CN107501270B - A kind of compound containing sulphonyl ethylene imine structure, pharmaceutical composition and its application - Google Patents

Abstract

The present invention provides a kind of compounds or its pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotopic label, isomers or prodrug containing sulphonyl ethylene imine structure as shown in general formula (I), and the present invention also provides a kind of pharmaceutical compositions and application comprising it.Compound provided by the invention or its pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotopic label, isomers or prodrug and pharmaceutical composition have excellent BTK inhibitory activity, can be used for preparing BTK inhibitor.

Description

A kind of compound containing sulphonyl ethylene imine structure, pharmaceutical composition and its application

Technical field

The present invention relates to field of medicaments, and in particular to a kind of compound containing sulphonyl ethylene imine structure includes describedization Close the pharmaceutical composition and their applications as bruton's tyrosine kinase inhibitor of object.

Background technique

Bruton's tyrosine kinase (Bruton ' s tyrosine kinase, BTK) is nonreceptor tyrosine kinase Tec man Family member.During pre-B lymphocyte transition is later period B cell, BTK is the necessary gene of cell differentiation and proliferation institute, and in B There is expression in cell lymphoma, acute type lymphocytic leukemia (ALL) and plasmacytoma.

After 2006, researcher has found that phosphorylation activation BTK is the crucial composition of B-cell receptor (BCR) signal path Part is the fine site of the diseases such as targeted therapy B cell lymphoma.BTK participates in Multiple Type access, with PI3K ((phosphatide Acyl inositol -3- kinases), G2 albumen amboceptor etc. activated after combining, pass through PLCg2 (phospholipase C g2), PKC- β I (albumen Kinase c-β I) etc. downstream signaling molecules, participate in adjusting to angiogenesis, cell Proliferation and apoptosis and cell movement.Except this In addition, BTK also participates in many other hematopoietic cell signal pathways, for example, participating in Toll-like receptor and cell in macrophage The signal path that factor acceptor mediates participates in the signal transduction etc. of IgE receptor in mast cell.

Recent study shows that BTK signal path is current non-Hodgkin lymphoma (NHL), and especially chronic lymphatic is thin New hot spot in born of the same parents' leukaemia (CLL), B cell lymphoma and the research of autoimmune disease clinical treatment.

According to Shandong for Buddhist nun (Ibrutinib) be a kind of oral BTK inhibitor pioneering new drug, the medicine by with target protein BTK Active site cysteine residue (Cys-481) selectively covalent bond, inhibits BTK to irreversibility, thus effective ground resistance Only tumour moves to the lymphoid tissue for being adapted to tumour growth environment from B cell.In addition, grinding medicine there are also multiple BTK inhibitor Object is in different clinical stages, such as Spebrutinib, Acalabrutinib.

Summary of the invention

It is an object of the present invention to provide a kind of new compound or its pharmaceutically acceptable salt, solvate, work Property metabolin, polymorph, isotopic label, isomers or prodrug, have excellent BTK inhibitory activity.

It is a further object of the present invention to provide a kind of pharmaceutical compositions.

It is a further object of the present invention to provide new compound or its pharmaceutically acceptable salt, solvate, active generations Thank to the application of object, polymorph, isotopic label, isomers or prodrug.

The present invention provides the compound containing sulphonyl ethylene imine structure shown in such as general formula (I) or its is pharmaceutically acceptable Salt, solvate, active metabolite, polymorph, isotopic label, isomers or prodrug,

Wherein, ring A is selected from following group:

Ring B, which is selected from, contains at least one heteroatomic 4~7 yuan of saturated heterocyclic group, and passes through hetero atom and group Y phase Even, the hetero atom is selected from N, S or O；

Ar is selected from substituted or unsubstituted monocycle or bicyclic aryl or heteroaryl, and substituent group is selected from C_1-8Alkyl, C_1-8Alkane Oxygroup, C_2-8Alkenyl, C_2-8Alkynyl, C_3-7Naphthenic base, C_2-9Heterocycle, aryl, heteroaryl, hydroxyl, carboxyl, sulfydryl, amino, cyanogen Base, halogen or C_1-8Halogenated alkoxy；

X is selected from singly-bound ,-O- ,-S- ,-CH₂,-NH- ,-S (=O)-,-S (=O)₂,-C (=O)-,-C (=O) NH- or - NHC (=O)-；

Y is selected from-S (=O)₂,-C (=O) NH- or-C (=O)-；

R₁-R₄Separately it is selected from substituted or unsubstituted following group: H, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl ,- (CH₂)_nC_3-7Naphthenic base ,-(CH₂)_nC_2-9Heterocycle ,-(CH₂)_nAryl ,-(CH₂)_nHeteroaryl ,-(CH₂)_n-OH、 -(CH₂)_n- (CHOH)_n-H、-(CH₂)_n-O-(CH₂)_nCH₃、-(CH₂)_n-NH₂、-(CH₂)_n-NH(C_1-8Alkyl) or-(CH₂)_n-N(C_1-8Alkane Base)₂；N indicates that 0~8 integer, substituent group are selected from hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, halogen or C_1-8Halogenated alkoxy.

Further, the ring B is selected from 4~7 yuan of saturated heterocyclic groups containing a N atom, and passes through N atom and base Group Y is connected.Optionally, the ring B is selected from 5~6 yuan of saturated heterocyclic groups containing a N atom.

Further, the ring B is selected from following heterocyclic group:

Further, R₁-R₄In at most group be selected from substituted or unsubstituted following group, remaining is selected from H:C_1-4 Alkyl, C_2-4Alkenyl, C_2-4Alkynyl ,-(CH₂)_nC_3-5Naphthenic base ,-(CH₂)_nC_2-7Heterocycle ,-(CH₂)_nPhenyl ,-(CH₂)_nNaphthalene Base ,-(CH₂)_nHeteroaryl ,-(CH₂)_n-OH、-(CH₂)_n-(CHOH)_n-H、-(CH₂)_n-O-(CH₂)_nCH₃、-(CH₂)_n-NH₂、 - (CH₂)_n-NH(C_1-4Alkyl) or-(CH₂)_n-N(C_1-4Alkyl)₂；N indicates 0~3 integer, when containing substituent group, substituent group definition Ibid.

Further, the Ar is selected from the aryl or heteroaryl of substituted or unsubstituted monocycle, and substituent group is selected from C_1-4Alkane Base, C_1-4Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl, C_3-5Naphthenic base, C_2-7Heterocycle, F, Br, I or C_1-4Halogenated alkoxy.

Compound provided by the invention is preferably selected from flowering structure:

The present invention also provides a kind of pharmaceutical composition, it includes the described in any item compounds of above technical scheme or its Pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotopic label, isomers or prodrug, and Pharmaceutically acceptable carrier.

Described pharmaceutical composition includes but is not limited to peroral dosage form, parenteral dosage forms, exterior-applied formulation, rectally agent Type etc..In some embodiments, described pharmaceutical composition can be oral tablet, capsule, pill, pulvis, sustained release preparation, Solution and suspension, for the sterile solution, suspension or lotion of parental injection, for the ointment or emulsifiable paste of external application, or Suppository for rectally.

Described pharmaceutical composition can also include other active components or drug, with the compound or its pharmaceutically may be used Salt, solvate, active metabolite, polymorph, isotopic label, isomers or the prodrug drug combination of receiving.

Compound containing sulphonyl ethylene imine structure shown in general formula (I) provided by the invention can swash with bruton's tyrosine Enzyme, bruton's tyrosine kinase homologue or bruton's tyrosine kinase cysteine homolog Irreversible binding.Specifically, It is shown below,

Wherein,Indicate the tie point between compound and bruton's tyrosine kinase.Further, describedization Close the cysteine residues covalent bond on object and bruton's tyrosine kinase.The compound of the present invention or its is pharmaceutically acceptable Salt, solvate, active metabolite, polymorph, isotopic label, isomers or prodrug and drug of the invention Composition can be used for preventing or treating disease relevant to excessive BTK activity, including but not limited to cancer, autoimmune disease Disease, heteroimmunity disease, inflammatory disease, thrombotic diseases etc. can reach prevention by inhibiting bruton's tyrosine kinase Or the purpose for the treatment of related disease.

The present invention also provides the compound or its pharmaceutically acceptable salt, solvate, active metabolisms as a result, Object, polymorph, isotopic label, isomers or prodrug are preparing the application in bruton's tyrosine kinase inhibitor.Into One step, application of the invention is the bruton's tyrosine kinase inhibitor for preparing irreversible.

The present invention also provides aforementioned pharmaceutical compositions to prepare the application in bruton's tyrosine kinase inhibitor.Into one Step ground, application of the invention is the bruton's tyrosine kinase inhibitor for preparing irreversible.

The present invention also provides the compound or its pharmaceutically acceptable salt, solvate, active metabolite, polycrystalline The application of type object, isotopic label, isomers or prodrug in the drug that preparation treats or prevents following disease: cancer, from Body immunity disease, heteroimmunity disease, inflammatory disease or thrombotic diseases.

