CN105399756B - BTK inhibitor and application thereof - Google Patents

Abstract

The present invention provides a kind of BTK inhibitor compound (structure as shown in formula (I)) and its purposes in drug.Compound provided by the invention and its pharmaceutical composition can be used for treating diffusivity large B cell lymphoid tumor, follicular lymphoma or chronic lymphocytic leukemia.

Description

BTK inhibitor and application thereof

Technical field

The present invention provides a kind of BTK inhibitor, discloses a series of compound and its pharmaceutical composition, also discloses this Class compound and its pharmaceutical composition are for treating autoimmune disease or illness, heteroimmunity disease or illness, cancer Purposes or illness including lymthoma and inflammatory disease.

Background technique

BTK kinases, a kind of member of nonreceptor tyrosine kinase Tec family, is in addition to T lymphocyte and natural kill The key signal enzyme expressed in all hematopoetic cell types except cell.BTK is in connection cell surface B-cell receptor (B- Cell receptor, BCR) it stimulates and plays the part of vital angle into the B cell signal transduction path of response in downstream cellular Color.

The Dasatinib of listing in 2006 is multiple target point inhibitor, has BTK compared with high inhibition effect, slow for treating Property myelomatosis；Furthermore in November, 2013 is also multiple target point inhibitor by the PCI-32765 of FDA approval listing, is pressed down to BTK Production is with for irreversibility, for treating lymthoma, leukaemia and autoimmune disease.Not yet selective BTK inhibits at present Agent listing, studying most fast drug is CC-292, is studied in by the end of October, 2013 into the clinic II phase, as irreversible selection Property inhibit BTK, for treating rheumatoid arthritis.

It is thin it can be used to prevent and/or treat B the object of the present invention is to provide excellent highly selective BTK inhibitor The relevant leukemia of born of the same parents, inflammatory and/or autoimmune disease.

Summary of the invention

The present invention is to develop while have the drug of excellent antitumor action and treating autoimmune diseases effect Target, it was found that the highly selective compound as tyrosine kinase inhibitor, and activity and existing marketed drug Ibrutinib is suitable.

On the one hand, the present invention provides a kind of compound, is the structure as shown in formula (I), or the structure as shown in formula (I) Stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmacy Upper acceptable salt or its prodrug,

Wherein, R C_5-12Condense miscellaneous bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_5-12The miscellaneous bicyclic group of bridge or-L-R¹；

R¹For C_5-12Condense miscellaneous bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_5-12The miscellaneous bicyclic group of bridge or C_2-9Heterocycle；

L is-(CH₂)_n-；

N is 1,2,3 or 4；

The C_5-12Condense miscellaneous bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_5-12The miscellaneous bicyclic group of bridge and C_2-9Heterocycle can be only On the spot by hydrogen, oxo (=O), hydroxyl, cyano, nitro, halogen, amino, carboxyl, alkyl, alkoxy, alkylamino, alkylthio group, hydroxyl Base alkyl, aminoalkyl, halogenated alkyl, naphthenic base, heterocycle, aryl, heteroaryl or aminoacyl are monosubstituted or identical or not Same is polysubstituted.

In some embodiments,

R is Or-L-R¹；

R¹For

Each X¹, X²And X³It independently is-(CH₂)_b,-O- ,-NH- or-S (=O)_t-；

Each X⁴, X⁵And X⁶It independently is-CH-, or-N-；

Each b independently is 0,1,2,3 or 4；

Each q, m and p independently are 0,1,2,3 or 4；

Each t independently is 0,1 or 2；

The R¹, can be independently by hydrogen with subformula representated by R, oxo (=O), hydroxyl, cyano, nitro, Halogen, amino, carboxyl, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkylamino, C_1-4Alkylthio group, hydroxyl C_1-4Alkyl, amino C_1-4Alkyl, Halogenated C_1-4Alkyl, C_3-9Naphthenic base, C_2-9Heterocycle, C_6-12Aryl, C_1-9Heteroaryl or aminoacyl are monosubstituted or identical or not Same is polysubstituted.

In some embodiments,

R is following subformula:

In some embodiments, the compounds of this invention is such as one of flowering structure:

Or the stereoisomer of the compound, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug.

On the one hand, the present invention provides a kind of pharmaceutical composition, includes compound of the present invention.

In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, figuration At least one of agent, diluent, adjuvant and medium.

On the one hand, the present invention provides a kind of use compound of the present invention or pharmaceutical composition of the present invention is used In the purposes of the drug of preparation, prevention, processing or protection B cell proliferation disease.

In some embodiments, of the present invention on the way, the B cell proliferation disease is Diffuse large B cell Lymthoma, follicular lymphoma or chronic lymphocytic leukemia.

On the one hand, the present invention provides a kind of use compound of the present invention or pharmaceutical composition of the present invention is used Inhibit the purposes of the inhibitor of BTK kinases in preparation.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This hair Bright intention covers all replacement, modification and equivalent technical solutions, they are included in the model of the present invention defined such as claim In enclosing.Those skilled in the art will appreciate that many can be used in practicing with similar or equivalent method and material described herein The present invention.The present invention is not limited to method described herein and material.At one of the document, patent and the similar material that are combined More it is different from the application or in the case where contradicting it is (term defined in including but not limited to, term application, described Technology, etc.), it is subject to the application.

It will further be appreciated that certain features of the invention, are clearly visible, the progress in multiple independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise stated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.

There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.

Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or non-substituted ".In general, art " substituted " the one or more hydrogen atoms indicated in given structure of language are replaced specific substituent group.Unless other aspect tables Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not Only a position can be replaced one or more substituent groups selected from specific group, then substituent group can identical or differently Replace at various locations.It only includes the substitution for forming stable compound that the present invention considered, which replaces,.In some embodiments, certain Suitable optionally substituent group 1 can further be replaced by corresponding suitable optional substituent group 2.In other embodiments, accordingly Suitable optional substituent group 2 be not further substituted.Wherein the substituent group can be, but be not limited to: hydrogen, oxo (=O), hydroxyl, cyano, nitro, halogen, amino, carboxyl, alkyl, alkoxy, alkylamino, alkylthio group, hydroxy alkyl, amino alkane Base, halogenated alkyl, naphthenic base, heterocycle, aryl, heteroaryl or aminoacyl.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C₁-₆Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 A carbon atom；In another embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1- 4 carbon atoms；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- amyl, 3- amyl, 2- methyl-2- butyl, 3- methyl-2- butyl, 3- methyl-1-butyl, 2-methyl-1-butene base, n-hexyl, 2- hexyl, 3- hexyl, 2- methyl -2- amyl, 3- methyl -2- amyl, 4- methyl -2- amyl, 3- methyl -3- amyl, 2- methyl -3- amyl, 2,3- bis- Methyl -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, n-octyl, etc..

Terminology used in the present invention " halogen ", " halogen atom " or " halogen atom " include fluorine, chlorine, bromine, iodine.

Term used in the present invention " alkoxy ", is related to alkyl, as defined in the present invention, is connected by oxygen atom It is connected in main carbochain.Some of embodiments are that alkoxy is the C of lower level_1-3Alkoxy, some embodiments include, but It is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..

Term " halogenated alkyl " or " halogenated alkoxy " indicate that alkyl or alkoxy can be by one or more identical or not With situation replaced halogen atom.Wherein alkyl and alkoxy base have meaning as described in the present invention, such example Include, but is not limited to trifluoromethyl, trifluoromethoxy etc..

Term " alkylthio group " includes C_1-10The alkyl of linear chain or branched chain is connected on the sulphur atom of divalent, wherein alkyl group With meaning as described in the present invention.Some of embodiments are that alkylthio group is the C of lower level_1-3Alkylthio group, such example It includes, but is not limited to, methyl mercapto (CH₃S-), ethylmercapto group etc..

Term " alkyl acyl " includes C_1-10The alkyl of linear chain or branched chain is connected on-C (=O)-, and wherein alkyl group has There is meaning as described in the present invention.Some of embodiments are that alkyl acyl is the C of lower level_1-3Alkyl acyl, such reality Example includes, but is not limited to, acetyl group, propiono etc..

