CN105399756A - BTK inhibitor and uses thereof - Google Patents

BTK inhibitor and uses thereof Download PDF

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CN105399756A
CN105399756A CN201510553396.7A CN201510553396A CN105399756A CN 105399756 A CN105399756 A CN 105399756A CN 201510553396 A CN201510553396 A CN 201510553396A CN 105399756 A CN105399756 A CN 105399756A
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compound
group
alkyl
base
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CN105399756B (en
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刘兵
柏舜
张英俊
郑常春
杨悌平
周有柏
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a BTK inhibitor compound (having s structure represented by a formula (I)) and uses of the BTK inhibitor compound in medicines. According to the present invention, the compound and the pharmaceutical composition can be used for treatment of diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. The formula (I) is defined in the specification.

Description

BTK inhibitor and uses thereof
Technical field
The invention provides a kind of BTK inhibitor, disclose a series of compound and pharmaceutical composition thereof, also disclose this compounds and pharmaceutical composition thereof are used for the treatment of autoimmune disorder or illness, heteroimmunity disease or illness, cancer comprises lymphoma and inflammatory diseases purposes or illness.
Background technology
BTK kinases, a kind of member of nonreceptor tyrosine kinase Tec family is the key signal enzyme of expressing in all hematopoetic cell types except T lymphocyte and natural killer cell.BTK stimulates in the B cell signal transduction path of replying to downstream cellular play the part of vital role in connection cell surface B-cell receptor (B-cellreceptor, BCR).
The Dasatinib of listing in 2006 is Mutiple Targets inhibitor, has comparatively high inhibition effect, be used for the treatment of chronic lymphocytic leukemia to BTK; In addition in November, 2013 is also Mutiple Targets inhibitor by the PCI-32765 of FDA approval listing, is non-reversibility, is used for the treatment of lymphoma, leukemia and autoimmune disease to BTK restraining effect.At present not yet selective BTK inhibitor listing, the fastest medicine of research is CC-292, enters the clinical II phase in by the end of October, 2013 to study, and it, as irreversible Selective depression BTK, is used for the treatment of rheumatoid arthritis.
The object of this invention is to provide excellent highly selective BTK inhibitor, it can be used in preventing and/or treating B cell relevant leukemia, inflammatory and/or autoimmune disorder.
Summary of the invention
The present invention has the medicine of excellent antitumor action and treating autoimmune diseases effect for target with exploitation simultaneously, has found the compound as tyrosine kinase inhibitor of highly selective, and active suitable with existing marketed drug Ibrutinib.
On the one hand, the invention provides a kind of compound, it is for such as formula the structure shown in (I), or such as formula the steric isomer of the structure shown in (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein, R is C 5-12condense assorted bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12bridge is mixed bicyclic group or-L-R 1;
R 1for C 5-12condense assorted bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12bridge is mixed bicyclic group or C 2-9heterocyclic radical;
L is-(CH 2) n-;
N is 1,2,3 or 4;
Described C 5-12condense assorted bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12bridge is mixed bicyclic group and C 2-9heterocyclic radical can independently by hydrogen, oxo (=O), hydroxyl, cyano group; nitro, halogen, amino; carboxyl, alkyl, alkoxyl group; alkylamino, alkylthio, hydroxyalkyl; aminoalkyl group, haloalkyl, cycloalkyl; heterocyclic radical, aryl, heteroaryl or monosubstituted or identical or different polysubstituted of aminoacyl.
In some embodiments,
R is or-L-R 1;
R 1for
Each X 1, X 2and X 3be-(CH independently 2) b-,-O-,-NH-or-S (=O) t-;
Each X 4, X 5and X 6be-CH-independently, or-N-;
Each b is 0,1,2,3 independently, or 4;
Each q, m and p are 0,1,2,3 independently, or 4;
Each t is 0,1 or 2 independently;
Described R 1with the subformula representated by R, can independently by hydrogen, oxo (=O), hydroxyl, cyano group, nitro, halogen, amino, carboxyl, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, hydroxyl C 1-4alkyl, amino C 1-4alkyl, halo C 1-4alkyl, C 3-9cycloalkyl, C 2-9heterocyclic radical, C 6-12aryl, C 1-9heteroaryl or monosubstituted or identical or different polysubstituted of aminoacyl.
In some embodiments,
R is following subformula:
In some embodiments, the compounds of this invention is one of following structure:
or the steric isomer of described compound, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
On the one hand, the invention provides a kind of pharmaceutical composition, comprise compound of the present invention.
In some embodiments, pharmaceutical composition of the present invention, comprises pharmaceutically acceptable carrier, vehicle, thinner further, assistant agent and vectorial at least one.
On the one hand, the invention provides a kind of compound of the present invention or pharmaceutical composition of the present invention of using for the preparation of the purposes of the medicine of, prevention, process or protection B cell proliferation disease.
In some embodiments, in purposes of the present invention, described B cell proliferation disease is Diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
On the one hand, the invention provides a kind of compound of the present invention or pharmaceutical composition of the present invention of using for the preparation of the purposes suppressing the kinase whose inhibitor of BTK.
Detailed description of the invention book
Definition and general terms
Present detailed description some embodiment of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, this paper institute should be applied and use to obtain following definition.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork:2007, its full content is incorporated to herein by reference.
Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 1994.
Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-enantiomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.
By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2ndEd.RobertE.Gawley, JeffreyAub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH & Co.KGaA, Weinheim, Germany, 2007).
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (lowenergybarrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropictautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valencetautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.The replacement that the present invention considers only comprises the replacement forming stable compound.In certain embodiments, some suitable optional substituting group 1 can be replaced by corresponding suitable optional substituting group 2 further.In other embodiment, optional substituting group 2 suitable is not accordingly further substituted.Wherein said substituting group can be, but be not limited to: hydrogen, oxo (=O), hydroxyl, cyano group, nitro, halogen; amino, carboxyl, alkyl, alkoxyl group, alkylamino, alkylthio, hydroxyalkyl; aminoalkyl group, haloalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aminoacyl.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C 1- 6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl isophthalic acid-butyl, 2-methyl-1-butene base, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 3-methyl-3-amyl group, 2-methyl-3-amyl group, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, etc.
The term " halogen " that the present invention uses, " halogen atom " or " halogen atom " comprises fluorine, chlorine, bromine, iodine.
The term " alkoxyl group " used in the present invention, is related to alkyl, defines as the present invention, be connected in main carbochain by Sauerstoffatom.Some of them embodiment is, alkoxyl group is more rudimentary C 1-3alkoxyl group, some embodiments comprise, but are not limited to, methoxyl group, oxyethyl group, propoxy-etc.
Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxyl group can by one or more identical or different halogen atom situation about replacing.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to trifluoromethyl, trifluoromethoxy etc.
