CN105523955B - Compound and its purposes in medicine preparation - Google Patents

Compound and its purposes in medicine preparation Download PDF

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CN105523955B
CN105523955B CN201510925699.7A CN201510925699A CN105523955B CN 105523955 B CN105523955 B CN 105523955B CN 201510925699 A CN201510925699 A CN 201510925699A CN 105523955 B CN105523955 B CN 105523955B
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CN105523955A (en
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何伟
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Beijing Jialin Pharmaceutical Co., Ltd.
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BEIJING JIALIN PHARMACEUTICAL Co Ltd
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Priority to PCT/CN2016/109961 priority patent/WO2017101791A1/en
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Abstract

Application the invention discloses compound and its in drug, specifically, the present invention provide the stereoisomer of the compound as shown in formula (I) compound represented or formula (I), geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, the purposes that the invention also discloses the compounds of this invention in preparing drug, the drug are used for treating cancer.

Description

Compound and its purposes in medicine preparation
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of new compound and the new compound are preparing medicine Purposes in object.
Background technology
Medically, cancer refers to the malignant tumour originating from epithelial tissue, is most common one kind in malignant tumour.Relatively It answers, the malignant tumour originating from mesenchymal tissue is referred to as sarcoma.There are a small number of malignant tumours not named by mentioned above principle, such as kidney mother Cytoma, malignant teratoma etc.." cancer " described in general people traditionally refers to all malignant tumours.
Tumour is body under the effect of various tumorigenesis factors, and the cell of local organization is lost at the genetic level to growth Normal regulation cause paraplasm with differentiation and formed neoformation.Neoformation once being formed, does not stop because the cause of disease is eliminated Growth, his growth destroy normal structure and organ not by normal body Physiological effect, this point malignant tumour especially Obviously.Compared with benign tumour, malignant growth speed is fast, is in infiltrative growth, and bleeding, necrosis, ulcer etc. easily occurs, and Often there is DISTANT METASTASES IN, cause human body to become thin, inability, anaemia, loss of appetite, fever and serious organ function are impaired etc., most Death is caused eventually.
Lung cancer is one of most common malignant tumour in the world, has become China's urban population Death Cause for Malignant Tumors 1st.Non-small cell type lung cancer includes squamous cell carcinoma (squamous carcinoma), gland cancer, large cell carcinoma, its cancer cell compared with small cell carcinoma Growth division is slower, and diffusion transfer is relatively late.Non-small cell lung cancer accounts for about the 80% of all lung cancer, about 75% Finding case When be in middle and advanced stage, survival rate is very low within 5 years.
Brg1 genes find that it is a kind of important suppression in the research of many tumours as a kind of new tumor suppressor gene Oncogene, the generation of many tumours and its functionally inactive or gene mutation, missing occur related.Find itself and cell mitogenic simultaneously Signal transduction in fission process is related, has close relationship with many important tumor suppressor genes such as Rb genes, CD44 etc..
However, the drug for the treatment of cancer especially non-small cell lung cancer still needs further to be studied at present.
Invention content
The present invention proposes a kind of compound, is the solid of the compound as shown in formula (I) compound represented or formula (I) Isomers, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmacy Upper acceptable salt or prodrug：
Wherein, Q indicates that C or N, R1 indicate H,Or optionally by C1~5Alkyl, C1~5The five of alkyl ester group substitution Member heterocyclic ring containing nitrogen, R6 are key, H, C1~5Alkylidene, optionally by C1~5The 5-member heterocyclic ring containing nitrogen of alkylidene substitution, or optionally by C1~5 The imino group of alkylidene substitution, R7 H, C1~5Alkyl, or optionally by C1~5Alkyl, C1~5Alkoxy, C1~5Alkylidene cycloalkanes The alkylidene of base, C1~5 cycloalkenyl group, aryl, alkylidene aryl, hexa-member heterocycle, alkylidene hexa-member heterocycle, cyano, cyanoimino C1~5Alkyl-substituted imino group or secondary amino；And each of R2, R3, R4, R5 and R6 are separately H, halogen, hydroxyl Base, C1~5Alkoxy, amido, C1~5Carbonylimino either imino group, aryl, nitro or cyano, on condition that R2, R3, R4, It is H when R5 with R6 differences；Or in R1~R6 adjacent two constituted optionally by C together with the carbon atom being connect with it1~5Alkane Base, aryl, five~heptatomic ring or condensed-bicyclic optionally containing at least one aerobic, sulphur and nitrogen.Inventor was it was unexpectedly observed that should Compound can be efficiently used for treating cancer, especially non-small cell lung cancer.
In the second aspect of the present invention, the present invention proposes the purposes of compound noted earlier in medicine preparation, described Drug is used for treating cancer.Optionally, the cancer is lung cancer.Optionally, the lung cancer is non-small cell lung cancer.Optionally, The non-small cell lung cancer is BRG1 gene delections.
In addition, the invention also provides a kind of methods for treating cancer, including it is that study subject such as patient is administered Aforesaid compound or composition containing the compound.
In turn, the invention also provides a kind of compositions for treating cancer, contain compound conduct noted earlier Active constituent.
It should be noted that other equally applicable aspects of the feature and advantage of various aspects described above.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects and other aspect Content will make more specific complete description below.
Specific implementation mode
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case of (include but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March,John Wiley & Sons,New York:Description in 2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise Content.
" stereoisomer " refers to having identical chemical constitution, but atom or the group spatially different change of arrangement mode Close object.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to detach by closing object.
Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley & Sons,Inc.,New York,1994。
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains, there are one double bonds, and substituent group may be E or Z configurations；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
Can the racemic modification of any gained final product or intermediate be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is detached by its diastereoisomeric salt to acquisition.Racemic production Object can also be detached by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is can refer to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH & Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally replacing " this term with " substituted or non-substituted ".In general, art " substituted " expression of language is replaced to one or more of structure hydrogen atom by specific substituent group.Unless other aspect tables Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not Only a position can be replaced by one or more substituent groups selected from specific group, then substituent group can identical or differently Replace at various locations.Wherein the substituent group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitre Base, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, alkoxy alkylamino, aryloxy group, heteroaryl oxygen Base, heterocycle oxygroup, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, cycloalkyl alkoxy, alkylamino, alkylamino Alkyl, alkylamino alkylamino, cycloalkyl amino, amino-n-cycloalkyl, alkylthio group, halogenated alkyl, halogenated alkoxy, hydroxyl substitution Alkyl, hydroxyl substitution alkylamino, cyano substitution alkyl, cyano substitution alkoxy, cyano substitution alkylamino, amino Substituted alkyl, alkyl acyl, miscellaneous alkyl, naphthenic base, cycloalkenyl group, cycloalkyl-alkyl, heterocycle, heterocyclylalkyl group, heterocycle Acyl group, aryl, aryl alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, amide groups, sulfonyl, aminosulfonyl Base etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, not influencing mutually, can also indicating in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-C5Alkyl " or " C1-5Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl and C5Alkyl.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Substitution.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyls (- CH (CH3)CH2CH2CH3), 3- amyls (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1s-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyls (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyls (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyls (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyls (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " Cx-yAlkyl " refers to the alkyl that C atomicities are x-y.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Oxygroup (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the saturation comprising 3-12 annular atom or portion Divide undersaturated monocyclic, bicyclic or tricyclic, aromatic rings, and at least one annular atom are not included wherein in monocyclic, bicyclic or tricyclic Selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can be optionally It is substituted by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optionally by oxygen It is melted into N- oxygen compounds.The example of heterocycle includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, sulphur Heterocycle butyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, (1- oxos)-are thio Morpholinyl, (1,1- dioxo)-thio-morpholinyl, piperazinyl , alkyl dioxins, dithianyl , thioalkyls, high piperazine base are high Piperidyl, oxepane alkyl, thia cycloheptyl alkyl, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases, tetrahydro pyridyl. - CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine bases, oxo -1,3- thiophene by the example of-C (=O)-substitutions Oxazolidinyl, 2- piperidone bases, 3,5- dioxy piperazine piperidinyls.The example that sulphur atom is aoxidized in heterocycle includes, but are not limited to ring Fourth sulfuryl, 1,1- dioxothiomorpholinyl.The heterocyclyl groups can be retouched optionally by one or more present invention The substituent group stated is replaced.When the structure clearly needs linking group, answered for the Markush variable cited by the group It is interpreted as linking group.For example, if the structure needs linking group and is enumerated for the Markush group definition of the variable " heterocycle ", then it should be understood that should " heterocycle " represent the sub- heterocyclyl groups of connection.
Term " condensed-bicyclic " and " condensed-bicyclic base " are used interchangeably here, refer to saturation or the portion of unit price or multivalence Divide undersaturated bridged-ring system, the bridged-ring system refers to bicyclic system.Term " bridged ring " refers to that any two ring shares two The atom for being connected directly or not being connected directly.For example, as described in following formula a and formula b, ring A and ring A ' share two directly Connected C atoms, ring B and ring B ' share two C atoms not being connected directly.Or each ring in condensed-bicyclic is carbocyclic ring It is heterocycle.
Term " hetero atom " refers to O, S, N, P and Si, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl replaced as N-).
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " aryl " indicates to contain 6-14 annular atom or the monocycle of 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one member ring systems are aromatic, and wherein each member ring systems includes 3-7 former Molecular ring, and there are one or multiple attachment points be connected with the rest part of molecule.Term " aryl " can be with term " fragrance Ring ", which exchanges, to be used.The example of aryl group may include phenyl, indenyl, naphthalene and anthracene.The aryl group can be individually optional Ground is replaced by one or more substituent groups described in the invention.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " aryl ", then it should be understood that being somebody's turn to do the arylene group that " aryl " represents connection.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.It is completely begged for about pro-drug By following documents can be referred to：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
Any disease of term " treatment " or illness as used in the present invention, in some of these embodiments, " treatment " Referring to improves disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other realities It applies in scheme, " treatment " refers to mitigation or improve at least one body parameter, including the body parameter that may not be discovered by patient. In other embodiments, " treatment " refer to from body (such as stablizing perceptible symptom) or physiologically (such as stablize The parameter of body) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease Breaking-out, generation or the deterioration of disease or illness.
