

R2 is selected from

Further, X is selected from CH；Y is selected from N；R₁Selected from H, halogen, cyano, C₁-C₄Alkyl.

Further, ring A is substituted phenyl ring, pyridine ring, and the substituent group is selected from hydrogen, halogen, C₁-C₄Alkyl, C₃- C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl；L is-O- ,-C (O) NH-.

Further, ring B is to be substituted phenyl ring, piperidines, morpholine, pyrrolidines, azaspiro [3.4] octane, the substituent group Selected from hydrogen, halogen, C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl.

Further X is selected from CH；Y is selected from N；R₁Selected from H, halogen, cyano, C₁-C₄Alkyl.Ring A is substituted benzene Ring, pyridine ring, the substituent group are selected from hydrogen, halogen, C_i-C₄Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl；L is-O- ,-C (O)NH-；Ring B is to be substituted phenyl ring, piperidines, morpholine, pyrrolidines, azaspiro [3.4] octane, and the substituent group is selected from hydrogen, halogen Element, C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl.R₂It is selected from

The more specific compound is selected from:

Such BTK inhibitor can be used for treating the application in the drug of inflammatory and/or autoimmune disorder, especially class wind Wet arthritis.

In order to examine compound provided by the invention for the exposure level of protein kinase, surveyed using biochemistry level enzymatic activity Examination and the test of cellular level enzymatic activity are to determine various compounds of the invention to the activity and exposure level of one or more PK. Using method well known in technique, similar experiment can be designed in the same way for any kinases.

In the test of biochemistry level enzymatic activity, using the activity of HTRF technology detection tyrosine kinase, when HTRF is a kind of Between resolved fluorescent resonance ability transfer techniques, can be carried out according to known specification or literature method, referring to Kolb etc., “Tyrosine kinase assays adapted to homogenous time-resolved fluorescence” .Drug .3 volumes: PP 333-342 of Discovery Today magazine.HTRF (homogeneous phase time discrimination fluorescence) is homogeneous for detecting A kind of most common method of determinand, this technology combine fluorescence resonance energy transfer (FRET) and time resolution in system Technology (TR), has been widely used in the different phase of the medicament research and development based on cell experiment and biochemical test.According to HTRF Pure enzyme is incubated with biotinylated substrate and ATP after reacting by the measuring principle of method, and the XL- of Avidin label is added 665 and identification substrate phosphorylation Eu label antibody, after substrate is by Btk phosphorylation, Eu label antibody can identify The Phosphorylated products form time-resolved fluorescence resonance energy transfer (FRET) with the XL665 of Avidin label, and not by phosphorus The substrate of acidification due to cannot the identification of times antibody and FRET signal can not be formed, pass through the fluorescence signal of measurement 665nm and 620nm Difference measures determinand under various concentration to the inhibitory activity of Btk tyrosine kinase.Thus, the present invention can be measured using this method Compound utilizes method well known in the art to the active function of the biochemistry level of Btk tyrosine kinase, can be to other Protein kinase uses similar measuring method.

It in the measurement of cellular level enzyme activity is realized by measuring calcium current.The experiment uses Fluo-4 Direct^TM Calcium Assay Kits kit.Main dyestuff to be used is Fluo 4-AM in its kit.Fluo 4-AM is Fluo A kind of 4 acetoxymethyl ester derivative can be entered in cell easily by culture.AM can be by esterase institute intracellular after entering cell Hydrolysis, the Fluo 4 of generation then can with calcium binding and issue fluorescence, laser confocal microscope or streaming can be used The variation of the instruments such as cell instrument detection intracellular calcium concentration.

The test method for taking medicine generation experiment in general rat body, can also investigate compound in the intracorporal efficacy of rat Matter.

The Arthus Reaction model of general mouse or arthritis (rCIA) model of anti-rat collagen induction are taken, Internal drug effect of the compound on mouse or rat can be investigated.

Structure prepared by the present invention such as formula (I) compound represented, which has Bu Ludun kinase activity, to be inhibited to make well With half-inhibitory concentration (IC₅₀) generally 10^-7Mol/L or less.Meanwhile what is prepared in the embodiment of the present invention has Formulas I knot The compound of structure has good oral medicine for property, and in the joint that Arthus Reaction model or anti-rat collagen induce Specific internal drug effect is shown on scorching (rCIA) model.There is this to deduce, there is the present invention compound of formula (I) structure can apply The drug of the relevant disease inflammatory of Bu Ludun kinases and/or autoimmune disorder in preparation treatment organism.

Detailed description of the invention

Unless stated to the contrary, following that there are following meanings with term in the specification and in the claims.