Term " aminoacyl " refers to-C (=O) NH₂。

Term " amino-sulfonyl " refers to-S (=O)₂NH₂。

Term " amino " refers to formula-NH₂。

Term " aminoalkyl " refers to formula R ' R " group of N- alkyl, wherein R ' and R " be separately alkyl or Halogenated alkyl.Alkyl has meaning as described in the present invention.Some of embodiments are that aminoalkyl is the amino of lower level C_1-4Alkyl, some of embodiments are, but are not limited to, amino-ethyl, amino methyl, aminopropyl etc..

Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.

Term " hydroxy alkyl " or " hydroxy alkoxy base " indicate that alkyl or alkoxy can be taken by one or more hydroxyls For the case where.Wherein alkyl and alkoxy base have meaning as described in the present invention, and such example includes, but is not limited to Methylol, 1- ethoxy, hydroxypropyl, 1,2- dihydroxypropyl, hydroxyl methoxyl group, 1- hydroxy ethoxy etc..

Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, it can be monocycle, bicyclic and tricyclic carbocyclic ring system, in certain embodiments of the present invention, can substitute arlydene makes With.Wherein, at least one ring system of aryl is aromatic, and wherein each ring system includes 3-7 atom.Term " aryl " It can be used interchangeably with term " aromatic rings ", if aromatic rings may include phenyl, naphthalene and anthryl.Depending on structure, aryl can For monoradical or bivalent group (that is, arlydene)." arlydene " is that at least one ring system of divalent is the carbocyclic ring of armaticity System, and each ring system includes 3-7 atom, some embodiments are phenylene, naphthylene etc..Hydrogen on one or more rings Atom is individually optionally replaced one or more substituent groups described in the invention.

Term " heteroaryl ", " hetero-aromatic ring " are used interchangeably here, can be used alone or as " heteroaryl alkyl " Or a part of " heteroarylalkoxy " can substitute inferior heteroaryl use in certain embodiments of the present invention.All refer to list Ring, bicyclic, tricyclic or tetracyclic ring system, wherein Bicyclic heteroaromatic rings, tricyclic hetero-aromatic ring or Fourth Ring heteroaromatic ring systems are with condensed Form cyclization.Wherein, heteroaromatic ring systems are armaticity, and one or more atoms are individually optionally replaced hetero atom on ring (hetero atom is selected from N, O, P, S, optionally obtains replaced one or more oxygen atoms in this S or P as SO, SO₂, PO, PO₂'s Group).Heteroaryl system can be connected in main structure to form stable compound on any hetero atom or carbon atom. Heteroaryl system group can be 3-7 former molecular monocycle or 7-10 former molecular bicyclic or 10-15 atom group At tricyclic.It can be two rings [4,5] with 7-10 the bicyclic of atom, [5,5], [5,6] or [6,6] system, there is 10-15 The tricyclic of a atom can be tricyclic [5,5,6], [5,6,6] or [6,5,6] system.Depending on structure, heteroaryl can be unit price Group or bivalent group (that is, inferior heteroaryl)." inferior heteroaryl " is the heteroaryl of divalent.Hydrogen atom on one or more rings is only It stands optionally replaced one or more substituent groups described in the invention.

Other embodiment is that heteroaryl system (including heteroaryl, hetero-aromatic ring) includes following example, but is not limited to this A little examples: 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- are different Oxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methylisoxazole -5- base, N- pyrrole radicals, 2- pyrrole Cough up base, 3- pyrrole radicals, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, etc..

Term " naphthenic base " refers to monovalence or multivalence, non-aromatic, saturation or part unsaturated ring, and does not include miscellaneous original Son, two rings or tricyclic of monocycle or 7-12 carbon atom including 3-12 carbon atom.Double carbon with 7-12 atom Ring can be two rings [4,5], [5,5], [5,6] or [6,6] system, while there is the bicyclic carbocyclic ring of 9 or 10 atoms can be two Ring [5,6] or [6,6] system.Depending on structure, " naphthenic base " can be monoradical or bivalent group, i.e., of the invention certain In embodiment, it can substitute or be used as cycloalkylidene.Example includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc..One or Hydrogen atom on multiple rings is individually optionally replaced one or more substituent groups described in the invention.

Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to monocycle, Bicyclic, tricyclic or tetracyclic ring system, individually optionally replaced hetero atom, ring can be one or more atoms in middle ring It is fully saturated or comprising one or more degrees of unsaturation, but definitely not aromatic.Depending on structure, " heterocycle " is " miscellaneous Ring ", " heteroalicyclic " can be monoradical or bivalent group, i.e., in certain embodiments of the present invention, can substitute or as Sub- heterocycle uses.Heterocyclic system can be connected in main structure to be formed on any hetero atom or carbon atom stable Compound.Hydrogen atom on one or more rings is taken by one or more substituent groups described in the invention individually optionally Generation.Some of embodiments are " heterocycles ", " heterocycle ", " sub- heterocycle " " heteroalicyclic " or " heterocycle " group is 3-7 member The monocycle of ring (1-6 carbon atom and is selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more oxygen originals It is obtained replaced son as SO, SO₂, PO, PO₂Group；When the ring is a three-membered ring, only one of them hetero atom), or 7-10 former molecular bicyclic (4-9 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one It is obtained replaced a or multiple oxygen atoms as SO, SO₂, PO, PO₂Group).

" heterocycle " can be carbon-based or heteroatom group." heterocycle " equally also include heterocyclic group and saturation or part not Saturated rings or heterocycle and close be formed by group.The example of heterocycle includes, but is not limited to, 1,2,3,6- tetrahydro pyridyl, piperazine Piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, Tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- Suberyl, thiocycloheptyl, N- morpholinyl, 2- morpholinyl, morpholinyl, thio-morpholinyl, high piperazine base, 4- methoxyl group-piperazine Pyridine -1- base, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrolinyl, two Hydrogen indoles base, 2- indoline base.

Term " condensing miscellaneous bicyclic group " indicates saturated or unsaturated fused ring system, is related to the bicyclic body of non-aromatic A degree of unsaturation is at most contained in system, and at least one ring system includes one or more hetero atoms, wherein each ring system Comprising 3-7 former molecular ring, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S is appointed in this S or P Selection of land is obtained replaced one or more oxygen atoms as SO, SO₂, PO, PO₂Group, in addition, carbon atom can also be by oxo Formation-C (=O)-；Such example includes, but is not limited to, hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrrole radicals, 3- nitrogen Miscellaneous bicyclic [3.3.0] octyl, 8- azabicyclo [4.3.0] nonyl, 8- azabicyclo [4.3.0] nonane 3- base, 3- azepine Bicyclic [4.3.0] nonane -3- base, isoindoline base, 1,2,3,4- tetrahydric quinoline group, 3- nitrogen -7- oxabicyclo [3.3.0] octane Base, 3,7- diazabicyclos [3.3.0] octyl, 2,6- diazabicyclos [3.3.0] octyl, 2,7- diazabicyclos [3.3.0] octyl, 2,8- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclo [4.3.0] nonyl, 2- oxygen - 8- azabicyclo [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclo [4.3.0] nonyls, 4,9- diazabicyclos [4.3.0] nonyl, 2,9- diazabicyclos [4.3.0] nonyl, 3- oxo -2,4, tri- azabicyclo of 8- [4.3.0] nonane Base, 3- oxo -4- oxygen -2,8- diazabicyclo [4.3.0] nonyl, 3- oxo -2,8- diazabicyclo [4.3.0] nonane Base, 3,8- diazabicyclos [4.3.0] nonyl, 3,7- diazabicyclos [4.3.0] nonyl, 3,9- diazabicyclos [4.3.0] nonyl, 3- oxygen -8- azabicyclo [4.3.0] nonyl, 3- sulphur -8- azabicyclo [4.3.0] nonyl, 5,6- Dihydro -4H- pyrrolo- [3,4-c] isoxazolyl, [1,2,4] triazole [4,3-a] and piperidyl, isoxazole simultaneously [4,3-c] piperazine Piperidinyl, 4,5,6,7- tetrahydro isoxazoles simultaneously [3,4-c] pyridyl group, [1,2,4] triazole simultaneously [4,3-a] piperazinyl, 2- oxo -3- Oxygen -8- azabicyclo [4.3.0] nonyl, 2- oxygen -7- azabicyclo [4.4.0] decyl, 1,5- dioxy -9- azabicyclo [4.4.0] decyl, 3- azabicyclo [4.4.0] decyl, 2,7- diaza decahydro naphthalenes or 2- oxygen -8- azabicyclo [4.4.0] decyl etc..