Term " cancer " refer to or description patient in physiological conditions usually characterized by cell growth out of control.It is " swollen Tumor " includes one or more cancer cells.The example of cancer include but not limited to cancer (carcinoma), lymthoma, enblastoma, Sarcoma and leukaemia or malignant lymph proliferative disease (lymphoid malignancies).The more specific reality of such cancer Example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including Small Cell Lung Cancer, non-small cell lung cancer (NSCLC), lung Gland cancer and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellular cancer), gastric cancer (gastric or Stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (liver Cancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, carcinoma of endometrium or Uterine cancer, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, thyroid gland Cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.
The description of the compounds of this invention
The present invention proposes a kind of compound, is the solid of the compound as shown in formula (I) compound represented or formula (I) Isomers, geometric isomer, tautomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmacy Upper acceptable salt or prodrug：
Wherein, Q indicates that C or N, R1 indicate H,Or optionally by C1~5Alkyl, C1~5The five of alkyl ester group substitution Member heterocyclic ring containing nitrogen, R6 are key, H, C1~5Alkylidene, optionally by C1~5The 5-member heterocyclic ring containing nitrogen of alkylidene substitution, or optionally by C1~5 The imino group of alkylidene substitution, R7 H, C1~5Alkyl, or optionally by C1~5Alkyl, C1~5Alkoxy, C1~5Alkylidene cycloalkanes The alkylidene of base, C1~5 cycloalkenyl group, aryl, alkylidene aryl, hexa-member heterocycle, alkylidene hexa-member heterocycle, cyano, cyanoimino C1~5Alkyl-substituted imino group or secondary amino；And each of R2, R3, R4, R5 and R6 are separately H, halogen, hydroxyl Base, C1~5Alkoxy, amido, C1~5Carbonylimino either imino group, aryl, nitro or cyano, on condition that R2, R3, R4, It is H when R5 with R6 differences；Or in R1~R6 adjacent two constituted optionally by C together with the carbon atom being connect with it1~5Alkane Base, aryl, five~heptatomic ring or condensed-bicyclic optionally containing at least one aerobic, sulphur and nitrogen.Inventor was it was unexpectedly observed that should Compound can be efficiently used for treating cancer, especially non-small cell lung cancer.
Optionally, R1 is the iminocarbonyl, secondary amino carbonyl or 5-member heterocyclic ring containing nitrogen optionally replaced.Optionally, institute It is F or Cl to state halogen.Optionally, R1 and R2 is constituted together with the carbon atom being connect with it optionally by C1~5Alkyl, is appointed at aryl Select five~heptatomic ring containing at least one aerobic, sulphur and nitrogen either condensed-bicyclic or R2 and R3 together with the carbon being connect with it Atomic building is optionally by C1~5Alkyl, aryl, five~heptatomic ring or condensed-bicyclic optionally containing at least one aerobic, sulphur and nitrogen. Optionally, R1 and R2 constitutes the five~heptatomic ring containing 1~3 nitrogen-atoms optionally replaced together with the carbon atom being connect with it Either at least one carbonyl is formed on the ring of the optionally described five~heptatomic ring of condensed-bicyclic or condensed-bicyclic.Optionally, The compound is the stereoisomer of compound shown in the compound being shown below or following formula, and geometric isomer mutually makes a variation Structure body, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or prodrug：
In the second aspect of the present invention, the present invention proposes the purposes of compound noted earlier in medicine preparation, described Drug is used for treating cancer.Optionally, the cancer is lung cancer.Optionally, the lung cancer is non-small cell lung cancer.Optionally, The non-small cell lung cancer is BRG1 gene delections.
In addition, the invention also provides a kind of methods for treating cancer, including it is that study subject such as patient is administered Aforesaid compound or composition containing the compound.
In turn, the invention also provides a kind of compositions for treating cancer, contain compound conduct noted earlier Active constituent.
It should be noted that other equally applicable aspects of the feature and advantage of various aspects described above.
Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, raceme, nitrogen oxides, hydrate, solvate, metabolite, metabolic precursor thereof, salt and pharmaceutically acceptable prodrug are all Belong to the scope of the present invention.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.
The salt of the compound of the present invention further includes being used to prepare or purifying the intermediate of compound or formula (I) shown in formula (I) The salt of the enantiomter of shown compound separation, but it is not necessarily pharmaceutically acceptable salt.
Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can obtain the inorganic base of salt by its derivative includes, for example, the I races of ammonium salt and periodic table to XII races metal. In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
It includes primary amine, secondary amine and tertiary amine that can obtain the organic base of salt by its derivative, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid of metered amount reacts to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it needs to use non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,1985；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the other suitable for salt can be found in.
In addition, compound disclosed by the invention including their salt, in the form of their hydrate or can also include it The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, and is used for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H,14C and18Those of F compounds, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound can be ripe by those skilled in the art shown in the formula (I) of isotope enrichment Embodiment and preparation process in the routine techniques or the present invention known is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution certain treatment advantages can be provided, these advantages are It is brought by metabolic stability higher.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula (I).Isotope enrichment factor can be used To define the concentration of such higher isotope especially deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, The compound at least 3500 (52.5% deuterium incorporation at each specified D-atom), at least for each specified D-atom 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutical solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、 DMSO-d6Those of solvate.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, and it includes disclosed compound of present invention and pharmaceutically acceptable figuration Agent, carrier, adjuvant, solvent or combination thereof.The amount of compound refers to effectively examining in pharmaceutical composition disclosed by the invention Measure the amount for inhibiting biological sample or patient's body protein kinase.
It will also be appreciated that certain compounds of the present invention can exist for treating in a free form, or if it is appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
Drug pharmaceutical compositions disclosed by the invention can prepare and be packaged as (bulk) form in bulk, wherein extractable safety A effective amount of formula (I) compound represented, then gives patient with powder or syrup form.Alternatively, drug disclosed by the invention Composition can prepare and be packaged as unit dosage forms, wherein each physically discrete unit contains formula (I) institute of safe and effective amount The compound shown.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can usually contain, for example, 0.5mg to 1g, Or the compound disclosed by the invention of 1mg to 700mg or 5mg to 100mg.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Each excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid that can substantially reduce disclosed compound of present invention when administering to a patient and can cause not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, each excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Contribute to carry or transport when may be selected to administer to a patient disclosed compound of present invention from an organ of body or part to Another organ of body or partial certain pharmaceutically acceptable excipient.Certain medicines of enhancing patient compliance may be selected Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are those other Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy,Lippincott Williams & Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object acts on, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof, the technique include that mixing is each Kind ingredient.Include the pharmaceutical composition of disclosed compound of present invention, can be mixed under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes the dosage form that those are suitable for following administration route：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.
Sugar coated tablet is the compressed tablets that sugar-coat surrounds, and can be conducive to cover taste or smell beastly and can prevent Tablet aoxidizes.Thin membrane coated tablet is the compressed tablets covered with the thin layer or film of water-soluble substances.Film coating includes, but unlimited In hydroxyethyl cellulose, sodium carboxymethylcellulose, Macrogol 4000 and cellulose acetate phthalate ester.Film coating Possesses general characteristic identical with sweet tablet.Multiple compressed tablet is the compressed tablets by being prepared more than a press cycles, including multilayer Piece and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Illustrative pharmaceutically acceptable carrier or its component are carbohydrate, such as lactose, dextrose and saccharose；Starch, example Such as cornstarch and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and Methyl cellulose Element；Powdered tragacanth；Malt；Gelatin；Talcum；Kollag, such as stearic acid and magnesium stearate；Calcium sulfate；Synthetic oil；It plants Object oil, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil；Polyalcohol, such as propylene glycol, glycerine, sorbierite, sweet dew Alcohol and polyethylene glycol；Alginic acid；Phosphate buffer solution；Emulsifier, such as Tweens；Wetting agent, such as lauryl sodium sulfate； Colorant；Flavoring agent；Tablet agent；Stabilizer；Antioxidant；Preservative；Apirogen water；Isotonic saline solution；It is molten with phosphate-buffered Liquid.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plasticized by the way that glycerine, sorbierite or similar polyalcohol is added.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative be as described in the present invention those, including methyl hydroxybenzoate and nipalgin and refer to and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution in propene carbonate, vegetable oil or triglycerides and suspension.Including the capsule of such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, for example, low alkyl group aldehyde two (low alkyl group) acetals, such as acetaldehyde diethyl acetal；With tool there are one or it is more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to include active constituent provided by the invention and two level Change those of mono- or poly- alkylene glycol dosage form, described mono- or poly- alkylene glycol includes：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second Glycol -750- dimethyl ether (wherein 350,550,750 refer to the approximate average molecular weight of polyethylene glycol).These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanol amine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, coke Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral medication.It can also be prepared into extending or tie up Hold the composition of release, such as by being coated by microparticle material or be embedded in polymer, wax or the like.
Combination of oral medication provided by the invention can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella dosage form can be prepared with the method that U.S.Pat.No.6,350,458 is described.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis may include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.
Colorant and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl Amine phenol or the oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can in reality A kind of Biodegradable polymeric used in the control release of existing drug combines, for example, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, the crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block are total Polymers.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect Prepare, or with the substance co-formulation that is acted on expected from supplement.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can according to conventional method known to the technical staff in pharmaceutical science field come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
The pharmaceutical composition for being intended for parenteral administration may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter：Water, brine, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injections, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injections.Non- transporter includes, but are not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but are not limited to the poly- second of ethyl alcohol, 1,3-BDO, liquid two Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propylene glycol, glycerine, n-methyl-2-pyrrolidone, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but are not limited to phenol, cresols, mercurial, benzyl alcohol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitable isotonic agent includes, but are not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but are not limited to phosphate and citrate.Suitable antioxidant is such as those of present invention description, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is such as those of present invention description, including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable emulsifier includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene is de- Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrins (CyDex,Lenexa,KS)。
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, drug Composition is provided with sterile dried soluble product, including freeze-dried powder and hypodermic tablet, and carrier is used before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions are formulated into the sterile dry insolubility product reconstructed with carrier before use.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition disclosed in this invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, Pulse-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition can be configured to suspension, solid, semisolid or thixotropic liquid, be used as the reservoir administration of implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, be insoluble to body fluid but The external polymeric membrane that the active constituent in pharmaceutical composition diffuses through is allowed to be surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
Suitable external polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Object, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable for any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention Object can be configured to be suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Pass through the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and it is one or more it is fine powdered pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient be especially suitable for dry powder doses is known to those skilled in the art Dawn comprising lactose, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding preparation It obtains.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with swashing What optical diffraction method measured) it defines.