" alkyl " refers to the aliphatic hydrocarbon group of saturation.Linear chain or branched chain group including 1 to 20 carbon atom.Preferably comprise 1 To the median size alkyl of 6 carbon atoms, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tert-butyl, amyl Deng.Low alkyl group more preferably containing 1 to 4 carbon atom, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl Base or tert-butyl etc..Alkyl can be substituted or unsubstituted, when substituted, preferred group are as follows: halogen, C₂-C₆Alkene Base, C₆-C₁₀Aryl, C₅-C₁₀Heteroaryl, halogenated C₁-C₆Alkyl, 4 to 8 yuan of heteroalicyclyls, hydroxyl, C₁-C₆Alkoxy, C₆-C₁₀Virtue Oxygroup.

" alkylidene " indicates that the divalent of 1 to 10 carbon atom is saturated direct-connected alkyl (such as (CH₂)_n) or 2 to 10 carbon atoms Branch saturated divalent hydrocarbon radical (such as-CHMe), unless otherwise.Other than in the case where methylene, the opening of alkylidene State is not connected on identical atom.The embodiment of alkylidene is including but not limited to methylene, ethylidene, propylidene, 2- first Base-propylidene, 1,1- dimethyl-ethylidene, butylidene, 2- ethylbutylene.

" naphthenic base " refers to that 3 to 8 yuan of full carbon monocycles, 5 yuan/6 yuan of full carbon or 6 yuan/6 yuan thick and rings or polycyclic thick and ring are (" thick With " ring means each ring in system and shared a pair of of the carbon atom adjoined of other rings in system) group, one of them or Multiple rings have the electronic system that is fully connected, the example (being not limited to) of naphthenic base be cyclopropane, cyclobutane, pentamethylene, Cyclopentene, hexamethylene, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene.Naphthenic base is substitutive and is to replace.When When being substituted, substituent group is preferably that one or more each is selected from group below, comprising: hydrogen, hydroxyl, sulfydryl, oxo, rudimentary Alkyl, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, lower halogenated alkane Base, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, Alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, Arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.

" aryl " indicates the full carbon monocycle or fused polycycle group of 6 to 14 carbon atoms, the pi-electron system with total conjugated System." aryl " includes:

Hexa-atomic carbon aromatic rings, e.g., benzene；

Bicyclic, wherein at least one ring is carbon aromatic rings, e.g., naphthalene, indenes and 1,2,3,4- tetrahydroquinolines；And

Tricyclic, wherein at least one ring are carbon aromatic rings, e.g., fluorenes.

For example, aryl includes containing hexa-atomic carbon aromatic rings and a hexa-member heterocycle, this heterocycle includes one or more choosings From the hetero atom of nitrogen, oxygen and sulphur, condition is tie point on carbon aromatic rings.But aryl does not include, not in any manner yet It is Chong Die with the heterocyclic aryl defined separately below.Therefore, it defines herein, if one or more carbon aromatic rings and a heteroaryl perfume (or spice) Ring and ring, resulting loop system is heteroaryl, rather than aryl.The non-limiting example of aryl has phenyl, naphthalene.Aryl It can be substituted or unsubstituted.When substituted, preferred group are as follows: hydrogen, hydroxyl, nitro, cyano, oxo, lower alkyl Base, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, lower halogenated alkane Base, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, Alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, Arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.

" heteroaryl " indicates the monocycle or fused ring group of 5 to 14 annular atoms, contains one, two, three or four Ring hetero atom selected from N, O or S, remaining annular atom are C, in addition with the pi-electron system of total conjugated.Heteroaryl refers to:

The mononuclear aromatics of 5-8 member, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, in some realities It applies in scheme, 1-3 hetero atom, other atoms are carbon atoms on ring；

The double ring arene of 8-12 member, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings；And

The thrcylic aromatic hydrocarbon of 11-14 member, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings.

For example, heteroaryl includes the miscellaneous aromatic rings of a 5-6 member and the naphthenic base of a 5-6 member.For such bicyclic And the heteroaryl to get up, only one of them ring contain one or more hetero atoms, connection site is on miscellaneous aromatic rings.

When on heteroaryl sulphur atom and oxygen atom sum be more than 1 when, these hetero atoms will not be adjacent one by one.In some realities It applies in scheme, the sum of sulphur atom and oxygen atom in heteroaryl is no more than 2.In some embodiments, sulphur atom and oxygen are former Sum of the son in heteroaryl is no more than 1.