The present invention also provides application of the aforementioned pharmaceutical compositions in the drug that preparation treats or prevents following disease: cancer Disease, autoimmune disease, heteroimmunity disease, inflammatory disease or thrombotic diseases.

Cancer of the present invention, autoimmune disease, heteroimmunity disease, inflammatory disease, thrombotic diseases packet Include but be not limited to lupus erythematosus, inflammatory bowel disease, graft versus host disease(GVH disease), asthma, arthritis, diffusivity large B cell lymphoid tumor, slow The disease types such as property lymphocytic lymphoma, follicular lymphoma, chronic lymphocytic leukemia, myocardial infarction.

The present invention also provides the prevention or treatment method of the relevant disease of excessive BTK activity, including to for having demand The compound of the present invention or its pharmaceutically acceptable salt, solvate, active metabolite, polycrystalline of body application therapeutically effective amount Type object, isotopic label, isomers or prodrug, or the medicine group of the invention to the individual application therapeutically effective amount for having demand Close object.The excessive active relevant disease of BTK, including but not limited to cancer, autoimmune disease, heteroimmunity disease, inflammation Property disease, thrombotic diseases etc., by inhibiting bruton's tyrosine kinase, can reach prevention or treating the mesh of related disease 's.

Above-mentioned cancer, autoimmune disease, heteroimmunity disease, inflammatory disease, thrombotic diseases include but not It is limited to lupus erythematosus, inflammatory bowel disease, graft versus host disease(GVH disease), asthma, arthritis, diffusivity large B cell lymphoid tumor, chronic lymphatic The disease types such as cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, myocardial infarction.

The above-mentioned individual for having demand preferably can be mammal, such as can be the mankind.

Compound prepared in accordance with the present invention or its pharmaceutically acceptable salt, solvate, active metabolite, polymorphic Object, isotopic label, isomers or prodrug or pharmaceutical composition can pass through intravenous injection, subcutaneous injection, intramuscular injection, rectum It is interior administration, collunarium, sucking, transdermal or oral.May be made as conventional pharmaceutical preparation, as tablet, enteric coatel tablets, capsule, powder, One or more conventional inert carriers and/or dilution is added if appropriate in suspension, solution, metering-type aerosol or suppository Agent, for example, cornstarch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water/glycerol, water/D-sorbite, water/polyethylene glycol, propylene glycol, cetyl stearoylketene ethyl alcohol, carboxymethyl cellulose or rouge Fat substance such as hardens fat or other mixtures appropriate.

For the metering for obtaining necessary therapeutic effect, when intravenously administrable, convenient from 1 to 200 mg/kg weight, It is preferred that the compound of the present invention of mg/kg or its pharmaceutically acceptable salt, solvate, active metabolism from 15 to 150 Object, polymorph, isotopic label, isomers or prodrug, in oral administration, from 10 to 200 mg/kg weight are excellent 20 to 150 mg/kg weight are selected, it is 1-3 times daily in all cases.

It is described in detail

Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology The normally understood connotation of personnel is identical.Unless otherwise indicated, all patents, patent application, the public material being cited in full text herein It is integrally incorporated by reference herein.If there are multiple definition to term herein, it is subject to the definition of this chapter.In reference URL Or when other such identifiers or address, it should be understood that such identifier can carry out changing and can with the specifying information on internet into Row exchange can also obtain information of equal value by Internal retrieval or other suitable reference channels.Reference obtained The availability and public propagation of data proof this type of information.

It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without being done to this paper subject matter Any restrictions.In this application, unless otherwise expressly specified, otherwise using odd number when also include plural number.It has to be noticed that unless text In separately have clear explanation, otherwise in the present specification and claims used singular include referents plural number Form.It shall yet further be noted that unless otherwise stated, "or" used, "or" indicate "and/or".In addition, term " includes " used And other forms, such as it is "comprising", " containing " and " containing " and non-limiting.

The definition of standard chemistry terms can be found in reference works, " the Advanced including Carey and Sundberg Organic Chemistry 4^thEd,Vol A(2000)and B(2001),Plenum Press,New York.Unless otherwise Illustrate, otherwise using the conventional method within the scope of art technology, as mass spectrum, NMR, HPLC, protein chemistry, biochemistry, Recombinant DNA technology and pharmacological method.Unless propose be specifically defined, otherwise herein analytical chemistry, Synthetic Organic Chemistry and The relevant name chemically such as medicine and pharmaceutical chemistry and laboratory operation and technology, are known to the skilled in the art. Standard technique can be used for chemical synthesis, chemical analysis, medicine preparation, and preparation passs medicine and the treatment of patient.Standard technique can be with For recombinant DNA, oligonucleotide synthesis and tissue cultures and conversion (such as electroporation, lipid infect method).For example, The kit that the specification provided with raw manufacturer is provided, perhaps according to method well known in the art or according to this hair The method of bright statement, to implement reaction and purification technique.In general, aforementioned techniques and step can pass through this field many institute's weeks The sum known conventional method described in various general literatures or more specific document is implemented, these documents are drawn in the present invention With and discuss.

When the conventional chemical formulas by writing from left to right describes substituent group, which similarly includes from right to left Write obtained equivalent substituent group in chemistry when structural formula.For example, CH₂O is equal to OCH₂。

Unless otherwise stated, general chemical terms used, such as, but not limited to, " alkyl ", " aryl " it is equivalent with Its form optionally replaced.For example, " alkyl " used herein includes the alkyl optionally replaced.

Compound described herein can have one or more stereogenic centres, and each stereogenic centers can be with R or S structure The form of type or combinations thereof exists.Similar, compound described herein can have one or more double bonds, and each double bond can be with The form of E (trans-) or Z (cis-) configuration or combinations thereof exists.It is one specific stereoisomer, constitutional isomer, diastereomeric Isomers, enantiomter should be read to include all possible stereoisomer, constitutional isomer, diastereoisomer, Enantiomter and its mixture.Therefore, compound described herein includes that stereoisomer different on all configurations, structure are different Structure body, diastereoisomer, enantiomeric forms and its corresponding mixture.For converting particular stereoisomer or making Particular stereoisomer keeps the technology of original state, and splitting the technology of stereoisomer mixture is that this field is known well, this Field technical staff can select suitable method with regard to concrete condition.See, e.g. Fumisset, Vogel ' s Encyclopedia of Practical Organic Chemistry 5^th ED.,Longman Scientific and Technical Ltd., Essex,1991,809-816；and Heller,Acc.Chem.Res.,1990,23,128.

It should be understood that the method and composition that the present invention describes is not restricted to the specific side that the present invention describes Method, bill, cell line, construct and reagent can be changed in this regard.It will also be appreciated that the present invention makes Term is only used for the purpose of description specific embodiment, and is not intended to limit the method and composition that the present invention describes Range is only limited by the attached claims.

The publication and patent that all present invention refer to are fully incorporated herein by reference, for describing With disclosed purpose, such as construct and method described in publication, the method that can be used for describing with the present invention is combined Object and compound combination.It is provided solely for disclosure of the publication of the invention discussed before the application day.It does not solve herein Be interpreted as a kind of license inventor described herein be not authorized to because formerly invention or due to any other in advance in this way Disclosure.

Terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer in molecule Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.

Term " key " or " singly-bound " refer to that so that two atoms or two parts is connected by key obtains more big structure part Chemical bond.

Term " optionally/any " or " optional/arbitrary " refer to that the event then described or situation may occur or can It can not occur, which includes that the event or situation occurs and the event or situation does not occur.For example, according to determining hereafter Justice, " alkyl optionally replaced " refer to " unsubstituted alkyl " or " substituted alkyl ".In addition, the group optionally replaced can make It is unsubstituted, replace completely, monosubstituted or part replaces.

C used herein₁-C_nIncluding C₁-C₂、C₁-C₃、……C₁-C_n.For example, the described " C₁-C₄" group refers to the portion There is 1-4 carbon atom, i.e. group includes 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms in point.Therefore, For example " C₁-C₄Alkyl " refers to that in the alkyl for having 1-4 carbon atom, i.e., the described alkyl is selected from methyl, ethyl, propyl, isopropyl Base, normal-butyl, isobutyl group, sec-butyl and tert-butyl.Digital scope herein, for example, " 1-8 " refer to it is each in given range A integer, such as " 1-8 carbon atom " refer to that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon Atom, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or 8 carbon atoms.