Term " the miscellaneous bicyclic group of bridge " indicates saturated or unsaturated bridged-ring system, is related to the bicyclic system of non-aromatic, At most contain a degree of unsaturation, and at least one ring system includes one or more hetero atoms, wherein each ring system packet Containing 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one Or it is obtained replaced multiple oxygen atoms as SO, SO₂, PO, PO₂Group, in addition, carbon atom can also by oxo formation-C (= O)-；Such example includes, but is not limited to 2- oxygen -5- azabicyclo [2.2.1] heptane base, the thio -5- azabicyclo of 2- [2.2.1] heptane base, 2- oxo -5- azabicyclo [2.2.1] heptane base, 2,5- diazabicylos [2.2.1] heptane base, 2- first Base -2,5- diazabicylo [2.2.1] heptane base etc..

Term " the miscellaneous bicyclic group of spiral shell " indicates a ring originating from particularly ring-shaped carbon on another ring.For example, as institute above Description, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", otherwise the ring that ring A and ring B is saturated at two A carbon atom is shared in system, then is referred to as " loop coil ".And at least one ring system includes one or more hetero atoms, wherein Each ring system includes 3-7 atom, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P is optionally obtained replaced one or more oxygen atoms as SO, SO₂, PO, PO₂Group, such example includes, but not It is limited to 4- azaspiro [2.4] heptane base, 4- oxaspiro [2.4] heptane base, 5- azaspiro [2.4] heptane base, 7- hydroxyl -5- azepine Spiral shell [2.4] heptane base, 2- azaspiro [4.5] decyl, 2- azepine spiroheptane base, 2- azaspiro [4.4] nonyl, 2- Methyl -2,6- diaza spiro [4.5] decyl, 3- azaspiro [5.4] decyl, 2- methyl -2- azepine spiroheptane base, 2- oxygen -6- azepine spiroheptane base, 2,6- diaza spiroheptane bases, 2- sulphur -6- azepine spiroheptane base 2- mono- Oxide, 2- sulphur -6- azepine spiroheptane base 2,2- dioxide etc..

As described in the present invention, substituent R is keyed to the ring system formed on the ring at center by one and represents substituent R It any on ring can may replace or any reasonable position is replaced.For example, formula a represents any possibility quilt on A ring or B ring Substituted position can be replaced by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.

As described in the present invention, substituent group (R)_nThe ring system formed on the ring at center, which is keyed to, by one represents n Substituent R can be replaced any substitutive position on ring.For example, formula i is represented and any on A ring or B ring may be taken The position in generation can be replaced by n R.

As described in the invention, can be connected with molecule rest part on ring C there are two tie point, for example, such as formula j institute Show, indicate either the end E be also possible to E ' end be connected with the rest part of molecule, i.e. the connection type at both ends can be interchanged.

As described in the present invention, attachment point can be connect any attachable position on ring with molecule rest part.Example Such as, formula k, which represents any possible connected position on A ring or B ring, can be used as the point of connection.

" hydrate " of the invention refers to compound or its salt provided by the present invention, further includes chemical quantity or non-chemical The water that equivalent is combined by non-covalent intermolecular forces can also say be solvent molecule to be that water is formed by associated matter.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.

" ester " of the invention refers to that formula (I) compound containing hydroxyl can form internal hydrolyzable ester.Such ester is Such as hydrolysis generates the pharmaceutically acceptable ester of parent alcohol in human or animal's body.In formula (I) compound body containing hydroxyl The group of hydrolyzable ester includes, but are not limited to phosphate, acetoxymethoxy, 2,2- dimethylpropionyloxymethoxies, Alkanoyl, benzoyl, the first and second acyl group of benzene, alkoxy carbonyl, dialkyl carbamoyl and N- (di-alkyaminoethyl group)-N- Alkyl-carbamoyl etc..

" nitrogen oxides " of the invention refer to when compound is containing several amine functional groups, can nitrogen by 1 or greater than 1 it is former Son oxidation forms N- oxide.The particular example of N- oxide is the N- oxidation of the N- oxide or nitrogen-containing heterocycle nitrogen-atoms of tertiary amine Object.Available oxidant example, as hydrogen peroxide or peracid (such as peroxycarboxylic acid) handle corresponding amine formed N- oxide (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxide can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example molten in inertia In agent, such as methylene chloride, react amine compounds with m- chloroperoxybenzoic acid (MCPBA).

Compound may be present a variety of different geometric isomers and tautomer, formula (I) compound include it is all this Class form.For the avoidance of doubt, when compound exists with one of several geometric isomers or tautomer and only specifically describes Or when showing a kind of, it is clear that all other form is included in formula (I).

Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.

Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term is " pharmaceutically acceptable Salt " refers to that those salt forms are it will be apparent that i.e. they are substantially nontoxic and needed for capable of providing for pharmaceutical chemistry man Pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, it is more practical in nature, for choosing Select also critically important, these are: the costs of raw material, being easy of crystallization, the stream of yield, stability, hygroscopicity and result bulk pharmaceutical chemicals Dynamic property.Simply, pharmaceutical composition can be prepared by effective component and pharmaceutically acceptable carrier.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described in the books or literature Other methods such as ion-exchanges obtains these salt.Other pharmaceutically acceptable salts include adipate, malate, 2- Hydracrylate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, first Hydrochlorate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydrogen Iodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, the third two Hydrochlorate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt. The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion Product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically may be used The salt of receiving further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, Hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Sulphonic acid compound and aromatic sulphonic acid compound.Amine salt, example Such as, but not limited to, N, N '-dibenzyl-ethylenediamin, chloroprocanine, choline, ammonia, isopropylamine, tardocillin (benzathine), Choline salt (cholinate), lysine, meglumine (meglumine), piperazine, tromethamine, diethanol amine and other hydroxyalkyls Amine, ethylenediamine, N- methyl glucamine, procaine, N- benzyl-1-phenylethylamine, p- chlorobenzyl -2- pyrrolidines-the 1 '-Ji Jia of 1- Base-benzimidazole, diethylamine and other alkylamines, piperazine and three (methylol) aminomethanes；Alkali salt, for example, but it is unlimited In barium, calcium and magnesium；Transition metal salt, such as, but not limited to zinc.

Any disease of term " treatment " or illness as used in the present invention, some embodiment middle fingers improve disease wherein Or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In further embodiments, it " controls Treat " refer to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.In other implementations Example in, " treatment " refer to from body (such as stablizing perceptible symptom) or physiologically (such as parameter of stable body) or on It states two aspects and adjusts disease or illness.In further embodiments, " treatment " refers to the breaking-out for preventing or delaying disease or illness, hair Raw or deterioration.

" inflammatory disease " used in the present invention refers to excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue damage or function of organization any disease for losing, disorder or symptom." inflammatory disease " also refers to by leucocyte The pathologic state that inflow and/or Neutrophil chemotaxis mediate.

" inflammation " used in the present invention refers to by tissue damaged or topical protective response caused by destroying, it is for breaking Tissue that is bad, diluting or separate (isolation) harmful substance and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant connection.Inflammation can produce in the infection and non-infectious mode of pathogenic organism and virus, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, this can be used The inflammatory disease of disclosure of the invention compound treatment includes: to react with specific system of defense and non-specific defense system reaction Relevant disease.

Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.

In addition, compound disclosed by the invention, the salt including them, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.

" joint " indicates the medicine box of the fixed Combination in single dose unit form or the part for combined administration, Middle disclosed compound of present invention and combined partner can be in same time individual applications or can be at a certain time interval It applies respectively, so that joint is closed companion and show cooperation, for example act synergistically.Term " co-administered " as used herein Or " administering drug combinations " etc. are intended to include single individual (such as the patient) for being applied to selected COMBINATION OF THE INVENTION and needing it, and anticipate Be intended to include wherein substance without going through identical administration method or the therapeutic scheme being administered simultaneously.Term " drug as used herein Combination product " indicates to mix or combine obtained product for more than one active constituents, and both consolidating including active constituent Fixed combination also includes non-fixed combinations.Term " fixing joint " indicates active constituent such as disclosed compound of present invention and COMBINATION OF THE INVENTION It is administered simultaneously in the form of single entities or dosage in patient.Term " on-fixed joint " indicates that the active constituent such as present invention discloses Compound and composition are used as corpus separatum to be successively applied to patient simultaneously, jointly or without specific time limitation ground, wherein should It is applied in patient's body and provides the treatment effective level of two kinds of compounds.The latter applies also for cocktail therapy, such as application 3 Kind or more active constituent.