The example of heteroaryl, including but not limited to, pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, triazole, Pyrimidine, pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzimidazole, benzotriazole, indoline, indoles Ketone, quinoline, isoquinolin, quinazoline, thienopyridine, Thienopyrimidine etc..The preferred embodiment of such group is pyrrole radicals, pyrrole Oxazolyl, imidazole radicals, triazol radical, furyl, oxazolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazole.Heteroaryl In one or all hydrogen atom can be replaced by following groups: hydrogen, hydroxyl, nitro, cyano, oxo, low alkyl group, rudimentary alcoxyl Base, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, low-grade halogenated alkyl, rudimentary hydroxyl alkane Base, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkyl amino, alkane Base sulfonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, aryl sulfonyl ammonia Base, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl." Heterocyclylalkyl " indicate by one or The monovalence saturated cyclic group of multiple rings, preferably 1 to 2 ring (including spiral ring system) composition, 3 to 8 atoms of each ring, knot Conjunction has one or more ring hetero atoms (selected from N, O or S (O)_0-2), and it can be optionally independently one or more, preferably 1 or 2 substituent groups replace, and the substituent group is selected from: hydrogen, hydroxyl, sulfydryl, oxo, low alkyl group, lower alkoxy, low It is grade naphthenic base, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, rudimentary Naphthenic base alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkyl amino, alkyl sulfonyl Base, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkane Base amino carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.Unless otherwise noted.The example of Heterocyclylalkyl Including but not limited to, morpholinyl, piperazinyl, piperidyl, azetidinyl, pyrrolidinyl, hexahydro azepineGrassBase, oxa- ring fourth Alkyl, tetrahydrofuran base, tetrahydro-thienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, THP trtrahydropyranyl, thio beautiful jade Base, quininuclidinyl and narrows imidazolinyl, preferably W is selected from O, S or NR¹², respectively Group is as previously mentioned, example can also be bicyclic, such as, for example, bicyclic [3.2.1] octane of 3,8- diazas-, 2,5- phenodiazine Miscellaneous bicyclic [2.2.2] octane or octahydro-pyrazine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines.Its Heterocyclylalkyl (and derivative) includes its ion Form.

" alkoxy " expression-O- (unsubstituted alkyl) and-O (unsubstituted naphthenic base).Representative example include but It is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..

" aryloxy group " expression-O- aryl and-O- heteroaryl.Representative example include but is not limited to phenoxy group, pyridine oxygroup, Furans oxygroup, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygroup etc. and its derivative.

" aryl alkylene " indicates alkyl, and low alkyl group preferably as defined above, it is substituted as described above for aryl groups, Such as-CH₂Phenyl ,-(CH₂)₂Phenyl ,-(CH₂)₃Phenyl, CH₃CH(CH₃)CH₂Phenyl and its derivative.

" heteroarylalkylenyl " indicates alkyl, and low alkyl group preferably as defined above, it is by heteroaryl as described above Replace, such as-CH₂Pyridyl group ,-(CH₂)₂Pyrimidine radicals ,-(CH₂)₃Imidazole radicals etc. and its derivative.

" hydroxyl " expression-OH group.

" sulfydryl " expression-SH group.

" halogen " indicates fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

" halogenated alkyl " indicates alkyl, and low alkyl group preferably as defined above, it is by one or more identical or different Halogen atom replace, such as-CH₂Cl、-CF₃、-CCl₃、-CH₂CF₃、-CH₂CCl₃Deng.

" cyano " expression-CN group.

" amino " expression-NH₂Group.

" nitro " expression-NO₂Group.So-called " optionally " is meant that the event of subsequent descriptions or situation may It may not occur, and the description includes that things or situation may may also will not occur, and the description includes things Or situation occurs and two kinds of situations does not occur.

In some embodiments, one referred in specified atom or group " is replaced " by one or more groups It is a, two, three or four hydrogen atoms be designated the identical or different group replacement selected in the group of range respectively.

Wave indicates connection site；

" pharmaceutically acceptable salt " indicates to retain those of biological effectiveness and the property of parent compound salt.This kind of salt Include:

(1) it is obtained by the free alkali of parent compound with inorganic acid or reacting for organic acid, inorganic acid packet with acid at salt Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc. are included, organic acid includes acetic acid, propionic acid, propylene Acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, adjacent benzene Dioctyl phthalate, methanesulfonic acid, ethanesulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, cream Acid, mandelic acid, succinic acid or malonic acid etc..

(2) acid proton being present in parent compound is replaced or given birth to organic base ligand compound by metal ion At salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example ethanol amine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..

" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten Agent compound, hydrate or prodrug and other chemical component, such as pharmaceutically acceptable carrier, mixing.The mesh of pharmaceutical composition Be promote administration to animal process.

" pharmaceutical carrier " refers to not causing apparent irritation to organism and does not interfere the biology of given compound Activity and property pharmaceutical composition in non-active ingredient, such as, but not limited to: calcium carbonate, calcium phosphate, it is various sugar (such as cream Sugar, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or methacrylic polymeric Object, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or rilanit special or more ethoxy aluminium castor oil, sesame Oil, corn oil, peanut oil etc..

