CN110452253A - Mcl-1 selective depressant and its preparation and use - Google Patents

Mcl-1 selective depressant and its preparation and use Download PDF

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Publication number
CN110452253A
CN110452253A CN201810425784.0A CN201810425784A CN110452253A CN 110452253 A CN110452253 A CN 110452253A CN 201810425784 A CN201810425784 A CN 201810425784A CN 110452253 A CN110452253 A CN 110452253A
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base
phenyl
alkyl
methyl
acid
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刘志华
陈坤成
袁保昆
焦楠
刘松峻
解博闻
王树龙
闵汪洋
许新合
刘希杰
孙莹
张慧
徐枫
孙颖慧
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Centaurus Biopharma Co Ltd
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Priority to CN201810425784.0A priority Critical patent/CN110452253A/en
Priority to PCT/CN2018/117014 priority patent/WO2019101144A1/en
Priority to CN201880075917.4A priority patent/CN111372936B/en
Publication of CN110452253A publication Critical patent/CN110452253A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Abstract

The present invention provides selective depressant and its preparation and uses；The present invention provides it is a series of by lead to formula (I) represented by compounds and its pharmaceutically acceptable salt, solvate, polymorph or prodrug, comprising the pharmaceutical composition of these compounds, and with this compounds for treating as caused by the MCL-1 albumen for over-expressing or lacking of proper care or aggravate disease method.

Description

Mcl-1 selective depressant and its preparation and use
Technical field
The present invention relates to the active compounds of selective depression Mcl-1 anti-apoptotic proteins, further relate to the system of these compounds Preparation Method and and its pharmaceutical composition purposes.
Background technique
Apoptosis (Apoptosis) is the autonomous orderly death process of cell by several genes control.It is related to one Activation, expression and regulation (J.Cell Mol Life Sci, 2008,66 (8): 1326- 1336) of serial genes.Bcl-2 Family plays important regulating and controlling effect in apoptosis process.Mcl-1 as anti-apoptotic proteins in Bcl-2 family it is important one Member, body early embryo formed and lymphocyte, nerve cell, fibroblast and liver stem cells function maintain in play weight The effect (J.Cell D eath D iffer, 2013,20 (11): 1475-1484.) wanted.Research has shown that many pernicious swollen Oncocyte can over-express Mcl-1 albumen (J.Cell death&disease, 2010.1 (5): p.e 40.), lead to anti-wither The interaction dying member and promoting between apoptosis member is unbalance, causes tumour cell malignant proliferation.In recent years, in central nervous system It unites tumour, breast cancer, colon cancer, lung cancer, oophoroma, prostate cancer detects Mcl-1 in the different cell line of melanoma Gene genetic make a variation (J.Bioorg Med Chem, 2013,21 (21): 6642-6649.).Mcl-1 participates in tumour cell The dependent interaction (J.Proc Natl Acad Sci USA, 2007,104 (49): 19512-19517) of survival and drug resistance.No Pipe is single application Mcl-1 micromolecular inhibitor, or shares with other anti-tumor drugs and preferable therapeutic effect is presented, and is Mcl-1 targeted therapies treatment tumour provides new approach.
In the past 10 years, it is continued to bring out for the micromolecular inhibitor of anti-apoptotic proteins, such as polyphenol analog derivative AT- 101 (J.Thorac.Oncol, 2011,6 (10): 1757-1760) and APOG2, research shows that the treatment of kinds of tumors obtained compared with Good curative effect is currently in II/III phase clinical investigation phase.But the compound make since adverse reaction is numerous its clinical application by Limit.Known several sulfonamides protein inhibitorsIncludingSimulated albumin object (ABT-737), (ABT-263) and (ABT- of BH3 199) etc..But multinomial research has shown that, the excessive up-regulation of Mcl-1 inhibits sulfonamides protein inhibitor in kinds of tumors treatment Activity, and ABT-263 etc. be applied individually to any oncotherapy the not satisfactory of effect (J.Clin.Oncol, 2011,29 (7): 909-916.).Currently, the Mcl-1 albumen of inhibition overexpression has become the important research direction of therapeutic field of tumor, especially Mcl-1 micromolecular inhibitor can effectively overcome oncotherapy drug resistance problems, and new it is therefore necessary to continual exploitation, activity is more Height, drug resistance are strong, the smaller Mcl-1 inhibitor of clinical side effects is applied to clinical treatment.
Summary of the invention
The present invention provides a series of compounds and its pharmaceutically acceptable salt, solvation by represented by leading to formula (I) Object, polymorph or prodrug, the pharmaceutical composition comprising these compounds, and with this compounds for treating by overexpression or Caused by the MCL-1 albumen of imbalance or the method for disease that aggravates.
The present invention provides formula as described below (I) compound or its pharmaceutically acceptable salt, solvate, polymorph Object or prodrug:
Wherein,
X is O, NH or S；
A and b is each independently singly-bound or double bond, and at most only one can be double bond in a and b；
R1Selected from H and 3-8 unit's heteroaryl, the heteroaryl is optionally by C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8 Naphthenic base, C1-6Alkyl-O- or 6-10 member aryl base replace, the C1-6Alkyl is optionally replaced by 1-3 halogen, and The 6-10 member aryl is optionally by 1-3 independently selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces；
When a and b are singly-bound, R2And R3It is each independently selected from H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, halogen and cyano or R2、R33-8 member naphthenic base is formed together with the carbon atom being attached thereto；
When a is double bond, R3It is not present, R2For
When b is double bond, R3It is not present, R2Selected from H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, halogen and Cyano；
R4It is each independently halogen, C1-6Alkyl, C1-6Alkyl-O- or cyano；
R5Selected from phenyl and 3-8 unit's heteroaryl, the phenyl and 3-8 unit's heteroaryl optionally by 1-3 selected from halogen and C1-6The group of alkyl replaces；
R6Selected from 3-8 circle heterocyclic ring base, the heterocycle is optionally by C1-6Alkyl ,-C1-6Alkylidene-O- P (=O) (OH)2、 C1-6Alkyl-O- replaces；
R7And R8It is each independently selected from H and C1-6Alkyl；
P and q is each independently 1,2,3,4,5 and 6；
M is 0,1,2,3 or 4.