Term " alkylthio " comprises C 1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkylthio is more rudimentary C 1-3alkylthio, such example comprises, but is not limited to, methylthio group (CH 3s-), ethylmercapto group etc.
Term " alkyl acyl " comprises C 1-10the alkyl of straight or branched be connected to-C (=O)-on, wherein alkyl group has implication as described in the present invention.Some of them embodiment is, alkyl acyl is more rudimentary C 1-3alkyl acyl, such example comprises, but is not limited to, ethanoyl, propionyl etc.
Term " aminoacyl " refers to-C (=O) NH 2.
Term " amino-sulfonyl " refers to-S (=O) 2nH 2.
Term " amino " refers to have formula-NH 2.
Term " aminoalkyl group " refers to have formula R ' R " group of N-alkyl, wherein R ' and R " be separately alkyl or haloalkyl.Alkyl has implication as described in the present invention.Some of them embodiment is, aminoalkyl group is more rudimentary amino C 1-4alkyl, some of them embodiment is, but is not limited to, amino-ethyl, amino methyl, aminopropyl etc.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group, wherein alkyl group has implication as described in the present invention.
Term " hydroxyalkyl " or " hydroxy alkoxy base " represent that alkyl or alkoxyl group can be optionally substituted with one or more hydroxyl replaced situation.Wherein alkyl and alkoxy base have implication as described in the present invention, and such example comprises, but is not limited to methylol, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, hydroxyl methoxyl group, 1-hydroxy ethoxy etc.
Term " aryl " can be used alone or as " aralkyl ", most of " aralkoxy " or " aryloxy alkyl ", and can be monocycle, dicyclo, and the carbocyclic ring system of three rings, in certain embodiments of the present invention, can substitute arylidene and use.Wherein, at least one member ring systems of aryl is aromatic, and wherein each member ring systems comprises 3-7 atom.Term " aryl " can exchange with term " aromatic nucleus " and use, as aromatic nucleus can comprise phenyl, and naphthyl and anthryl.TV structure and determining, aryl can be monoradical or divalent group (that is, arylidene).The carbocyclic ring system of " arylidene " to be at least one member ring systems of divalence be aromaticity, and each member ring systems comprises 3-7 atom, some embodiments are phenylene, naphthylidene etc.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.
Term " heteroaryl ", " hetero-aromatic ring " be commutative use herein, can be used alone or as the part of " heteroarylalkyl " or " heteroarylalkoxy ", in certain embodiments of the present invention, can substitute inferior heteroaryl and use.All refer to monocycle, dicyclo, three rings or tetracyclic ring system, wherein, Bicyclic heteroaromatic rings, three ring hetero-aromatic rings or Fourth Ring heteroaromatic ring systems are with the form Cheng Huan condensed.Wherein, heteroaromatic ring systems is aromaticity, on ring one or more atom independent optionally replace by heteroatoms (heteroatoms is selected from N, O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain picture SO, SO 2, PO, PO 2group).Assorted fragrant system can be connected in main structure thus to form stable compound on any heteroatoms or carbon atom.Assorted fragrant system group can be 3-7 former molecular monocycle, or 7-10 former molecular dicyclo, or 10-15 former molecular three rings.The dicyclo with 7-10 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and three rings with 10-15 atom can be three rings [5,5,6], [5,6,6] or [6,5,6] system.TV structure and determining, heteroaryl can be monoradical or divalent group (that is, inferior heteroaryl).The heteroaryl that " inferior heteroaryl " is divalence.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.
Other embodiment is, assorted fragrant system (comprising heteroaryl, hetero-aromatic ring) comprises following example, but be not limited to these examples: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methyl-isoxazole-5-base, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidine-5-base, etc.
Term " cycloalkyl " refers to monovalence or multivalence, non-aromatic, the unsaturated ring of saturated or part, and does not comprise heteroatoms, comprising the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom or three rings.The bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic ring simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.TV structure and determining, " cycloalkyl " can be monoradical or divalent group, namely in certain embodiments of the present invention, can substitute or use as cycloalkylidene.Example comprises, but is never limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, adamantyl etc.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.
Term " heterocyclic radical ", " heterocycle ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo, three rings or tetracyclic ring system, wherein on ring one or more atom independent optionally replace by heteroatoms, ring can be completely saturated or comprise one or more degree of unsaturation, but is never the fragrant same clan.TV structure and determining, " heterocyclic radical ", " heterocycle ", " assorted alicyclic " can be monoradical or divalent group, namely in certain embodiments of the present invention, can substitute or use as sub-heterocyclic radical.Heterocyclic system can be connected in main structure thus to form stable compound on any heteroatoms or carbon atom.One or more ring hydrogen atom independent optionally replace by one or more substituting group described in the invention.Some of them embodiment is, " heterocyclic radical ", " heterocycle "; " sub-heterocyclic radical " " assorted alicyclic " or " heterocycle " group be 3-7 ring monocycle (1-6 carbon atom and be selected from N; 1-3 the heteroatoms of O, P, S; at this S or P optionally replace by one or more Sauerstoffatom and obtain as SO, SO 2, PO, PO 2group; When described ring is triatomic ring, wherein only have a heteroatoms), or 7-10 former molecular dicyclo (4-9 carbon atom be selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group).
" heterocyclic radical " can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and the saturated or unsaturated ring of part or heterocycle and closes the group formed.The example of heterocycle comprises, but be not limited to, 1, 2, 3, 6-tetrahydro pyridyl, piperidyl, piperazinyl, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, azacycloheptyl, oxepane base, thia suberyl, N-morpholinyl, 2-morpholinyl, morpholinyl, thio-morpholinyl, homopiperazine base, 4-Methoxy-piperidin-1-base, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, pyrroline-1-base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2-indoline base.
Term " condenses assorted bicyclic group " and represents saturated or undersaturated fused ring system, relate to the bicyclic system of non-aromatic, at the most containing a degree of unsaturation, and at least one member ring systems comprises one or more heteroatoms, and wherein each member ring systems comprises 3-7 former molecular ring, namely comprise 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, in addition, carbon atom also can by oxo formed-C (=O)-, such example comprises, but be not limited to, six hydrogen-2H-[1, 4] dioxin [2, 3-c] pyrryl, 3-azabicyclo [3.3.0] octyl, 8-azabicyclo [4.3.0] nonyl, 8-azabicyclo [4.3.0] nonane 3-base, 3-azabicyclo [4.3.0] nonane-3-base, isoindoline base, 1, 2, 3, 4-tetrahydric quinoline group, 3-nitrogen-7-oxabicyclo [3.3.0] octyl, 3, 7-diazabicyclo [3.3.0] octyl, 2, 6-diazabicyclo [3.3.0] octyl, 2, 7-diazabicyclo [3.3.0] octyl, 2, 8-diazabicyclo [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] nonyl, 4, 9-diazabicyclo [4.3.0] nonyl, 2, 9-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 4, 8-tri-azabicyclo [4.3.0] nonyl, 3-oxo-4-oxygen-2, 8-diazabicyclo [4.3.0] nonyl, 3-oxo-2, 8-diazabicyclo [4.3.0] nonyl, 3, 8-diazabicyclo [4.3.0] nonyl, 3, 7-diazabicyclo [4.3.0] nonyl, 3, 9-diazabicyclo [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, isoxzzole also [4, 3-c] piperidyl, 4, 5, 6, 7-tetrahydrochysene isoxzzole also [3, 4-c] pyridyl, [1, 2, 4] triazole also [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 naphthyl or 2-oxygen-8-azabicyclo [4.4.0] decyl etc.