Term " alkyl " refers to the representative examples of saturated aliphatic hydro carbons of the straight chain optionally replaced or the branch optionally replaced.This paper's " alkyl " can preferably have about 20 carbon atoms of 1-, such as with about 10 carbon atoms of 1-, more preferably have about 8 carbon originals of 1- About 3 carbon atoms of about 4 carbon atoms of about 6 carbon atoms of son or 1- or 1- or 1-.The alkyl embodiment of this paper includes but unlimited In methyl, ethyl, n-propyl, isopropyl, 2- methyl-l- propyl, 2- methyl-2-propyl, 2-methyl-1-butene base, 3- methyl- L- butyl, 2- methyl -3- butyl, 2,2- dimethyl -1- propyl, 2- methyl-1-pentene base, 3- methyl-1-pentene base, 4- methyl-l- Amyl, 2- methyl -2- amyl, 3- methyl -2- amyl, 4- methyl -2- amyl, 2,2- dimethyl-l- butyl, 3,3- dimethyl - 1- butyl, 2- ethyl -1- butyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl, Hexyl etc. and longer alkyl group, such as heptyl and octyl.There is digital scope in group defined herein, such as " alkyl " When, such as " C_1-8Alkyl " refers to can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 The case where alkyl that a carbon atom, 7 carbon atoms, 8 carbon atoms are constituted, the alkyl of this paper also includes not specified digital scope.

Term " alkenyl " refers to the monovalent hydrocarbon of the straight chain optionally replaced or the branch optionally replaced, has at least one C=C double bond.The alkenyl has but is not limited to about 8 carbon atoms of 2-, such as about 6 carbon atoms of 2-, about 4 carbon atoms of 2-.This Double bond in a little groups can be cis or trans conformation, and should be understood comprising described two isomers.Alkenyl embodiment Including but not limited to vinyl (CH=CH₂), 1- acrylic (CH₂CH=CH₂), isopropenyl (C (CH₃)=CH₂), cyclobutenyl and 1,3- butadienyl etc..When there is digital scope in alkenyl defined herein, such as " C_2-8Alkenyl " refers to can be by 2 carbon atoms, 3 The alkenyl that a carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms are constituted, the alkene of this paper Base is also covered by the case where not specified digital scope.

Term " alkynyl " refers to the monovalent hydrocarbon of the linear chain or branched chain optionally replaced, has at least one tri- key of C ≡ C. The alkynyl has but is not limited to about 8 carbon atoms of 2-, such as about 4 carbon atoms of about 6 carbon atoms of 2- or 2-.The alkynes of this paper Base embodiment includes but is not limited to acetenyl, 2-propynyl, 2- butynyl and 1,3- diacetylene base etc..Alkynyl defined herein goes out When existing digital scope, such as " C_2-8Alkynyl " refers to can be by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 The alkynyl group that carbon atom, 7 carbon atoms, 8 carbon atoms are constituted, the alkynyl of this paper are also covered by the feelings of not specified digital scope Condition.

Term " halogenated " or " halogen " refer to optionally substituted group (such as alkyl, alkenyl, alkynyl, alkoxy) Wherein at least one hydrogen atom is replaced by halogen (such as fluorine, chlorine, bromine, iodine or combinations thereof).In some embodiments, that are used This identical halogen replaces two or more hydrogen (such as difluoromethyl, trifluoromethyl)；In other embodiments using each other Not fully identical halogen replaces two or more hydrogen (such as the fluoro- 1- iodine ethyl of the chloro- 1- of 1-).

Term " alkoxy " refers to that alkylether radicals (O- alkyl), the nonlimiting examples of alkoxy include methoxyl group, second Oxygroup, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy etc..

Term " aryl " refers to the aryl radical optionally replaced, with 6- about 20, such as 6-12 or 6-10 cyclization Carbon atom can be monocyclic aryl, bicyclic aryl or more base.Bicyclic aryl or more base can be a list Cyclophane base and other free rings, as alicyclic ring, heterocycle, aromatic ring, heteroaromatic mutually condense.The nonlimiting examples of monocyclic aryl include The monocyclic aryl of 6 to about 12,6 to about 10 or 6 to about 8 ring carbons, such as phenyl；Bicyclic aryl is, for example, naphthalene Base；Polyaromatic is, for example, phenanthryl, anthryl, azulenyl.

Term " heteroaryl " refers to any substituted heteroaryl, it includes about 5 to about 20, such as 5 to 12 or 5 to 10 A skeleton ring member nitrogen atoms, wherein at least one (such as 1-4,1-3,1-2) ring member nitrogen atoms are hetero atom, and the hetero atom is only The on the spot hetero atom in oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but not limited to this.Heteroaryl includes that bicyclic heteroaryl (has One ring), bicyclic heteroaryl (tool there are two ring) or polyheteroaromatic (there are more than two rings).In ring occur two or In more heteroatomic embodiments, described two or more hetero atoms can be mutually the same or described two or more miscellaneous original Some or all of son is different from each other.Bicyclic heteroaryl or more can be a bicyclic heteroaryl and it is other solely Vertical ring, as alicyclic ring, heterocycle, aromatic ring, heteroaromatic mutually condense (can be collectively referred to as fused ring heteroaryl).

Term " naphthenic base " refers to non-aromatic containing carbocyclic ring, including saturated carbon ring (such as naphthenic base) or unsaturated carbocyclic are (such as Cycloalkenyl).Carbocyclic ring includes monocyclic carbocyclic ring (having a ring), such as can be monocyclic cycloalkyl；Bicyclic carbocyclic ring (there are two rings for tool), example It such as can be bicyclic cycloalkyl；More carbocyclic rings (there are more than two rings).It can be bridge conjunction or loop coil between ring.Carbocyclic ring (such as ring Alkyl or cycloalkenyl) it can have 3 to 20 carbon atoms, such as with about 10 cyclization of about 15 ring carbons of 3- or 3- Carbon atom or 3-7 ring carbons.

Term " heterocycle " refers to nonaromatic heterocycles comprising saturated heterocyclic or unsaturated heterocycle (containing unsaturated bond).Its In atom of one or more (such as 1-4,1-3,1-2) cyclization be hetero atom, such as oxygen, nitrogen or sulphur atom.Heterocycle can To include that single heterocycle (with a ring) or double heterocycles (there are two the rings that bridge closes for tool) or more heterocycles (there are more than two bridges to close Ring)；It also include loop coil.Heterocycle can have 3 to about 20, such as 3- about 10,3- about 8,4-8,4-7,5- about 8 Or about 6 ring member nitrogen atoms of 5-.

Term " member " refers to the number for constituting the skeletal atom of ring.Such as pyridine is hexatomic ring, pyrroles is five-membered ring.

Term " substitution " means that one or more appointed groups of hydrogen on a specific atom is substituted, such as The normal chemical valence of the specified atom of fruit is in existing situation without departing from then the result is that a stable chemical combination after replacing Object.

Medicine terms

Term " bruton's tyrosine kinase " refers to the bruton's tyrosine kinase from homo sapiens (Homo Sapiens), Have been proposed in such as U.S. Patent No. 6326469.

Term " bruton's tyrosine kinase homologue " refers to the ortholog of bruton's tyrosine kinase, such as from Ortholog and the aforementioned arbitrary fusion protein of mouse, dog, rat, chicken or zebra fish, to one or more cloth Shandongs The tyrosine kinase substrate that pauses shows kinase activity.

Term " individual " refers to the individual with disease, illness or the patient's condition etc., including mammal and nonmammalian.It feeds The embodiment of newborn animal includes but is not limited to any member of class of mammals: people, inhuman primate (such as chimpanzee With other apes and monkey)；Domestic animal, such as ox, horse, sheep, goat, pig；Domestic animal, such as rabbit, dog and cat；Laboratory is dynamic Object, including rodent, such as rat, mouse and cavy etc..The embodiment of non-human mammal includes but is not limited to birds With fish etc..

Term " treatment " includes alleviating, mitigate or improving disease or condition symptoms with other similar synonyms, prevents it Its symptom improves or prevents the potential metabolism reason for leading to symptom, inhibits disease or illness, such as prevent the hair of disease or illness Disease or illness are alleviated in exhibition, and disease or illness is made to improve, and alleviate the symptom as caused by disease or illness, or stop disease or The symptom of illness, in addition, the term also may include the purpose of prevention.The term further includes obtaining therapeutic effect and/or pre- preventive effect Fruit.The therapeutic effect refers to the potential disease that healing or improvement are treated.In addition, to relevant to potential disease a kind of or more The healing or improvement of kind physiological signs are also therapeutic effect, such as although patient may nevertheless suffer from the influence of potential disease, Observe that patient profiles improve.It, can be to the patient's applying said compositions for suffering from specified disease risk for preventive effect Or compound, even if not yet make medical diagnosis on disease, but applied to the patient for one or more physiological signs of the disease occur With the composition or compound.

Term " metering for obtaining necessary therapeutic effect " or " therapeutically effective amount " refer to application metapedes to a certain degree At least one medicament of the upper one or more symptoms for alleviating treated disease or illness or the amount of compound.Its result can be with For the abatement of sign, symptom or the cause of disease and/or alleviation or any other required variation of biosystem.Such as dosage can be used The technology of escalation trial measures the effective quantity being suitable in any individual case.