In some embodiments of the present invention, R1Selected from H and 3-8 unit's heteroaryl, the heteroaryl is optionally by C1-6 Alkyl, C1-6Alkyl-O- or 6-10 member aryl base replace, the C1-6Alkyl is optionally replaced by 1-3 halogen, and institute 6-10 member aryl is stated optionally by 1-3 independently selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces；
In some embodiments of the present invention, R1Selected from H and 5-8 unit's heteroaryl, the heteroaryl is optionally by C1-6 Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, C1-6Alkyl-O- or 6-10 member aryl replace, the C1-6Alkyl can be optional Ground is replaced by 1-3 halogen, and the 6-10 member aryl is optionally by 1-3 independently selected from C1-6Alkyl and C1-6Alkane The group of base-O- replaces；
In some embodiments of the present invention, R1Selected from H and 5-8 unit's heteroaryl, the heteroaryl is optionally by C1-6 Alkyl, C1-6Alkyl-O- or 6-10 member aryl replace, the C1-6Alkyl is optionally replaced by 1-3 halogen, and described 6-10 member aryl is optionally by 1-3 independently selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces；
In some embodiments of the present invention, R1Selected from H, pyrazolyl and pyrimidine radicals, the pyrazolyl and pyrimidine radicals can Optionally by C1-6Alkyl, C1-6Alkyl-O- or 6-10 member aryl replace, the C1-6Alkyl is optionally taken by 1-3 halogen Generation, and the 6-10 member aryl is optionally by 1-3 independently selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces；
In some embodiments of the present invention, a is singly-bound or double bond, and b is singly-bound；
When a and b are singly-bound, R2And R3It is each independently selected from H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, halogen and cyano or R2、R33-8 member naphthenic base, R are formed together with the carbon atom being attached thereto2And R3Cannot be simultaneously Hydrogen；
In some embodiments of the present invention, when a and b are singly-bound, R2And R3It is each independently selected from H, C1-6Alkane Base, halogen and cyano or R2、R33-8 member naphthenic base, R are formed together with the carbon atom being attached thereto2And R3Cannot be simultaneously Hydrogen；
In some embodiments of the present invention, when a and b are singly-bound, R2And R3It is each independently selected from H, C1-6Alkane Base or halogen or R2、R33-8 member naphthenic base, R are formed together with the carbon atom being attached thereto2And R3It cannot simultaneously be hydrogen；
In some embodiments of the present invention, when a and b are singly-bound, R2And R3It is each independently selected from H, C1-6Alkane Base or halogen or R2、R33-6 member naphthenic base, R are formed together with the carbon atom being attached thereto2And R3It cannot simultaneously be hydrogen；
When a is double bond, R3It is not present, R2ForWherein R7And R8For hydrogen；
In some embodiments of the present invention, R5Selected from phenyl and furyl, the phenyl and furyl optionally by 1-3 are selected from halogen and C1-6The group of alkyl replaces；
In some embodiments of the present invention, R6For piperazinyl, the piperazinyl is optionally by C1-6Alkyl replaces；
In some embodiments of the present invention, 1,2 or 3 p, preferably 1 or 2, more preferably 1；
In some embodiments of the present invention, 1,2,3 or 4 q, preferably 1 or 2, more preferably 2；
In some embodiments of the present invention, 0,1 or 2 m；
In some embodiments of the present invention, the compounds of this invention is selected from:
Or its pharmaceutically acceptable salt, solvate, isomers or prodrug,
The compounds of this invention can be used for treating treatment as caused by the MCL-1 albumen for over-expressing or lacking of proper care or aggravate Disease；In some embodiments, the disease is cancer.In some embodiments, the disease is to chemotherapy or radiotherapy Resistant cancer；In some embodiments, the cancer is selected from: bladder cancer, the cancer of the brain, breast cancer and uterine cancer, chronic Lymphatic leukemia, colon cancer, cancer of the esophagus and liver cancer, lymphoblast leukaemia, acute myeloid leukaemia, lymthoma, ovary Cancer or non-small cell lung cancer.
Another aspect of the present invention further relates to pharmaceutical composition, and it includes compound of formula I defined in the present invention or its pharmacy Upper acceptable salt and pharmaceutically acceptable carrier.
On the other hand, the present invention provides treatment as caused by the MCL-1 albumen for over-expressing or lacking of proper care or aggravate The method of disease comprising apply a effective amount of formula (I) compound or its pharmaceutically acceptable salt, solvation to required object Object, polymorph, isomers or prodrug or above-mentioned composition.In some embodiments, the disease is cancer.In some realities It applies in mode, the disease is the cancer resistant to chemotherapy or radiotherapy；In some embodiments, the cancer is selected from: Bladder cancer, the cancer of the brain, breast cancer and uterine cancer, chronic lymphatic leukemia, colon cancer, cancer of the esophagus and liver cancer, lymphoblast are white Blood disease, acute myeloid leukaemia, lymthoma, oophoroma or non-small cell lung cancer.
In certain embodiments of the present invention, the object of the present invention is the mammal for including the mankind.
On the other hand, the present invention provides formula (I) compound or its pharmaceutically acceptable salt, solvate, polycrystalline Type object, isomers or prodrug are used to treat the disease as caused by the MCL-1 albumen for over-expressing or lacking of proper care or aggravated in preparation Drug in purposes.In some embodiments, the disease is cancer.In some embodiments, the disease is pair Chemotherapy or the resistant cancer of radiotherapy；In some embodiments, the cancer is selected from: bladder cancer, the cancer of the brain, breast cancer and son Palace cancer, chronic lymphatic leukemia, colon cancer, cancer of the esophagus and liver cancer, lymphoblast leukaemia, acute myeloid leukaemia, leaching Bar tumor, oophoroma, non-small cell lung cancer, Huppert's disease, acute lymphatic leukaemia or myelodysplastic syndrome.
On the other hand, the present invention provides formula (I) compound or its pharmaceutically acceptable salt, solvate, polycrystalline Type object, isomers or prodrug are used to treat the disease as caused by the MCL-1 albumen for over-expressing or lacking of proper care or aggravated in preparation Drug in purposes.In some embodiments, the disease is cancer.In some embodiments, the disease is pair Chemotherapy or the resistant cancer of radiotherapy；In some embodiments, the cancer is selected from: bladder cancer, the cancer of the brain, breast cancer and son Palace cancer, chronic lymphatic leukemia, colon cancer, cancer of the esophagus and liver cancer, lymphoblast leukaemia, acute myeloid leukaemia, leaching Bar tumor, oophoroma or non-small cell lung cancer.
Detailed description of the invention
It set forth the illustrative embodiments using the principle of the invention in detailed description of the invention below.By reference to issue Bright content is better understood the features and advantages of the present invention.
It should be understood that the protection scope of various aspects of the present invention is determined by claims, and in these scopes of the claims Method and structure and its method and structure of equal value within the scope of the claims cover.
Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology The normally understood connotation of personnel is identical.Unless otherwise indicated, all patents, patent application, the public material being cited in full text herein It is integrally incorporated by reference herein.
It should be understood that above-mentioned summary and detailed description hereafter are all exemplary, are explanatory, rather than it is main to any present invention The limitation of topic.It unless otherwise expressly specified, also include plural number when otherwise using singular.Unless otherwise stated, used "or", "or" indicate "and/or".In addition, term " includes " used and other forms, such as "comprising", " containing " and " contain Have " and it is non-limiting.
Certain technical terms of chemistry
Term " optional ", " optional " or " optionally " refer to that the event then described or situation may occur may not also Occur, which includes that the event or situation occurs and the event or situation does not occur.For example, " alkyl optionally replaced " It indicates " unsubstituted alkyl " or " substituted alkyl ".Also, the group optionally replaced can be it is unsubstituted (such as :- CH2CH3), be completely replaced (such as :-CF2CF3), it is mono-substituted (such as :-CH2CH2F) or between monosubstituted and completely take Between instead of any level (such as :-CH2CHF2、- CF2CH3、-CFHCHF2Deng).Those skilled in the art are it is understood that for packet Any group containing one or more substituent groups, will not introduce any can not spatially exist and/or what cannot be synthesized takes Generation or substitute mode.