In pharmaceutical composition above-mentioned, other than including pharmaceutically acceptable carrier, medicine (agent) can also be included in Upper common adjuvant, such as: antibacterial agent, antifungal agent, antimicrobial, preservative, toner, solubilizer, thickener, table Face activating agent, complexing agent, protein, amino acid, fat, carbohydrate, vitamin, minerals, microelement, sweetener, pigment, perfume (or spice) Essence or their combination etc..

Specific embodiment

With reference to embodiments for further describing the present invention, but these embodiments not limit model of the invention It encloses.

Embodiment 1:N- (3- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidin-7-yl) phenyl) propylene The preparation of amide (EXP 1)

1) preparation of the chloro- 7- of 5- (3- nitrobenzophenone) pyrido [2,3-d] pyrimidine -4- amine (compound B)

By the bromo- 5- chloropyridine of 7- simultaneously [2,3-d] pyrimidine -4- amine (2590mg, 10mmol), (3- nitrobenzophenone) boric acid (1730mg, 10mmol), Pd (dppf)₂Cl₂·CH₂Cl₂(2340mg, 2.3mmol) is placed in the three-neck flask of 100mL, uses argon Gas displacement is added Isosorbide-5-Nitrae-dioxane (50mL) afterwards three times and stirs 5 minutes afterwards, and cesium carbonate (19600mg, 60mmol) is added and uses afterwards Argon gas displacement is warming up to 100 DEG C afterwards three times and reacts 20 hours, stops reaction and is cooled at room temperature, pads suction filtered through kieselguhr, filtrate decompression Precipitation, residue obtain faint yellow solid B 1506mg through column chromatographic purifying, yield: 50%, MS m/z (ESI): 302 [M+1].

2) system of 7- (3- nitrobenzophenone) -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidine -4- amine (compound C) It is standby.

By the chloro- 7- of 5- (3- nitrobenzophenone) pyrido [2,3-d] pyrimidine -4- amine (compound B) (151mg, 0.5mmol), (4- Phenoxyphenyl) boric acid (107mg, 0.5mmol), tris(dibenzylideneacetone) dipalladium (160mg, 0.18mmol), cesium carbonate (325mg, 1mmol) is dissolved in the anhydrous Isosorbide-5-Nitrae-dioxane of 20mL, nitrogen protection, is warming up to reflux, is reacted 12 hours.Stop anti- Should be cooled at room temperature, pad suction filtered through kieselguhr, after filtrate decompression precipitation, column chromatography for separation compound C (119.7mg, yield: 55%), MS m/z (ESI): 436 [M+1].

3) system of 7- (3- aminophenyl) -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidine -4- amine (compound D) It is standby.

By 7- (3- nitrobenzophenone) -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidine -4- amine (compound C) (118mg, 0.27mmol), palladium charcoal (20mg), anhydrous methanol (10mL) are added in 50mL eggplant-shape bottle, and hydrogen replaces 3 times and in hydrogen It is stirred at room temperature under atmosphere 2 hours.Decompression precipitation rear pillar chromatographs to obtain off-white powder compound D (67mg, yield: 61%).

4) N- (3- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidin-7-yl) phenyl) acrylamide The preparation of (EXP 1)

By 7- (3- aminophenyl) -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidine -4- amine (compound D) (41mg, 0.1mmol), acryloyl chloride (91mg, 0.56mmol), the drop of triethylamine 5 and methylene chloride 10mL mixing, is stirred at 0 DEG C Reaction 1 hour.It is quenched after reaction with 10g ice water.It is extracted with 30mL ethyl acetate * 3, organic phase is dried over anhydrous sodium sulfate Rear pillar chromatographs to obtain off-white powder EXP1 19mg, yield: 41%.MS (ESI) m/z:[M+H]⁺=460.7.¹H-NMR(DMSO- D6,400MHz): δ 9.22 (s, 1H), 8.27 (s, 1H), 8.07-8.13 (m, 2H), 7.84 (m, 1H), 7.67-7.69 (m, 4H), 7.42 (m, 2H), 7.19-7.32 (m, 3H), 7.01-7.06 (m, 4H), 6.48 (m, 1H), 6.09 (dd, 1H), 5.74 (dd, 1H) ppm。

Embodiment 2:1- (3- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidin-7-yl) piperidines -1- Base) propyl- 2- alkene -1- ketone (EXP 2) preparation

Referring to the method for embodiment 1,1- (3- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidine -7- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone (EXP2) 25mg, yield: 35%.MS (ESI) m/z:[M+H]⁺=452.50.¹H-NMR (DMSO-d6,400MHz):¹H-NMR (DMSO-d6,400MHz): δ 8.29 (s, 1H), 7.87 (s, 1H), 7.67 (d, 2H), 7.44 (m, 2H), 7.18-7.27 (m, 3H), 7.00-7.08 (m, 4H), 6.61 (d, 1H), 6.03 (d, 1H), 5.61 (d, 1H), 3.50-3.80 (m, 4H), 2.89 (m, 1H), 1.56-1.97 (m, 4H) ppm.