Term " bridge mix bicyclic group " represents saturated or undersaturated bridged-ring system, relate to the bicyclic system of non-aromatic, at the most containing a degree of unsaturation, and at least one member ring systems comprises one or more heteroatoms, and wherein each member ring systems comprises 3-7 atom, namely comprise 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, in addition, carbon atom also can by oxo formed-C (=O)-; Such example comprises, but be not limited to 2-oxygen-5-azabicyclo [2.2.1] heptane base, 2-sulfo--5-azabicyclo [2.2.1] heptane base, 2-oxo-5-azabicyclo [2.2.1] heptane base, 2,5-diazabicylo [2.2.1] heptane base, 2-methyl-2,5-diazabicylo [2.2.1] heptane base etc.
Term " spiral shell mix bicyclic group " represents that a ring originates from ring-type carbon special on another ring.Such as, as described above, a saturated bridged-ring system (ring B and B') is called as " condensed-bicyclic ", otherwise ring A and ring B shares a carbon atom in two saturated member ring systems, be then called as " volution ".And at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 atom, namely comprises 1-6 carbon atom and is selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO 2, PO, PO 2group, such example comprises, but be not limited to 4-azaspiro [2.4] heptane base, 4-oxaspiro [2.4] heptane base, 5-azaspiro [2.4] heptane base, 7-hydroxyl-5-azaspiro [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 base, 2-sulphur-6-azepine spiroheptane base 2-monoxide, 2-sulphur-6-azepine spiroheptane base 2, 2-dioxide etc.
As described in the present invention, substituent R is connected to by a key member ring systems that the ring at center is formed and represents substituent R and can replace in any desirable generation or any rational position on ring.Such as, formula a represents any position that may be substituted on A ring or B ring and all can be replaced by R, such as formula b, and formula c, formula d, formula e, formula f, formula g, and shown in formula h.
As described in the present invention, substituting group (R) nbe connected to by a key member ring systems that the ring at center is formed to represent n substituent R and can replace any commutable position on ring.Such as, formula i represents any position that may be substituted on A ring or B ring and all can be replaced by n R.
As described in the invention, ring C has two tie points can be connected with molecule rest part, such as, shown in j, expression both can be E end also can be that E ' end is connected with the rest part of molecule, and namely the mode of connection at two ends can be exchanged.
As described in the present invention, attachment point can be connected with molecule rest part any attachable position on ring.Such as, formula k represents any position that may be connected on A ring or B ring and all can be used as the point of connection.
" hydrate " of the present invention refers to compound or its salt provided by the present invention, and it also comprises chemical quantity or the non-chemically water that combined by non-covalent intermolecular forces of equivalent, also can say be solvent molecule to be the associated complex that water is formed.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.
" ester " of the present invention refers to that formula (I) compound containing hydroxyl can hydrolyzable ester in organizer.Such ester is that such as in human or animal body, hydrolysis produces the pharmaceutically acceptable ester of parent alcohol.In formula (I) chemical combination object containing hydroxyl, the group of hydrolyzable ester comprises; but be not limited to; phosphate, acetoxymethoxy, 2; 2-dimethylpropionyloxymethoxy; alkyloyl, benzoyl, benzene first and second acyl group; alkoxy carbonyl, dialkyl carbamoyl and N-(di-alkyaminoethyl group)-N-alkyl-carbamoyl etc.
" oxynitride " of the present invention refers to when compound is containing several amine functional group, 1 or the nitrogen-atoms oxidation being greater than 1 can be formed N-oxide compound.The particular example of N-oxide compound is the N-oxide compound of tertiary amine or the N-oxide compound of nitrogen heterocyclic ring nitrogen-atoms.Available oxidant example, forms N-oxide compound (see AdvancedOrganicChemistry, WileyInterscience, the 4th edition, JerryMarch, pages) as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine.Especially, N-oxide compound can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, wherein such as at inert solvent, such as, in methylene dichloride, amine compound and m-chloroperoxybenzoic acid (MCPBA) is reacted.
Can be there is multiple different geometrical isomer and tautomer in compound, described formula (I) compound comprises this type of forms all.For avoiding feeling uncertain, when compound to exist with one of several geometrical isomer or tautomer and only specifically describe or display is a kind of time, obviously other forms all are included in formula (I).
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal, Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal, ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
The various pharmacy acceptable salt forms of the compounds of this invention are all useful.Term " pharmacy acceptable salt " refers to that those salt forms are apparent for pharmaceutical chemistry man, and namely they are substantially nontoxic and can provide required pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, more practical in nature, also very important for selection, these are: easy, productive rate, stability, the water absorbability of raw-material cost, crystallization and the mobility of result bulk drug.Simply, pharmaceutical composition can be prepared by effective constituent and pharmaceutically acceptable carrier.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, malate, 2 hydroxy propanoic acid salt, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.Amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, ammonia, Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), Methionin, meglumine (meglumine), piperazine, Trometamol, diethanolamine and other hydroxyalkyl amine, quadrol, N-methyl glucamine, PROCAINE HCL, PHARMA GRADE, N-benzyl-1-phenylethylamine, the p-chlorobenzyl of 1--2-tetramethyleneimine-1 '-ylmethyl-benzoglyoxaline, diethylamine and other alkylamine, piperazine and three (methylol) aminomethane; Alkaline earth salt, such as but not limited to barium, calcium and magnesium; Transition metal salt, such as but not limited to zinc.
Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In further embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In further embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In further embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.
" inflammatory diseases " used in the present invention refers to any disease that excessive inflammatory symptoms because inflammatory responses excessive or out of control causes, host tissue infringement or function of organization lose, disorderly or symptom." inflammatory diseases " also refers to by the pathologic state that white corpuscle flows into and/or Neutrophil chemotaxis mediates.