Unless otherwise stated, using the conventional method within the scope of art technology, such as mass spectrum, nuclear-magnetism, efficient liquid phase Chromatography, infrared and ultraviolet/visible light spectrometry and pharmacological method.Unless propose be specifically defined, otherwise herein in analytical chemistry, have The related term and experimental procedure and technology of machine synthesis chemistry and drug and medical chemistry are known in the art.It can change Learn synthesis, chemical analysis, medicine preparation, preparation and delivering and to using standard technique in the treatment of patient.For example, can benefit With manufacturer to the operation instruction of kit, or implement according to mode well known in the art or explanation of the invention reaction and into Row purifying.Usually can according in this specification quote and discuss multiple summary and more specific document in description, according to Conventional method well known in the art implements above-mentioned technology and methods.In the present specification, base can be selected by those skilled in the art Group and its substituent group are to provide stable structure division and compound.
When the conventional chemical formulas by writing from left to right describes substituent group, which similarly includes from right to left Write obtained equivalent substituent group in chemistry when structural formula.For example ,-CH2O- is equal to-OCH2-。
Terms used herein " group ", " chemical group " refer to a specific part or the functional group of molecule.Chemical base Group is often considered for the chemical entities being embedded or attached in a molecule.
Some chemical groups named herein can indicate the total number of carbon atom with simple mark.For example, C1-C6Alkyl An alkyl group is described, as given a definition, there is 1 to 6 carbon atoms in total.Carbon atom shown in simple mark is always a Number does not include the carbon atom on possible substituent group.
Term " halogen ", " halogenated " or " halide " refers to bromine, chlorine, fluorine or iodine.
Terms used herein " fragrance ", " aromatic rings ", " fragrant ", " armaticity ", " aromatic rings " refer to plane A ring or multiple rings loop section, have the delocalized electronics π-conjugated systems containing 4n+2 electronics, wherein n be integer. Aromatic ring can be formed by 5,6,7,8,9 or 9 or more atoms.Aromatic compounds can be optionally substituted, and can be monocycle or thick Cyclization it is polycyclic.Term aromatic compound includes all carbocyclic rings (such as phenyl ring) and containing one or more heteroatomic ring (such as pyrroles Pyridine).
Herein individually or as the term " hetero atom " that uses of a part of other ingredients or " miscellaneous " refer to except carbon and hydrogen it Outer atom.Hetero atom is not limited to these atoms independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin.Occur two or In more heteroatomic embodiments, described two or more hetero atoms can be mutually the same or described two or more miscellaneous original Some or all of son is different from each other.
It is one or more that the term " thick " being used alone or in combination herein or " condensed ring " refer to that two or more rings are shared The cyclic structure of a key.
It is one or more that the term " spiral shell " being used alone or in combination herein or " loop coil " refer to that two or more rings are shared The cyclic structure of a atom.
The term " alkyl " used herein individually or as a part (such as: alkyl monosubstituted amino) of other components, which refers to, appoints The straight chain in generation or the monovalence saturated hydrocarbons of the branch optionally replaced are chosen, with 1-12 carbon atom, preferably 1-8 carbon atom, More preferable 1-6 carbon atom, is connected by singly-bound with the other parts of molecule, such as methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2- methylhexyl, 3 methylhexyls, n-octyl, just Nonyl, positive decyl etc..
Term " alkylidene ", which refers to, removes the bivalent group that a hydrogen is formed by alkyl defined above.
Term " alkenyl " refers to a kind of alkyl, and wherein the two of the starting of alkyl atom forms double bond, which is not virtue The component part of perfume base.That is, alkenyl starts from-C (R)=C (R)-R, wherein R refers to the rest part of alkenyl, and each R can be with It is identical or different.Alkenyl can have 2-10 carbon atom.Alkenyl is also possible to " low-grade alkenyl " with 2-6 carbon atom.
Term " alkynyl " refers to a kind of alkyl, and wherein the two of the starting of alkyl atom forms three keys.That is, alkynyl Atom-C ≡ C-R is started from, wherein R refers to alkynyl rest part." R " in alkynyl moiety partially can be branch, straight chain or ring Shape.Alkynyl can have 2-10 carbon atom.Alkynyl is also possible to " low alkyl group " with 2-6 carbon atom.
The term " naphthenic base " used herein individually or as a part of other ingredients refers to stable monovalent non-aromatic Monocycle or polycyclic hydrocarbon group only include carbon atom and hydrogen atom, may include condensed ring, loop coil or bridge ring systems, include 3-15 A ring carbons preferably comprise 3-10 ring carbons, include more preferably 3-8 ring carbons, saturable can not also Saturation, is connected by singly-bound with the other parts of molecule.The non-limiting example of " naphthenic base " includes but is not limited to cyclopropyl, ring Butyl, cyclopenta, cyclohexyl and suberyl etc..
It is individually or as a part term " heterocycle ", " Heterocyclylalkyl ", " heterocycle " that use of other ingredients herein Refer to stable 3-18 member monovalent non-aromatic ring, including 2-12 carbon atom, the 1-6 hetero atoms selected from nitrogen, oxygen and sulphur.Unless another It explains, heterocyclyl groups can be monocycle, bicyclic, tricyclic or four loop systems, may include condensed ring, loop coil or bridged ring system It unites, nitrogen, carbon or the sulphur on heterocycle are optionally oxidized, and nitrogen-atoms is optionally quaternized, and heterocycle can portion Divide or fully saturated.Heterocycle can be connected by the rest part of carbon atom or hetero atom and molecule on ring by a singly-bound It connects.It may include one or more aromatic rings or hetero-aromatic ring in heterocycle comprising condensed ring, as long as the rest part with molecule is connect Be atom on non-aromatic ring.For the application, heterocycle is preferably a stable 4-11 member monovalent non-aromatic monocycle Or two rings, it includes the 1-3 hetero atom selected from nitrogen, oxygen and sulphur, more preferably one stable 4-8 member monovalent non-aromatic list Ring, it includes the hetero atoms that 1- 3 are selected from nitrogen, oxygen and sulphur.The non-limiting example of heterocycle includes nitrogen heterocyclic heptyl, nitrogen Heterocycle butyl, Decahydroisoquinolinpreparation base, dihydrofuryl, indolinyl, dioxolane base, 1,1- dioxido-thiomorpholine base, miaow Oxazolidinyl, imidazolinyl, isothiazole alkyl, isoxazolidinyl, morpholinyl, octahydro indyl, octahydro isoindolyl, oxazines base, Oxazolidinyl, 1- oxygen-thio-morpholinyl, 2- oxygen piperazinyl, 2- Oxypertine base, 2- oxygen pyrrolidinyl, phthalimido, piperazine Piperazine base, piperidyl, 4- piperidone base, pyranose, pyrazolidinyl, pyrrolidinyl, quinazinyl, quininuclidinyl, tetrahydrofuran base, four Hydrogen isoquinoline base, THP trtrahydropyranyl, thiazolidinyl, thiophene [1,3] dithianyl, thio-morpholinyl, trithiane base etc..