The purposes, preparation and composition of the compound of the present invention

One or more physiologically acceptable carriers can be used and prepare Pharmaceutical composition, the carrier in a conventional manner Including excipient and auxiliary material, be conducive to for reactive compound to be processed as preparation that can be medicinal.Preparation appropriate depends on choosing The administration route selected.Technology known to any, carrier and excipient can be used suitably, and as understood in the art. The summary of Pharmaceutical composition described herein may refer to such as Remington:The Scienceand Practice of Pharmacy, the 19th edition (Easton, Pa.:Mack PublishingCompany, 1995)；Hoover, John E., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania1975；Liberman, H.A. and Lachman, L. write, Pharmaceutical DosageForms, Marcel Decker, NewYork, N.Y., 1980；And " Pharmaceutical Dosage Forms and DrugDelivery Systems " the 7th edition (Lippincott Williams&Wilkins 1999), it herein will by reference It is fully incorporated herein.

Pharmaceutical composition used herein refers to compound described herein such as formula (I) compound and other chemical constituents Such as carrier, stabilizer, diluent, dispersing agent, suspending agent, thickener and/or excipient mixture.The Pharmaceutical composition Be conducive to compound and give organism.In practicing treatment provided herein or application method, treatment is had with Pharmaceutical composition The compound described herein of effect amount gives the mammal with disease to be treated, obstruction and illness.Preferably, the food in one's mouth Newborn animal is people.Therapeutically effective amount can vary greatly, depending on the severity of disease, age of subject and relatively strong The other factors such as the effect of health situation, the compound used.The compound can be used alone or with as mixture One or more medicines of component are used in combination.

In some embodiments, composition also may include one or more pH adjusting agents or buffer, including acid is such as Acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid；Alkali, such as sodium hydroxide, sodium phosphate, Boratex, sodium citrate, acetic acid Sodium, sodium lactate and trishydroxymethylaminomethane；And buffer, such as citric acid/glucose, sodium bicarbonate and ammonium chloride.Including The desired amount of these acid, alkali and buffers are to maintain within the acceptable range the pH of composition.

In other embodiments, composition also may include required amount one or more salt so that composition weight Measure Morie osmolarity within the acceptable range.These salt include having sodium, potassium or ammonium cation and chloride ion, citric acid Root, Vitamin C acid group, borate, phosphate radical, bicarbonate radical, sulfate radical, thiosulfate anion or weight sulfinite anion that A little salt；Suitable salt includes sodium chloride, potassium chloride, sodium thiosulfate, sodium hydrogensulfite and ammonium sulfate.

The production that terms used herein " pharmaceutical composition " refer to the mixing by more than one active constituent or are composed Product, and fixation and non-fixed combinations including active constituent.Term " fixed Combination " refers to active constituent, and example is described herein Compound and adjuvant (co-agent) are both given patient simultaneously in the form of single entirety or dosage.Term " on-fixed Combination " refers to active constituent, such as compound described herein and mixture, simultaneously, together or continuously as separated individual Patient is given without specific interval time restriction, wherein this, which gives, provides the effective level of two kinds of compounds in patient's body. The latter is also applied to cocktail therapy, such as the combination medicine of three kinds or more active constituents.

Pharmaceutical preparation described herein can give subject by a variety of administration routes, the administration route include but It is not limited to take orally, parenteral (such as intravenous, subcutaneous, intramuscular), intranasal, buccal, part, rectum or percutaneous dosing way Diameter.Pharmaceutical preparation described herein includes but is not limited to aqueous liquid dispersion, self-emulsifying dispersion, solid solution, liposomal dispersion Agent, aerosol, solid dosage forms, powder, immediate release formulations, controlled release preparation, dissolution formulation, tablet, capsule, pill, sustained release preparation, The instant and controlled release preparation of delayed release dosage system, pulse delivery formulations, more granular preparations and mixing.

It can be produced in a usual manner including compound described herein Pharmaceutical composition, for example, only for example, logical Cross the techniques such as conventional mixing, dissolution, granulation, sugar coating, grinding, emulsification, Rubber Capsule, encapsulating or compacting.

Compositions described herein can be configured to for giving subject, the routine by any conventional mode Mode include but is not limited to oral, parenteral (such as intravenous, subcutaneously or intramuscularly), buccal, intranasal, rectum or percutaneous Administration route.Terms used herein " subject " are for indicating animal, preferably mammal, including the mankind or inhuman Class.Term patient and subject may be used interchangeably herein.

Moreover, Pharmaceutical composition described herein, it includes the compounds of formula (I), can be formulated into any suitable Dosage form, the including but not limited to agent such as aqueous oral dispersion, liquid preparation, gelling agent, syrup, elixir, paste, suspension Type, for the orally ingestible of patient to be treated, solid oral dosage form, aerosol, controlled release preparation, dissolution formulation, effervescent formulation, jelly Dry preparation, tablet, powder, pill, dragee, capsule, sustained release preparation, delayed release dosage system, pulsation delivery formulations, more granular preparations With releasing and controlled release preparation for mixing.

Compound described herein, which can be used for preparing, inhibits BTK or its homologue or for treating at least partly from inhibition The drug of the disease or illness that benefit in BTK or its homologue.In addition, for treating in the subject for needing these treatments The method of any disease described herein or illness, including Pharmaceutical composition is given, it includes at least one formulas described herein (I) compound or its pharmaceutically acceptable salt, pharmaceutically acceptable N- oxide, pharmaceutical active metabolite, pharmaceutically acceptable Pro-drug or pharmaceutically acceptable solvate give the subject with therapeutically effective amount.

The composition comprising compound described herein can be given, to carry out preventative and/or therapeutic treatment.It is controlling It treats in application, the composition is given to the patient for having suffered from disease or illness, to cure enough or at least partly prevent disease The symptom of disease or illness.To the effective quantity of this application will depend on the severity and the course of disease of disease or illness, treatment before, The health status of patient, weight and to the reaction of drug and the judgement of attending physician.It is well known that passing through routine experiment (packet Include but be not limited to incrementally increase dose clinical test) determine that this therapeutically effective amount is considered as within the skill of the art.

In the case where the situation of patient does not improve, based on the considerations of doctor, compound can continuously be given；Alternatively, institute The dosage for the drug given can be temporarily reduced or suspend a period of time (that is, " withdrawal time ").The length of withdrawal time can be between 2 Between it and 1 year, including only for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 It, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days Or 365 days.During drug withdrawal, dosage reduction can be 10%-100%, only for example, include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

Once the illness of patient improves, if it is desired, give maintenance dose.Then, dosage or administration frequency or it The two, according to symptom difference can be reduced to can keep disease, obstruction and illness improve degree.But patient can need Will be long-term, periodically treatment, this symptom based on any recurrence.

The change of the amount of given drug corresponding to this amount depends on factors, such as particular compound, disease or illness With the uniqueness (such as weight) of its seriousness, subject in need for the treatment of or host, still, nevertheless, can be according to spy Fixed ambient conditions, including for example used specific drug, administration route, the illness for the treatment of and the subject for the treatment of Or host, it is routinely determined with methods known in the art.But, the dosage used typically for adult treatment, typically exists 0.02-5000mg/ days or about 1-1500mg/ days ranges.The required metering is expressed as one or simultaneously in which can be convenient (or in a short time) of administration or divided dose at interval appropriate, such as daily two, three, four doses or more divided agent.

General synthetic method

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein the definition of substituent group is as shown in formula (I) compound.Following reaction scheme and embodiment is for further illustrating Illustrate the contents of the present invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃,d⁶-DMSO,CD₃OD or d⁶Acetone is solvent (report is as unit of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.

Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered For analyzing, the source ESI is applied to LC-MS spectrometer.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:

Table 1

Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

The use of logogram word below is through the present invention:

BOC, Boc tert-butoxycarbonyl

CHCl₃Chloroform

CDC1₃Deuterated chloroform

DMF N,N-dimethylformamide

Pd(dppf)Cl₂[bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

DCM,CH₂Cl₂Methylene chloride

EDC, EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride

H₂Hydrogen

H₂O₂Hydrogen peroxide

K₂CO₃Potassium carbonate

ML, ml milliliters

Pd/C palladium/carbon

NaOH sodium hydroxide

THF tetrahydrofuran

HOBt I-hydroxybenzotriazole

Et₃N, TEA triethylamine

TFA trifluoroacetic acid

TBSCl tert-butyl chloro-silicane

TBAF tetrabutyl ammonium fluoride

NBS N-bromo-succinimide

H₂O water

The following examples can be with the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright range.

The synthetic schemes 1 of intermediate

Compound 7a can be prepared, wherein R by the method for the synthetic schemes 1 of intermediate¹With institute such as of the present invention The meaning stated.Commercially available glycol is handled with TBSCl, obtains the glycol that a hydroxyl is protected by TBS.Then, by oxalyl chloride Oxidation obtains aldehyde 1a.Compound 1a is carried out with wittig reagent 2a (reacting to obtain with triphenylphosphine by methyl 2- bromacetate) Wittig reacts to obtain compound 3a.Compound 3a reacts deprotection with TBAF and obtains compound 4a.Then pass through and methylsulfonyl Chlorine reacts to obtain compound 5a.Compound 5a and R¹H reacts in acetonitrile obtains compound 6a, then hydrolyzes under alkaline condition To compound 7a.

The synthetic schemes 2 of intermediate

Compound 9a can react to obtain compound 9a with mesyl chloride by compound 8a under alkaline condition.

Synthetic schemes 1

Compound 5 can be prepared by the method for synthetic schemes 1, and wherein R has meaning as described in the present invention. Commercially available 1H- pyrazolo [3,4-d] pyrimidine -4- amine is handled with N-iodosuccinimide, obtains the iodo- 1H- pyrazolo [3,4- of 3- D] pyrimidine -4- amine.Then, the phenylboric acid that iodo- 1H- pyrazolo [3, the 4-d] pyrimidine -4- amine of 3- and phenoxy group replace is in alkaline item Palladium mediated cross-coupling is carried out under part, forms intermediate 1.Intermediate 1 passes through Mitsunobu reaction and N-Boc-3- (methylsulphur Acyl group) coupling of oxygroup piperidines, obtain the intermediate 2 of Boc (i.e. tertbutyloxycarbonyl) protection.It is obtained after the acid deprotection of intermediate 2 Compound 3.Compound 3 and acyl chlorides are coupled, such as, but not limited to 4- bromo but-2-ene acyl chlorides, obtain compound 4.Compound 4 with The RH reaction such as (alkali can be but be not limited to potassium carbonate, triethylamine) under alkaline condition, obtains compound 5.

Synthetic schemes 2

Compound 7 can be prepared, wherein L and R by the method for synthetic schemes 2¹With containing as described in the present invention Justice.Compound 3 and the condensation of compound 6 (condensing agent can be but be not limited to HOBt, EDCI etc.) obtain compound 7.

Synthetic schemes 3

Compound 9 can be prepared by synthetic schemes 3.(alkali is carbon to compound 4 under alkaline condition with compound 10 Sour potassium, but be not limited to) nucleophilic substitution occurs, obtain compound 8；Compound 8 is deprotected obtains chemical combination in acid condition Object 9.

Embodiment 1 (E) -1- ((R) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -4- ((4aR, 7aS)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) but-2-ene -1- Ketone

The synthesis of step 1) 3- iodo -1H- pyrazolo [3,4-d] pyrimidine -4- amine:

1H- pyrazolo [3,4-d] pyrimidine -4- amine (15.0g, 111.1mmol) is dissolved in DMF (150mL), then to It is slowly added into reaction solution N- N-iodosuccinimide (37.5g, 166.6mmol), is stirred to react 12h at 80 DEG C.Stop heating, It is cooling, water (40mL) is added into reaction solution, filters, solid is washed with water (80mL), and ethyl alcohol (60mL) is washed, and it is solid to be dried to obtain yellow Body (24.9g, 86%).

The synthesis of step 2) (S)-tert-butyl 3- ((mesyl) oxygroup) piperidines -1- carboxylate:

(S)-tert-butyl 3- hydroxy piperidine -1- carboxylate (1.50g, 7.47mmol) is dissolved in methylene chloride (30mL) In, triethylamine (1.35mL, 9.71mmol) then is added into reaction solution, be added under ice-water bath mesyl chloride (0.64mL, 8.21mmol), 4-dimethylaminopyridine (91mg, 0.75mmol).7h is stirred at room temperature, methylene chloride extracts (150mL × 3), has Machine is mutually washed with saturated salt solution (60mL), and anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, silica gel column chromatography separating purification (petroleum Ether/ethyl acetate (V/V)=4/1), obtain product as white solid (2.04g, 98%).

MS-ESI:(ESI, pos.ion) m/z:224.1 [M-55]⁺；

The synthesis of step 3) 3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -4- amine:

In 250mL heavy wall reaction flask, be separately added into 3- iodo -1H- pyrazolo [3,4-d] pyrimidine -4- amine (1.31g, 5.0mmol), (4- Phenoxyphenyl) boric acid (1.28g, 6.0mmol), potassium carbonate (1.73g, 12.5mmol), 1,4- dioxy six Ring (30mL) and water (6mL) under nitrogen protection, add Pd (dppf) Cl₂(300mg, 0.41mmol), then at 140 DEG C Tube sealing reaction is stayed overnight, and after having reacted, filtering, methylene chloride extracts (200mL × 3), and saturated common salt washes (60mL), anhydrous slufuric acid Sodium is dry, and evaporating solvent under reduced pressure, silica gel column chromatography separating purification (methylene chloride/methanol (V/V)=20/1) obtains ashen solid (635mg, 42%).

MS-ESI:(ESI, pos.ion) m/z:304.1 [M+1]⁺；

Step 4) (R)-tert-butyl -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidines -1- carboxylate synthesis:

3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -4- amine (1.14g, 3.76mmol) is dissolved in DMF In (30mL), then into reaction solution be added (S)-tert-butyl 3- ((mesyl) oxygroup) piperidines -1- carboxylate (4.2g, 15.04mmol), cesium carbonate (0.64mL, 8.21mmol), 4-dimethylaminopyridine (3.67g, 11.28mmol).It is stirred at 90 DEG C 8h after having reacted, removes DMF under reduced pressure, and methylene chloride extracts (150mL × 3), and saturated common salt washes (60mL), anhydrous sodium sulfate Dry, evaporating solvent under reduced pressure, product crude product silica gel column chromatography separating purification (methylene chloride/methanol (V/V)=40/1) obtains product (1.28g, 70%).

MS-ESI:(ESI, pos.ion) m/z:487.2 [M+1]⁺；

Step 5) (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo [3,4-d] pyrimidine -4- amine Synthesis:

By (R)-tert-butyl -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperazine Pyridine -1- carboxylate (1.28g, 2.63mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (6mL), and hydrochloric acid is then added into reaction solution 16h is stirred at room temperature in (6mL, 4mol/L), and after having reacted, dilute sodium hydrate aqueous solution is added, and is adjusted to PH=9, methylene chloride extraction It takes (150mL × 3), saturated common salt washes (60mL), and anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product silica gel column layer Analysis isolates and purifies (methylene chloride/methanol (V/V)=12/1-6/1), obtains product (840mg, 83%).

MS-ESI:(ESI, pos.ion) m/z:387.2 [M+1]⁺；

¹H NMR(600MHz,CDCl₃): δ 8.32 (d, J=15.2Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 7.41- 7.34 (m, 2H), 7.15 (d, J=8.6Hz, 2H), 7.12-7.04 (m, 2H), 6.08-5.81 (m, 1H), 4.94-4.82 (m, 1H), 3.75-3.55 (m, 2H), 3.36 (dt, J=22.0,10.5Hz, 2H), 3.13 (s, 1H), 2.81 (dd, J=17.0, 6.6Hz, 1H), 2.30 (dt, J=11.7,7.8Hz, 1H), 2.19 (dd, J=19.7,10.5Hz, 1H), 1.93-1.87 (m, 1H),1.77-1.71(m,1H),1.26(s,1H).