" inflammation " used in the present invention refer to caused by tissue damaged or destruction topical protective response, it for destroy, dilute or separate (completely cut off) be harmful to material and impaired tissue.Inflammation and white corpuscle flow into and/or Neutrophil chemotaxis has and contacts significantly.Inflammation can result from the infection of pathogenic organism and virus and non-infectious mode, as the wound after myocardial infarction or apoplexy or Reperfu-sion, to immunne response and the autoimmune response of exotic antigen.Therefore, can comprise by the inflammatory diseases of the open compounds for treating of the present invention: to react to specificity system of defense and non-specific defense system reacts relevant disease.
Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.
In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.
" associating " represents the medicine box of the fixed Combination in single dosage unit form or the part for combined administration, wherein the present invention come into the open compound and combined partner capable can individual application or can use respectively in certain time interval at one time, particularly make to combine and close companion and show cooperation, such as act synergistically." co-administered " or " Combined Preparation " etc. are intended to include the single individuality (such as patient) selected COMBINATION OF THE INVENTION being applied to and needing it as the term is employed herein, and be intended to comprise wherein material need not by identical route of administration or the treatment plan used simultaneously." pharmaceutical combination product " represents the mixing of more than one activeconstituentss or combines the product obtained as the term is employed herein, and the fixed Combination both having comprised activeconstituents also comprises non-fixed combinations.Term " fixing joint " represents that activeconstituents such as come into the open compound and COMBINATION OF THE INVENTION of the present invention is applied to patient with the form of single entities or dosage simultaneously.Term " on-fixed associating " represent activeconstituents as the present invention come into the open compound and composition all as separate entity simultaneously, common or be successively applied to patient without specified time restriction, wherein this is applied in patient body the treatment level of significance providing two kinds of compounds.The latter is also applicable to drug cocktail therapy (treatment), such as, use 3 kinds or more and plant activeconstituents.
The purposes of compound of the present invention, preparation and composition
One or more physiology acceptable carriers can be used to prepare medicinal compositions in a conventional manner, and described carrier comprises vehicle and auxiliary material, and it is conducive to active compound to be processed as preparation that can be medicinal.Suitable preparation depends on the route of administration of selection.Any technology, carrier and vehicle known can suitably be used, and as understood in the art.The summary of medicinal compositions described herein can see such as Remington:TheScienceandPracticeofPharmacy, the 19 edition (Easton, Pa.:MackPublishingCompany, 1995); Hoover, JohnE., Remington ' sPharmaceuticalSciences, MackPublishingCo., Easton, Pennsylvania1975; Liberman, H.A. and Lachman, L. writes, PharmaceuticalDosageForms, MarcelDecker, NewYork, N.Y., and 1980; And " PharmaceuticalDosageFormsandDrugDeliverySystems " the 7th edition (LippincottWilliams & Wilkins1999), by reference it is all attached to herein at this.
Medicinal compositions used herein refers to the mixture of compound described herein such as formula (I) compound and other chemical composition such as carrier, stablizer, thinner, dispersion agent, suspension agent, thickening material and/or vehicle.Described medicinal compositions is conducive to compound and gives organism.Putting into practice in treatment provided herein or using method, with medicinal compositions, the compound described herein for the treatment of significant quantity is being suffered from the Mammals of disease to be treated, obstacle or illness.Preferably, described Mammals is people.Treatment significant quantity can alter a great deal, and depends on the other factors such as effect of compound of the severity of disease, the age of curee and relative health, use.Described compound can be used alone or with one or more curative conbined usage of the component as mixture.
In some embodiments, composition also can comprise one or more pH adjusting agents or buffer reagent, comprises acid as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; Alkali, such as sodium hydroxide, sodium phosphate, Sodium Tetraborate, Trisodium Citrate, sodium acetate, Sodium.alpha.-hydroxypropionate and Tutofusin tris; And buffer reagent, such as citric acid/glucose, sodium bicarbonate and ammonium chloride.Comprising these acid of aequum, alkali and buffer reagent is to be maintained within the acceptable range by the pH of composition.
In other embodiments, composition also can comprise one or more salt of required amount to make the Osmolality of composition within the acceptable range.These salt comprise those salt with sodium, potassium or ammonium cation and chlorion, citrate, Vitamin C acid group, borate, phosphate radical, bicarbonate radical, sulfate radical, thiosulfate anion or heavy sulfinite anion; Suitable salt comprises sodium-chlor, Repone K, Sulfothiorine, sodium bisulfite and ammonium sulfate.
Term used herein " pharmaceutical composition " refers to by more than a kind of mixing of activeconstituents or the product that combines, and comprises the fixing of activeconstituents and non-fixed combinations.Term " fixed Combination " refers to activeconstituents, and routine compound described herein and assistant agent (co-agent), both given patient by with the form of single entirety or dosage simultaneously.Term " non-fixed combinations " refers to activeconstituents, such as compound described herein and mixture, it does not have specific interval time limitation to give patient as the individuality separated simultaneously, together or continuously, and wherein this gives the level of significance providing two kinds of compounds in patient body.The latter is also applied to drug cocktail therapy (treatment), such as the combination medicine of three kinds or more activeconstituents.
Pharmaceutical preparation described herein can give curee by multiple route of administration, described route of administration includes but not limited in oral, parenteral (such as intravenously, subcutaneous, intramuscular), nose, buccal, locally, rectum or transdermal administration routes.Pharmaceutical preparation described herein includes but not limited to the instant and controlled release preparation of aqueous liquid dispersion, self-emulsifying dispersion, sosoloid, liposomal dispersion agent, aerosol, solid dosage, powder, immediate release formulations, controlled release preparation, dissolution formulation, tablet, capsule, pill, sustained release preparation, delayed release dosage system, pulsation delivery formulations, many granular preparations and mixing.
Comprise compound medicinal compositions described herein can produce in a usual manner, such as, only illustrate, by the mixing of routine, dissolving, granulation, sugar coating, grinding, emulsification, Rubber Capsule, the technique such as encapsulating or compacting.
Composition described herein can be mixed with for giving curee by the mode of any routine, and the mode of described routine includes but not limited in oral, parenteral (such as intravenously, subcutaneous or intramuscular), buccal, nose, rectum or transdermal administration routes.Term used herein " curee ", for representing animal, is preferably Mammals, comprises the mankind or non-human.Term patient and curee can exchange use in this article.
And, medicinal compositions described herein, the compound of its contained (I), any suitable formulation can be formulated into, include but not limited to aqueous oral dispersion, liquid preparation, gelifying agent, syrup, elixir, paste, the formulations such as suspensoid, for the orally ingestible of patient to be treated, solid oral dosage form, aerosol, controlled release preparation, dissolution formulation, effervescent formulation, freeze-dried preparation, tablet, powder, pill, dragee, capsule, sustained release preparation, delayed release dosage system, pulsation delivery formulations, namely releasing and controlled release preparation of many granular preparations and mixing.