Term administering " is the method for referring to for compound or composition being delivered to the required site for carrying out biological effect. These methods include but is not limited to oral route, through intraduodenal routes, parental injection (including intravenous, subcutaneous, peritonaeum Interior, intramuscular, intra-arterial injection or infusion), external application and per rectum administration.It can be used for described hereinization known to those skilled in the art The application technique of object and method is closed, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences Those of (current edition), discuss in Mack Publishing Co., Easton, Pa.

Term " pharmaceutically acceptable " refers to the substance of the bioactivity or property that do not influence the compounds of this invention, and Relative nontoxic, the i.e. substance can be applied to individual without cause undesirable biological respinse or in a manner of bad with include in composition Any component interaction.

Term " pharmaceutical composition " refers to the optional biology for being mixed at least one pharmaceutically acceptable chemical component Reactive compound, the pharmaceutically acceptable chemical component include but is not limited to carrier, stabilizer, diluent, suspending agent, increasing Thick dose and/or excipient.

Term " carrier " refers to the chemical compound or reagent of relative nontoxic, help for compound to be introduced into cell or In tissue.

Term " pharmaceutically acceptable salt " refers to the biopotency of the free acid and free alkali that remain appointed compound, And the not no salt of ill-effect on biologically or otherwise.The application compound further includes pharmaceutically acceptable Salt.Pharmaceutically acceptable salt refers to the form for the base group in parent compound being converted into salt.It is pharmaceutically acceptable Salt is include but are not limited to, the inorganic or organic acid salt of base group such as amine (ammonia) base.The application is pharmaceutically acceptable Salt can be synthesized by parent compound, i.e., the acid of the basic group in parent compound and 1-4 equivalent is in a solvent system Reaction.Suitable salt is enumerated in Remingtong ' s Pharmaceutical Scicences, and 17^th ed.,Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, In 66,2 (1977).

In addition to special instructions, the salt in the application refers to the acid salt formed with organic acid/inorganic acid, and with organic base/ The basic salt that inorganic base is formed.

Term " solvate " refers to the combination of the application compound and solvent molecule that are formed by solvation.? In some cases, solvate refers to hydrate, i.e. solvent molecule is hydrone, and the combination of the application compound and water forms hydration Object.One or more compounds in the application may exist in the form of solvate, just as with it is pharmaceutically acceptable The solvate forms that water, ethyl alcohol equal solvent are formed are the same, and therefore, the application includes two kinds of shapes of solvate and non-solvate Formula." solvate " refers to a compound in the application and the physical agglomeration of one or more solvent molecule formation, this Physical agglomeration includes the different degrees of and covalent bond of ion, such as hydrogen bond.Having proven to this solvate can be separated, example Such as, when being mixed with one or more solvent molecules in the lattice of crystal." solvate " includes solvent phase and separable solvent Compound two parts.Corresponding solvate example has very much, including alcohol solvent compound, Methanol Solvate etc.." hydrate " It is one kind with water (H₂O) molecule is the solvate of solvent.

One or more compounds in the application can arbitrarily prepare solvate.The preparation of solvate is many It is well known.Such as M.Caira et al, J.Pharmaceutical Sci., 93 (3) describe in 601-611 (2004) anti- The preparation of the solvate of fungi medicine Fluconazole is prepared with ethyl acetate and water.E.C.van Tonder et al,AAPS PharmSciTech., 5(1),article 12(2004)；With A.L.Bingham et al, Chem.Commun., 603-604 (2001) the similar preparation method of solvate, hydrate is also illustrated in.A kind of typical, unrestricted preparation process is Be higher than room temperature temperature when the compound of invention is dissolved in requirement ideal solvent in (organic solvent or water or they Mixed solvent), crystallization is placed in cooling, then chooses crystal with the separation of the method for standard.It can with I.R. spectroscopy analysis technology To confirm to be formed the presence of the solvent (water) of solvate (hydrate) in crystallization.

Term " active metabolite " refers to the active derivative of the compound formed in compound metabolism.

Term " polymorph " refers to the application compound existing for different form crystal lattices.

Term " isotopic label " refers to the application compound for having isotope labelling.Such as in the compound of the application Isotope include H, C, N, O, P, the various isotopes of F, S, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁸O,¹⁷O,³¹P,³²P,³⁵S,¹⁸F With³⁶S。

Term " pharmaceutically acceptable prodrug " or " prodrug " refer to any pharmaceutically acceptable of the application compound Salt, ester, ester salt or other derivatives, can directly or indirectly be provided after being applied to receptor the application compound or Its metabolin or residue with pharmaceutical active.Particularly preferred derivative or prodrug are that this can be improved when being applied to patient Apply those of compound bioavailability compound (for example, oral compound can be made to be more readily absorbed blood In), or promote parent compound to those of biologic-organ or action site (such as brain or lymphatic system) delivering chemical combination Object.

Various prodrug forms are well known in the art.Referring in the written Pro-drugs of T.Higuchi and V.Stella as Novel Delivery Systems(1987)Vol.14of the A.C.S.Symposium Series, Bioreversible Carriers in Drug Design,(1987)Edward B.Roche,ed.,American Pharmaceutical Association and the discussion in relation to prodrug is provided in Pergamon Press.Design of Prodrugs,Bundgaard,A.Ed.,Elseview, 1985and Method in Enzymology,Widder,K.et al.,Ed.；Academic,1985,vol.42,p.309-396； Bundgaard,H."Design and Application of Prodrugs"in A Textbook of Drug Design and Development,Krosgaard-Larsen and H.Bundgaard, Ed., 1991, chapter 5,113-191 pages；And Bundgaard, H., Advanced Drug Delivery Review, 1992,8,1-38, document above is incorporated herein by reference.

Term " stereoisomer " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule.Formula I compound contains asymmetric or chiral centre, and accordingly, there exist different stereoisomeric forms in any ratio.All three-dimensional knots of molecular formula I Structure is as mixture, including racemic mixture, as a part applied at present.Non-enantiomer mixture can be separated into Individual diastereomer, based on their different physicochemical properties, using well-known means, for example, enantiomter Fractionation can by with optically active substance appropriate (such as chiral alcohol or Mosher`s Mohs acyl chlorides) reaction conversions be it is non-right Isomers is reflected, be isolated and is converted (as hydrolyzed) as corresponding single isomers.Some compounds in Formulas I may be Atropisomer (such as substituted aryl) is also a part in the application.Chiral chromatogram post separation can also be used in enantiomter. There may be different tautomeric forms, these forms are included within the scope of the application compound in Formulas I.For example, The compound of keto-enol and imine-enamine forms.

Term " IC₅₀" refer to that the 50% of ceiling effect is obtained in the analysis for measuring such effect inhibits, such as BTK Amount, concentration or the dosage of the fc-specific test FC compound of inhibition.

Detailed description of the invention

Fig. 1 is the test result figure of test case 3 of the present invention.

Specific embodiment

To make the object, technical solutions and advantages of the present invention clearer, it will be further described below example of the invention The technical solution of property embodiment.

The present invention can prepare compound of the present invention by following methods.Following methods and embodiment are to say These bright methods.These processes and embodiment are not construed in any way as limitation of the present invention.Ability can also be used Standard synthetic techniques known to field technique personnel synthesize compound as described herein, or be applied in combination means known in the art and Methods described herein.

Embodiment

Synthetic route:

Compound shown in formula (1) can be prepared according to said synthesis route.Each resulting production is reacted in route Object can be obtained by conventional separation techniques, and this traditional technology includes but is not limited to filter, distillation, crystallize, chromatography point From etc..Starting material required for synthesizing oneself can be synthesized or be obtained from commercial undertaking's purchase.These raw materials can be used Conventional means are characterized, such as physical constant and spectroscopic data.Synthetic method can be used in compound described in the invention Obtain the mixture of single isomers either isomers.

Starting material 1 can directly be bought by commercial sources or be obtained by organic synthesis, can be with by two kinds of approach Obtain intermediate 4.Which kind of specifically used approach obtains intermediate 4, depending on specific reaction feasibility, raw material obtain complexity and It is fixed.One approach is to act on obtaining intermediate 2 by commercialization reagent chlorosulphonyl isocyanate and the tert-butyl alcohol.Utilize intermediate 2 The acidity and chlorethanol of amino in structure among sulfonyl and carbonyl or substituted chlorethanol are in azoformic acid diisopropyl Ester and the lower Mitsunobu that occurs of triphenylphosphine effect react, available intermediate 3.Intermediate 3 in acid condition, is sloughed Tertbutyloxycarbonyl obtains compound 4.Another approach is to first pass through two-step reaction to synthesize to obtain reaction reagent 6, recycles starting The nucleophilicity of exposed amino in raw material 1, the sulfonyl in attack reagent 6, while the oxazoline ketone segment in reagent 6 is left away, it can To obtain intermediate 4.The cyclization under alkaline condition of intermediate 4, can finally obtain product 5.