The term " heteroaryl " used herein individually or as a part of other ingredients refers to 5-16 member ring system, Comprising 1-15 carbon atom, preferred 1-10 carbon atom, the 1-4 hetero atoms selected from nitrogen, oxygen and sulphur, at least one fragrance Ring.Unless otherwise mentioned, heteroaryl can be monocycle, bicyclic, tricyclic or four loop systems, may include condensed ring or bridged ring system System, as long as the tie point with molecule other parts is aromatic ring atom.Nitrogen-atoms, carbon atom and sulphur atom on hetero-aromatic ring can select Selecting property is oxidized, and nitrogen-atoms is optionally quaternized.For the present invention, it is single that heteroaryl is preferably stable 4-11 member Aromatic rings, the hetero atom being selected from it includes 1-3 selected from nitrogen, oxygen and sulphur, the more preferably stable single aromatic rings of 5-8 member, Comprising 1-3 selected from the hetero atom selected from nitrogen, oxygen and sulphur.The non-limiting example of heteroaryl includes acridinyl, azatropylidene base, benzene And imidazole radicals, benzindole base, Isosorbide-5-Nitrae-benzodioxane base, benzo [6] [Isosorbide-5-Nitrae] dioxane heptyl, benzo dioxin base, Benzo two dislikes cyclopentadienyl, benzofuran ketone group, benzofuranyl, benzo [4,6] imidazo [1,2-a] pyridyl group, benzo naphtho- furan It mutters base, chromene ketone group, benzopyranyl, benzopyrene oxazolyl, diazosulfide base, benzothiazolyl, benzothienyl, benzene And triazolyl, benzoxazolyl, carbazyl, card quinoline base, cinnoline base, dibenzofuran group, dibenzothiophene, furanone Base, furyl, imidazole radicals, indazolyl, indolinyl, indolizine base, indyl, iso indazolyl, iso-dihydro-indole-group, iso-indoles Base, isothiazolyl, isoxazolyl, naphthyridines base, oxadiazoles base, dislikes triazolyl, oxazolyl, 1- Oxopyrazine base, 1- at isoquinolyl Oxopyridazin base, 1- oxo pyridine base, 1- oxo-pyrimidine base, Oxyranyle, 2- oxygen azatropylidene base, oxo pyridine base, phenanthridines Base, phenanthroline, phenazinyl, phenothiazinyl, phenoxazine base, 1- phenyl -1H- pyrrole radicals, phthalazinyl, pteridine radicals, purine Base, pyrazinyl, pyrazolyl, pyridazinyl, 1H- pyridine -2- base, 1H- pyridin-4-yl, 1H- pyridin-2-ones -4- base, pyridyl group, Pyrimidine radicals, pyrrole radicals, quinazolyl, quinolyl, quinoxaline base, quinine base, tetrahydric quinoline group, 4,5,6,7- tetrahydro benzos [b] Thienyl, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazine radical, triazolyl etc..In the application, heteroaryl is preferably 5-8 Unit's heteroaryl, it includes 1-3 selected from the hetero atom selected from nitrogen, oxygen and sulphur, more preferably pyridyl group, pyrimidine radicals, thiazolyl, oxygen For pyridyl group, 1H- pyridine -2- ketone -4- base or thienyl.
Term " cyano " refers to group-CN.
It is a variety of that terminology used in the present invention " polymorph " or " polymorphic (phenomenon) " refer to that the compound of the present invention has Lattice form.Some compounds of the invention may have more than one crystal form, and the present invention covers all polycrystalline kenels Or mixtures thereof.
The midbody compound and its polymorph of the compounds of this invention are also within the scope of the invention.
Unless otherwise specified, the olefinic double bonds contained by the compounds of this invention include E and Z isomers.
It should be understood that the compounds of this invention may contain asymmetric center.These asymmetric centers can be independently R or S Configuration.Some the compounds of this invention can also show cis-trans isomerization phenomenon, this is aobvious and easy to those skilled in the art See.It should be understood that the compounds of this invention includes their individual geometric isomer and stereoisomer and their mixing Object, including racemic mixture.By implementing or modify known method, such as chromatographic technique and recrystallization technology can be from them Mixture in separate these isomers, or they can be prepared by the suitable isomers of their intermediate respectively.
Terms used herein " pharmaceutically acceptable salt " both includes acid adding salt, also includes adding alkali salt.
" pharmaceutically acceptable acid adding salt " refers to that those remain the biopotency of the free alkali of compound and characteristic, In Biologically or other aspects it is not undesirable, with inorganic acid, such as but be not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitre Acid, phosphoric acid etc. or organic acid, such as, but not limited to, acetic acid, 2,2- dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, asparagus fern Propylhomoserin, benzene sulfonic acid, benzoic acid, 4- acetaminobenzoic acid, camphoric acid, camphor -10- sulfonic acid, capric acid, caproic acid, octanoic acid, carbonic acid, Cinnamic acid, citric acid, cyclamic acid, dodecyl sulphate, ethane -1,2- disulfonic acid, ethylsulfonic acid, 2- hydroxyl ethanedioic acid, formic acid, Fumaric acid, galactosaccharic acid, gentianic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2- oxo-penta Diacid, glycerophosphate glycolic, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, the third two Acid, mandelic acid, methane sulfonic acid, mucic acid, naphthalene -1,5- naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, 1- hydroxyl -2- naphthoic acid, niacin, oleic acid, Orotic acid, oxalic acid, palmitinic acid, pa not acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-ASA, decanedioic acid, hard Resin acid, succinic acid tartaric acid, thiocyanic acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, the salt of the formation such as undecenoic acid.It is " pharmaceutically acceptable Plus alkali salt " refer to those remain the biopotency of the free acid of compound and characteristic, biologically or other aspects simultaneously Non- undesirable salt.These salt are by free acid with inorganic base or organic base reaction preparation.It is generated by being reacted with inorganic base Salt include, but are not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..It is excellent The inorganic salts of choosing are ammonium salt, sodium salt, sylvite, calcium salt and manganese salt.
The organic base of forming salt includes, but are not limited to primary amine, secondary amine, tertiary amine, amine is replaced (to take including what nature occurred The amine in generation), cyclammonium and basic ion exchange resin, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), two Ethanol amine, ethanol amine, Deanol, 2- dimethylethanolamine, 2-diethylaminoethanol, dicyclohexyl amine, lysine, smart ammonia Acid, histidine, caffeine, procaine, Hydrabeamine Penicillin, choline, glycine betaine, phenylethylbenzylamine, tardocillin, second two Amine, Glucosamine, meglumine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidines, N-ethylpiperidine, polyamines Resin etc..Particularly preferred organic base is isopropylamine, diethylamine, ethanol amine, trimethylamine, dicyclohexyl amine, choline and caffeine
Crystallization often generates the solvate of the compounds of this invention.Terms used herein " solvate " refer to by one or The zoarium that multiple the compounds of this invention molecules and one or more solvent molecules are composed.
Solvent can be water, and in this case, solvate is hydrate.In addition it being organic solvent.Therefore, originally Invention compound can be used as hydrate presence, including monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate Deng, and corresponding solvation form.The compounds of this invention can be true solvate, but in some other cases, this hair Bright compound only accidentally may also remain water or water with the mixture of some other solvents.The compounds of this invention can be in one kind Reaction or precipitating or crystallization in a kind of solvent in solvent.The solvate of the compounds of this invention is also included within the scope of the present invention It is interior.
Present invention also contemplates that the prodrug of the compounds of this invention." prodrug " refers to that a compound can be under physiological status Or the compounds of this invention with biological action is converted under solvation.Therefore, term " prodrug " refers to the present invention The pharmaceutically acceptable metabolic precursor thereof of compound, prodrug may be inactive when giving required administered, but can be It is converted to active the compounds of this invention in vivo.Prodrug usually in vivo, hydrolyzes in blood for example, passing through, and converts rapidly At parent compound of the invention.Prodrug is often in terms of dissolubility, tissue compatibility or extended release in mammalian organism With advantage.Prodrug includes amido protecting group and carboxy protective group, these blocking groups are known to those skilled in the art 's.Method for preparing specific prodrug can refer to, for example, Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald, R. B., et al., J.Med.Chem.2000, 43,475.