Compound described herein may be used for preparing and suppresses BTK or its homologue or be used for the treatment of at least partly from the medicine suppressing disease or the illness benefited BTK or its homologue.In addition, be used for the treatment of the disease any described herein in curees of these treatments of needs or the method for illness, comprise and give medicinal compositions, it comprises at least one formula (I) compound described herein or the acceptable salt of its medicine, medicine acceptable N-oxide compound, pharmaceutical active metabolite, the acceptable prodrug of medicine or the acceptable solvate of medicine, gives described curee to treat significant quantity.
The composition of compound described herein can be comprised, to carry out preventative and/or therapeutic treatment.In treatment use, give described composition the patient suffering from disease or illness, enough to cure or to stop at least partly the symptom of disease or illness.The severity of disease or illness and the course of disease, treatment before, the state of health of patient, body weight and to the reaction of medicine and the judgement of doctor in charge will be depended on to significant quantity of this application.As everyone knows, determine that this treatment significant quantity is considered to be within the scope of art technology by normal experiment (including but not limited to progressively increased dosage amount clinical trial).
When the situation of patient is not improved, based on the consideration of doctor, compound can give continuously; Or the dosage of the medicine given can be temporarily reduced or suspend for some time (that is, " withdrawal time ").The length of withdrawal time can between 2 days and 1 year, comprise and only illustrating, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 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.Between withdrawal time, it can be 10%-100% that dosage reduces, only illustrate, comprise 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 is improved, if needed, give maintenance dose.Subsequently, dosage or administration frequency or they both, the difference according to symptom can be reduced to the degree that disease, obstacle or illness can be kept to improve.But patient can need long-term, periodically treat, this is based on the symptom of any recurrence.
Factors is depended in change corresponding to the amount of the given medicine of this amount, as particular compound, disease or illness and its seriousness, need the curee for the treatment of or the uniqueness (such as body weight) of host, but, however, can according to specific ambient conditions, comprise such as used concrete medicine, route of administration, treatment illness and treatment curee or host, with methods known in the art routine determine.But, usually, for the dosage that adult treatment uses, typically in the scope of 0.02-5000mg/ days or about 1-1500mg/ days.This required metering can be expressed as (or at short notice) of potion or simultaneously administration or the divided dose at suitable interval easily, such as point agent every day two, three, four doses or more.
General synthetic method
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I) compound.Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemicalCompany, ArcoChemicalCompanyandAlfaChemicalCompany, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and aG1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315BDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316ATCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315DDAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with AgilentZorbaxSB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, ZorbaxSB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
BOC, Boc tert-butoxycarbonyl
CHCl 3chloroform
CDC1 3deuterochloroform
DMFN, dinethylformamide
Pd (dppf) Cl 2[two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride
DMAP4-Dimethylamino pyridine
DMSO dimethyl sulfoxide (DMSO)
DCM, CH 2cl 2methylene dichloride
EDC, EDCI1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
H 2hydrogen
H 2o 2hydrogen peroxide
K 2cO 3salt of wormwood
ML, ml milliliter
Pd/C palladium/carbon
NaOH sodium hydroxide
THF tetrahydrofuran (THF)
HOBt1-hydroxybenzotriazole
Et 3n, TEA triethylamine
TFA trifluoroacetic acid
TBSCl TERT-BUTYL DIMETHYL CHLORO SILANE
TBAF tetrabutyl ammonium fluoride
NBSN-bromo-succinimide
H 2o water
The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.
The synthetic schemes 1 of intermediate
Compound 7a, can be prepared by the method for the synthetic schemes 1 of intermediate, wherein R 1there is implication as described in the present invention.Commercially available glycol TBSCl process, obtains the glycol that a hydroxyl is protected by TBS.Then, the oxidation through oxalyl chloride obtains aldehyde 1a.Compound 1a and wittig reagent 2a (being obtained by reacting by methyl 2-bromacetate and triphenylphosphine) is carried out wittig and is obtained by reacting compound 3a.Compound 3a and TBAF reacts deprotection and obtains compound 4a.Then through being obtained by reacting compound 5a with methylsulfonyl chloride.Compound 5a and R 1h is obtained by reacting compound 6a in acetonitrile, then hydrolysis obtains compound 7a in the basic conditions.
The synthetic schemes 2 of intermediate
Compound 9a can be obtained by reacting compound 9a in the basic conditions by compound 8a and methylsulfonyl chloride.
Synthetic schemes 1
Compound 5, can be prepared by the method for synthetic schemes 1, wherein R has implication as described in the present invention.Commercially available 1H-pyrazolo [3,4-d] pyrimidine-4-amine N-iodosuccinimide process, obtains 3-iodo-1H-pyrazolo [3,4-d] pyrimidine-4-amine.Then, the phenyl-boron dihydroxide that 3-iodo-1H-pyrazolo [3,4-d] pyrimidine-4-amine and phenoxy group replace carries out palladium mediated cross-coupling in the basic conditions, forms intermediate 1.Intermediate 1, by Mitsunobu reaction and the coupling of N-Boc-3-(methylsulfonyl) oxygen phenylpiperidines, obtains the intermediate 2 that Boc (i.e. tertbutyloxycarbonyl) protects.Intermediate 2 obtains compound 3 after going protection with acid.Compound 3 and acyl chlorides coupling, such as but not limited to 4-bromo but-2-ene acyl chlorides, obtain compound 4.Compound 4 and RH in the basic conditions (alkali can be but be not limited to salt of wormwood, triethylamine etc.) react, and obtain compound 5.
Synthetic schemes 2
Compound 7, can be prepared by the method for synthetic schemes 2, wherein L and R 1there is implication as described in the present invention.Compound 3 obtains compound 7 with compound 6 condensation (condensing agent can be but be not limited to HOBt, EDCI etc.).
Synthetic schemes 3
Compound 9 can be prepared by synthetic schemes 3.There is nucleophilic substitution reaction in compound 4 and compound 10 in the basic conditions (alkali is salt of wormwood, but is not limited to), obtains compound 8; Compound 8 in acid condition deprotection obtains compound 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)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) but-2-ene-1-ketone
Step 1) synthesis of 3-iodo-1H-pyrazolo [3,4-d] pyrimidine-4-amine:
By 1H-pyrazolo [3,4-d] pyrimidine-4-amine (15.0g, 111.1mmol) is dissolved in DMF (150mL), then in reaction solution, slowly adds N-N-iodosuccinimide (37.5g, 166.6mmol), stirring reaction 12h at 80 DEG C.Stop heating, cooling, in reaction solution, add water (40mL), suction filtration, solid water (80mL) is washed, and ethanol (60mL) is washed, and drying obtains yellow solid (24.9g, 86%).