Aerosol can be prepared by the way that compound disclosed in this invention to be suspended or dissolved in liquefied propellant.It is suitble to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representative propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- difluoros Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Including the aerosol of compound disclosed in this invention usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art.
Aerosol may include pharmaceutically acceptable excipient that is additional, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
Discontinuous patch agent can be prepared by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 1986,3 (6), the general description in 318.
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.Made according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can use water or oil matrix to prepare, and generally also contain one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickener.
Externally-applied powder can be molded in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersing agents, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential It is used.Adhesiveness store system can realize continuous or extended administration.
When treating eyes or other organs such as face and skin, the combination as topical ointment or cream can be applied Object.When being formulated as ointment, compound disclosed in this invention can be used together with paraffin or water-soluble ointment matrix.Or Person, compound disclosed in this invention can be configured to cream together with Oil-in-water emulsifiable paste agent matrix or oil-in-water base.
Combination therapy
The compounds of this invention can be used as individual active agent to be administered, or can be administered with other therapeutic agents, Including being determined as safe and efficient other compounds with same or similar therapeutic activity and for such administering drug combinations.
On the one hand, the present invention provides treatment, prevents or improve the method for disease or illness, including gives safe and effective amount Include the combination medicine of disclosed compound of present invention and one or more therapeutically active agents.In one embodiment, combination medicine Including one or two kinds of other therapeutic agents.
The example of other therapeutic agents includes but not limited to：Anticancer agent, including chemotherapeutics and antiproliferative；Anti-inflammatory agent；With exempt from Epidemic disease conditioning agent or immunosuppressor.
Therapy
In one embodiment, therapy disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention includes by having The patient needed gives the disclosed compound of present invention of safe and effective amount or the pharmaceutical composition comprising disclosed compound of present invention, Method to treat disease mentioned above.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is administered by any suitable administration route, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral medication, stomach and intestine External administration, cutaneous penetration and rectally.Typical parenteral refer to by injection or administered by infusion, including it is intravenous, Intramuscular and hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal Administration.In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with It is oral medication.In another embodiment, disclosed compound of present invention or the pharmaceutical composition comprising disclosed compound of present invention Object can be inhalation.In a further embodiment, disclosed compound of present invention or comprising disclosed compound of present invention can be Intranasal administration.
In one embodiment, disclosed compound of present invention or pharmaceutical composition comprising disclosed compound of present invention can be with Once daily, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, every It is administered once, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, daily It is administered twice.It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.It is of the invention public Open medicine generation of the appropriate dosage regimen of compound or the pharmaceutical composition comprising disclosed compound of present invention depending on the compound Kinetic property, such as dilution, distribution and half-life period, these can be by determination of technical staff.In addition, disclosed compound of present invention Or the appropriate dosage regimen of the pharmaceutical composition comprising disclosed compound of present invention, including implement the duration of the program, it takes Certainly in treated disease, the severity of disease being treated, the age of patient under consideration and physical condition, patient under consideration The factor within the scope of technical staff's knowledge and experience such as the property of medical history while therapy, desired therapeutic effect.It is such Technical staff should also be understood that the reaction to dosage regimen for individual patient, or individual patient needs to become as time goes by When change it may require that adjust the dosage regimen of matters.
Disclosed compound of present invention can simultaneously, or before it or later be administered with one or more other therapeutic agents. The compounds of this invention can be respectively administered with other therapeutic agents by identical or different administration route, or therewith with with medicine group Solvate form is administered.
For the individual of about 50-70kg, the present invention pharmaceutical composition disclosed and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active constituents Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depending on individual species, weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its severity.Has the doctor of common technical ability Teacher, clinician or animal doctor can be easy to determine to prevent, treat or inhibit disease (disorder) or disease (disease) development The effective quantity of each active constituent needed in the process.
Dose Characteristics cited above using advantageous mammal (such as mouse, rat, dog, monkey) or its from It is confirmed in the external and in vivo studies of body organ, tissue and sample.Disclosed compound of present invention is with solution, such as aqueous solution form Use in vitro, can also such as enteral of suspension or aqueous solution form in vivo, it is parenteral, it is especially intravenous to use.
In one embodiment, the treatment effective dose of disclosed compound of present invention is daily about 0.1mg to about 2, 000mg.Its pharmaceutical composition should provide about 0.1mg to the compound of about 2,000mg dosage.In a particular embodiment In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, and about 10mg to about 1,000mg, about 20mg is to about The combination of each main component in 500mg, or the main active of about 25mg to about 250mg or every dosage unit form.One In particular embodiment, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.
In addition, compound disclosed by the invention can be administered with prodrug forms.In the present invention, disclosed compound of present invention " prodrug " be that can finally release the functional derivatives of disclosed compound of present invention in vivo when administering to a patient.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement one kind or more in following manner：(a) Change the internal onset time of compound；(b) the internal acting duration of compound is changed；(c) change compound is internal Conveying or distribution；(d) the internal solubility of compound is changed；And the side effect for (e) overcoming compound to be faced or other difficult points. The typical functional derivatives of prodrug are used to prepare, including in vivo chemically or the mode of the enzyme compound that cracks Variant.Including preparing these variants of phosphate, amide, ester, monothioester, carbonate and carbaminate to people in the art It is well-known for member.
General building-up process
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by being further purified when use, unless other aspects show (by route N Unify legislations to be number in following Word is numbered, and is repeated no more).
(1. 1 indicates route 1, is below digital number by route N Unify legislations, repeats no more) synthesizing amide class compound (3)：
The special condensing agent (BOP, 1.2eq.) of substituted aromatic carboxylic acids (1,1eq.), card and n,N-diisopropylethylamine (DIEA, 2.5eq) it is added in the N,N-dimethylformamide solvent of appropriate volume.10min is stirred at room temperature in the mixed liquor of gained.Amino Class compound (2,2.5eq.) instills in reaction solution in batches or dropwise.5h is stirred at room temperature in gained reaction solution.After reaction, Reaction solution is gone out using isometric water quenching, and the ethyl acetate of double volume is used in combination to be extracted three times.Combined ethyl acetate phase, it is organic It is mutually washed using water and salt, and is dried using anhydrous sodium sulfate.After filtering, ethyl acetate, gained are removed using Rotary Evaporators After crude product mixes silica white, dry method loading is isolated and purified using the method for silica gel column chromatography.
2. the synthesis of pyrazole compound (7)：
It dissolves the benzaldehyde (4,1eq.) replaced in ethanol and NaOH is added portionwise in alkyl ethyl ketone (5,1.5eq.) In the aqueous solution of (3eq.).The mixed-liquor return 4h of gained.Reaction solution is down to room temperature, and uses the hydrochloric acid tune pH to 4~5 of 2N. Gained mixed liquor is extracted three times using isometric ethyl acetate.After organic phase is using water and salt washing, anhydrous sodium sulfate is used It is dried.After filtering out sodium sulphate, after organic phase is using Rotary Evaporators removal, gained crude intermediate (6) is directly used In in next step.
Intermediate (6,1eq.), unifor (2eq.) and tetrabutylammonium bromide (TBAB, 1eq.) slowly add in batches It is stirring while adding in the aqueous solution for entering NaOH (3eq.).The mixed liquor of gained stirs 12h at 95 DEG C.Reaction solution is down to room temperature, And use the hydrochloric acid tune pH to 4~5 of 2N.Gained mixed liquor is extracted three times using isometric ethyl acetate.Organic phase using water and After salt washing, it is dried using anhydrous sodium sulfate.After filtering out sodium sulphate, organic phase is removed using Rotary Evaporators. Gained crude product is isolated and purified using the method for recrystallization or silica gel column chromatography.
The synthetic route 2 of hydroxyl indone class 3. (11) structure：
Phenolic compound (8,1eq.) is dissolved in methylene chloride (DCM), and reaction bulb is full of argon gas, uses argon gas Ball is protected.At room temperature, pyridine (1.2eq.) is added using syringe.3- chlorine propionyl chloride (9,1.1eq.) is slow by syringe It is added dropwise in reaction bulb.1h is stirred at room temperature in the mixed liquor of gained.After reaction, reaction solution makes to be quenched with water.After liquid separation, Dichloromethane mutually uses water and salt to wash.After dichloromethane mutually uses anhydrous magnesium sulfate drying, filtering is used in combination Rotary Evaporators to go Except organic solvent, crude product uses silica gel column chromatography separating purification, obtains intermediate 10.Intermediate (10,1eq.) and AlCl3 (3eq.) is added in reaction bulb, no solvent the case where under, be heated to 180 DEG C of reaction 6h.After reaction is cooled to room temperature, use Ice-cold 2M hydrochloric acids simultaneously stir, and black solid is made to dissolve.Make to be extracted with ethyl acetate three times.Organic phase merges, salt washing, After anhydrous sodium sulfate drying, it is spin-dried for more than rotary evaporation, crude product is detached using silica gel column chromatography, obtains hydroxyl indone class chemical combination Object (11).
4. the synthetic route of isoquinolinol class compound：
Hydroxyl indanone compounds (11,1eq.) are added in ice-cold concentrated hydrochloric acid, NaN3(2eq.) is slowly added in batches.Instead Liquid is answered to stir 20h in 0 DEG C~r.t..After reaction, reaction solution is quenched with water.Water phase dichloromethane extracts three times, organic Mutually dried using anhydrous magnesium sulfate.After drier filtering, organic phase mixes silica gel, using silica gel column chromatography separating purification, obtains hydroxyl Base isoquinoline compound 12.Compound 12 (1eq.), NaH (2eq.) react 0.5h in solvents tetrahydrofurane, and iodo is added Object R ' I (3eq.), reaction can obtain compound 13 overnight.Compound 13 is stirred overnight at 180 DEG C and can must change with 48%HBr aqueous solutions Close object 14.