Embodiment 3:4- (4- amino -7- (1- (butyl- 2- alkynes acyl group) pyrrolidin-2-yl) pyrido [2,3-d] pyrimidine -5- Base)-N- (pyridine -2- base) benzamide (EXP 3) preparation

Referring to the method for embodiment 1,4- (4- amino -7- (1- (butyl- 2- alkynes acyl group) pyrrolidin-2-yl) pyrrole is prepared Pyridine simultaneously [2,3-d] pyrimidine -5- base)-N- (pyridine -2- base) benzamide (EXP 3) 58mg, yield: 45%.MS (ESI) m/z: [M+H]⁺=478.2.¹H-NMR (DMSO-d6,400MHz): δ 11.26 (m, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 8.04- 8.06 (m, 3H), 7.83 (d, 2H), 7.61 (m, 1H), 7.39 (d, 1H), 7.17 (m, 1H), 7.01 (m, 2H), 4.75 (m, 1H), 3.45-3.50 (m, 2H), 1.96-2.17 (m, 2H), 1.76-1.82 (m, 5H) ppm.

Embodiment 4:(E) -4- (4- amino -7- (1- (4- (dimethylamino) but-2-ene acyl group) pyrrolidin-2-yl) pyrrole Pyridine simultaneously [2,3-d] pyrimidine -5- base)-N- (pyridine -2- base) benzamide (EXP 4) preparation

Referring to the method for embodiment 1, (E) -4- (4- amino -7- (1- (4- (dimethylamino) but-2-ene acyl is prepared Base) pyrrolidin-2-yl) pyrido [2,3-d] pyrimidine -5- base)-N- (pyridine -2- base) benzamide (EXP 4) 38mg, yield: 49%.MS (ESI) m/z:[M+H]⁺=523.5.¹H-NMR (DMSO-d6,400MHz): δ 11.18 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 8.04-8.06 (m, 3H), 7.82 (d, 2H), 7.39-7.56 (m, 2H), 7.08-7.15 (m, 3H), 6.55- 6.70 (m, 2H), 4.72 (m, 1H), 3.43-3.51 (m, 2H), 3.02 (d, 2H), 2.75 (s, 6H), 1.74-1.99 (m, 4H) ppm。

Embodiment 5:1- (2- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidin-7-yl) -6- azepine - Spiral shell [3.4] octyl- 6- yl) propyl- 2- alkene -1- ketone (EXP 5) preparation

Referring to the method for embodiment 1,1- (2- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] is prepared Pyrimidin-7-yl) -6- aza-spiro [3.4] octyl- 6- yl) propyl- 2- alkene -1- ketone (EXP 5) 45mg, yield: 32%.MS(ESI)m/ Z:[M+H]⁺=478.6.¹H-NMR (DMSO-d6,400MHz): δ 8.26 (s, 1H), 7.85 (s, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.22-7.28 (m, 3H), 7.03-7.08 (m, 4H), 6.07-6.15 (m, 2H), 5.65 (d, 1H), 3.22-3.28 (m, 3H), 1.88 (m, 2H), 1.74 (m, 2H) ppm.

Embodiment 6:1- (2- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] pyrimidin-7-yl) pyrrolidines -1- Base) butyl- 2- alkynes -1- ketone (EXP 6) preparation

Referring to the method for embodiment 1,1- (2- (4- amino -5- (4- Phenoxyphenyl) pyrido [2,3-d] is prepared Pyrimidin-7-yl) pyrrolidin-1-yl) butyl- 2- alkynes -1- ketone (EXP 6) 44mg, yield: 22%.MS (ESI) m/z:[M+H]⁺= 450.6。¹H-NMR (DMSO-d6,400MHz): δ 8.31 (s, 1H), 8.11 (s, 1H), 7.65 (d, 2H), 7.43 (d, 2H), 7.27 (d, 2H), 7.20 (m, 3H), 7.04-7.06 (m, 4H), 4.71 (m, 1H), 3.42-3.48 (m, 2H), 2.01-2.14 (m, 2H), 1.76-1.83 (m, 2H) ppm.