Terms used herein " pharmaceutical composition ", which refers to, is mixed with the compounds of this invention and usually received in this field For biologically active compound is sent to mammal (such as mankind) medium preparation.This medium includes institute There is pharmaceutically acceptable carrier.
The totality used herein referred to the relevant term of preparation, composition or ingredient " acceptable " to treatment main body The not lasting adverse effect of health.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity or property for not influencing the compounds of this invention Substance (such as carrier or diluent), and relative nontoxic, the i.e. substance can be applied to individual without causing undesirable biological respinse Or it is interacted in a manner of bad with any component for including in composition.
" pharmaceutically acceptable carrier " include but is not limited to by relevant governmental administrative department ratify can by with In the adjuvant of the mankind and performing animal, carrier, excipient, auxiliary agent, deodorant, diluent, antistaling agent, dyestuff/colorant, wind Taste reinforcing agent, surfactant and wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
Terms used herein " main body ", " patient " or " individual " refers to the individual with disease, disorder or illness etc., including Mammal and nonmammalian.The example of mammal includes but is not limited to any member of class of mammals: people, inhuman Primate (such as chimpanzee and other apes and monkey)；Domestic animal, such as ox, horse, sheep, goat, pig；Domestic animal, example Such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and cavy etc..The reality of non-human mammal Example includes but is not limited to birds and fish etc..It is described in a method provided herein and the embodiment of composition Mammal is behaved.
Terms used herein " treatment " refers to the treatment of the related disease or illness to the mammal especially mankind, including
(i) prevent mammal, especially before leaked and under some disease or illness but be not yet diagnosed with cruelly The mammal of the disease or illness generates corresponding disease or illness；
(ii) inhibit disease or illness, that is, control its development；
(iii) alleviate disease or illness, even if disease or illness subside；
(iv) alleviate symptom caused by disease or illness.
Terms used herein " disease " and " illness " can substitute mutually, be also possible to the different meanings, because certain specific There are no known virulence factor (so pathogenic factor are unclear) for disease or illness, thus disease can't be construed to and only It can be seen as undesired situation or syndrome, the syndrome more or less there are some specific symptoms by clinical research people Member confirms.
Term " effective quantity ", " therapeutically effective amount " or " pharmacy effective dose " used herein, which refers to, takes metapedes at certain Alleviate at least one medicament of one or more symptoms of treated disease or illness or the amount of compound in degree.Its result It can be sign, the abatement of symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for controlling " effective quantity " treated is the composition needed for clinically providing significant remission effect comprising compound is disclosed herein Amount.The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.
Terms used herein " taking ", " application ", " administration " etc. are to refer to for compound or composition to be delivered to progress The method in the required site of biological effect.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including in intravenous, subcutaneous, peritonaeum, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.Preferred Embodiment in, the compound and composition being discussed herein pass through oral administration.
In general, the compound of the present invention or its pharmaceutically acceptable salt, can by with pharmaceutically acceptable one Or multiple carriers form pharmaceutical composition appropriate to apply.Pharmaceutical composition of the invention can form solid, semisolid, liquid The prepared product of body or gas form, for example, tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant, Gel, microballoon and aerosol.
Pharmaceutical composition of the invention can be prepared by using the method known to pharmaceutically.For example, application side Formula be injection pharmaceutical composition can in such a way that the compounds of this invention is formed solution combined with sterile, distilled water come Preparation.Surfactant can be added to help to be formed homogeneous phase solution or suspension.Person skilled in the art is come It says, it is known or obvious for preparing the practical methods of these dosage forms.
The path for typically applying these pharmaceutical compositions includes, but are not limited to take orally, external application, Transdermal absorption, sucking, Parenteral, sublingual, rectum, vagina and intranasal.For example, be used to oral suitable dosage form include capsule, tablet, granule and Syrup.The compounds of this invention included by these dosage forms can be solid powder or particle；In aqueous solvent or nonaqueous solvents In solution or suspension；Oil droplet type in water, dripping water type emulsion etc. in oil.Above-mentioned dosage form can be from active ingredient Object and one or more carriers or auxiliary agent are prepared by usual pharmaceutical method.Carrier should be simultaneous with reactive compound or other auxiliary agents Hold.For solid pharmaceutical preparation, usually used non-toxic carrier includes, but are not limited to mannitol, lactose, starch, stearic acid Magnesium, cellulose, glucose, sucrose etc..Liquid preparation carrier include, but are not limited to water, physiological saline, glucose, ethylene glycol, Aqueous Solutions of Polyethylene Glycol etc..Reactive compound can form a solution or a suspension with the above carrier.Specific application Path and dosage form will according to the physical/chemical properties and the severity of disease to be treated of combound itself, and It can routinely be determined by those skilled in the art.
The preparation of the compounds of this invention
Following reaction route formula shows the method for preparing the compounds of this invention.
It will be appreciated that in being described below, substituent group and/or described is only just allowed in the case where forming stable compound The variable of molecular formula is combined.
It will also be appreciated that in process as described below, the functional group of midbody compound may need those skilled in the art It to be protected by suitable blocking group.These functional groups include hydroxyl, amino, sulfydryl and carboxyl.Suitable hydroxy-protective group Including trialkyl silyl or alkyl diaryl silicon substrate (such as tertbutyl methyl silicon substrate, tert-butyl diphenyl silicon substrate or trimethyl silicane Base), THP trtrahydropyranyl, benzyl etc..Suitable amino, amidino groups and guanidine blocking group include tertbutyloxycarbonyl, benzyloxycarbonyl group etc..Mercapto The suitable protecting group of base includes that-C (O)-R " (R " indicates alkyl, aryl or aryl alkyl), to methoxy-benzyl, trityl Deng.Suitable carboxy protective group includes alkyl, aryl or alkyl aryl.Blocking group can pass through those skilled in the art The standard technique method known adds or removes.
Embodiment
Following non-limiting embodiments are merely illustrative, are not limit the invention in any way.
Unless otherwise indicated, temperature is Celsius temperature.Reagent is purchased from Chinese medicines group chemical reagent Beijing Co., Ltd, A Fa The commercial suppliers such as Ai Sha (Alfa Aesar) or Beijing lark prestige Science and Technology Ltd., and these reagents can be used directly Without being further purified, unless otherwise indicated.
Unless otherwise indicated, following reaction in room temperature, anhydrous solvent, the direct draught of nitrogen or argon gas or use drying tube It carries out；Diaphragm of rubber is housed on reaction flask, substrate and reagent is added will pass through syringe；Glassware drying and/or heating It is dry.
Unless otherwise indicated, column chromatography purifying uses the 200-300 mesh silica gel of Haiyang Chemical Plant, Qingdao；Prepare thin-layer chromatography The thin-layer chromatography silica gel prefabricated board (HSGF254) produced using Yantai Chemical Industry Research Inst.；The measurement Thermo of MS LCQ Fleet type (ESI) liquid chromatograph-mass spectrometer；Polariscopy uses SGW-3 automatic polarimeter, Shanghai Shen light instrument Finite instrument company.