Step 2) synthesis of (S)-tertiary butyl 3-((methylsulfonyl) oxygen base) piperidines-1-carboxylicesters:
By (S)-tertiary butyl 3-hydroxy piperidine-1-carboxylicesters (1.50g, 7.47mmol) be dissolved in methylene dichloride (30mL), then in reaction solution, triethylamine (1.35mL is added, 9.71mmol), methylsulfonyl chloride (0.64mL is added under ice-water bath, 8.21mmol), DMAP (91mg, 0.75mmol).Stirring at room temperature 7h, dichloromethane extraction (150mL × 3), organic phase saturated aqueous common salt (60mL) is washed, anhydrous sodium sulfate drying, remove solvent under reduced pressure, silica gel column chromatography separating purification (petrol ether/ethyl acetate (V/V)=4/1), obtains product as white solid (2.04g, 98%).
MS-ESI:(ESI,pos.ion)m/z：224.1[M-55] +；
Step 3) synthesis of 3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine:
In 250mL heavy wall reaction flask; add 3-iodo-1H-pyrazolo [3 respectively; 4-d] pyrimidine-4-amine (1.31g; 5.0mmol), (4-Phenoxyphenyl) boric acid (1.28g; 6.0mmol), salt of wormwood (1.73g, 12.5mmol), Isosorbide-5-Nitrae-dioxane (30mL) and water (6mL); under nitrogen protection, then add Pd (dppf) Cl 2(300mg, 0.41mmol), then at 140 DEG C, tube sealing reaction spends the night, after having reacted, filter, dichloromethane extraction (200mL × 3), saturated common salt washing (60mL), anhydrous sodium sulfate drying, remove 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) synthesis of (R)-tertiary butyl-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-carboxylicesters:
By 3-(4-Phenoxyphenyl)-1H-pyrazolo [3; 4-d] pyrimidine-4-amine (1.14g; 3.76mmol) be dissolved in DMF (30mL); then in reaction solution, add (S)-tertiary butyl 3-((methylsulfonyl) oxygen base) piperidines-1-carboxylicesters (4.2g; 15.04mmol), cesium carbonate (0.64mL; 8.21mmol), DMAP (3.67g, 11.28mmol).8h is stirred at 90 DEG C, after having reacted, remove DMF under reduced pressure, dichloromethane extraction (150mL × 3), saturated common salt washing (60mL), anhydrous sodium sulfate drying, remove 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) synthesis of (R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] pyrimidine-4-amine:
By (R)-tertiary butyl-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidine-1-base) piperidines-1-carboxylicesters (1.28g, 2.63mmol) be dissolved in 1, in 4-dioxane (6mL), then in reaction solution, hydrochloric acid (6mL is added, 4mol/L) stirring at room temperature 16h, after having reacted, add rare aqueous sodium hydroxide solution, be adjusted to PH=9, dichloromethane extraction (150mL × 3), saturated common salt washing (60mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product silica gel column chromatography separating purification (methylene chloride/methanol (V/V)=12/1-6/1), obtain product (840mg, 83%).
MS-ESI:(ESI,pos.ion)m/z：387.2[M+1] +；
1HNMR(600MHz,CDCl 3):δ8.32(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) synthesis of (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:
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 dichloride (20mL), (E)-4-bromo but-2-ene acyl chlorides (0.90g is slowly added under ice-water bath, 5mmol), 10min is reacted under ice-water bath, add water (30mL), dichloromethane extraction (100mL × 3), saturated common salt washing (30mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product silica gel column chromatography separating purification (methylene chloride/methanol (V/V)=30/1), obtain product (1.48g, 68%).
MS-ESI:(ESI,pos.ion)m/z：533.1[M+1] +；
1HNMR(600MHz,CDCl 3):δ8.33(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)-tetrahydrochysene-2H-[1,4] dioxin [2,3-c] pyrroles-6 (3H)-Ji) synthesis of but-2-ene-1-ketone:
(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 (210mg, 0.39mmol) be dissolved in DMF (15mL), add (4aR, 7aS)-3, 4a, 5, 6, 7, 7a-six hydrogen-2H-[1, 4] dioxin [2, 3-c] pyrroles (101mg, 0.79mmol) with salt of wormwood (193mg, 1.38mmol), stirring reaction 4h at 60 DEG C, TLC monitors, after having reacted, remove solvent under reduced pressure, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=10/1) obtains product (138mg, 61%).
MS-ESI:(ESI,pos.ion)m/z：583.2[M+1] +；
1HNMR(600MHz,CDCl 3):δ8.37(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) piperidin-1-yl)-4-bromo but-2-ene-1-ketone (200mg, 0.37mmol) be dissolved in DMF (15mL), add 2-oxygen-6-aza-spiro [3,3] heptane oxalate (0.14g, 0.75mmol) and salt of wormwood (149mg, 1.50mmol), 4h is reacted at 60 DEG C.Remove solvent under reduced pressure, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, removes solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=10/1), obtain white powder (79mg, 40%).
MS-ESI:(ESI,pos.ion)m/z：276.7[M/2+1] +；
1HNMR(400MHz,CDCl 3):δ7.63(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).
Own-2-alkene-1-the ketone of embodiment 3 (R, E)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-6-morpholinyl
Step 1) synthesis of 4-((tertiary butyl (dimethyl) is silica-based) oxygen base) fourth-1-alcohol:
Fourth-Isosorbide-5-Nitrae-glycol (6.5g, 72mmol) is dissolved in methylene dichloride, add the tertiary butyl (dimethyl) chlorosilane (5.4g, 36mmol), under ice-water bath, slowly add triethylamine (5mL, 35.9mmol), then at stirring at room temperature reaction 5h, dichloromethane extraction (150mL × 3), saturated common salt washing (60mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain product (6.82g, 93%).
Step 2) synthesis of 4-((tertiary butyl (dimethyl) is silica-based) oxygen base) butyraldehyde:
Under nitrogen protection, add oxalyl chloride (10mL), methylene dichloride (150mL), DMSO (5mL) is slowly dripped at-78 DEG C, after stirring 15min, 4-((tertiary butyl (dimethyl) is silica-based) oxygen base) fourth-1-alcohol (6.29g is slowly added at-78 DEG C, 30.8mmol), triethylamine (5mL) is added after stirring 1h at-78 DEG C, then slowly room temperature is raised to, add water (100mL), dichloromethane extraction (200mL × 3), saturated aqueous ammonium chloride is washed (70mL), 1N salt pickling (70mL), remove solvent under reduced pressure, obtain product (5.1g, 82%).
Step 3) synthesis of methyl 2-(triphenylphosphoroanylidene) acetic ester:
By triphenylphosphine (18g, 69mmol) be dissolved in ethyl acetate (300mL), add methyl 2-bromacetate (6.5mL wherein, ethyl acetate solution (30mL) 69mmol), stirring at room temperature reaction is spent the night, and filters, gained solid petroleum ether, product (29g, 93%) is obtained after vacuum-drying.