Embodiment 7: external biochemistry level inhibits protein kinase activity experiment

Materials and methods: BTK kinases derives from Invitrogen；HTRF KinEASE；TK kit (Cisbio company)； 384 orifice plates (Greiner company)；ATP (sigma company), MgCl₂(sigma) company；PHERAstar FS multi-function microplate reader (BMG company)；Low speed centrifuge (StaiteXiangyi company)；Insulating box (Binder company).The positive drug of selection is Ibrutinib, structure are as follows:

Test-compound: being configured to the mother liquor of 0.5-10mmol/L depending on dissolubility by compound dissolution and preservation with DMSO, - 20 DEG C of preservations after packing；

The preparation of compound working solutions: taking out the compound of packing from refrigerator before test, 50 are diluted to pure DMSO × Required concentration；Then with deionized water by diluted chemical compound to 4 × required concentration；

The preparation of 1.33 × Enzymatic buffer: 5 × Enzymatic buffer is derived from into HTRF kit) it spends Ionized water is diluted to 1.33 ×, and the corresponding ingredient of 1.33 × final concentration: 1.33mmol/L DTT and 1.33mmol/L is added MgCl2；

The preparation of kinases working solution: Btk is diluted to 2 with 1.33 × Enzymatic buffer × required final concentration 0.2ng/μL；

The preparation of substrate working solution: substrate-biotin (is derived from 1.33 × Enzymatic buffer HTRF kit) and ATP (10mM) be diluted to 4 × mixed liquor of required final concentration；

Detect the preparation of working solution: with HTRF detection buffer by the Streptavidin- of 16.67 μm of ol/L XL665 is diluted to 4 × required final concentration, it is then mixed with isometric Antibody-Cryptate and (derives from HTRF kit)。

Enzyme reaction step: the kinases working solution of 4 μ L μ l is added into each hole of 384 microwell plate of low volume, while being added 4 1.33 × Enzymatic buffer of μ L is as negative control (Negative)；The compound working solutions of 2 μ l are added to hole, together When the 8%DMSO aqueous solution of 2 μ L is added as zero compound concentrations control (i.e. positive control, Positive)；In 25 DEG C (or 30 DEG C) it is incubated for 5-10min；Xiang Kongzhong is added 2 μ L substrate working solutions and starts enzyme reaction, in 25 DEG C of (or 30 DEG C) oscillating reactions 15- 60min。

HTRF reagent detecting step: the detection working solution that 8 μ L are added to hole terminates reaction；25 DEG C of reaction 1h；

The reading of HTRF signal: using PHERAstar FS reading detection signal, instrument is accordingly provided that

Optic module

Integration delay(lag time)50μs

Integration time 400μs

Number of flashes 200

For the initial data that every hole is read, ratio=665nm/620nm；

The calculating of inhibiting rate:

IC₅₀The calculating of value: using the logarithm of compound concentration as abscissa, inhibiting rate is ordinate, in GraphPad In Prism 5, fit non-linear curve: log (inhibitor) vs.response--Variable slope finds out enzyme activity suppression Untested compound concentration, that is, IC when rate processed is 50%₅₀。

Experimental result: BTK kinase activity half-inhibitory concentration (IC₅₀.nM)

The present invention provides structure compound shown in formula I to the half-inhibitory concentration (IC of BTK kinase activity₅₀)

Ibrutinib

EXP 1

EXP 2

EXP 3

EXP 4

EXP 5

EXP 6

2.6nM

3.4nM

1.8nM

4.3nM

5.4nM

0.6nM

0.1nM

Embodiment: 8: cell in vitro level inhibits protein kinase activity experiment

Materials and methods: Fluo-4 Direct^TMCalcium Assay Kits kit, Invitrogen company； RPMl1640 culture medium: GIBCO company；96 hole blackboards: CORNING company；PHERAstar FS multi-function microplate reader (BMG)； Low speed centrifuge (StaiteXiangyi).The positive drug of selection is RN486.

Cell processing: cell is cleaned with serum free medium, removes serum.

Dyestuff is prepared: then with the culture medium of serum-free by the dye-dilution of 2 χ at 1 ×.

Cell is resuspended: with 1 × dyestuff of above-mentioned preparation, the cell cleaned is resuspended.

Cell inoculation: 200,000/hole, 40 holes μ l/, 96 orifice plates need black siding.

Dyestuff is incubated for: being put into incubator, is incubated for 40min.

Dosing: and then a series of prepared compounds are added, 10 holes μ l/ continue to act on 20min.

Equilibrium at room temperature: test board is taken out, equilibrium at room temperature 5min.

Establishment of base line: before no addition agonist, baseline first is detected with PHERStar microplate reader.

Agonist is added: the IgM of final concentration of 10 μ g/ml, 10 holes μ l/ are added.

Measurement: it after agonist is added, is detected immediately with PHERStar microplate reader, every 10s, detects 8min altogether.

Data processing: OD (peak) OD (baseline) then calculates IC50 value with 5 software of GraphPad Prism.