Nuclear magnetic data (1H NMR) it is run using Varian equipment in 400MHz.The solvent that nuclear magnetic data uses has CDCl3、 CD3OD、D2O, DMSO-d6 etc., on the basis of tetramethylsilane (0.00ppm) or (CDCl on the basis of residual solvent3: 7.26ppm；CD3OD:3.31ppm；D2O:4.79ppm；D6-DMSO:2.50 ppm).It is simple below when indicating peak shape diversity Writing indicates different peak shapes: s (unimodal), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd are (double Doublet), dt (double triplets).If giving coupling constant, with Hertz (Hz) for unit.
Abbreviation:
Intermediate 1:2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) Phenyl) methyl butyrate synthesis
Step 1:2- ((t-butyldimethylsilyi) oxygroup) benzaldehyde
At room temperature, imidazoles (36.7g) is added to salicylide (24.4g) and tert-butyl chloro-silicane (36.2g) In DMF (300mL) solution, it is stirred at room temperature 2 hours, pours into 500mL water, be extracted twice with 300mL ethyl acetate, organic phase With saturated common salt water washing, anhydrous sodium sulfate is dry, and evaporated under reduced pressure obtains crude product 47.2g, without purifying, is directly used in next step Reaction.
Step 2:2- ((t-butyldimethylsilyi) oxygroup) benzyl alcohol
The resulting crude product 2- of previous step ((t-butyldimethylsilyi) oxygroup) benzaldehyde is dissolved in 300mL methanol, At 0 DEG C, it is slowly added to sodium borohydride (7.6g), is warmed to room temperature after adding, and stirred 30 minutes at room temperature, reaction solution is poured into In (400mL) saturated aqueous ammonium chloride, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, Evaporated under reduced pressure obtains crude product 47.6g, without purifying, is directly used in and reacts in next step.
Step 3:2- ((t-butyldimethylsilyi) oxygroup) benzyl bromine
The resulting crude product 2- of previous step ((t-butyldimethylsilyi) oxygroup) benzyl alcohol is dissolved in 500mL methylene chloride In, triphenylphosphine (62.8g) and carbon tetrabromide (79.6g) are sequentially added at room temperature, are stirred at room temperature 1 hour, evaporated under reduced pressure solvent, Residue purifies to obtain title compound with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=50: 1 (V: V)) (59.0g)。
Step 4:2- ((t-butyldimethylsilyi) oxygroup) benzene acetonitrile
At room temperature, 2- ((t-butyldimethylsilyi) oxygroup) benzyl bromine is dissolved in 500mL acetonitrile, trimethyl cyanogen is added Silane (29.1g) and potassium carbonate (54.2g), are heated to 60 DEG C and are stirred overnight, and reaction solution is poured into water, and ethyl acetate extraction has Machine mutually uses saturated common salt water washing, and anhydrous sodium sulfate is dry, silica gel column chromatography (eluent: petroleum ether: ethyl acetate=30: 1 (V: V)) purify to obtain title compound (30.2g).
Step 5:2- (2- ((t-butyldimethylsilyi) oxygroup) phenyl) -2- methyl propionitrile
At -78 DEG C, the tetrahydrofuran solution (1M, 300mL) of lithium diisopropyl amido is added drop-wise to 2- ((tert-butyl diformazan Base silane base) oxygroup) benzene acetonitrile (25g) tetrahydrofuran (300mL) solution in, stir 30 minutes, continue keep -78 DEG C, to Iodomethane (42.6g) is added dropwise in solution, stirs 30 minutes, is then warmed to room temperature.Reaction solution is poured into saturated aqueous ammonium chloride In (500mL), ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, uses silica gel column chromatography (eluent: petroleum ether: ethyl acetate=30: 1 (V: V)) purifies to obtain title compound (25.4g).
Step 6:2- (2- ((t-butyldimethylsilyi) oxygroup) phenyl) -2 methyl propanal
At -78 DEG C, the toluene solution (1M, 300mL) of diisobutyl aluminium hydride is added drop-wise to 2- (2- ((fert-butyidimethylsilyl Silylation) oxygroup) phenyl) and -2- methyl propionitrile (25.0g) tetrahydrofuran (300mL) solution in, stir 30 minutes, then rise To room temperature, reaction solution is poured into saturated aqueous ammonium chloride (500mL), ethyl acetate extraction, organic phase saturated salt solution Washing, anhydrous sodium sulfate is dry, purifies to obtain mark with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=50: 1 (V: V)) It inscribes compound (22.1g).
Step 7:3- (2- ((t-butyldimethylsilyi) oxygroup) phenyl) -3- methyl -2- ((trimethyl silyl) Oxygroup) butyronitrile
At room temperature, trimethylsilyl cyanide (15.9g) and triethylamine (16.2g) are added separately to 2- (2- ((tert-butyl two Methyl-monosilane base) oxygroup) phenyl) and -2 methyl propanal (22g) acetonitrile (300mL) solution in, be stirred at room temperature 1 hour, reaction solution It is poured into water, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, (is washed with silica gel column chromatography De- liquid: petroleum ether: ethyl acetate=30: 1 (V: V)) purify to obtain title compound (21.2g).
Step 8:2- hydroxyl -3- (2- hydroxy phenyl) -3- methylbutyronitrile
At room temperature, tetrabutyl ammonium fluoride (2.8g) is added to 3- (2- ((t-butyldimethylsilyi) oxygroup) benzene Base) -3- methyl -2- ((trimethyl silyl) oxygroup) butyronitrile (2g) methylene chloride (200mL) solution in, be stirred at room temperature 5 Minute, reaction solution is poured into saturated aqueous ammonium chloride (200mL), ethyl acetate extraction, organic phase is washed with saturated common salt It washs, anhydrous sodium sulfate is dry, purifies to obtain title with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=10: 1 (V: V)) Compound (0.63g).
Step 9:2- methyl -2- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) propionic aldehyde
At room temperature, by (1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methyl mesylate (1.35g) and potassium carbonate (0.97g) is added separately in DMF (20mL) solution of 2- hydroxyl -3- (2- hydroxy phenyl) -3- methylbutyronitrile (0.63g), is added Heat is stirred overnight to 60 DEG C.Reaction solution is poured into water after being cooled to room temperature, ethyl acetate extraction, organic phase saturated salt solution Washing, anhydrous sodium sulfate is dry, purifies to obtain mark with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=5: 1 (V: V)) It inscribes compound (0.30g).
Step 10:3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) -2- ((trimethyl silyl) oxygroup) butyronitrile
According to the method for 1 step 7 of intermediate implement that title compound (0.30g) is made.
Step 11:2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) benzene Base) butyric acid
At room temperature, 3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) -2- ((trimethyl silyl) oxygroup) butyronitrile (0.30g) is dissolved in 30mL concentrated hydrochloric acid, is heated to 110 DEG C, is stirred 6 hours, cooling Reaction solution is poured into water after to room temperature, ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, Evaporated under reduced pressure obtains title compound crude product (0.30g) without purifying, is directly used in and reacts in next step.
Step 12:2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) benzene Base) methyl butyrate
At room temperature, the 3mL concentrated sulfuric acid is added to 2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrrole Azoles -5- base) methoxyl group) phenyl) and butyric acid (0.30g) methanol (50mL) solution in, be heated to 60 DEG C, stir 2 hours, it is cooling Reaction solution is poured into water afterwards, and ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, uses silicagel column Chromatography (eluent: petroleum ether: ethyl acetate=4: 1 (V: V)) purifies to obtain title compound (0.23g).