Embodiment 1 (R) -1- (1- (sulphonyl ethylenimine) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4- D] and pyrimidine -4- amine

Process 1:

Step A:(R) -1- (1- (N- tertbutyloxycarbonyl sulfonamide) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrrole Azoles [3,4-d] and pyrimidine -4- amine

In 100mL reaction flask, (R) -1- (piperidines -3- base) is added, and -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] is simultaneously Pyrimidine -4- amine 10g, methylene chloride 60mL, add triethylamine 4.4mL, ice bath is cooled to 0 DEG C or so under nitrogen protection under stirring For use.Methylene chloride 20mL is added in another 50mL reaction flask, chlorosulphonyl isocyanate 4.4g is added under nitrogen protection, it is rear to be added dropwise The dichloromethane solution of the tert-butyl alcohol (the 3mL tert-butyl alcohol is dissolved in 16mL methylene chloride).It drips off stirring after twenty minutes, this is reacted into drop Enter in aforementioned 100mL reaction flask, 0 DEG C of temperature control or so, drips off continuation insulation reaction 30 minutes, then reaction solution is concentrated, uses silicon Glue carries out column chromatographic purifying, obtains 6.5g grease product, m/z=566 [M+H]⁺。

Step B:(R) -1- (1- (N-2- chloroethyl-N- tertbutyloxycarbonyl sulfonamide) piperidines -3- base) -3- (4- phenoxy group Phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

(R) -1- (1- (N- tertbutyloxycarbonyl sulfonamide) piperidines -3- base) -3- (4- phenoxy group benzene is added in 50mL reaction flask Base) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine 3.4g, ethylene chlorhydrin 1.5g, tetrahydrofuran 30mL, triphenylphosphine 4.87g, nitrogen Diisopropyl azodiformate 3.8g is added dropwise under ice salt bath, drips off nature and rises again for gas shielded, to after completion of the reaction, by reaction solution Silica gel column chromatography is added after concentration, obtains 3g off-white powder, m/z=628 [M+H]⁺。

Step C:(R) -1- (1- (N-2- chloroethylsulfonamide) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

(R) -1- (1- (N-2- chloroethyl-N- tertbutyloxycarbonyl sulfonamide) piperidines -3- base) -3- is added in 50mL reaction flask 3mL trifluoro second is added dropwise under ice bath in (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine 3g, 25mL methylene chloride Acid is stirred at room temperature 2 hours, and solvent is concentrated under reduced pressure, and crude product is added silicagel column and carries out column chromatographic purifying, obtains 2.3g yellow solid, M/z=528 [M+H]⁺。

Step D:(R) -1- (1- (sulphonyl ethylenimine) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] And pyrimidine -4- amine

(R) -1- (1- (N-2- chloroethylsulfonamide) piperidines -3- base) -3- (4- phenoxy group benzene is added in 50mL reaction flask Base) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine 2.3g and acetone 25mL, 25mL water is added, Anhydrous potassium carbonate is added with stirring 2.5g is stirred at room temperature reaction overnight, after the reaction was completed, is diluted with water, product is extracted with dichloromethane three times, organic phase nothing Aqueous sodium persulfate is dry, and silica gel column chromatography is added after concentration, obtains white solid 1.5g, m/z=492 [M+H]⁺,¹HNMR (400MHz,CDCl₃), δ 8.37 (s, 1H), 7.64 (d, J=6.4Hz, 2H), 7.39 (t, J=5.6Hz, 2H), 7.17 (m, 3H), 7.08 (d, J=5.6Hz, 2H), 5.55 (br, 2H), 5.05 (m, 1H), 4.08 (m, 1H), 3.92 (br d, 1H), 3.55 (t, J=7.2Hz, 1H), 3.01 (t, J=7.2Hz, 1H), 2.31 (br s, 4H), 2.25 (m, 2H), 1.98 (m, 2H).

Or use following scheme 2:

Step A:N- (2- chloroethene oxygen carbonyl)-N '-(2- chloroethyl) sulfonic acid diamine

Methylene chloride 60mL, chlorosulphonyl isocyanate 17.6g are added in the reaction flask of 250mL, ice bath is cooled to 0 DEG C of left side The dichloromethane solution of ethylene chlorhydrin is added dropwise in the right side (10g ethylene chlorhydrin is dissolved in 60mL methylene chloride).It is added dropwise, 10 minutes Ice-water bath is removed in recession, returns and warms to room temperature naturally, places after the reaction was completed spare.500mL reaction flask is separately taken, methylene chloride is added 150mL and 2-chloroethyl amine hydrochloride 14.4g, ice-water bath cooling, is added dropwise triethylamine 26.4g, continues that aforementioned gained dichloromethane is added dropwise Alkane solution drips off nature and rises again.50mL water is added after the reaction was completed, crude product is filtered to obtain, with ethyl acetate and petroleum ether system It recrystallizes, obtains 17.8g off-white powder.

Step B:N- (2- chloroethyl) -2- oxazoline ketone -3- sulfonamide

Methylene chloride 45mL is added in 100mL reaction flask, adds N- (2- chloroethene oxygen carbonyl)-N '-(2- chloroethyl) Sulfonic acid diamine 15g is added with stirring triethylamine 15mL.It finishes, after first reacting 1 hour at room temperature, next time then at 50 DEG C of water-baths Stream reaction.End of reaction after about 1 hour, concentration stir cooling after falling part methylene chloride, filter out solid, and mother liquor concentrations do to obtain nothing Color grease is cooled to crystallizing at room temperature and obtains 10.7g off-white powder.

Step C:(R) -1- (1- (N- chloroethylsulfonamide) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3, 4-d] and pyrimidine -4- amine

(R) -1- (piperidines -3- base) is added in 100mL reaction flask, and -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] is simultaneously Pyrimidine -4- amine 2.3g, acetonitrile 45mL, triethylamine 2g and N- (2- chloroethyl) -2- oxazoline ketone -3- sulfonamide 2.5g, stirring rise Temperature is reacted after 30 minutes and is completed to flowing back, and after concentrated solvent, silica gel column chromatography is added, obtains 2.1g yellow solid, m/z= 528[M+H]⁺。

Embodiment 2 (R) -1- (1- (sulphonyl ethylenimine) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3, 4-d] and pyrimidine -4- amine

Process 3:

Step A:(R) -1- (1- tertbutyloxycarbonyl pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] And pyrimidine -4- amine

3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine 3g, dry four are added in 100mL reaction flask Hydrogen furans 30mL, triphenylphosphine 3.89g, (S)-N- tertbutyloxycarbonyl -3- hydroxyl pyrrolidine 5.74g, under nitrogen protection, ice salt bath Lower dropwise addition diisopropyl azodiformate 8.0g is stirred in cooling.It drips off, overnight, after completion of the reaction, concentrated solvent adds for heating naturally Enter silica gel column chromatography and obtains 3g light yellow oil, m/z=473 [M+H]⁺。

Step B:(R) -1- (pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

(R) -1- (1- tertbutyloxycarbonyl pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- is added in 50mL reaction flask Pyrazoles [3,4-d] and pyrimidine -4- amine 3g, ethyl alcohol 25mL stirring and dissolving add acidic alcohol 25mL, are stirred to react at room temperature Overnight, there are a solid precipitation, concentration of reaction solution, residue adds water, after stirring and dissolving, is washed twice with methyl tertiary butyl ether(MTBE), water phase PH=9 is adjusted with sodium hydroxide solution, then product is extracted with dichloromethane, is concentrated to give 1.75g khaki solid, m/z=373 [M+H]⁺。

Step C:(R) -1- (1- (N- chloroethylsulfonamide) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

By the operation in the step C of process 2 in similar embodiment 1, obtaining product is yellow solid, m/z= 514[M+H]⁺。

Step D:(R) -1- (1- (sulphonyl ethylenimine) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4- D] and pyrimidine -4- amine

By the operation in the step D of process 1 in similar embodiment 1, obtaining product is white solid, m/z= 478[M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.64 (d, J=6.4Hz, 2H), 7.39 (t, J= 7.6Hz, 2H), 7.16 (m, 3H), 7.09 (d, J=7.6Hz, 2H), 5.62 (m, 1H), 5.53 (br, 2H), 4.03 (m, 1H), 3.92(m,2H),3.72(m,1H),2.67(m,1H),2.53(m,1H),2.30(br s,4H)。

Embodiment 3 (R) -1- (1- (sulphonyl ethylenimine) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- amino-pyrazol - 4- formamide

Process 4:

Step A:(R) -1- (1- tertbutyloxycarbonyl pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- amino-pyrazol -4- Formamide