The synthesis of benzoyl guanidine radicals (18) and benzoyl amidino groups (20) compound：
Septichen class compound (15,1eq.) is added in reaction dissolvent dichloromethane, SOCl2(3eq.) is added dropwise to In solution.After gained reaction solution reacts 1h at 50 DEG C, revolving removes SOCl2 on a rotary evaporator.Gained crude product uses dichloro Methane dissolves, and then instills the mixed liquor of phenol (phenol, 1eq.) and triethylamine (TEA, 3eq.) in methylene chloride.Gained After reaction solution stirs 1h at r.t., water quenching is added to go out.It is extracted using dichloromethane, organic phase is dried using anhydrous magnesium sulfate.It is dry After drying prescription is filtered, organic phase mixes silica gel, using silica gel column chromatography column separating purification, obtains intermediate 16.Intermediate 16 (1eq.) With 1,1,3,3- tetramethylguanidine (TMG, 1.5eq.) is added in reaction dissolvent n,N-Dimethylformamide, after stirring 5min, is added Guanidine compound (17,1.6eq.), is stirred overnight at room temperature.Reaction terminates to make to be quenched with water, and silica gel is used after ethyl acetate extraction Column chromatography for separation can obtain benzoyl guanidine base class compound (18).Intermediate 16 (1eq.), O- benzotriazole-tetramethylurea hexafluoro Phosphate (HBTU, 1.6eq.), n,N-diisopropylethylamine (DIEA, 3eq.) are added in solvent n,N-Dimethylformamide.Instead Answer liquid that 30min is stirred at room temperature, amidino compounds (19,1.2eq.) are added in reaction solution.After reaction solution is stirred overnight at room temperature, add water It is quenched.Make after being extracted with ethyl acetate, silica gel column chromatography separation can obtain benzoyl amidine compound (20).
The synthesis of indazole compounds (23)：
By substituted fluorobenzonitrile (21,1eq.), round-bottomed flask is added in hydrazine hydrate (4eq.) and appropriate solvent, n-butanol.Instead It should be heated to 100 DEG C overnight.Thickening filtration after reaction obtains intermediate 22, is directly used in next step.Intermediate 22 (1eq.) is dissolved in appropriate tetrahydrofuran solvent, aldehyde compound (5eq.), and palladium carbon (0.04eq.) is separately added into reaction, Hydrogen is provided with hydrogen balloon, overnight, TLC detections are reacted for room temperature reaction.It is filtered to remove palladium carbon after reaction, after solution mixes silica gel It is detached using the method for silica gel column chromatography, obtains target indazole compounds.
The synthesis of triazole type (26) compound：
Substituted salicylamide (24,1eq.) is dissolved in acetone, adds triethylamine (Et3N, 1.2eq.), acetic anhydride (1.1eq) is heated to reflux four hours.TLC is detected after reaction, is removed using Rotary Evaporators and is held agent, crude product silica gel Column chromatography purifies, and obtains intermediate 26.By HClO4(70%, 1eq.) instill in acetic anhydride (3eq.), and mixed liquor is instilled In the acetic acid solution of mesosome 25 (1eq.), 95 DEG C of heating reaction solution 1.5h, solution becomes congo red color, adds hydrazine hydrate Temperature is down to 80 DEG C, stirs half an hour by (2eq.).After reaction is cooled to room temperature, diluted with ethyl acetate, with unsaturated carbonate hydrogen Sodium solution washes away acid solution, and organic phase is dried with anhydrous magnesium sulfate, and silica gel column chromatography purifies after removing solvent using Rotary Evaporators Obtain target triazole class compounds 26.
The synthesis of 4- carbamoyl ester glyoxaline compounds (29)：
The aqueous solution of hydroxylamine hydrochloride (4eq.) and sodium carbonate (2eq.) is added to substituted hydroxy-phenylformonitrile (27,1eq.) Ethanol solution in, flow back 10 hours.Ethyl alcohol is removed with Rotary Evaporators after reaction, is extracted with ethyl acetate, anhydrous sulphur After sour magnesium drying, silica gel column chromatography purifies to obtain intermediate 28.Ethyl propiolate (2eq.) is instilled into intermediate 28 (1eq.) It in ethanol solution, is heated to reflux 10 hours, 190 DEG C of diphenyl ether is added after removing ethyl alcohol with Rotary Evaporators and is heated three hours. After reaction stops, it is down to room temperature, entire reaction solution is poured into larger silicagel column, is rinsed using petroleum ether, after removing diphenyl ether, made Remaining component is gone out with ethyl acetate.Merge component, after mixing silica white, the smaller silica gel column chromatography separating purification of use obtains Target product glyoxaline compound 29.
The synthesis of 4- carbamoyl ester glyoxaline compounds (30)：
4- carbamoyl ester glyoxaline compounds 29 (1eq.) are dissolved in the in the mixed solvent of tetrahydrofuran and water, then are instilled 40% methylamine water solution (20eq.), 60 DEG C of heating reaction 4h.After reaction, removal tetrahydrochysene furan is depressurized using Rotary Evaporators It mutters, remaining water phase is extracted with ethyl acetate.Organic phase after merging, is dried using anhydrous sodium sulfate.After drier is filtered out, have Machine mutually mixes silica gel, purifies to obtain 4- carbamoyl ester glyoxaline compounds 30 by silica gel column chromatography.
The synthesis of quinazoline diones class (35)：
Compound 32 (1eq.) is added to the dichloromethane solution of compound 31 (1eq.), and N is added, two miaow of N'- carbonyls Azoles (CDI, 1.3eq.) and n,N-diisopropylethylamine (DIPEA, 2eq.), react 6h at room temperature, and Rotary Evaporators remove dichloro Methane passes through the isolated intermediate of silica gel column chromatography 33.Triphosgene is added in the dichloromethane solution of intermediate 33 (1eq.) (0.4eq.), flow back 12h, obtains intermediate 34.In the reaction system, it is directly added into Boron tribromide (3eq.) reaction, obtains quinoline Oxazoline cyclohexadione compounds 35.
The synthesis of pyrazolo quinolines (KQ76, KQ77)：
Compound 36 (1eq.) is dissolved in acetone, and KOH (4eq.) is added, dimethyl suflfate is added under stiring (1.5eq.), reaction solution stir 1 hour, add 1ml water, stir 1.5h.It is extracted with ethyl acetate after reaction, anhydrous sulphur After sour magnesium drying, purified to obtain intermediate 37 with silica gel column chromatography.Intermediate 37 (1eq.) is dissolved in glacial acetic acid, then by acrylic acid (2eq.) is instilled, and is added with stirring 98% sulfuric acid (0.1eq.), 80 DEG C of heating 5h.After reaction, saturated sodium bicarbonate solution It neutralizes, ethyl acetate extraction, after the drying of organic phase anhydrous magnesium sulfate, silica gel column chromatography purifies to obtain intermediate 38.Intermediate 38 (1mmol) is dissolved in 6ml Eaton ' s reagents, and reaction solution is heated to 65 DEG C overnight.Sodium hydroxide solution is used after reaction It neutralizes, ethyl acetate extraction, after the drying of organic phase anhydrous magnesium sulfate, silica gel column chromatography purifies to obtain intermediate 39.Compound 39 (1eq.) is dissolved in anhydrous methylene chloride, and reaction bulb is replaced with argon gas, -78 DEG C of addition BBr3(5eq.), is gradually warming up to room Temperature is quenched and is neutralized with saturated sodium bicarbonate solution after reacting 5h, ethyl acetate extraction, after organic phase drying, silica gel column chromatography Purifying obtains intermediate 40.Compound 40 (1eq.) is dissolved in acetone, and Cs is added2CO3(6eq.), strictly by reaction bulb nitrogen Chloromethyl methyl ether (3eq.) is added under ice bath for gas shielded, and temperature is raised to 10 DEG C, reacts 2h.It uses in 2N hydrochloric acid after reaction And reaction, ethyl acetate extraction, silica gel column chromatography purifies after organic phase drying, obtains intermediate 41.Compound 41 is dissolved in nothing In water tetrahydrofuran, -40 DEG C are added LDA (2eq.), and butyl chloride (1.1eq.) is added after half an hour, reaction is raised to room temperature, React 0.5h, water quenching be added and goes out reaction, tetrahydrofuran is walked in decompression rotation, is extracted with ethyl acetate, after organic phase drying pressurization revolves Solvent, crude product are dissolved with ethyl alcohol, add hydrazine hydrate (3eq.), 60 DEG C of reaction 2h.It is pure by silica gel column chromatography after reaction Change obtains intermediate 42.Compound 42 (1eq.) is added in trifluoroacetic acid, and 1h is stirred at room temperature, and after reaction, decompression is spin-dried for Solvent purifies with silica gel column chromatography crude product to obtain target product 43.Compound 43 is dissolved in dry tetrahydrofuran, is added Sodium borohydride (5eq.), is stirred at room temperature 3h, after reaction, water quenching is added and goes out reaction, decompression revolves tetrahydrofuran, with acetic acid second Ester extracts, and silica gel column chromatography purifies to obtain compound K Q77 after anhydrous magnesium sulfate drying.
The synthesis of pyrazolo quinolinones compound (KQ78)：
Compound 45 (1eq.) is positioned in seal pipe, and trifluoroacetic acid is added, adds methenamine (1.1eq.), will be close After tube sealing is replaced with argon gas, 100 DEG C, after reaction for 24 hours are heated to, cooling reaction solution to room temperature.Isometric 4N hydrochloric acid is added anti- It answers in liquid, stirs 1h.It is spin-dried for solvent after reaction, appropriate distilled water is added, is extracted with dichloromethane.Crude product silica gel column layer Analysis purifying obtains compound 46.By DBU (2eq.), iodomethane (3eq.) is added in the acetone soln of compound 46 (1eq.), It is stirred overnight at room temperature.After reaction, decompression is spin-dried for solvent, and crude product is purified with silica gel column chromatography to obtain compound 47.It will change It closes object 47 to be dissolved in acetone, the saturated solution of sodium chlorite (5eq.) is added, add 2N hydrochloric acid (8eq.), reaction is overnight. After reaction, decompression is spin-dried for solvent, then is extracted with ethyl acetate, and after crude product drying, silica gel column chromatography purifies to obtain compound 48.Compound 48 is dissolved in dry methylene chloride, two drop DMF is instilled, adds oxalyl chloride (2eq.), 2h is stirred at room temperature, It is for use that it is spin-dried for solvent after reaction.Compound 49 (1.2eq.) is dissolved in dry THF, NaH (1.5eq.) is added, room temperature is stirred Mix 0.5h.The reaction product of compound 48 is dissolved with dry THF again, instills in the reaction solution of compound 49,1h is stirred at room temperature. A small amount of water quenching is added after reaction to go out reaction, after being spin-dried for solvent, crude product is purified to obtain compound 50 with silica gel column chromatography.It will change It closes object 50 to be dissolved in ethyl alcohol, hydrazine hydrate (2eq.) is added, 60 DEG C of stirring 2h are spin-dried for solvent, crude product silica gel after reaction Column chromatography purifies to obtain compound 51.Compound 51 (1eq.) is dissolved in glycol dimethyl ether, reduced iron powder is added (10eq.) is added 0.1N hydrochloric acid (10eq.), is heated to 82 DEG C, reacts 5h, is spin-dried for solvent, crude product silicagel column after reaction Chromatographic purifying obtains compound 52.Compound 52 is dissolved in ethyl alcohol, isometric 2N hydrochloric acid, 40 DEG C of heating stirrings are added 5h obtains white opacity liquid, white solid is obtained by filtration, and with a small amount of ethyl acetate rinse, obtains compound 53.By compound 53 are dissolved in anhydrous methylene chloride, -30 DEG C of addition BBr3(10eq.), then by even 40 DEG C of temperature, react 3 days, reaction terminates Afterwards, solvent and BBr are walked in directly decompression rotation3.Crude product is dissolved with ethyl acetate, washing is primary, anhydrous magnesium sulfate drying, decompression Silica gel column chromatography purifies to obtain compound 54 after being spin-dried for solvent.