1H NMR (400MHz, CDCl3) δ 7.61 (d, J=1.6Hz, 1H), 7.23-7.28 (m, 2H), 6.87- 7.01 (m, 2H), 6.46 (d, J=2.0Hz, 1H), 5.16 (s, 2H), 4.82-4.88 (m, 3H), 3.50 (s, 3H), 2.78 (d, J= 7.6Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H).
The synthesis of intermediate 2:2- hydroxyl -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
Step 1:(Z) -5 (4H) -one of -4- (2- benzylidene) -2- methyl oxazole
N- acetoglycocoll (19.6g) and sodium acetate (22.9g) are added separately to Benzaldehyde,2-methoxy (13.6g) Acetic anhydride (300mL) solution in, be heated to 130 DEG C stir 2 hours, poured into ice water after being cooled to room temperature, filter and use water Crude title compound is washed to obtain, is directly used in without purifying and reacts in next step.
Step 2:2- methoxybenzene pyruvic acid
- 5 (4H) the -one crude product of (Z) -4- (2- benzylidene) -2- methyl oxazole of previous step is all added to In 400mL hydrochloric acid (4M) solution, 110 DEG C are heated to, is stirred 2 hours, reaction solution is poured into water after being cooled to room temperature, ethyl acetate Extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and evaporated under reduced pressure obtains title compound crude product (20.0g), Without purifying, it is directly used in and reacts in next step.
Step 3:2- (1- (2- methoxyphenyl) cyclopropyl) -2- Oxoacetic Acid
By potassium hydroxide (3.4g) and 1,2- Bromofume (5.8g) is separately added into the methoxybenzene of falling 2- pyruvic acid (3g) 100mL tetrahydrofuran: water=1: in 1 mixed solution, being stirred at room temperature 5 hours, and reaction solution is poured into water, ethyl acetate extraction, Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and evaporated under reduced pressure obtains title compound crude product (1.0g), without pure Change, is directly used in and reacts in next step.
Step 4:2- (1- (2- methoxyphenyl) cyclopropyl) -2- ethyl
The 10mL concentrated sulfuric acid is added to the ethyl alcohol of 2- (1- (2- methoxyphenyl) cyclopropyl) -2- Oxoacetic Acid (1.0g) In (50mL) solution, 60 DEG C are heated to, is stirred 2 hours, reaction solution is poured into water after cooling, and ethyl acetate extraction, organic phase is used Saturated common salt water washing, anhydrous sodium sulfate are dry, with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=10: 1 (V: V title compound (0.80g))) is purified to obtain.
Step 5:2- hydroxyl -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
2- (1- (2- methoxyphenyl) cyclopropyl) -2- ethyl (0.80g) is dissolved in 50mL methanol, it is cooling To 0 DEG C, it is slowly added to sodium borohydride (0.12g), stirring 30 minutes is warmed to room temperature, reaction solution is poured into saturated aqueous ammonium chloride In (50mL), ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, (is washed with silica gel column chromatography De- liquid: petroleum ether: ethyl acetate=5: 1 (V: V)) purify to obtain title compound (0.50g).
The synthesis of intermediate 3:2- hydroxyl -2- (1- (2- methoxyphenyl) cyclobutyl) ethyl acetate
Step 1:2- (1- (2- methoxyphenyl) cyclobutyl) -2- Oxoacetic Acid
According to the method for 2 step 3 of intermediate implement that title compound is made.
Step 2:2- (1- (2- methoxyphenyl) cyclobutyl) -2- ethyl
According to the method for 2 step 4 of intermediate implement that title compound is made.
Step 3:2- hydroxyl -2- (1- (2- methoxyphenyl) cyclobutyl) ethyl acetate
According to the method for 2 step 5 of intermediate implement that title compound is made.
Intermediate 4:2- hydroxyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) butyl- The synthesis of 3- olefin(e) acid ethyl ester:
Intermediate 5:2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) Cyclopropyl) ethyl acetate synthesis:
Step 1:(1- (2,2,2- trifluoroethyl) -1H- pyrazole-3-yl) methylmethanesulfonate ester
At 0 DEG C, to (1- (2,2,2- trifluoroethyl) -1H- pyrazole-3-yl) methanol (10.0g) and triethylamine (11.2g) Methylene chloride (150mL) solution in mesyl chloride (9.58g) is slowly added dropwise, be warmed to room temperature after being added dropwise and continue to stir 2h.Reaction solution is poured into water, methylene chloride extraction, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filter Liquid is concentrated to give title compound (10.3g).
Step 2:1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) second -1- ketone
At room temperature, to o-hydroxyacetophenone (7.07g) and (1- (2,2,2- trifluoroethyl) -1H- pyrazole-3-yl) methyl first Potassium carbonate powder (14.4g) is added in DMF (100mL) solution of sulphonic acid ester (10.3g), 65 DEG C of stirring 12h are risen to after finishing. Reaction solution is poured into water, ethyl acetate extraction, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate is dense Contracting, purifies to obtain title compound with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=3: 1 (V: V)) for residue (13.0g)。
Step 3:3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) epoxy Ethane -2- carboxylic acid, ethyl ester
At 0 DEG C, metallic sodium (2g) is added in batches in dehydrated alcohol (40mL), is warmed to room temperature and is stirred to complete after finishing It is molten, then it is cooled to -20 DEG C with ice salt bath, by 1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) benzene Base) toluene (10mL) solution of second -1- ketone (13.0g) and ethyl chloroacetate (10.8g) is slowly added dropwise to above-mentioned alcohol sodium solution In, 15h is warmed to room temperature and stirred after finishing, and reaction solution is poured into AcOH: H2O (1: 100) (450mL) in the mixed solvent, dichloro Methane extraction, extract liquor are washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue silicagel column color Spectrometry (eluent: petroleum ether: ethyl acetate=5: 1 (V: V)) purifies to obtain title compound (15.8g).
Step 4:2- hydroxyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) butyl- 3- Olefin(e) acid ethyl ester
At 0 DEG C, to 3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) The concentrated sulfuric acid (3.90g) is slowly added dropwise in ether (150mL) solution of ethylene oxide -2- carboxylic acid, ethyl ester (13.8g), after being added dropwise It is warmed to room temperature and continues to stir 12h.Reaction solution is poured into water, sodium bicarbonate powder adjusts pH to neutrality, and ethyl acetate extracts, Extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue silica gel column chromatography (elution Liquid: petroleum ether: ethyl acetate=5: 1 (V: V)) purify to obtain title compound (5.8g).
1H NMR (400MHz, CDCl3) δ 7.54 (d, J=2.0Hz, 1H), 7.30 (td, J=8.0Hz, 1.6Hz, 1H), 7.14 (dd, J=7.2Hz, 1.6Hz, 1H), 7.01 (t, J=8.4Hz, 1H), 6.95 (d, J=8.4Hz, 1H), 6.37 (d, J =2.0Hz, 1H), 5.60 (s, 1H), 5.27 (s, 1H), 5.14 (d, J=12.4Hz, 1H), 5.10 (d, J=12.4Hz, 1H), 4.99 (d, J=7.2Hz, 1H), 4.82-4.87 (m, 2H), 3.96-4.06 (m, 2H), 3.14 (d, J=7.2Hz, 1H), 1.05 (t, J=7.2Hz, 3H).