Step 6) (R, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) Piperidin-1-yl) -4- bromo but-2-ene -1- ketone synthesis:

By (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo [3,4-d] pyrimidine -4- amine (1.58g, 4.09mmol) be dissolved in methylene chloride (20mL), be slowly added under ice-water bath (E) -4- bromo but-2-ene acyl chlorides (0.90g, 5mmol), 10min is reacted under ice-water bath, is added water (30mL), and methylene chloride extracts (100mL × 3), saturated common salt washing (30mL), anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product silica gel column chromatography separating purification (methylene chloride/methanol (V/V)=30/1 product (1.48g, 68%)), is obtained.

MS-ESI:(ESI, pos.ion) m/z:533.1 [M+1]⁺；

¹H NMR(600MHz,CDCl₃): δ 8.33 (d, J=26.5Hz, 1H), 7.61 (s, 2H), 7.39 (t, J=7.9Hz, 2H), 7.23-7.11 (m, 3H), 7.08 (d, J=8.1Hz, 2H), 6.95-6.83 (m, 1H), 6.49 (dd, J=50.1, 14.6Hz, 1H), 4.88 (s, 1H), 4.81 (d, J=11.5Hz, 0.6H), 4.49 (d, J=12.1Hz, 0.6H), 4.21-4.08 (m, 1H), 4.08-3.88 (m, 3H), 3.86-3.72 (m, 1H), 3.40 (t, J=11.4Hz, 0.63H), 3.23 (t, J= 12.4Hz, 0.66H), 2.97 (t, J=11.4Hz, 0.58H), 2.46-2.30 (m, 1H), 2.27-2.19 (m, 1H), 2.03 (d, J=9.6Hz, 1H), 1.79-1.65 (m, 1H)

Step 7) (E) -1- ((R) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -4- ((4aR, 7aS)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) but-2-ene -1- The synthesis of ketone:

(R, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines -1- Base) -4- bromo but-2-ene -1- ketone (210mg, 0.39mmol) is dissolved in DMF (15mL), it is added (4aR, 7aS) -3,4a, 5,6, 7,7a- hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles (101mg, 0.79mmol) and potassium carbonate (193mg, 1.38mmol), 4h is stirred to react at 60 DEG C, TLC monitoring, after having reacted, evaporating solvent under reduced pressure is added water (20mL), and methylene chloride extracts (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product column chromatographic isolation and purification (two Chloromethanes/methanol (V/V)=10/1) obtain product (138mg, 61%).

MS-ESI:(ESI, pos.ion) m/z:583.2 [M+1]⁺；

¹H NMR(600MHz,CDCl₃): δ 8.37 (d, J=14.3Hz, 1H), 7.66 (d, J=7.7Hz, 2H), 7.40 (t, J=7.4Hz, 2H), 7.18 (dd, J=16.1,7.6Hz, 3H), 7.10 (d, J=7.8Hz, 2H), 6.85 (s, 1H), 6.49 (dd, J=59.7,14.6Hz, 1H), 5.75 (s, 2H), 4.88 (s, 1H), 4.16 (dd, J=58.7,28.1Hz, 3H), 3.81 (d, J=43.0Hz, 2H), 3.58 (d, J=33.1Hz, 2H), 3.45-3.31 (m, 2H), 2.92 (d, J=51.1Hz, 4H), 2.31 (ddd, J=32.5,25.1,10.4Hz, 4H), 2.04 (d, J=22.5Hz, 2H), 1.80-1.59 (m, 2H)

Embodiment 2 (S, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) Piperidin-1-yl) -4- (2- oxygen -6- azepine spiroheptane -6- base) but-2-ene -1- ketone

(R, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines -1- Base) -4- bromo but-2-ene -1- ketone (200mg, 0.37mmol) is dissolved in DMF (15mL), it is added 2- oxygen -6- aza-spiro [3,3] Heptane oxalate (0.14g, 0.75mmol) and potassium carbonate (149mg, 1.50mmol) react 4h at 60 DEG C.Evaporating solvent under reduced pressure, It is added water (20mL), methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, removes under reduced pressure Solvent, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=10/1), obtains white powder (79mg, 40%).

MS-ESI:(ESI, pos.ion) m/z:276.7 [M/2+1]⁺；

¹H NMR(400MHz,CDCl₃): δ 7.63 (d, J=7.6Hz, 2H), 7.38 (t, J=7.2Hz), 7.11 (m, 4H), 6.68(s,1H),5.80(m,1H),4.99-4.62(m,5H),4.43(m,1H),4.17(m,1H),3.85-3.50(m,4H), 3.50-3.27 (m, 2H), 3.25-2.76 (m, 2H), 2.48-2.15 (m, 2H), 2.00 (d, J=5.6Hz, 1H), 1.80-1.53 (m,1H).

Embodiment 3 (R, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) Piperidin-1-yl) -6- morpholinyl hex- 2- alkene -1- ketone

The synthesis of step 1) 4- ((tert-butyl (dimethyl) silicon substrate) oxygroup) butyl- 1- alcohol:

Butyl- Isosorbide-5-Nitrae-glycol (6.5g, 72mmol) is dissolved in methylene chloride, tert-butyl (dimethyl) chlorosilane is added (5.4g, 36mmol) is slowly added into triethylamine (5mL, 35.9mmol) under ice-water bath, and reaction 5h, dichloro is then stirred at room temperature Methane extracts (150mL × 3), and saturated common salt washes (60mL), and anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure obtains product (6.82g, 93%).

The synthesis of step 2) 4- ((tert-butyl (dimethyl) silicon substrate) oxygroup) butyraldehyde:

It under nitrogen protection, is added oxalyl chloride (10mL), methylene chloride (150mL), DMSO (5mL) is slowly added dropwise at -78 DEG C, Stir 15min after, be slowly added at -78 DEG C 4- ((tert-butyl (dimethyl) silicon substrate) oxygroup) butyl- 1- alcohol (6.29g, 30.8mmol), triethylamine (5mL) is added after 1h is stirred at -78 DEG C, is then slowly raised to room temperature, is added water (100mL), dichloro Methane extracts (200mL × 3), and saturated aqueous ammonium chloride is washed (70mL), and 1N salt pickling (70mL), evaporating solvent under reduced pressure must produce Object (5.1g, 82%).

The synthesis of step 3) methyl 2- (triphenylphosphoroanylidene) acetic acid esters:

Triphenylphosphine (18g, 69mmol) is dissolved in ethyl acetate (300mL), methyl 2- bromacetate is added thereto Reaction is stirred at room temperature overnight in the ethyl acetate solution (30mL) of (6.5mL, 69mmol), and filtering, obtained solid is washed with petroleum ether It washs, obtains product (29g, 93%) after vacuum drying.

The synthesis of step 4) (E)-methyl 6- ((t-Butyldimethylsilyl) oxygroup) hex- 2- olefin(e) acid ester:

4- (tert-butyl (dimethyl) silicon substrate) oxygroup butyraldehyde (2.6g, 13mmol) is added in toluene, wittig examination is added Agent (4.3g, 13mmol), is heated to reflux 4h, and after having reacted, ethyl acetate extracts (150mL × 3), saturated common salt washing (60mL), anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/ V)=16/1), product (1.81g, 55%) is obtained.

The synthesis of step 5) (E)-methyl 6- hydroxyl hex- 2- olefin(e) acid ester:

Methyl (E) -6- (tert-butyl (dimethyl) silicon substrate) oxygroup hex- 2- olefin(e) acid ester (1.21g, 4.68mmol) is dissolved in It in THF (30mL), is added tetrabutyl ammonium fluoride (5.2mL, 5.2mmol), 4h is stirred at room temperature, be added water (40mL), ethyl acetate It extracts (100mL × 3), saturated common salt washes (50mL), and anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product column chromatography (petrol ether/ethyl acetate (V/V)=2/1) is isolated and purified, product (0.42g, 62%) is obtained.

The synthesis of step 6) (E)-methyl 6- ((methyl sulphonyl) oxygroup) hex- 2- olefin(e) acid ester:

Methyl (E) -6- hydroxyl hex- 2- olefin(e) acid ester (0.42g, 2.9mmol) is dissolved in methylene chloride (15mL), ice-water bath Lower addition mesyl chloride (0.40g, 3.5mmol) and triethylamine (0.73mL, 5.2mmol), are stirred at room temperature 4h, after having reacted, add Enter water (20mL), methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, removes under reduced pressure molten Agent, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=2/1), obtains product (0.56g, 86%).