The synthesis of the pyrazolo quinolines (KQ79) of cyclopropane substitution：
Compound 53 (1eq.) is dissolved in dry n,N-Dimethylformamide, and NaH (60% oil dispersed, 3eq.) is added, 0.5h is stirred at room temperature, adds cylite (4eq.), heating reaction 4h.After reaction, ethyl acetate is added, reaction is washed with water Three times, after organic phase is dried with anhydrous magnesium sulfate, silica gel column chromatography purifies to obtain compound 55 liquid.By Ti (OiPr)4(1eq.) It is dissolved in anhydrous tetrahydro furan, by reaction bulb argon gas displaced air, -78 DEG C are added EtMgBr (3M in THF, 3eq.), After stirring 2min, then the tetrahydrofuran solution of compound 55 (1eq.) is slowly instilled, room temperature is mentioned into reaction after adding, is stirred 5h.Saturated ammonium chloride solution is added after reaction, stirs 10min, then be extracted with ethyl acetate, organic phase anhydrous magnesium sulfate is dry After dry, silica gel column chromatography purifying obtains compound 56.Compound 56 (1eq.) is dissolved in methanol, Pd/C is added (0.1eq.), reaction bulb is replaced with hydrogen, and a hydrogen balloon is inserted on reaction bulb, is reacted at room temperature 3h, is filtered after reaction Reaction solution removes Pd/C, obtains compound 57.Compound 57 (1eq.) is dissolved in dry methylene chloride, -78 DEG C of additions BBr3(6eq.), reaction is warmed to room temperature, and for 24 hours, after reaction, solvent is walked in decompression rotation, and crude product ethyl acetate is molten for stirring Solution, sodium bicarbonate solution are washed once, and saturated nacl aqueous solution is washed once, and after anhydrous magnesium sulfate drying, silica gel column chromatography purifies To compound K Q79.
The synthesis of the pyrazolo quinolines (KQ80) of dimethyl substitution：
Compound 51 (1eq.) is dissolved in n,N-Dimethylformamide, cesium carbonate (1eq.), tolysulfonyl is added Chlorine (2eq.), stirs 5h, is diluted after reaction with ethyl acetate at room temperature, and three times, organic phase anhydrous magnesium sulfate is dried for washing Afterwards, silica gel column chromatography purifies to obtain compound 59.Compound 59 is dissolved in glycol dimethyl ether, reduced iron powder is added (10eq.), 0.1N hydrochloric acid (6eq.), is stirred at room temperature 15h.Solvent is walked in decompression rotation after reaction, and product is extracted with ethyl acetate, Crude product obtains compound 60 with silica gel column chromatography after purification.Compound 60 is dissolved in anhydrous n,N-Dimethylformamide, is added NaH (1.5eq.), is stirred at room temperature 15min, adds cylite (2eq.), reacts at room temperature 5h, and acetic acid second is added after reaction Ester dilutes, and three times, silica gel column chromatography purifies to obtain compound 61 after the drying of organic phase anhydrous slufuric acid for washing.Compound is dissolved in In anhydrous methylene chloride, DTBMP (1eq.) is added, -78 DEG C are added trifluoromethanesulfanhydride anhydride (1eq), and reaction is warmed to room temperature, is stirred 1h is mixed, reaction is cooled to -78 DEG C again, methyl Grignard (3eq.) is added, stirs and reaction is warming up to room temperature after 10min 5h to be stirred, ethyl acetate is added after reaction, washing is primary, and salt washing is primary, after the drying of organic phase anhydrous magnesium sulfate, silica gel Column chromatography purifies to obtain compound 62.Compound 62 (1eq.) is dissolved in methanol, Pd/C (0.1eq.) is added, in hydrogen ring Benzyl protecting group is taken off in reduction under border.It is directly removed by filtration Pd/C after reaction.6N hydrochloric acid will be added in filtrate (10eq.) is heated to 50 DEG C, after stirring 5h, room temperature is down in reaction, decompression rotation walks organic solvent, production is extracted with ethyl acetate Object, silica gel column chromatography purifies to obtain compound 63 after organic phase drying.Compound 63 (1eq.) is dissolved in anhydrous methylene chloride In, -78 DEG C of addition BBr3Then reaction is warming up to room temperature by (10eq.), for 24 hours, after reaction, solvent is walked in decompression rotation for reaction, After crude product is dissolved with ethyl acetate, washing is primary, and salt washing is primary, and silica gel column chromatography purifies to obtain compound after organic phase drying KQ80。
The synthesis of benzazepine and pyrazole compound (KQ81)：
Compound 65 is restored to obtain intermediate 66 by Pd/C.Intermediate 66 (1eq.) is dissolved in tetrahydrofuran solution, Trifluoroacetic anhydride (1eq.) is slowly added dropwise to above-mentioned solution under ice bath, reacts 1h, dichloromethane extracts later, and what is obtained is organic Dissolving mutually is removed by Rotary Evaporators, intermediate 67 is finally obtained, is directly used in the next step.Compound 68 (3eq.) is slow It is slow to be added dropwise in the n,N-Dimethylformamide solution of intermediate 67 (1eq.) and potassium carbonate (5eq.), reaction reflux 12h.Reaction stops Cool down after only, extracted by ethyl acetate, obtained organic phase is concentrated, passes through the isolated intermediate of silica gel column chromatography 69. Intermediate 69 (1eq.) is added to the acetonitrile solution of ferric trichloride (5%), and flow back 8h, removes solvent, obtains intermediate 70, directly uses It is reacted in next step.The methanol solution of unifor (1.1eq.) is added in intermediate 70 (1eq.), and room temperature reaction overnight, removes Solvent is removed, the aqueous solution of NaOH (2eq.) is subsequently added into, at 95 DEG C, reacts 12h.After being cooled to room temperature, the hydrochloric acid tune of 2N is used PH to 4~5, is extracted with ether, and organic phase merges, and the isolated intermediate 71 of silica gel column chromatography, intermediate 71 is dissolved in dichloro Methane, -78 DEG C of addition BBr3Then reaction is warming up to room temperature by (10eq.), for 24 hours, after reaction, decompression rotation is walked molten for reaction Agent, after crude product is dissolved with ethyl acetate, washing is primary, and salt washing is primary, silica gel column chromatography purifying after organic phase drying Close object KQ81.
Those skilled in the art can be according to the structure of the compound of desired synthesis, synthetic route as described above It is effectively performed and prepares corresponding compound.
Synthetic example
In the present embodiment, inventor is prepared for change listed in table 1 according to general synthetic method described above Object is closed, corresponding synthetic method is summarised in table 1, and the synthesis qualification result of each compound is as follows：
KQ1:1H NMR(400 MHz,d6-DMSO,ppm)δ 8.03(br s,1H),7.86(m,1H),7.53(m,1H), 7.19 (m, 1H), 6.95 (m, 1H), 5.35 (s, 1H), 3.28 (q, 2H, J=7.2 Hz), 1.04 (t, 3H, J=7.2 Hz)
KQ2:1H NMR(400 MHz,d6-DMSO,ppm)δ 8.05(br s,1H),7.92(m,1H),7.59(m,1H), 7.19 (m, 1H), 7.17 (m, 1H), 3.83 (s, 3H), 3.26 (q, 2H, J=7.2 Hz), 1.02 (t, 3H, J=7.2 Hz)
KQ3:1H NMR(400 MHz,d6-DMSO,ppm)δ 8.02(br s,1H),7.64(m,1H),7.10(m,1H), 6.99 (m, 1H), 6.81 (m, 1H), 6.27 (br s, 2H), 3.23 (q, 2H, J=7.2 Hz), 1.07 (t, 3H, J=7.2 Hz).
KQ4:1H NMR(300 MHz,CDCl3, ppm) and δ 12.11 (s, 1H), 8.16 (d, J=2.44 Hz, 1H), 7.33 (dd, J=8.79 Hz, 1H), 7.30 (br s, 1H), 6.92 (d, J=8.79 Hz, 1H), 2.63 (s, 3H), 2.18 (s, 3H)
KQ5:1H NMR(400 MHz,d6-DMSO,ppm)δ 11.65(s,1H),10.29(br s,1H),7.81(d,1H, ), J=2.6Hz 7.49 (dd, 1H, J1=8.8 Hz, J2=2.6 Hz), 2.61 (s, 3H)
KQ6:1H NMR(400 MHz,d6-DMSO,ppm)δ 8.10(br s,1H),7.09(m,1H),7.06(m,1H), 6.89(m,1H),6.83(m,1H),5.35(s,1H),4.47(s,2H),3.29(s,2H),2.51(m,4H),1.68(m,4H).
KQ7:1H NMR(400 MHz,d6-DMSO,ppm)δ 8.78(br s,1H),7.19-7.14(m,1H),6.74- 6.71(m,1H),3.31-3.11(m,2H),2.76-2.73(m,2H).