(R) -1- (1- tertbutyloxycarbonyl pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- is added in 2000mL reaction flask Amino-pyrazol -4- formonitrile HCN 42.3g, dimethyl sulfoxide 570mL, potassium carbonate 40g, stirring are warming up to 60 DEG C or so, maintain 60 DEG C of left sides It is right that hydrogen peroxide 400mL is slowly added dropwise.Continuation insulation reaction is dripped, is diluted with water after completion of the reaction, add methylene chloride extraction, Organic phase is washed with sodium sulfite aqueous solution, is concentrated after dry, and silica gel column chromatography is added, obtains 19.2g grease, m/z= 464[M+H]⁺。

Step B:(R) -1- (pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- aminopyrazoles-4-formamide

(R) -1- (1- tertbutyloxycarbonyl pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) is added in 500mL stand up reaction bottle - 5- aminopyrazoles-4-formamide 15.5g and ethyl alcohol 45mL, stirs dissolved clarification, adds acidic alcohol 200mL under room temperature, fluid-tight, 2 hours end of reaction are stirred, solid filtering adds water and stirs dissolution, washed twice with methyl tertiary butyl ether(MTBE), water phase sodium hydroxide Solution adjusts pH=9, then product is extracted with dichloromethane, and is concentrated to give 7.8g yellow solid, m/z=364 [M+H]⁺。

Step C:(R) -1- (1- (N- chloroethylsulfonamide) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- amino pyrrole Azoles -4- formamide

By the operation in the step C of process 2 in similar embodiment 1, obtaining product is brown yellow oil liquid, M/z=505 [M+H]⁺。

Step D:(R) -1- (1- (sulphonyl ethylenimine) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- amino-pyrazol - 4- formamide

By the operation in the step D of process 1 in similar embodiment 1, products obtained therefrom is white solid, m/z= 469[M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 7.49 (d, J=6.8Hz, 2H), 7.38 (t, J=7.2Hz, 2H), 7.16 (t, J=7.2Hz, 1H), 7.07 (m, 4H), 5.62 (br, 2H), 4.77 (m, 1H), 3.91 (m, 1H), 3.84 (m, 2H), 3.62 (m,1H),2.62(m,1H),2.44(m,1H),2.30(br s,4H)。

Embodiment 4 (R) -1- (1- (sulphonyl (2- methyl ethylenimine)) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrrole Azoles [3,4-d] and pyrimidine -4- amine

Process 5:

Synthesis in embodiment 4 is using 1- methyl -2-chloroethyl amine as raw material, by the step A of process 2 in similar embodiment 1, (see process 5) is completed in the operation in step B, step C and embodiment 1 in the step D of process 1, and products obtained therefrom is that class is white Color solid, m/z=506 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.63 (d, J=6.4Hz, 2H), 7.38 (t, J=6.0Hz, 2H), 7.17 (m, 3H), 7.08 (d, J=6.0Hz, 2H), 5.54 (br, 2H), 5.04 (m, 1H), 4.08 (m, 1H), 3.92 (br d, 1H), 3.55 (t, J=7.2Hz, 1H), 3.00 (t, J=7.2Hz, 1H), 2.56 (m, 1H), 2.40 (m, 2H), 2.25 (m, 2H), 1.98 (m, 2H), 1.35 (d, J=7.2Hz, 3H).

Embodiment 5 (R) -1- (1- (sulphonyl (2- methyl ethylenimine)) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- Pyrazoles [3,4-d] and pyrimidine -4- amine

Process 6:

The synthesis of embodiment 5 with (R) -1- (pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] simultaneously Pyrimidine -4- amine (see 2 step B of embodiment) is raw material, is completed by step described in similar embodiment 4, obtains product as white Solid, m/z=492 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.64 (d, J=6.4Hz, 2H), 7.39 (t, J=7.6Hz, 2H), 7.16 (m, 3H), 7.09 (d, J=7.6Hz, 2H), 5.62 (m, 1H), 5.53 (br, 2H), 4.03 (m, 1H), 3.92 (m, 2H), 3.72 (m, 1H), 2.67 (m, 1H), 2.54 (m, 2H), 2.40 (m, 2H), 1.37 (d, J=7.2Hz, 3H)。

Embodiment 6 (R) -1- (1- (sulphonyl ethylenimine) pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

Process 7:

Step A:3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

The iodo- 1H- pyrazoles [3,4-d] of 3- and pyrimidine -4- amine 5g, dioxane 50mL, 4- are added in 100mL reaction flask to fluorine Phenyl phenyl boric acid 4.8g, potassium carbonate 2g and tetra-triphenylphosphine palladium 0.5g, reaction system use nitrogen protection, following reaction after vacuumizing It is heated to 90 DEG C overnight, after completion of the reaction, filtering is added silica gel column chromatography, obtains 4.5g brown solid, m/ after filtrate concentration Z=322 [M+H]⁺。

Step B:(R) -1- (1- tertbutyloxycarbonyl pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3, 4-d] and pyrimidine -4- amine

By the operation in step A in similar embodiment 2, obtaining product is light yellow solid, m/z=491 [M+H]⁺。

Step C:(R) -1- (pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] and pyrimidine - 4- amine

By the operation in step B in similar embodiment 2, obtaining product is yellow solid, m/z=391 [M+H]⁺。

Step D:(R) -1- (1- (N- chloroethylsulfonamide) pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- Pyrazoles [3,4-d] and pyrimidine -4- amine

By the operation in the step C of process 2 in similar embodiment 1, obtaining product is light yellow solid, m/z= 532[M+H]⁺。

Step E:(R) -1- (1- (sulphonyl ethylenimine) pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

By the operation in the step D of process 1 in similar embodiment 1, obtaining product is off-white powder, m/z= 496[M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.64 (d, J=6.4Hz, 2H), 7.45 (dd, J= 7.6Hz, 6.4Hz, 2H), 7.22 (dd, J=9.6Hz, 7.6Hz, 2H), 7.16 (d, J=6.4Hz, 2H), 5.62 (m, 1H), 5.53 (br,2H),4.04(m,1H),3.91(m,2H),3.72(m,1H),2.66(m,1H),2.52(m,1H),2.30(br s,4H)。

Embodiment 7 (R) -1- (1- (sulphonyl ethylenimine) piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

Process 9:

Step A:(R) -1- (1- t-butoxycarbonylpiperidin -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4- D] and pyrimidine -4- amine

Using (S)-N- tertbutyloxycarbonyl -3- hydroxy piperidine as raw material, pass through the behaviour in step A in similar embodiment 2 Make, obtaining product is light yellow solid, m/z=505 [M+H]⁺。

Step B:(R) -1- (piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- Amine

By the operation in step B in similar embodiment 2, obtaining product is light yellow solid, m/z=405 [M+H]⁺。

Step C:(R) -1- (1- (N- chloroethylsulfonamide) piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrrole Azoles [3,4-d] and pyrimidine -4- amine

By the operation in the step C of process 2 in similar embodiment 1, obtaining product is light yellow solid, m/z= 546[M+H]⁺。

Step D:(R) -1- (1- (sulphonyl ethylenimine) piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3, 4-d] and pyrimidine -4- amine

By the operation in the step D of process 1 in similar embodiment 1, obtaining product is off-white powder, m/z= 510[M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.36 (s, 1H), 7.63 (d, J=6.4Hz, 2H), 7.45 (dd, J= 7.6Hz, 6.4Hz, 2H), 7.22 (dd, J=9.6Hz, 7.6Hz, 2H), 7.16 (d, J=6.4Hz, 2H), 5.55 (br, 2H), 5.05 (m, 1H), 4.07 (m, 1H), 3.92 (br d, 1H), 3.55 (t, J=7.2Hz, 1H), 3.01 (t, J=7.2Hz, 1H), 2.31(br s, 4H),2.24(m,2H),1.98(m,2H)。

Embodiment 8 (R) -1- (1- (sulphonyl (2- methyl ethylenimine)) piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) - 1H- pyrazoles [3,4-d] and pyrimidine -4- amine

Synthesis in embodiment 8 is with (R) -1- (piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4- D] and pyrimidine -4- amine (see 7 step B of embodiment) be raw material, completed by step described in similar embodiment 4, products obtained therefrom is Off-white powder, m/z=524 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.62 (d, J=6.4Hz, 2H), 7.45 (dd, J=7.2Hz, 6.4Hz, 2H), 7.22 (dd, J=9.6Hz, 7.2Hz, 2H), 7.16 (d, J=6.4Hz, 2H), 5.54 (br, 2H), 5.04 (m, 1H), 4.08 (m, 1H), 3.92 (br d, 1H), 3.55 (t, J=7.2Hz, 1H), 3.00 (t, J=7.2Hz, 1H), 2.55 (m, 1H), 2.40 (m, 2H), 2.25 (m, 2H), 1.97 (m, 2H), 1.34 (d, J=7.2Hz, 3H)。

(4- is to fluorophenoxy benzene by -3- by embodiment 9 (R) -1- (1- (sulphonyl (2- methyl ethylenimine)) pyrrolidin-3-yl) Base) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

The synthesis of embodiment 9 is with (R) -1- (pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4- D] and pyrimidine -4- amine (see 6 step C of embodiment) be raw material, by step described in similar embodiment 4 complete, obtaining product is White solid, m/z=510 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.62 (d, J=6.4Hz, 2H), 7.44 (dd, J=7.2Hz, 6.4Hz, 2H), 7.20 (dd, J=9.6Hz, 7.2Hz, 2H), 7.15 (d, J=6.4Hz, 2H), 5.62 (m, 1H), 5.53 (br, 2H), 4.03 (m, 1H), 3.92 (m, 2H), 3.72 (m, 1H), 2.67 (m, 1H), 2.54 (m, 2H), 2.40 (m, 2H), 1.37 (d, J=7.2Hz, 3H).