The synthesis of step 7) (E)-methyl -6- morpholinyl hex- 2- olefin(e) acid ester:

(E)-methyl 6- ((methyl sulphonyl) oxygroup) hex- 2- olefin(e) acid ester (0.56g, 2.5mmol) is dissolved in acetonitrile It in (10mL), is added morpholine (0.66mL, 7.6mmol), stirs 6h at 60 DEG C, after having reacted, stop heating, remove under reduced pressure molten Agent is added water (20mL), and methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, decompression Solvent is evaporated off, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=50/1) obtains product (0.46g, 86%).

MS-ESI:(ESI, pos.ion) m/z:214.3 [M+1]⁺；

The synthesis of step 8) (E) -6- morpholinyl hex- 2- olefin(e) acid:

Methyl (E) -6- morpholinyl hex- 2- olefin(e) acid ester (0.23g, 1.1mmol) is dissolved in THF (10mL), water is added (10mL), be added NaOH (0.22g, 5.5mmol), be stirred overnight at room temperature and concentrated hydrochloric acid be added, filter, obtain product (0.20g, 93%).

MS-ESI:(ESI, pos.ion) m/z:200.2 [M+1]⁺；

Step 9) (R, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) Piperidin-1-yl) -6- morpholinyl hex- 2- alkene -1- ketone synthesis:

(E) -6- morpholinyl hex- 2- olefin(e) acid (141mg, 0.71mmol) is dissolved in DMF (15mL), HOBt is separately added into (112mg, 0.83mmol), EDCI (239mg, 1.25mmol), 3- (4- Phenoxyphenyl)-1-((3R)-3- piperidyl) pyrazoles And [3,4-d] pyrimidine -4- amine (161mg, 0.42mmol), 4h is stirred at room temperature, methylene chloride extracts (50mL × 3), saturated common salt It washes (20mL), anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=12/1-8/1), obtain product (50mg, 21%).

MS-ESI:(ESI, pos.ion) m/z:568.2 [M+1]⁺；

¹H NMR(600MHz,CDCl₃): δ 8.28 (d, J=32.5Hz, 1H), 7.60 (d, J=7.2Hz, 2H), 7.42 (t, J=7.9Hz, 2H), 7.21 (t, J=7.4Hz, 1H), 7.16 (d, J=8.6Hz, 2H), 7.10 (d, J=7.8Hz, 2H), 6.84-6.73 (m, 1H), 6.37 (dd, J=59.4,15.0Hz, 1H), 4.90-4.78 (m, 1H), 4.24-4.04 (m, 1H), 3.98 (d, J=21.9Hz, 3H), 3.74 (s, 2H), 3.33 (t, J=11.2Hz, 1H), 3.22-3.15 (m, 1H), 3.01 (d, J =27.7Hz, 2H), 2.87 (s, 1H), 2.35 (s, 2H), 2.27 (s, 2H), 1.97 (d, J=43.6Hz, 3H), 1.72 (d, J= 13.3Hz,1H).

Embodiment 4 (E) -1- ((S) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -4- ((1S, 4S) -2,5- diazabicylo [2.2.1] heptane -2- base) but-2-ene -1- ketone

Step 1) (1S, 4S)-tert-butyl 5- ((E) -4- ((S) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazoles And [3,4-d] pyrimidine -1- base) piperidin-1-yl) -4- oxo-but-2-ene -1- base) -2,5- diazabicylo [2.2.1] heptane - The synthesis of 2- formic acid esters:

(S, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines -1- Base) -4- bromo but-2-ene -1- ketone (80mg, 0.15mmol) is dissolved in DMF (15mL), add potassium carbonate (44mg, 0.30mmol) Add 2,5- diazabicylo [2.2.1] heptane -2- carboxylate (60mg, 0.30mmol).60 DEG C of reaction 4h are concentrated under reduced pressure DMF is removed, is added water (20mL), methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, subtracts Solvent is evaporated off in pressure, and product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=20/1) obtains white powder (80mg, 81%).

MS-ESI:(ESI, pos.ion) m/z:651.35 [M+1]⁺；

Step 2) (E) -1- ((S) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -4- ((1S, 4S) -2,5- diazabicylo [2.2.1] heptane -2- base) but-2-ene -1- ketone synthesis:

(1S, 4S)-tert-butyl 5- ((E) -4- ((S) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4- D] pyrimidine -1- base) piperidin-1-yl) -4- oxo-but-2-ene -1- base) -2,5- diazabicylo [2.2.1] heptane -2- formic acid Ester (66mg, 0.1mmol) is dissolved in methylene chloride (5mL), is added TFA (2mL), is reacted 5h at room temperature.It is spin-dried for solvent, adds water PH is adjusted to 8 with saturated sodium bicarbonate solution by (20mL), and methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), Anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=6/1), It obtains product (15mg, 27%).

MS-ESI:(ESI, pos.ion) m/z:551.25 [M+1]⁺.

Embodiment 5 (E) -1- ((S) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -4- ((1S, 4S) -2- oxygen -5- azabicyclic [2.2.1] heptane -5- base) but-2-ene -1- ketone

(S, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines -1- Base) -4- bromo but-2-ene -1- ketone (200mg, 0.38mmol) is dissolved in DMF (15mL), be added potassium carbonate (74mg, 0.75mmol) and 2- oxygen -5- azabicyclo [2.2.1] heptane (74mg, 0.75mmol).60 DEG C of reaction 4h, evaporating solvent under reduced pressure, It is added water (20mL), methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, removes under reduced pressure Solvent, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=8/1) obtain product (173mg, 83.7%).

MS-ESI:(ESI, pos.ion) m/z:283.75 [M/2+1]⁺；

¹H NMR (600MHz, DMSO): δ 8.25 (s, 1H), 7.65 (t, J=6.7Hz, 2H), 7.43 (t, J=7.7Hz, 2H),7.19(s,1H),7.18-7.07(m,4H),6.66(m,1H),6.56-6.42(m,1H),4.30(m,1H),4.05(d,J =11.9Hz, 1H), 3.88-3.73 (m, 1H), 3.46-3.29 (m, 6H), 3.25-3.16 (m, 2H), 2.83-2.58 (m, 1H), 2.42 (m, 1H), 2.25 (d, J=12.0Hz, 1H), 2.11 (m, 1H), 2.00-1.89 (m, 1H), 1.72 (m, 1H), 1.55 (m, 2H).

Embodiment 6 (E) -1- ((R) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- Base) piperidin-1-yl) -4- ((1R, 4R) -2- sulphur -5- azabicyclo [2.2.1] heptane -5- base) but-2-ene -1- ketone

(E) -1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidines Base] the bromo- but-2-ene -1- ketone (50mg, 0.11mmol) of -4- be dissolved in DMF (15mL), it is double that (1S, 4S) -2- sulphur -5- azepine is added Ring [2.2.1] heptane (20mg, 0.17mmol) and potassium carbonate (48mg, 0.35mmol) stir 4h at 60 DEG C, remove under reduced pressure molten Agent is added water (20mL), and methylene chloride (50mL × 3) extraction, saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, decompression Be evaporated off solvent, product crude product column chromatographic isolation and purification (dichloromethane/ethyl acetate (V/V)=10/1) product (15mg, 28%).

MS-ESI:(ESI, pos.ion) m/z:568.2 [M+1]⁺；

¹H NMR(400MHz,CDCl₃) δ 8.39 (s, 1H), 7.66 (d, J=8.6Hz, 2H), 7.41 (t, J=8.0Hz, 2H), 7.24-7.03 (m, 5H), 6.83 (s, 1H), 6.53 (dd, J=50.4,16.0Hz, 1H), 5.69 (s, 2H), 4.87 (s, 2H), 4.55 (d, J=9.9Hz, 1H), 4.15 (dd, J=49.2,15.7Hz, 1H), 3.89-3.68 (m, 2H), 3.52-3.26 (m, 4H), 3.11 (dd, J=35.4,9.4Hz, 2H), 2.98-2.79 (m, 3H), 2.46-2.13 (m, 5H), 2.02 (d, J= 12.9Hz,2H),1.88-1.64(m,2H).