KQ8:1H NMR(400 MHz,CDCl3, ppm) and δ 7.55 (d, 1H, J=8.0 Hz), 7.36-7.28 (m, 2H), 7.03 (d, 1H, J=7.5 Hz), 3.50 (q, 2H, J=7.1 Hz), 1.34 (t, 3H, J=7.1 Hz)
KQ9:1H NMR(400 MHz,CDCl3,ppm)δ 9.37(br s,1H),7.07-7.02(m,1H),6.98-6.93 (m, 2H), 3.52 (q, 4H, J=7.1Hz), 1.28 (t, 6H, J=7.1 Hz)
KQ10:1H NMR(400 MHz,CD3Cl,ppm)δ 9.40(br s,1H),7.00-6.94(m,2H),6.90- 6.86 (m, 1H), 3.50 (q, 2H, J=7.0 Hz), 3.08 (s, 3H), 1.23 (t, 3H, J=7.0 Hz)
KQ11:1H NMR(400 MHz,CD3Cl,ppm)δ 12.64(br s,1H),7.30-7.27(m,1H),6.82- 6.80(m,1H),6.62-6.60(m,1H),3.58-3.55(m,2H),3.13(s,3H),3.00-2.97(m,1H).
KQ12:1H NMR(400 MHz,CD3Cl, ppm) δ 12.74 (br s, 1H), 7.30 (d, J=8.92 Hz, 1H), 6.77 (d, J=8.92 Hz, 1H), 3.57 (t, J=6.88 Hz, 2H), 3.12 (s, 3H), 3.05 (t, J=6.92 Hz, 2H)
KQ13:1H NMR(400 MHz,CD3Cl,ppm)δ 12.76(br s,1H),7.35-7.31(m,1H),6.67- 6.64 (m, 1H), 6.57-6.53 (m, 1H), 6.21 (br s, 1H), 3.48 (m, 2H), 1.26 (t, 1H, J=7.2 Hz)
KQ14:1H NMR(400 MHz,CD3Cl,ppm)δ 10.79(br s,1H),7.96-7.95(m,1H),7.53- 7.51 (m, 1H), 6.89-6.87 (m, 1H), 4.41 (m, 2H), 1.42 (t, 3H, J=7.1 Hz)
KQ15:1H NMR(400 MHz,CD3Cl, ppm) δ 12.68 (br s, 1H), 7.12 (d, 1H, J=8.5 Hz), 6.18 (s, 1H), 6.12 (d, 1H, J=8.5 Hz), 5.98 (br s, 1H), 3.97 (br s, 2H), 3.45 (m, 2H), 1.24 (t, 3H, J=7.2Hz)
KQ16:1H NMR(400 MHz,CD3OD, ppm) δ 7.61 (br s, 1H), 7.20 (d, 1H, J=8.28 Hz), 6.93 (d, 1H, J=8.28 Hz), 3.42 (q, 2H, J=7.2 Hz), 1.23 (t, 3H, J=7.2 Hz)
KQ17:1H NMR(400 MHz,d6-DMSO,ppm)δ 12.43(br s,1H),8.81(br s,1H),7.73- 7.70 (m, 1H), 7.30-7.25 (m, 1H), 6.93-6.90 (m, 1H), 3.24 (t, 2H, J=6.4 Hz), 1.60-1.50 (m, 2H), 0.90 (t, 3H, J=7.2 Hz)
KQ18:1H NMR(400 MHz,CD3Cl,ppm)δ 12.06(br s,1H),7.13-7.08(m,1H),7.06- 7.03(m,1H),6.95-6.91(m,1H),6.30(br s,1H),3.47-3.42(m,2H),1.65-1.57(m,2H), 1.46-1.1.36 (m, 2H), 0.96 (t, 3H, J=7.3 Hz)
KQ19:1H NMR(400 MHz,CD3Cl,ppm)δ 12.40(br s,1H),7.39-7.35(m,2H),6.98- 6.96(m,1H),6.84-6.80(m,1H),6.45(br s,1H),3.43-3.38(m,2H),1.69-1.60(m,2H),0.98 (t, 3H, J=7.4 Hz)
KQ20:1H NMR(400 MHz,CD3Cl,ppm)δ 12.41(br s,1H),7.39-7.34(m,2H),6.98- 6.96(m,1H),6.84-6.81(m,1H),6.40(br s,1H),3.47-3.3.42(m,2H),1.64-1.57(m,2H), 1.45-1.36 (m, 2H), 0.95 (t, 3H, J=7.3 Hz)
KQ21:1H NMR(400 MHz,CD3Cl,ppm)δ 12.37(br s,1H),7.38-7.34(m,2H),6.97- 6.95(m,1H),6.83-6.80(m,1H),6.52(br s,1H),3.44-3.3.39(m,2H),1.64-1.57(m,2H), 1.35-1.34 (m, 4H), 0.90 (t, 3H, J=7.4 Hz)
KQ22:1H NMR(400 MHz,CD3Cl,ppm)δ 8.07(s,1H),7.86(br s,1H),7.57-7.55(d, 1H, J=8.4 Hz), 6.96-6.94 (d, 1H, J=8.5 Hz), 3.48 (m, 2H), 1.28 (t, 3H, J=7.2 Hz)
KQ23:1H NMR(400 MHz,CD3Cl, ppm) δ 12.70 (br s, 1H), 7.23-7.21 (d, 1H, J=8.7 ), Hz 6.40 (s, 1H), 6.35-6.33 (d, 1H, J=8.8 Hz), 6.06 (br s, 1H), 3.50-3.44 (m, 2H), 1.25 (t, 3H, J=7.8 Hz)
KQ24:1H NMR(400 MHz,CD3Cl, ppm) δ 7.87 (br s, 1H), 7.37 (d, 1H, J=8.24 Hz), 7.03 (d, 1H, J=8.24 Hz), 3.37-3.31 (m, 2H), 1.65-1.60 (m, 2H), 0.95 (t, 3H, J=7.32 Hz)
KQ25:1H NMR(400 MHz,CD3Cl, ppm) δ 9.06 (br s, 1H), 7.46 (t, 1H, J=7.6 Hz), 6.93(dd,1H,J1=8.0 Hz, J2=0.4 Hz), 6.74 (t, 1H, J=7.6 Hz), 3.12-3.09 (m, 2H), 2.72- 2.70(m,2H).
KQ26:1H NMR(400 MHz,CD3Cl,ppm)δ 7.16(m,1H),6.78(m,1H),6.70(m,1H),5.64 (m,1H),5.35(br s,1H),3.65(s,1H),2.74(m,2H),2.64(m,2H),2.26(s,3H).
KQ27:1H NMR(400 MHz,d6- DMSO, ppm) δ 9.97 (s, 1H), 8.34 (t, 1H, J=5.6 Hz), 7.21 (dd,1H,J1=J2=9.2 Hz), 6.80 (dd, 1H, J1=4.0 Hz, J2=9.2 Hz), 3.21 (dq, 2H, J1=5.6 Hz, J2=7.2 Hz), 1.08 (t, 3H, J=7.2 Hz)
KQ28:1H NMR(400 MHz,CD3Cl,ppm)δ 12.47(br s,1H),7.19-7.14(m,1H),6.79- 6.75 (m, 1H), 6.13 (br s, 1H), 3.52-3.45 (m, 2H), 1.27 (t, 3H, J=7.2 Hz)
KQ29:1H NMR(400 MHz,d6- DMSO, ppm) δ 9.40 (s, 1H), 8.15 (t, 1H, J=5.2 Hz), 6.94 (dd,1H,J1=J2=9.2 Hz), 6.65 (dd, 1H, J1=4.4 Hz, J2=8.8 Hz), 3.24-3.17 (m, 2H), 2.05 (d, 3H, J=2.0Hz), 1.08 (t, 3H, J=7.2 Hz)
KQ30:1H NMR(400 MHz,CDCl3, ppm) and δ 12.44 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 6.63 (d, 1H, J=11.0 Hz), 6.12 (s, 1H), 3.52-3.45 (m, 2H), 2.20 (s, 3H), 1.27 (t, 3H, J=7.2 Hz)
KQ31:1H NMR(400 MHz,CDCl3, ppm) and δ 12.46 (s, 1H), 6.98 (d, 1H, J=11.6 Hz), 6.27 (d, 1H, J=7.9 Hz), 6.04 (s, 1H), 3.48-3.41 (m, 2H), 1.24 (t, 3H, J=7.2 Hz)
KQ32:1H NMR(400 MHz,CDCl3,ppm)δ 8.24(br s),8.08(m,1H),7.59(m,1H),7.52- 7.41 (m, 5H), 5.35 (br s, 1H), 3.42 (t, J=7.2 Hz, 2H), 1.64 (m, 2H), 0.90 (t, J=7.2 Hz, 3H).
KQ33:1H NMR(400 MHz,CDCl3, ppm) and δ 7.41 (d, 2H, J=8.32 Hz), 7.33-7.29 (m, 3H), 6.96 (d, 1H, J=8.32 Hz), 6.98 (d, 1H, J=7.48 Hz), 5.28 (br s, 1H), 3.07 (q, 2H, J=6.84 ), Hz 1.17 (m, 3H), 0.65 (t, 3H, J=7.4 Hz)
KQ34:1H NMR(400 MHz,CDCl3,ppm)δ 7.90(s,1H),7.82(s,1H),7.57-7.50(m,2H), 7.28 (m, 1H), 6.54 (br s, 1H), 3.48 (q, 2H, J=6.68 Hz), 1.71 (m, 2H), 1.04 (t, 3H, J=7.4 Hz).
KQ35:1H NMR(400 MHz,d6-DMSO,ppm)δ 11.5(s,1H),8.62(s,1H),8.17(s,1H), 7.77-7.53(m,2H),7.44(m,1H),5.35(br s,1H).