Embodiment 10 (R) -1- (1- (sulphonyl (2- methyl ethylenimine)) pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- Aminopyrazoles-4-formamide

The synthesis of embodiment 10 is with (R) -1- (pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- amino-pyrazol -4- first Amide (see 3 step B of embodiment) is raw material, is completed by the step in similar embodiment 4, and it is solid for off-white color to obtain product Body, m/z=483 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 7.49 (d, J=6.8Hz, 2H), 7.38 (t, J=7.2Hz, 2H), 7.17 (t, J=7.2Hz, 1H), 7.07 (m, 4H), 5.61 (br, 2H), 4.77 (m, 1H), 3.92 (m, 1H), 3.85 (m, 2H), 3.62 (m, 1H), 2.58 (m, 2H), 2.44 (m, 3H), 1.36 (d, J=7.6Hz, 3H).

Embodiment 11 (R) -1- (1- (sulphonyl (2- dimethylamino methyl ethylenimine)) piperidines -3- base) -3- (4- phenoxy group benzene Base) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

Process 10:

The chloro- 3- dimethylamino isopropanol of step A:1-

Ethyl alcohol 15mL, epoxychloropropane 4g are added in 25mL reaction flask, under nitrogen protection, ice salt bath be cooled to -5 DEG C with Under, dimethylamine solution (30% ethanol solution) 7.2g is added dropwise, drips off and continues -5 DEG C insulation reaction 2 hours, removes ice salt bath nature It is warming up to room temperature.After completion of the reaction, directly 5.8g colourless transparent oil liquid is done to obtain in concentration.

Step B:(R) -1- (1- (N- (1- chloroethyl -3- dimethylamino-propyl -2- base)-N- tertbutyloxycarbonyl sulfonamide) Piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

Using the chloro- 3- dimethylamino isopropanol of 1- as raw material, pass through the behaviour in the step B of process 1 in similar embodiment 1 Make, obtaining product is yellow solid, m/z=685 [M+H]⁺。

Step C:(R) -1- (1- (N- (1- chloroethyl -3- dimethylamino-propyl -2- base) sulfonamide) piperidines -3- base) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

By the operation in the step C of process 1 in similar embodiment 1, obtaining product is yellow-brown solid, m/z= 585[M+H]⁺。

Step D:(R) -1- (1- (sulphonyl (2- dimethylamino methyl ethylenimine)) piperidines -3- base) -3- (4- phenoxy group benzene Base) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

By the operation in the step D of process 1 in similar embodiment 1, obtaining product is faint yellow solid, m/z= 549[M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.63 (d, J=6.4Hz, 2H), 7.38 (t, J= 6.0Hz, 2H), 7.17 (m, 3H), 7.08 (d, J=6.0Hz, 2H), 5.54 (br, 2H), 5.04 (m, 1H), 4.08 (m, 1H), 3.92 (br d, 1H), 3.55 (t, J=7.2Hz, 1H), 3.00 (t, J=7.2Hz, 1H), 2.75 (m, 1H), 2.54 (m, 2H), 2.42(m, 2H),2.36(s,6H),2.25(m,2H),1.98(m,2H)。

Embodiment 12 (R) -1- (1- (sulphonyl (2- dimethylamino methyl ethylenimine)) pyrrolidin-3-yl) -3- (4- phenoxy group Phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

The synthesis of embodiment 12 with (R) -1- (pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -1H- pyrazoles [3,4-d] simultaneously Pyrimidine -4- amine (see 2 step B of embodiment) is raw material, by the step A and embodiment 11 of process 1 in similar embodiment 1 Step B, step C and step D described in operate complete, obtain product be off-white powder, m/z=535 [M+H]⁺,¹HNMR (400MHz,CDCl₃), δ 8.37 (s, 1H), 7.64 (d, J=6.4Hz, 2H), 7.39 (t, J=7.6Hz, 2H), 7.16 (m, 3H), 7.09 (d, J=7.6Hz, 2H), 5.62 (m, 1H), 5.53 (br, 2H), 4.03 (m, 1H), 3.92 (m, 2H), 3.72 (m, 1H), 2.77(m,1H),2.67(m,1H),2.52(m,3H),2.40(m,2H),2.35(s,6H)。

(4- is to fluorobenzene oxygen by -3- by embodiment 13 (R) -1- (1- (sulphonyl (2- dimethylamino methyl ethylenimine)) piperidines -3- base) Base phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

The synthesis of embodiment 13 is with (R) -1- (piperidines -3- base) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4-d] And pyrimidine -4- amine (see 7 step B of embodiment) is raw material, passes through the step A and embodiment 11 of process 1 in similar embodiment 1 In step B, step C and step D described in operate complete, obtain product be off-white powder, m/z=567 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.62 (d, J=6.4Hz, 2H), 7.45 (dd, J=7.2Hz, 6.4Hz, 2H), 7.22 (dd, J=9.2Hz, 7.2Hz, 2H), 7.17 (d, J=6.4Hz, 2H), 5.56 (br, 2H), 5.04 (m, 1H), 4.08 (m, 1H), 3.92 (br d, 1H), 3.55 (t, J=7.2Hz, 1H), 3.00 (t, J=7.2Hz, 1H), 2.75 (m, 1H), 2.53(m,2H),2.40(m,2H),2.35(s,6H),2.25(m,2H),1.96(m,2H)。

(4- is to fluorobenzene by -3- by embodiment 14 (R) -1- (1- (sulphonyl (2- dimethylamino methyl ethylenimine)) pyrrolidin-3-yl) Phenyl) -1H- pyrazoles [3,4-d] and pyrimidine -4- amine

The synthesis of embodiment 14 is with (R) -1- (pyrrolidin-3-yl) -3- (4- is to fluorophenoxy phenyl) -1H- pyrazoles [3,4- D] and pyrimidine -4- amine (see 6 step C of embodiment) be raw material, pass through the step A and embodiment of process 1 in similar embodiment 1 Completion is operated described in step B in 11, step C and step D, obtaining product is off-white powder, m/z=553 [M+H]⁺,¹HNMR(400MHz,CDCl₃), δ 8.37 (s, 1H), 7.62 (d, J=6.4Hz, 2H), 7.44 (dd, J=7.2Hz, 6.4Hz, 2H), 7.20 (dd, J=9.6Hz, 7.2Hz, 2H), 7.15 (d, J=6.4Hz, 2H), 5.62 (m, 1H), 5.53 (br, 2H), 4.03(m,1H),3.92(m,2H),3.72(m,1H),2.78(m,1H),2.66(m,1H),2.52(m,3H), 2.40(m, 2H),2.34(s,6H)。

Embodiment 15

The synthesis of embodiment 15 is with (R) -1- (pyrrolidin-3-yl) -3- (4- Phenoxyphenyl) -5- amino-pyrazol -4- first Amide (see 3 step B of embodiment) is raw material, passes through the step in the step A and embodiment 11 of process 1 in similar embodiment 1 It operates and completes described in B, step C and step D, obtaining product is off-white powder, m/z=526 [M+H]⁺,¹HNMR(400MHz, CDCl₃), δ 7.48 (d, J=6.8Hz, 2H), 7.38 (t, J=7.2Hz, 2H), 7.17 (t, J=7.2Hz, 1H), 7.07 (m, 4H),5.61(br,2H),4.77(m,1H),3.92(m,1H),3.85(m,2H),3.62(m,1H),2.77(m,1H), 2.59 (m,2H),2.51(m,1H),2.43(m,3H),2.35(s,6H)。

The test of test case 1BTK the enzyme activity

Embodiment compound and irreversible BTK inhibitor (PCI-32765) are measured in enzyme activity reaction to BTK kinase activity Rejection ability, take even phase time-resolved fluorescence (HTRF) method to establish the kinase activity detection platform of BTK, carry out chemical combination The active measurement of object.