Step 4) synthesis of oneself-2-olefin(e) acid ester of (E)-methyl 6-((t-Butyldimethylsilyl) oxygen base):
By 4-(tertiary butyl (dimethyl) is silica-based) oxygen base butyraldehyde (2.6g, 13mmol) add in toluene, add wittig reagent (4.3g, 13mmol), reflux 4h, after having reacted, extraction into ethyl acetate (150mL × 3), saturated common salt washing (60mL), anhydrous sodium sulfate drying, removes solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=16/1), obtain product (1.81g, 55%).
Step 5) synthesis of oneself-2-olefin(e) acid ester of (E)-methyl 6-hydroxyl:
By own for methyl (E)-6-(tertiary butyl (dimethyl) is silica-based) oxygen base-2-olefin(e) acid ester (1.21g, 4.68mmol) be dissolved in THF (30mL), add tetrabutyl ammonium fluoride (5.2mL, 5.2mmol), stirring at room temperature 4h, add water (40mL), extraction into ethyl acetate (100mL × 3), saturated common salt washing (50mL), anhydrous sodium sulfate drying, removes solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=2/1), obtain product (0.42g, 62%).
Step 6) synthesis of oneself-2-olefin(e) acid ester of (E)-methyl 6-((methyl sulphonyl) oxygen base):
By own for methyl (E)-6-hydroxyl-2-olefin(e) acid ester (0.42g, 2.9mmol) be dissolved in methylene dichloride (15mL), methylsulfonyl chloride (0.40g is added under ice-water bath, 3.5mmol) with triethylamine (0.73mL, 5.2mmol, ), stirring at room temperature 4h, after having reacted, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (petrol ether/ethyl acetate (V/V)=2/1), obtain product (0.56g, 86%).
Step 7) synthesis of oneself-2-olefin(e) acid ester of (E)-methyl-6-morpholinyl:
By own for (E)-methyl 6-((methyl sulphonyl) oxygen base)-2-olefin(e) acid ester (0.56g, 2.5mmol) be dissolved in acetonitrile (10mL), add morpholine (0.66mL, 7.6mmol), 6h is stirred at 60 DEG C, after having reacted, stop heating, remove solvent under reduced pressure, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=50/1), obtain product (0.46g, 86%).
MS-ESI:(ESI,pos.ion)m/z：214.3[M+1] +；
Step 8) synthesis of oneself-2-olefin(e) acid of (E)-6-morpholinyl:
By own for methyl (E)-6-morpholinyl-2-olefin(e) acid ester (0.23g, 1.1mmol) be dissolved in THF (10mL), add water (10mL), add NaOH (0.22g, 5.5mmol), stirred overnight at room temperature adds concentrated hydrochloric acid, filters, obtain product (0.20g, 93%).
MS-ESI:(ESI,pos.ion)m/z：200.2[M+1] +；
Step 9) synthesis of oneself-2-alkene-1-ketone of (R, E)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-6-morpholinyl:
By own for (E)-6-morpholinyl-2-olefin(e) acid (141mg, 0.71mmol) be dissolved in DMF (15mL), add HOBt (112mg respectively, 0.83mmol), EDCI (239mg, 1.25mmol), 3-(4-Phenoxyphenyl)-1 – ((3R)-3-piperidyl) pyrazolo [3, 4-d] pyrimidine-4-amine (161mg, 0.42mmol), stirring at room temperature 4h, dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove 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] +；
1HNMR(600MHz,CDCl 3):δ8.28(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)-tertiary 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) synthesis of-2,5-diazabicylos [2.2.1] heptane-2-manthanoate:
(S, 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 (80mg, 0.15mmol) be dissolved in DMF (15mL), add salt of wormwood (44mg, 0.30mmol) add 2,5-diazabicylo [2.2.1] heptane-2-carboxylate (60mg, 0.30mmol).60 DEG C of reaction 4h, concentrating under reduced pressure removing DMF, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, 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) synthesis of but-2-ene-1-ketone:
(1S, 4S)-tertiary 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-manthanoate (66mg, 0.1mmol) be dissolved in methylene dichloride (5mL), add TFA (2mL), under room temperature, react 5h.Be spin-dried for solvent, add water (20mL), with saturated sodium bicarbonate solution, pH is adjusted to 8, dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=6/1), 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) piperidin-1-yl)-4-bromo but-2-ene-1-ketone (200mg, 0.38mmol) be dissolved in DMF (15mL), add salt of wormwood (74mg, 0.75mmol) with 2-oxygen-5-azabicyclo [2.2.1] heptane (74mg, 0.75mmol).60 DEG C of reaction 4h, remove solvent under reduced pressure, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, removes solvent under reduced pressure, product crude product column chromatographic isolation and purification (methylene chloride/methanol (V/V)=8/1) obtains product (173mg, 83.7%).
MS-ESI:(ESI,pos.ion)m/z：283.75[M/2+1] +；
1HNMR(600MHz,DMSO):δ8.25(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]-piperidino] the bromo-but-2-ene of-4--1-ketone (50mg, 0.11mmol) be dissolved in DMF (15mL), add (1S, 4S)-2-sulphur-5-azabicyclo [2.2.1] heptane (20mg, 0.17mmol) with salt of wormwood (48mg, 0.35mmol), 4h is stirred at 60 DEG C, remove solvent under reduced pressure, add water (20mL), methylene dichloride (50mL × 3) extracts, saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (dichloromethane/ethyl acetate (V/V)=10/1) obtains product (15mg, 28%).
MS-ESI:(ESI,pos.ion)m/z：568.2[M+1] +；
1HNMR(400MHz,CDCl 3)δ8.39(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).
Embodiment 7 ((R, E) synthesis of-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidin-1-yl)-4-(2-oxygen-7-azaspiro [3.5] nonane-7-base) but-2-ene-1-ketone
(E)-1-((3R)-3-[4-amino-3-(4-Phenoxyphenyl) pyrazolo [3, 4-d] pyrimidine-1-base]-piperidino) the bromo-but-2-ene of-4--1-ketone (74mg, 0.14mmol) be dissolved in DMF (15mL), add 2-oxygen-7-azaspiro [3.5] nonane (36mg, 0.28mmol) with salt of wormwood (49mg, 0.35mmol), then stirring reaction at 60 DEG C, after TLC monitoring reacts completely, remove solvent under reduced pressure, add water (20mL), dichloromethane extraction (50mL × 3), saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, 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] +；
1HNMR(400MHz,CDCl 3)δ8.37(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) piperidin-1-yl)-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) piperidin-1-yl)-4-bromo but-2-ene-1-ketone (200mg, 0.38mmol) be dissolved in DMF (15mL), add salt of wormwood (150mg, 1.5mmol) with 2-oxygen-6-azaspiro [3.3] heptane oxalate (152mg, 0.75mmol), then at 60 DEG C, react 4h.Add water (20mL), methylene dichloride (50 × 3) extracts, saturated common salt washing (20mL), anhydrous sodium sulfate drying, remove solvent under reduced pressure, product crude product column chromatographic isolation and purification (dichloromethane/ethyl acetate (V/V)=8/1) obtains white solid (90mg, 42.43%).