KQ36:1H NMR(400 MHz,CDCl3,ppm)δ 7.98-7.91(m,2H),7.77(m,1H),7.75-7.58 (m, 2H), 7.48-7.34 (m, 3H), 6.57 (br s, 1H), 3.50 (q, 2H, J=6.64 Hz), 1.75-1.71 (m, 2H), 1.05 (t, 3H, J=6.64 Hz)
KQ37:1H NMR(400 MHz,CD3OD, ppm) δ 8.48 (d, 0.2H, J=2.2 Hz), 8.46 (d, 1H, J= 2.2 Hz),8.29-8.21(m,1H),7.67-7.65(m,0.2H),7.38-7.35(m,1H),6.58-6.55(m,0.2H), 3.39-3.35(m,0.4H),3.32-3.26(m,2H),1.68-1.62(m,2H),1.59-1.46(m,2H),0.99(t, 0.6H, J=7.4 Hz), 0.87 (t, 3H, J=7.4 Hz)
KQ38:1H NMR(400 MHz,CD3OD,ppm)δ 8.84(s,1H),8.26(m,1H),8.03(br s,1H), 6.66 (m, 1H), 5.35 (br s, 1H), 3.04 (q, 2H, J=7.4 Hz), 1.04 (t, 3H, J=7.4 Hz)
KQ39:1H NMR(400 MHz,CD3OD,ppm)δ 8.76(s,1H),8.04(m,1H),8.03(br s,1H), 8.02 (s, 1H), 5.35 (m, 1H), 3.04 (q, 2H, J=7.4 Hz), 1.04 (t, 3H, J=7.4 Hz)
KQ40:1H NMR(400 MHz,CDCl3,ppm)δ 10.54(br s,1H),8.55(s,1H),7.54(d,1H,J =6.1Hz), 7.12 (s, 1H), 6.60 (d, 1H, J=7.3 Hz), 3.40 (dd, 2H, J=12.9,6.8 Hz), 1.65 (dq, 2H, J=14.5,7.3 Hz), 1.00 (t, 3H, J=7.4 Hz)
KQ41:1H NMR(400 MHz,CDCl3,Ppm) δ 8.46 (s, 1H), 8.15 (d, 1H, J=5.2 Hz), 7.18 (d, 1H, J=5.2 Hz), 6.58 (br s, 1H), 3.52 (dt, 2H, J=14.2,7.2 Hz), 1.29 (t, 3H, J=7.3 Hz).
KQ42:1H NMR(400 MHz,CD3OD,ppm)δ 11.77(br s,1H),10.76(br s,1H),8.01(s, 1H), 5.60 (s, 1H), 4.25 (q, 2H, J=7.08 Hz), 1.28 (t, 3H, J=7.12 Hz)
KQ43:1H NMR(400 MHz,CDCl3,ppm)δ 12.02(br s,1H),7.13-7.07(m,2H),6.94- 6.90(m,1H),6.74(br s,1H),3.65-3.61(m,2H),3.58-3.55(m,1H),3.40(s,3H).
KQ44:1H NMR(400 MHz,CDCl3,ppm)δ 12.05(br s,1H),7.16-7.14(m,1H),7.10- 7.05 (m, 1H), 6.92-6.88 (m.1H), 6.73 (br s, 1H), 3.24 (t, 2H, J=6.5 Hz), 1.94-1.84 (m, 1H), 3.40 (d, 6H, J=6.6 Hz)
KQ45:1H NMR(400 MHz,CDCl3,ppm)δ 12.11(br s,1H),7.17-7.11(m,2H),7.00- 6.98(m,1H),6.34(br s,1H),3.36-3.33(m,2H),1.10(m,1H),0.65-0.63(m,2H),0.35-0.34 (m,2H).
KQ46:1H NMR(400 MHz,CDCl3,ppm)δ 12.07(br s,1H),7.14-7.09(m,1H),7.05- 7.02 (m, 1H), 6.95-6.92 (m.1H), 6.30 (br s, 1H), 3.38 (t, 2H, J=7.1 Hz), 2.20-2.12 (m, 1H),1.85-1.56(m,8H).
KQ47:1H NMR(400 MHz,CDCl3,ppm)δ 12.08(br s,1H),7.12-7.07(m,2H),6.94- 6.90 (m, 1H), 6.48 (br s, 1H), 3.27 (t, 2H, J=6.4 Hz), 1.80-1.55 (m, 6H), 1.28-1.14 (m, 2H),1.01-0.96(m,2H).
KQ48:1H NMR(400 MHz,CDCl3,ppm)δ 12.09(br s,1H),7.14-7.09(m,1H),6.96- 6.92(m,2H),6.20(br s,1H),3.53-3.48(m,2H),2.28-2.24(m,2H),1.68-1.62(m,4H), 1.61-1.55(m,4H).
KQ49:1H NMR(400 MHz,CDCl3,ppm)δ 12.09(br s,1H),7.14-7.09(m,1H),7.03- 7.00(m,1H),6.95-6.92(m.1H),6.17(br s,1H),3.49-3.44(m,2H),1.76-1.65(m,4H), 1.60-1.49(m,2H),1.39-1.30(m,1H),1.29-1.14(m,4H),1.00-0.91(m,2H).
KQ50:1H NMR(400 MHz,CDCl3,ppm)δ 11.65(br s,1H),7.14-7.09(m,1H),7.07- 7.05 (m, 1H), 6.95-6.91 (m, 1H), 3.75 (t, 4H, J=4.1 Hz), 3.55-3.51 (m, 2H), 2.62 (t, 4H, J= 5.8 Hz), 2.52 (t, 4H, J=4.2 Hz)
KQ51:1H NMR(400 MHz,CDCl3,ppm)δ 12.01(br s,1H),7.37-7.29(m,2H),7.27- 7.22(m,3H),7.14-7.09(m,1H),6.95-6.92(m,1H),6.88-6.85(m,1H),6.20(br s,1H), 3.72-3.69(m,2H),2.96-2.92(m,2H).
KQ52:1H NMR(400 MHz,CDCl3Ppm) δ 12.05 (br s, 1H), 8.02 (d, 1H, J=8.1 Hz), 7.92-7.86(m,2H),7.60-7.45(m,4H),7.13-7.08(m,1H),6.96-6.40(m,2H),6.40(br s, 1H), 5.7 (d, 2H, J=5.1 Hz)
KQ53:1H NMR(400 MHz,CDCl3,ppm)δ 8.03(br s,1H),7.44(m,1H),7.33-7.23(m, 6H),7.11(m,1H),5.35(br s,1H),4.35(m,2H).
KQ54:1H NMR(400M,CDCl3,ppm)δ 11.96(s,1H),7.49-7.32(m,5H),7.12(dd,1H,J1 =J2=8.0 Hz), 7.03 (d, 1H, J=8.6 Hz), 6.94 (dd, 1H, J1=9.0 Hz, J2=4.7 Hz), 6.33 (s, 1H), 5.33-5.26 (m, 1H), 1.63 (d, 1H, J=6.8 Hz)
KQ55:1H NMR(400M,CDCl3, ppm) δ 12.01 (s, 1H), 7.27 (d, 2H, J=8.8 Hz), 7.12 (dd, 1H,J1=J2=8.7 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.97-6.93 (m, 1H), 6.90 (d, 2H, J=7.8 Hz), 6.38 (s, 1H), 4.56 (d, 2H, J=5.3 Hz), 3.81 (s, 3H)
KQ56:1H NMR(400 MHz,CDCl3,ppm)δ 8.46(m,1H),8.03(br s,1H),7.73(m,1H), 7.44(m,1H),7.33-7.23(m,3H),7.11(m,1H),5.35(br s,1H),4.35(m,2H).
KQ57:1H NMR(400 MHz,CDCl3,ppm)δ 8.56(m,1H),8.55(m,1H),8.03(br s,1H), 7.44(m,1H),7.35-7.32(m,2H),7.11(m,1H),5.35(br s,1H),4.35(m,2H).
KQ58:1H NMR(400 MHz,CDCl3,ppm)δ 11.96(br s,1H),7.22-7.21(m,1H),7.15- 7.10 (m, 1H), 7.00-6.89 (m, 4H), 6.33 (br s, 1H), 3.75-3.70 (m, 2H), 3.16 (t, 2H, J=7.0 Hz).
KQ59:1H NMR(400 MHz,CD3OD, ppm) δ 7.95 (d, 1H, J=8.0 Hz), 7.48-7.44 (m, 1H), 6.98 (t, 2H, J=8.28Hz), 2.46 (s, 3H)
KQ60:1H NMR(400 MHz,d6-DMSO,ppm)δ 15.04(br s,0.2H),14.67(br s,0.8H), 9.03(br s,0.9H),8.67(br s,0.7H),7.83(m,1H),7.28(m,1.8H),7.07(m,0.2H),6.77(m, 2H), 2.72 (m, 3H) [tautomerism]
KQ61:1H NMR(400 MHz,d6-DMSO,ppm)δ 12.47(s,1H),10.04(s,1H),7.79(d,1H,J =7.9Hz), 7.37 (t, 1H, J=7.7Hz), 6.93-6.80 (m, 2H), 2.50 (s, 3H)
KQ62:1H NMR(400 MHz,CDCl3, ppm) and δ 7.53 (dd, 1H, J=7.7,1.4Hz), 7.25-7.15 (m, 1H), 7.03 (d, 1H, J=7.7Hz), 6.91 (dd, 1H, J=10.9,4.0Hz), 6.44 (s, 1H), 2.40 (s, 3H)13C NMR(101 MHz,CDCl3, ppm) and δ 156.02,152.63,139.97,129.24,126.59,119.42,116.91, 117.06,101.34,10.96.
KQ63:1H NMR(400 MHz,CDCl3,ppm)δ 7.78(s,1H),7.44–7.30(m,1H),7.09(d,1H,J =8.3Hz), 6.90 (t, 1H, J=7.5Hz), 4.46 (q, 2H, J=7.1Hz), 1.45 (t, 3H, J=7.1Hz)13C NMR (101 MHz,CDCl3,ppm)δ 161.07,158.07,149.31,131.89,131.54,124.62,119.20,118.18, 111.96,100.12,61.64,14.51.
KQ64:1H NMR(400 MHz,d6-DMSO,ppm)δ 13.09(s,1H),11.81(s,1H),8.36(s,1H), 7.90 (d, 1H, J=6.1Hz), 7.79 (s, 1H), 7.34-7.22 (m, 1H), 6.98 (d, 1H, J=8.2Hz), 6.93 (t, 1H, ), J=7.5Hz 2.77 (t, 3H, J=11.5Hz)
KQ65:1H NMR(400 MHz,CDCl3, ppm) and δ 11.47 (s, 1H), 7.85 (dd, 1H, J=7.8,1.4Hz), 7.04 (dd, 1H, J=8.3,0.6Hz), 6.90-6.82 (m, 1H), 2.82 (q, 2H, J=7.6Hz), 1.35 (t, 3H, J= 7.6Hz).13C NMR(101MHz,CDCl3,ppm)δ 159.74,158.80,156.95,131.62,125.97,119.55, 117.48,112.65,20.30,11.84.