Compound to be tested is carried out since 1mM with 100%DMSO to 3 times of gradient dilution (totally 11 concentration), often A concentration takes 4 μ L to be added in the reaction buffer of 96 μ L (50mM Hepes, pH 7.0,5mM MgCl₂, 0.1mM Orthovanadate, 0.01%BSA), take 2.5 μ L be added to 384 orifice plates (OptiPlate-384, purchase in PerkinElmer the BTK kinases (purchase is in Millipore) of 2 μ L) is then added, centrifugation mixes, and adds the ATP and 2 of 2 μ L μL TK-peptide(KinEASE^TM- TK is bought in Cisbio) mixture starting reaction.384 orifice plates are put in and are incubated It educates in case and reacts 90 minutes for 23 DEG C, be then added 5 μ L TK-Antibody (purchase is in Cisbio), 5 μ L XL-665 ( KinEASE^TM- TK is bought in Cisbio) stop reaction.After being incubated for 1 hour in incubator, Envision (purchase in PerkinElmer fluorescent value is read on), and (320nm excitation, detects the transmitting light of 665nm and 615nm, and the two ratio is enzyme activity Property).Each compound measures the activity of enzyme under 11 concentration respectively, and data use GraFit6.0 software (Erithacus Software the IC of the compound) is calculated₅₀Value.

The test of test case 2ITK the enzyme activity

Embodiment compound and irreversible BTK inhibitor (PCI-32765) are measured in enzyme activity reaction to ITK kinase activity Rejection ability, take even phase time-resolved fluorescence (HTRF) method to establish the kinase activity detection platform of ITK, carry out chemical combination The active measurement of object.

Compound to be tested is carried out since 1mM with 100%DMSO to 3 times of gradient dilution (totally 11 concentration), often A concentration takes 4 μ L to be added in the reaction buffer of 96 μ L (50mM Hepes, pH 7.0,5mM MgCl₂, 0.1mM Orthovanadate, 0.01%BSA), take 2.5 μ L be added to 384 orifice plates (OptiPlate-384, purchase in PerkinElmer the ITK kinases (purchase is in Millipore) of 1 μ L) is then added, centrifugation mixes, and adds the ATP and 2 of 2 μ L μL TK-peptide (KinEASE^TM- TK is bought in Cisbio) mixture starting reaction.384 orifice plates are put in and are incubated It educates in case and reacts 60 minutes for 23 DEG C, be then added 5 μ L TK-Antibody (purchase is in Cisbio), 5 μ L XL-665 ( KinEASE^TM- TK is bought in Cisbio) stop reaction.After being incubated for 1 hour in incubator, Envision (purchase in PerkinElmer fluorescent value is read on), and (320nm excitation, detects the transmitting light of 665nm and 615nm, and the two ratio is enzyme activity Property).Each compound measures the activity of enzyme under 11 concentration respectively, and data use GraFit6.0 software (Erithacus Software the IC of the compound) is calculated₅₀Value.

Test case 1 and the external inhibitory activity of the resulting BTK of test case 2 and selectivity test result such as table 1 for ITK It is shown.

Table 1

3 irreversible effect mechanism study of test case

BTK kinases (40nM) and BTK inhibitor (20nM) to be measured are incubated for 2.5hrs at 25 DEG C jointly, then should Mixture dilutes 100 times, and is reacted with enzyme reaction substrate (ATP+TK peptide).Then point is added in different times Acetonitrile (150 μ L) terminate reaction, measure enzymatic activity.The mixture of enzyme and BTK inhibitor is after 100 times of dilution, much Lower than IC₅₀Under the concentration conditions of value, the sample enzymatic activity of invertibity BTK inhibitor (CGI1746) processing is restored, and can not The sample of inverse BTK inhibitor (PCI-32765) processing is not restored then.It is consistent with PCI-32765,1 compound of embodiment The enzymatic activity of the sample of processing is not also restored, as shown in Figure 1.Illustrate (the i.e. compound 1) compound of embodiment 1 and BTK enzyme hair Given birth to irreversible combination, also illustrate sulphonyl ethylenimine be one can be with the covalently bound novel function of BTK Cys485 Group.

4 drug of test case (metabolism) dynamics research

Research is divided into two groups: first group animals (6 rats, half male and half female) single intravenous injection, dosage 1mg/ Kg, drug are dissolved in by 10%EtOH, 40%PEG400,50%H₂O (v/v/v) in the mixed solvent, concentration 2mg/mL, before administration Pass through 0.2- μm of membrane filtration, administered volume 2.5mL/kg.Second group of (6 rats, half male and half female) single oral gavage administration, Dosage is 5mg/kg, and drug is suspended in 20%SBE, and suspension concentration is respectively 0.6mg/mL, administered volume 5mL/kg.Stomach-filling The animal of administration group overnight fasting before experiment, fasting time is from administration first 10 hours to 4 hours after administration；Intravenously administrable group Animal non-fasting.

Intravenously administrable group before administration with 0.083 after administration, 0.25,0.5,1,1.5,2,3,4,6,8,12 and 24 hours Blood sampling, gastric infusion group before administration with 0.25 after administration, 0.5,1,1.5,2,3,4,6,8,12 and 24 hours take a blood sample.Using small Animal Anesthesia machine takes 0.3mL whole blood by eyeground vein clump after isoflurane is anaesthetized, and is put in anticoagulant heparin pipe, sample is in 4 DEG C, 4000rpm be centrifuged 5min, blood plasma is transferred in centrifuge tube, and is put in -80 DEG C of preservations.

The concentration analysis of drug uses Liquid Chromatography-tandem Mass method (LC-MS/MS) in plasma sample.Analysis It is preceding suspension and dilution quality-control sample (are equivalent to the suspension of the oral administration of the Fresh of quality-control sample concentration after dilution With the solution of intravenously administrable) 100 times of dilution in acetonitrile are used, then 10 times are diluted with rat blank plasma.Standard curve range be 1 to 1000ng/mL, lower limit of quantitation are respectively 1ng/mL.

The plasma concentration v. time data of individual animals are analyzed with WinNonlin software.Pharmacokinetic results such as table Shown in 2.

Table 2

The pharmacokinetic results that other compounds of embodiment are obtained according to identical test method, with 1 chemical combination of embodiment Object result is close.

By Fig. 1, Tables 1 and 2 result it is found that compound provided by the invention has excellent BTK inhibitory activity and is directed to The selectivity of ITK, while there is good metabolic characteristic, it can be used as one kind and have very much potential irreversible BTK inhibitor.

Although the preferred embodiments of the invention, those skilled in the art has been disclosed in order to illustrate the present invention Member can be the present invention it should be appreciated that in the case where not departing from present inventive concept defined by claims and range Various modifications, addition and replacement out.

Claims (11)

1. a kind of compound or its pharmaceutically acceptable salt containing sulphonyl ethylene imine structure as shown in general formula (I),

Wherein, ring A is selected from following group:

Ring B is selected from 4~7 yuan of saturated heterocyclic groups containing a N atom, and is connected by the N atom with group Y；

Ar is selected from substituted or unsubstituted phenyl, and substituent group is selected from F；

X is selected from-O-；

Y is selected from-S (=O)₂-；

R₁-R₄Separately it is selected from following group: H, C_1-8Alkyl ,-(CH₂)_n-NH₂、-(CH₂)_n-NH(C_1-8Alkyl) or- (CH₂)_n-N(C_1-8Alkyl)₂；N indicates 0~8 integer.

2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the ring B is selected from following heterocycle Group:

3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the R₁-R₄In at most one Group is selected from C_1-4Alkyl ,-(CH₂)_n-NH₂、-(CH₂)_n-NH(C_1-4Alkyl) or-(CH₂)_n-N(C_1-4Alkyl)₂, n expression 0~3 Integer；Remaining is selected from H.

4. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from following knot Structure:

5. a kind of pharmaceutical composition, it includes the described in any item compounds of claim 1-4 or its pharmaceutically acceptable salt, And pharmaceutically acceptable carrier.

6. the described in any item compounds of claim 1-4 or its pharmaceutically acceptable salt are preparing bruton's tyrosine kinase Application in inhibitor.

7. pharmaceutical composition described in claim 5 is preparing the application in bruton's tyrosine kinase inhibitor.

8. the described in any item compounds of claim 1-4 or its pharmaceutically acceptable salt treat or prevent following disease in preparation Application in the drug of disease: cancer, autoimmune disease, heteroimmunity disease, inflammatory disease or thrombotic diseases.

9. application according to claim 8, wherein the disease is lupus erythematosus, inflammatory bowel disease, graft-versus-host Disease, asthma, arthritis, diffusivity large B cell lymphoid tumor, chronic lymphocytic lymphoma, follicular lymphoma, chronic lymphatic Chronic myeloid leukemia or myocardial infarction.

10. application of the pharmaceutical composition described in claim 5 in the drug that preparation treats or prevents following disease: cancer, Autoimmune disease, heteroimmunity disease, inflammatory disease or thrombotic diseases.

11. application according to claim 10, wherein the disease is lupus erythematosus, inflammatory bowel disease, graft-versus-host Disease, asthma, arthritis, diffusivity large B cell lymphoid tumor, chronic lymphocytic lymphoma, follicular lymphoma, chronic lymphatic Chronic myeloid leukemia or myocardial infarction.