MS-ESI:(ESI,pos.ion)m/z：283.75[M/2+1] +；
1HNMR(600MHz,CDCl 3)δ8.37(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 inhibit activities of biological Examples 1 the compounds of this invention
Experimental technique: HEPES: hydroxyethyl piperazine second thiosulfonic acid; Brij-35: Brij-35; DTT: dithiothreitol (DTT); EDTA: ethylenediamine tetraacetic acid (EDTA); BTK: bruton's tyrosine kinase; PeptideFAM-P22: FAM-labeled peptide 22; ATP: triphosphoric acid adenosine monophosphate; Staurosporine: staurosporine; CoatingReagent#3:#3 fruit glaze agent
1.1 × kinase buffer liquid and the preparation of termination test buffer:
(1) 1 × kinase buffer liquid (50mMHEPES, pH7.5,0.0015%Brij-35,10mMMgCl 2, 2mMDTT); (2) test buffer (100mMHEPES, pH7.5,0.015%Brij-35,0.2%CoatingReagent#3,50mMEDTA) is stopped.
2. the compound of test kinase prepares: compound serial dilution
(1) adopt 100%DMSO by the highest final concentration 50 times of diluted chemical compound.The compound solution of 100 these concentration of μ L is transferred to a hole of 96 orifice plates.(2) in ratio diluted compounds 10 concentration successively that 20 μ L original solutions dilute with 60 μ LDMSO.(3) 100 μ L100%DMSO solution are joined in two emptying apertures, contrast as without compound control with without enzyme.(4) prepare an intermediate plate, respectively each concentration compound of 10 μ L is transferred to intermediate plate from raw sheet, and add 90 μ L1x kinase buffer liquid, vibration mixing 10 minutes.(5) preparing experiment plate: corresponding aperture transferase 45 μ L compound solution is in 384 orifice plates of correspondence from the intermediate plate of 96 orifice plates.
3. kinase reaction
(1) 2.5x enzyme solution is prepared: added by enzyme in 1x kinase buffer liquid.(2) 2.5x peptide solution is prepared: FAM-labeled peptide and ATP are added in 1x kinase buffer liquid.(3) being joined by 10 μ L2.5x enzyme solution containing 5 μ LDMSO content is in 384 hole brassboards of the compound solution of 10%, incubated at room 10 minutes.(4) 10 μ L2.5x peptide solutions are added in 384 hole brassboards.(5) kinase reaction and termination: hatch the corresponding time for 28 DEG C, adds 25 μ L stop buffer termination reactions.
4. DATA REASONING: reading of data is also collected.
5. fitting of a curve
(1) data of also converted measurement are copied; (2) inhibiting rate is converted to: inhibiting rate=(maximum value-sample value)/(maximum value-minimum value) * 100; " maximum value " is without compound control value; " minimum value " is without kinase control hole count value; (3) data are inputted corresponding analysis software Xlfit and draw IC 50value.
Experimental result is as follows:
The external zymetology inhibit activities of table 2 the compounds of this invention
Embodiment BTK IC 50(nM) Embodiment BTK IC 50(nM)
1 3.1 5 2.2
2 3.3 7 2.8
3 9.9 8 2.2
Contrast 2.5
Contrast is Ibrutinib, and concrete structure is:
Experiment conclusion: from table 2, the compounds of this invention has stronger restraining effect to BTK kinases, and substantially has the activity suitable with Ibrutinib.

Claims (9)

1. a compound, it is for such as formula the structure shown in (I), or such as formula the steric isomer of the structure shown in (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug
Wherein, R is C 5-12condense assorted bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12bridge is mixed bicyclic group or-L-R 1;
R 1for C 5-12condense assorted bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12bridge is mixed bicyclic group or C 2-9heterocyclic radical;
L is-(CH 2) n-;
N is 1,2,3 or 4;
Described C 5-12condense assorted bicyclic group, C 5-12spiral shell is mixed bicyclic group, C 5-12bridge is mixed bicyclic group and C 2-9heterocyclic radical can independently by hydrogen, oxo (=O), hydroxyl, cyano group; nitro, halogen, amino; carboxyl, alkyl, alkoxyl group; alkylamino, alkylthio, hydroxyalkyl; aminoalkyl group, haloalkyl, cycloalkyl; heterocyclic radical, aryl, heteroaryl or monosubstituted or identical or different polysubstituted of aminoacyl.
2. according to the compound shown in claim 1, wherein,
R is or-L-R 1;
R 1for
Each X 1, X 2and X 3be-(CH independently 2) b-,-O-,-NH-or-S (=O) t-;
Each X 4, X 5and X 6be-CH-independently, or-N-;
Each b is 0,1,2,3 independently, or 4;
Each q, m and p are 0,1,2,3 independently, or 4;
Each t is 0,1 or 2 independently;
Described R 1with the subformula representated by R, can independently by hydrogen, oxo (=O), hydroxyl, cyano group, nitro, halogen, amino, carboxyl, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-4alkylthio, hydroxyl C 1-4alkyl, amino C 1-4alkyl, halo C 1-4alkyl, C 3-9cycloalkyl, C 2-9heterocyclic radical, C 6-12aryl, C 1-9heteroaryl or monosubstituted or identical or different polysubstituted of aminoacyl.
3. compound according to claim 1, wherein,
R is following subformula:
4. a compound, it is following structure,
or the steric isomer of described compound, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, ester, pharmacy acceptable salt or its prodrug.
5. a pharmaceutical composition, comprises the compound described in any one of claim 1-4.
6. pharmaceutical composition according to claim 5, comprises pharmaceutically acceptable carrier, vehicle, thinner further, assistant agent and vectorial at least one.
7. the compound described in any one of claim 1-4 or the pharmaceutical composition described in any one of claim 5-6 are for the preparation of the purposes of the medicine of, prevention, process or protection B cell proliferation disease.
8. purposes according to claim 7, described B cell proliferation disease is Diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
9. the compound described in any one of claim 1-4 or the pharmaceutical composition described in any one of claim 5-6 are for the preparation of the purposes suppressing the kinase whose inhibitor of BTK.
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CN112375117A (en) * 2020-11-14 2021-02-19 湖南科瑞生物制药股份有限公司 Preparation method of lithocholic acid and intermediate thereof
CN114853764A (en) * 2022-04-21 2022-08-05 埃斯特维华义制药有限公司 Preparation process of ibrutinib
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