KQ66:1H NMR(400 MHz,CDCl3, ppm) and δ 11.49 (s, 1H), 7.85 (d, 1H, J=7.8Hz), 7.28 (dd, 1H, J=13.7,6.0Hz), 7.03 (d, 1H, J=8.3Hz), 6.87 (t, 1H, J=7.5Hz), 2.77 (t, 2H, J= 7.5Hz), 1.87-1.73 (m, 2H), 0.98 (t, 3H, J=7.3Hz)
KQ67:1H NMR(400 MHz,CD3OD, ppm) δ 7.79 (d, 1H, J=7.8Hz), 7.72 (s, 1H), 7.29 (t, 1H, J=7.8Hz), 7.00 (d, 1H, J=8.3Hz), 6.94 (t, 1H, J=7.6Hz), 3.37 (t, 2H, J=7.2Hz), 1.73-1.60 (m, 2H), 1.00 (t, 3H, J=7.4Hz)
KQ68:1H NMR(400 MHz,CDCl3, ppm) and δ 10.64 (s, 1H), 7.62 (d, 1H, J=7.7Hz), 7.27 (t, 1H, J=7.4Hz), 7.11 (d, 1H, J=8.2Hz), 6.97 (t, 1H, J=7.5Hz), 6.46 (s, 1H), 2.64 (t, 2H, J=7.6Hz), 1.79-1.63 (m, 2H), 0.99 (t, 3H, J=7.3Hz)13C NMR(101 MHz,CDCl3,ppm)δ 155.78,152.16,144.94,129.07,126.54,119.48,117.00,116.93,100.12,27.48,22.34, 13.72.
KQ69:1H NMR(400 MHz,CDCl3, ppm) and δ 7.56 (dd, 1H, J=7.7,1.5Hz), 7.25-7.17 (m, 1H), 7.02 (dd, 1H, J=8.2,0.7Hz), 6.94-6.86 (m, 1H), 6.45 (s, 1H), 2.75 (q, 2H, J=7.6Hz), 1.34 (t, 3H, J=7.6Hz)
KQ70:1H NMR(400 MHz,CDCl3, ppm) and δ 8.48 (d, 1H, J=2.7Hz), 8.11 (dd, 1H, J=9.1, 2.7Hz), 7.07 (d, 1H, J=9.1Hz), 6.58 (s, 1H), 2.73 (t, 2H, J=7.5Hz), 1.86-1.66 (m, 2H), 1.03 (t, 3H, J=7.4Hz)13C NMR(101 MHz,CDCl3,ppm)δ 161.96,150.73,145.57,140.52, 125.07,122.86,117.67,117.09,100.94,27.60,22.37,13.83.
KQ71:1H NMR(400 MHz,CD3Cl, ppm) δ 9.98 (br s, 2H), 7.50 (d, 1H, J=2.4Hz), 7.14 (dd, 1H, J=2.4Hz, 8.6Hz), 6.95 (d, 1H, J=8.8Hz), 6.42 (s, 1H), 2.68 (t, 2H, J=7.6Hz), 1.77-1.70 (m, 2H), 1.00 (t, 2H, J=7.2Hz)
KQ72:1H NMR(400 MHz,CD3Cl,ppm)δ 9.41(br s,2H),7.24-7.21(m,1H),6.97- 6.88 (m, 2H), 6.39 (s, 1H), 2.68 (t, 2H, J=7.6Hz), 1.77-1.69 (m, 2H), 1.00 (t, 3H, J= 7.6Hz).
KQ73:1H NMR(400 MHz,CDCl3)δ 6.89-6.84(m,1H),6.59(s,1H),6.37-6.34(m, 1H), 2.66 (t, J=7.2Hz, 2H), 1.72-1.69 (m, 2H), 0.98 (t, J=7.2Hz, 3H)；13C NMR(400MHz, CDCl3)δ 152.0,148.3,147.3,145.6,145.0,133.1,132.9,114.9,114.7,133.1,132.9, 114.9,114.7,106.5,105.3,105.2,103.2,27.8,22.4,13.9.
KQ74:1H NMR(400 MHz,d6-DMSO)δ 11.68(s,1H),11.54(s,1H),7.96-7.93(m,1H), 7.51-7.47 (m, 1H), 6.61-6.56 (m, 1H), 3.95 (t, J=6.0Hz, 2H), 3.33-3.30 (m, 2H), 1.72 (s, 3H)；13C NMR(400 MHz,d-DMSO)δ 169.9,167.5,160.5,150.0,140.6,137.0,109.1,105.2, 100.8,36.7,23.0.
KQ75:1H NMR(400 MHz,d6-DMSO)δ 11.67(s,1H),11.37(s,1H),7.48-7.43(m,1H), 6.54-6.50 (m, 1H), 3.83 (t, J=7.2Hz, 2H), 1.62-1.56 (m, 2H), 0.90 (t, J=7.6Hz, 3H)；13C NMR(400 MHz,d-DMSO)δ 166.6,156.2,149.6,142.7,140.4,128.2,128.1,122.8,122.6, 108.4,108.3,101.4,101.3,41.9,20.9,11.6.
KQ76:1H NMR(400 MHz,CDCl3, ppm) 6.76 (t, 1H, J=12Hz), 6.20 (s, 1H), 4.58 (s, 2H), 2.59 (s, 2H), 1.66 (d, 2H, J=4Hz), 0.98 (d, 3H, J=4Hz)
KQ77:1H NMR(400 MHz,CD3OD, ppm) 9.12 (s, 1H), 7.33 (dd, 1H, J=8.4,10.8Hz), 6.97 (dd, 1H, J=3.6,12.4Hz), 3.09 (t, 2H, J=7.6Hz), 1.91 (m, 2H) 1.04 (t, 3H, J=7.2Hz)
KQ78:1H NMR(400 MHz,d6-DMSO,ppm)13.03(br s,1H),10.88(br s,1H),7.17(dd, 1H, J=9.2,11.2Hz) 6.57 (dd, 1H, J=3.6,8.8Hz), 2.94 (t, 2H, J=7.2Hz), 1.76 (m, 2H) 0.92 (t, 3H, J=7.2Hz)13C NMR(101 MHz,d6- DMSO, ppm) 159.57,151.03,150.32 (d, J=2Hz), (144.24,141.90,127.32 d, J=4Hz), 115.51 (d, J=19Hz), 108.64,106.26,102.38,29.26, 22.30,14.16.
KQ79：HRMS(EI+):found 273.1276[M]+,(Calcd for C15H16FN3O:273.1277).
KQ80：HRMS(EI+):found 275.1431[M]+,(Calcd for C15H18FN3O:275.1434).
KQ81：HRMS(EI+):found 261.1279[M]+,(Calcd for C14H16FN3O:261.1277).
Active testing embodiment
Nmr chemical shift perturbation tests affinity (KD)：The method detection of NMR HSQC titration is disturbed by micromolecular compound Dynamic protein amino acid residues, and pass through the binding affinity of disturbing signal detecting small molecule and albumen.0.05mM to 0.2mM 's15The bromine structural domain of the BRM of N labels, with the molar ratio of micromolecular compound within the scope of the concentration ratio from 0.0 to 4.0 respectively into Row titration.The HSQC collection of illustrative plates of each titration data point is adopted using 500MH or 700MHz Agilent nuclear-magnetism instrument at a temperature of 293K Collect 18min.As a result it is summarised in table 1.
Cell survival rate is tested：Influence of the small molecule to the survival rate of cell, is detected using mtt assay.Cell is positioned over 96 In orifice plate, the test small molecule sample, KQ70 (negative control) and DMSO (blank control) of various concentration are given respectively, are administered 3~4 days, MTT liquid storages (5mg/ml, 20 μ L) are added later.96 orifice plates are in CO2Continue incubation 4h in incubator at 37 DEG C.Every DMSO (150 μ L) is added in a hole, mixing is until all crystal all dissolve.Use SpectraMax M5 (Molecular Devices, CA, USA) OD value of the test at 490nm.503nhibiting concentration IC50Value is calculated by nonlinear regression analysis. Cell survival rate experiment (belongs to non-in maxicell lung cancer (belonging to non-small cell lung cancer) H1299 cells and lung adenocarcinoma cell respectively Small Cell Lung Cancer) it is tested on A549 cells.H1299 cells and A549 cells are BRG1 gene delections (BRG1-), and BRM genes (BRM+) non-missing cell strain, which cannot express BRG1 albumen into the cell, but can normal expression BRM Albumen.The small molecule of BRM albumen and interaction between chromosomes can be prevented in the cell, you can prevent BRM albumen from exercising intracellular Function.According to lethal rule is cooperateed with, in the cell of BRG1 gene delections, the function of BRM albumen is prevented, then can lead to cell Death realizes that small molecule kills the effect of cancer cell.
According to common detection methods, it is determined that the half-inhibition concentration (IC of each compound (small molecule)50), as a result it is summarised in In table 1, in table 1, +++ representative has strong inhibitory activity, ++ representative has medium inhibitory activity ,+to represent inhibitory activity relatively low, but Still there is the inhibitory activity for being substantially better than existing known compound.
Table 1
Thus, it is possible to prove that the compound of the present invention KQ1~KQ81 can effectively treat cancer especially BRG1 genes The non-small cell lung cancer of missing.
It will be apparent to one skilled in the art that present disclosure is not limited to foregoing illustrative embodiment, and And it can be embodied in other concrete forms without departing from its essential characteristics.Therefore, it is contemplated that each embodiment is in all respects all It is considered illustrative and unrestricted, should refer to the appended claims, rather than previous embodiment, therefore, appended All changes in the meaning and scope of claims equivalents are included in this article.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms differ Surely identical embodiment or example are referred to.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in one or more embodiments or example.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective In the case of can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention.

Claims (5)

1. a kind of compound, which is characterized in that the compound is compound shown in the compound being shown below or following formula Stereoisomer, tautomer, raceme and pharmaceutically acceptable salt：
2. the purposes of compound described in claim 1 in medicine preparation, the drug is used for treating cancer.
3. purposes according to claim 2, which is characterized in that the cancer is lung cancer.
4. purposes according to claim 3, which is characterized in that the lung cancer is non-small cell lung cancer.
5. purposes according to claim 4, which is characterized in that the non-small cell lung cancer is BRG1 gene delections.
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