Experimental result: BTK cell calcium current half-inhibitory concentration (IC₅₀, nM)

The present invention provides structure compound shown in formula I to the half-inhibitory concentration (IC of BTK cell calcium current₅₀)

Ibrutinib

EXP 1

EXP 2

EXP 3

EXP 4

EXP 5

EXP 6

98nM

32nM

61nM

20nM

8.9nM

12nM

6.5nM

Embodiment 9: the drug efficacy study on arthritis (rCIA) model of anti-rat collagen induction

The compounds of this invention inhibits the effect of rheumatoid arthritis, DBA/1J mouse is selected, by 50ug ox II Collagen Type VI It is subcutaneously injected with after isometric complete Freund's adjuvant (CFA) completely emulsification.With 50ug same antigen and incomplete Freund after 21 days Adjuvant (after IFA is fully emulsified, booster immunization 1 time.It is observed and recorded since the 45th day.Using 1-4 point-score: 1 point, normally；2 Point, 1 arthroncus；3 points, the arthroncus more than 1, but do not accumulate whole joints；4 points, the serious swelling of entire pawl or It is tetanic.The scoring of every pawl, which is added, obtains the overall score of mouse arthritis disease.Mouse of the joint overall score greater than 1 is built for model It stands successfully.It is successfully established after mouse rheumatoid arthritis model and is administered using the compounds of this invention to intragastric administration on mice, after administration 2 weeks It scores the arthritis of mouse, this product has apparent therapeutic effect to mouse rheumatoid arthritis as the result is shown.

Compound group	Arthritis score
		Control	1
Saline control group	4
		Cyclosporin control group	2.5
EXP2	1.1

Embodiment 10: the research that compound EXP2, Ibrutinib act on hERG potassium-channel

Pilot system

1) cell culture: hERG cell line routine culture is passed on containing 10% fetal calf serum and 250 μ g/ml G418 In DMEM.

2) liquid configures: the ingredient that whole-cell patch-clamp tests extracellular fluid used is (mM): NaCl 145；MgCl21； KCl 4；Glucose10；HEPES 10；PH value is adjusted to 7.4 with NaOH by and CaCl22, with sucrose by osmotic pressure value tune To 300mOsm.Intracellular fluid ingredient is (mM): KCl 140；MgCl21；EGTA 5；HEPES 10and Na2ATP 4, uses KOH PH value is withered to 7.2, osmotic pressure value is adjusted to 290mOsm with sucrose.

Fluid of inside and outside cell main component

Test method

1) electrophysiological recording: a culture dish is taken out in experiment every time, is cleaned twice with extracellular fluid, and it is micro- to be placed in inversion On mirror objective table.Whole-cell patch-clamp experiment carries out at room temperature, and Pyrex microelectrode tip resistance used is 3~5M Ω.

2) voltage stimulation protocol and electric current record: after whole-cell recording technique pattern, film potential is clamped down in -80mV, every 30s The stimulation of cell+50mV depolarizing voltage is given, repolarization continues 3s, can draw hERG tail current to -50mV after continuing 2s. Before depolarizing voltage stimulation, cell 50ms is first given, -50mV repolarization voltage, the electric current recorded under the voltage is as calculating The baseline of hERG tail current.The cell for only reaching record standard can just be applied to the detection of untested compound.Chemical combination is added Before object, hERG tail current is at least stable recording 3 minutes in extracellular fluid.When the variation of hERG tail current amplitude is small after perfusion administration When < 5%, it is considered drug effect and reaches stable state.If electric current is not up to stable state in 6 minutes, also terminate the concentration Close analyte detection.

3) examination criteria: film resistance is greater than 1,000M Ω in experiment.Initial current is greater than 300pA.Whole-cell recording technique pattern Series resistance is less than 12M Ω after foundation.10% (- 80pA be maximum value) of the leakage current less than ion channel current.

Data analysis

Initial data is recorded using Clampex 10.2, with the preservation of * abf file.Data collection and analysis uses pCLAMP 10.1 software programs.4~5 sweep that electric current before compound is added is in stable state are chosen, peak average value are calculated, as right According to current amplitude.4~5 sweep that electric current after compound is added is in stable state are chosen, peak average value are calculated, as electric current Remaining amplitude after being suppressed.Untested compound calculates the inhibiting rate of hERG electric current according to following equation:

% inhibiting rate={ 1- (electric current residue amplitude)/(control current amplitude) } * 100

The multiple concentration of untested compound are obtained to the inhibiting rate (average value ± standard of hERG electric current according to above-mentioned calculation method Difference) after, data are fitted using logistic equation, obtain IC₅₀Value.

Test result

The suppression result of EXP 2, Ibrutinib to hERG electric current

Compound name	IC50Value
		EXP 2	40 μM of >
Ibrutinib	3.4μM

11 pharmacokinetic of embodiment

Compound configuration: EXP2 is configured to concentration with 0.5% methylated cellulose aqueous solution as the suspension of 0.5mg/mL Gastric infusion is carried out, concentration is configured to 400/60% water of 10%DMSO/30%PEG and carries out vein for the solution of 0.5mg/mL Administration.