((R, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- of embodiment 7 Base) piperidin-1-yl) -4- (2- oxygen -7- azaspiro [3.5] nonane -7- base) but-2-ene -1- ketone synthesis

(E) -1- ((3R) -3- [4- amino -3- (4- Phenoxyphenyl) pyrazolo [3,4-d] pyrimidine -1- base] -1- piperidines Base) the bromo- but-2-ene -1- ketone (74mg, 0.14mmol) of -4- be dissolved in DMF (15mL), 2- oxygen -7- azaspiro [3.5] nonyl is added Alkane (36mg, 0.28mmol) and potassium carbonate (49mg, 0.35mmol), are then stirred to react at 60 DEG C, and TLC monitors fully reacting Afterwards, evaporating solvent under reduced pressure is added water (20mL), and methylene chloride extracts (50mL × 3), and saturated common salt washes (20mL), anhydrous sulphur Sour sodium is dry, evaporating solvent under reduced pressure, and product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=10/1) obtains product (18mg, 23%).

MS-ESI:(ESI, pos.ion) m/z:583.2 [M+1]⁺；

¹H NMR(400MHz,CDCl₃) δ 8.37 (s, 1H), 7.66 (d, J=8.7Hz, 2H), 7.41 (t, J=7.9Hz, 2H), 7.19 (dd, J=12.8,8.0Hz, 3H), 7.10 (d, J=7.7Hz, 2H), 6.86 (s, 1H), 6.57-6.35 (m, 1H), 5.65 (s, 2H), 4.87 (s, 1H), 4.56 (s, 0H), 4.41 (d, J=12.6Hz, 4H), 4.18 (d, J=13.3Hz, 1H), 4.06 (d, J=15.5Hz, 1H), 3.78 (s, 1H), 3.66 (s, 1H), 3.38 (s, 0H), 3.14 (d, J=33.0Hz, 2H), 2.93 (s, 1H), 2.41 (d, J=26.5Hz, 5H), 2.26 (d, J=10.1Hz, 2H), 1.97 (dd, J=37.2,19.8Hz, 6H), 1.74 (d, J=13.2Hz, 1H)

Embodiment 8 (E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperazine Pyridine -1- base) -4- (2- oxygen -6- azaspiro [3.4] octane -6- base) but-2-ene -1- ketone

(S, E) -1- (3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) piperidines -1- Base) -4- bromo but-2-ene -1- ketone (200mg, 0.38mmol) is dissolved in DMF (15mL), be added potassium carbonate (150mg, 1.5mmol) with 2- oxygen -6- azaspiro [3.3] heptane oxalate (152mg, 0.75mmol), 4h then is reacted at 60 DEG C.Add Enter water (20mL), methylene chloride (50 × 3) extraction, saturated common salt washes (20mL), and anhydrous sodium sulfate is dry, removes under reduced pressure molten Agent, product crude product column chromatographic isolation and purification (dichloromethane/ethyl acetate (V/V)=8/1) white solid (90mg, 42.43%).

MS-ESI:(ESI, pos.ion) m/z:283.75 [M/2+1]⁺；

1H NMR(600MHz,CDCl₃) δ 8.37 (d, J=10.9Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.41 (t, J=7.8Hz, 2H), 7.18 (dd, J=16.7,7.8Hz, 3H), 7.10 (d, J=7.9Hz, 2H), 6.85 (d, J=15.3Hz, 1H), 6.48 (dd, J=55.6,14.7Hz, 1H), 5.71 (s, 2H), 4.88 (s, 1H), 4.62 (m, 4H), 4.13 (dd, J= 80.9,12.3Hz, 1H), 3.79 (t, J=11.2Hz, 1H), 3.71-3.58 (m, 1H), 3.24 (m, 2H), 2.87 (m, 2H), 2.60(m,2H),2.48-2.31(m,2H),2.30-2.23(m,1H),2.15(m,2H),2.03(m,2H),1.74(m,1H).

The external zymetology inhibitory activity of 1 the compounds of this invention of biological Examples

Experimental method: HEPES: hydroxyethyl piperazine second thiosulfonic acid；Brij-35: Brij-35；DTT: two sulphur Threitol；EDTA: ethylenediamine tetra-acetic acid；BTK: bruton's tyrosine kinase；Peptide FAM-P22: FAM-labeled peptide 22； ATP: triphosphoric acid adenosine monophosphate；Staurosporine: staurosporine；Coating Reagent#3:#3 fruit glaze agent

1. 1 × kinase buffer liquid and termination test buffer are prepared:

(1) 1 × kinase buffer liquid (50mM HEPES, pH 7.5,0.0015%Brij-35,10mM MgCl₂,2mM DTT)；(2) test buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating is terminated Reagent#3,50mM EDTA)。

2. the compound of test kinase prepares: compound serial dilution

(1) using 100%DMSO by 50 times of diluted chemical compound to highest final concentration.By the compound of the 100 μ L concentration Solution is transferred to a hole of 96 orifice plates.(2) in 20 μ L original solutions with the 60 diluted ratios of μ L DMSO successively diluted compounds 10 Concentration.(3) 100 μ L 100%DMSO solution are added in two emptying apertures, are compareed as no compound control and without enzyme.(4) Prepare an intermediate plate, each concentration compound of 10 μ L is transferred to intermediate plate from raw sheet respectively, and it is slow that 90 μ L 1x kinases are added Fliud flushing, oscillation mix 10 minutes.(5) preparing experiment plate: from the intermediate plate of 96 orifice plates corresponding aperture shift 5 μ L compound solutions to In corresponding 384 orifice plate.

3. kinase reaction

(1) prepare 2.5x enzyme solutions: enzyme is added in 1x kinase buffer liquid.(2) prepare 2.5x peptide solution: by fluorescein mark Remember that peptide and ATP are added in 1x kinase buffer liquid.(3) 10 μ L 2.5x enzyme solutions are added to containing 5 μ L DMSO contents is 10% Compound solution 384 hole experimental plates in, be incubated at room temperature 10 minutes.(4) experiment of 384 holes is added in 10 μ L 2.5x peptide solutions In plate.(5) kinase reaction and termination: 28 DEG C are incubated for the corresponding time, and 25 μ L stop buffers are added and terminate reaction.

4. DATA REASONING: reading data and collect.

5. curve matching

(1) data of copy and converted measurement；(2) inhibiting rate is converted to: inhibiting rate=(maximum value-sample value)/(maximum Value-minimum value) * 100；" maximum value " is no compound control value；" minimum value " is no kinase control hole numerical value；(3) by data Input corresponding analysis software Xlfit obtains IC₅₀Value.

Experimental result is as follows:

The external zymetology inhibitory activity of 2 the compounds of this invention of table

Embodiment	BTK IC50(nM)	Embodiment	BTK IC50(nM)
				1	3.1	5	2.2
2	3.3	7	2.8
				3	9.9	8	2.2

Control

2.5

Control is Ibrutinib, specific structure are as follows:

Experiment conclusion: as can be seen from Table 2, the compounds of this invention has a stronger inhibiting effect to BTK kinases, and it is basic have with The comparable activity of Ibrutinib.

Claims (8)

1. a kind of compound, different for the structure as shown in formula (I), or the stereoisomer of the structure as shown in formula (I), geometry Structure body, tautomer or pharmaceutically acceptable salt,

Wherein, R isWherein p is 1 or 2, q 0,1 or 2；Or

R isWherein each p and q independently are 0,1 or 2；

Each X¹, X²And X³It independently is-(CH₂)_b,-O- ,-NH- or-S (=O)_t-；

Each b independently is 1 or 2；

Each t independently is 0.

2. compound according to claim 1, wherein

R is following subformula:

3. compound according to claim 1 is such as flowering structure,

Or the stereoisomer of the compound, geometric isomer, tautomerism Body or pharmaceutically acceptable salt.

4. a kind of pharmaceutical composition includes the described in any item compounds of claim 1-3.

5. pharmaceutical composition according to claim 4 further includes pharmaceutically acceptable carrier, excipient, dilution At least one of agent, adjuvant and medium.

6. the described in any item compounds of claim 1-3 or the described in any item pharmaceutical compositions of claim 4-5 are for making The purposes of the drug of standby prevention, processing or protection B cell proliferation disease.

7. purposes according to claim 6, the B cell proliferation disease is Diffuse large B cell lymthoma, folliculus Property lymthoma or chronic lymphocytic leukemia.

8. the described in any item compounds of claim 1-3 or the described in any item pharmaceutical compositions of claim 4-5 are for making The purposes of the standby inhibitor for inhibiting BTK kinases.