Experimental design: healthy SD rat 6, male carries out jugular vein intubation, 200~250 grams of weight when experiment.Vein The free diet drinking-water of administration group；Fasting 12 hours before gastric infusion group is administered, free water, unified feed in 4 hours after administration.Tool Body arrangement see the table below:

Sample acquisition: each time point 3 big at the time point set above through jugular vein blood collection after the administration of SD rat Mouse, every animal collect about 0.25mL whole blood, and EDTA-K2 is anticoagulant, and 8000rpm is centrifuged 6min, separated plasma, in -80 DEG C of refrigerators Middle freezing.Using the concentration of compound in liquid chromatography tandem mass spectrometry measurement blood plasma.

Experimental result: according to gained plasma drug concentration data, using Phoenix1.3 software (Pharsight company, the U.S.) Non- compartment model calculates the pharmacokinetic parameter after administration.

Pharmacokinetic parameter after SD rat intravenous injection 1mg/kg and stomach-filling 5mg/kg compound EXP 2:

Experiment conclusion: compound EXP1 has good pharmacokinetic property, and bioavilability is on rat 46.5%, the 18-23% better than Ibrutinib.

(https: //www.accessdata.fda.gov/drugsatfda_docs/nda/2014/ 205552Orig2s000PharmR.pdf)。

Oneself has been described in detail foregoing invention through mode by way of illustration and example, for illustrating and managing The purpose of solution.It will be apparent to one skilled in the art that can be changed in the range of appended claim and It improves.It will therefore be appreciated that above description be intended to it is illustrative rather than restrictive.Therefore, the scope of the present invention Should not with reference to description above and determine, and should with reference to following appended claims and by claims issue etc. The full scope of valence object and determine.

Claims (9)

1. structure such as formula (I) compound represented or its pharmaceutically acceptable salt:

Wherein,

X, Y is independently selected from CH or N；

L is-O- ,-NHC (O)-,-C (O) NH-；

Ring A is substituted C₆-C₁₀Aryl, C₅-C₁₀Heteroaryl, the substituent group are selected from hydrogen, halogen, C₁-C₄Alkyl, C₃-C₆Ring Alkyl, C₃-C₁₀Heterocyclylalkyl；

Ring B is substituted C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl, C₆-C₁₀Aryl, C₅-C₁₀Heteroaryl, the substituent group choosing From hydrogen, halogen, C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl；

R₁Selected from H, halogen, cyano, C₁-C₄Alkyl, C₁-C₃Alkoxy, C₃-C₆Naphthenic base, C₃-C₆Heterocyclylalkyl, the alkyl, Alkoxy, naphthenic base, Heterocyclylalkyl are optionally by one or more halogens, C₁-C₆Alkyl, C₁-C₆Alkoxy, halogenated C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₆Heterocyclylalkyl replaces；

R₂It is selected from

2. structure according to claim 1 such as formula (I) compound represented or its pharmaceutically acceptable salt, feature exist In,

X is selected from CH；Y is selected from N；

R₁Selected from H, halogen, cyano, C₁-C₄Alkyl.

3. structure according to claim 1 such as formula (I) compound represented or its pharmaceutically acceptable salt, feature exist In ring A is substituted phenyl ring, pyridine ring, and the substituent group is selected from hydrogen, halogen, C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀ Heterocyclylalkyl；L is-O- ,-C (O) NH-.

4. structure according to claim 1 such as formula (I) compound represented or its pharmaceutically acceptable salt, feature exist In ring B is to be substituted phenyl ring, piperidines, morpholine, pyrrolidines, azaspiro [3.4] octane, and the substituent group is selected from hydrogen, halogen, C₁- C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl.

5. such as formula of structure described in -4 (I) compound represented or its pharmaceutically acceptable salt according to claim 1, feature It is,

X is selected from CH；Y is selected from N；

R₁Selected from H, halogen, cyano, C₁-C₄Alkyl.

Ring A is substituted phenyl ring, pyridine ring, and the substituent group is selected from hydrogen, halogen, C₁-C₄Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀ Heterocyclylalkyl；L is-O- ,-C (O) NH-；

Ring B is to be substituted phenyl ring, piperidines, morpholine, pyrrolidines, azaspiro [3.4] octane, and the substituent group is selected from hydrogen, halogen, C₁- C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₁₀Heterocyclylalkyl.

R₂It is selected from

6. compound or its pharmaceutically acceptable salt, the compound are selected from according to claim 5:

7. a kind of Pharmaceutical composition, it includes the compound of any one of the claim 1-6 of therapeutically effective amount or its pharmaceutically Acceptable salt and drug or acceptable excipient or diluent.

8. the compound of any one of claim 1-8 or its pharmaceutically acceptable salt are in preparation in BTK inhibitor Using.

9. according to claim 1 compound described in -8 or its pharmaceutically acceptable salt preparation for treat inflammatory and/or Application in the drug of autoimmune disorder, which is characterized in that the inflammatory conditions are rheumatoid arthritis.