Step 5:2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ring Propyl) ethyl acetate
At -20 DEG C, to 2- hydroxyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) benzene Base) diethyl zinc (n-hexane of 1.0M is slowly added dropwise in anhydrous methylene chloride (30mL) solution of butyl- 3- olefin(e) acid ethyl ester (1.5g) Solution, 23.5mL), diiodomethane (1.96mL) then is added, room temperature is slowly increased to after finishing and is stirred 30 hours, by reaction solution It pouring into saturated aqueous ammonium chloride, ethyl acetate extraction, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, Filtrate concentration, purifies titled by residue with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=4: 1 (V: V)) It closes object (130mg).
1H NMR (400MHz, CDCl3) δ 7.59 (d, J=2.0Hz, 1H), 7.23-7.29 (m, 2H), 6.94- 6.98 (m, 2H), 6.44 (d, J=1.6Hz, 1H), 5.16 (s, 2H), 4.90-5.09 (m, 2H), 4.03-4.11 (m, 1H), 3.90- 3.98 (m, 2H), 2.98 (d, J=7.6Hz, 1H), 1.19-1.26 (m, 1H), 1.12 (t, J=7.6Hz, 3H), 0.99-1.03 (m, 1H), 0.80-0.85 (m, 2H).
Intermediate 6:2- hydroxyl -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
Step 1:3- (2- methoxyphenyl) -3- methyl oxirane -2- carboxylic acid, ethyl ester
According to the method for 4 step 3 of intermediate implement that title compound is made.
Step 2:2- hydroxyl -3- (2- methoxyphenyl) butyl- 3- olefin(e) acid ethyl ester
According to the method for 4 step 4 of intermediate implement that title compound is made.
1H NMR (400MHz, CDCl3) δ 7.28 (td, J=7.2Hz, 1.6Hz, 1H), 7.13 (d, J=7.2Hz, 1.6Hz, 1H), 6.93 (t, J=7.2Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 5.60 (s, 1H), 5.33 (s, 1H), 5.08 (d, J=7.2, Hz, 1H), 4.07-4.13 (m, 2H), 3.82 (s, 3H), 3.39 (d, J=7.2Hz, 1H), 1.09 (t, J= 7.2Hz, 3H).
The synthesis of intermediate 7:2- hydroxyl -3- (2- methoxyphenyl) -3 Methylbutanoic acid ethyl ester:
Step 1:3- (2- methoxyphenyl) -3- methyl -2-Oxobutyric acid
At 0 DEG C, 3- (2- methoxyphenyl)-Acetylformic acid (1.95g) is dissolved in tetrahydrofuran (50mL) and 5N hydrogen In the mixed solution of aqueous solution of sodium oxide (10mL), it is slowly added to iodomethane (4.23g).This reaction solution is heated to 50 DEG C of stirrings 12 hours.Reaction solution is poured into ice water (100mL) after being cooled to room temperature, keeps its weakly acidic with dilute hydrochloric acid neutralization reaction liquid (pH=5).Mixed liquor is extracted with dichloromethane, and extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate is dense Contract to obtain title compound (0.80g).
Step 2:3- (2- methoxyphenyl) -3- methyl -2-Oxobutyric acid ethyl ester
At 0 DEG C, to 3- (2- methoxyphenyl) -3- methyl -2-Oxobutyric acid (0.50g) ethyl alcohol (15mL) solution In the concentrated sulfuric acid (0.50g) is slowly added dropwise, risen to after being added dropwise 80 DEG C continue stirring 1 hour.By reaction solution after being cooled to room temperature It pours into ice water, sodium bicarbonate powder adjusts pH to neutrality, and ethyl acetate extracts, and extract liquor is washed with saturated common salt, anhydrous sulphur Sour sodium dries, filters, filtrate concentration, by residue silica gel column chromatography (eluent: petroleum ether: ethyl acetate=10: 1 (V : V)) purify to obtain title compound (0.50g).
The synthesis of step 3:2- hydroxyl -3- (2- methoxyphenyl) -3 Methylbutanoic acid ethyl ester
At -0 DEG C, to 3- (2- methoxyphenyl) -3- methyl -2-Oxobutyric acid ethyl ester (0.30g) anhydrous methanol (10mL) solution is slowly added to sodium borohydride (20mg), and room temperature is slowly increased to after finishing and is stirred 1 hour, reaction solution is poured into cold In water, ethyl acetate extraction, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue Title compound (130mg) is purified to obtain with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=4: 1 (V: V)).
1H NMR (400MHz, CDCl3) δ 7.18-7.24 (m, 2H), 6.88-6.91 (m, 2H), 4.99 (d, J=8.0 Hz, 1H), 3.88-3.89 (m, 2H), 3.87 (s, 3H), 3.01 (d, J=8.0Hz, 1H), 1.48 (s, 3H), 1.37 (s, 3H), 0.93 (t, J=7.2Hz, 3H).
The synthesis of intermediate 8:2- hydroxyl -3- (2- methoxyphenyl) ethyl butyrate
Step 1:3- (2- methoxyphenyl) -2-Oxobutyric acid
At 0 DEG C, 3- (2- methoxyphenyl)-Acetylformic acid (1.95g) is dissolved in tetrahydrofuran (50mL) and 5N hydrogen In the mixed solution of aqueous solution of sodium oxide (10mL), it is slowly added to iodomethane (2.0g).50 DEG C of this reaction solution are stirred 12 hours. Reaction solution is poured into ice water (100mL) after being cooled to room temperature, makes its weakly acidic (pH=5) with dilute hydrochloric acid neutralization reaction liquid. Mixed liquor is extracted with dichloromethane, and extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give title Compound (1.0g).
Step 2, step 3 according to the synthetic method of intermediate 7 implements that title compound is made
1H NMR (400MHz, DMSO-d6) δ 7.22 (dd, J=7.6Hz, 1H), 7.44 (td, J=7.6Hz, 1.6 Hz, 1H), 6.90 (d, J=8.0Hz, 1H), 6.84 (t, J=7.6Hz, 1H), 5.30 (d, J=6.0Hz, 1H), 4.23 (t, J= 6.8Hz, 1H), 3.98 (dd, J=7.2Hz, 2H), 3.74 (s, 3H), 3.44-3.50 (m, 1H), 1.12 (d, J=7.2 Hz, 3H), 1.07 (t, J=7.2Hz, 3H).
The synthesis of fluoro- 2- hydroxyl -3- (2- methoxyphenyl) ethyl propionate of intermediate 9:3,3- bis-
Step 1:2,2- bis- fluoro- 2- (2- methoxyphenyl) ethyl acetate
2- iodanisol (4.68g), copper powder (6.4g), bromo- 2, the 2- difluoro second of 2- are sequentially added in 250mL reaction flask Acetoacetic ester (8.12g) and DMSO (100mL).This reaction solution is heated to 80 DEG C to stir 3 hours.After being cooled to room temperature, it is added 200mL water, is filtered with diatomite, and filtrate is extracted with ethyl acetate, organic phase saturated common salt water washing.The anhydrous sulphur of organic phase Sour sodium dries, filters, and residue is dried in vacuo to obtain title compound (3.0g) with silica gel column chromatography by filtrate concentration.
Step 2:2,2- bis- fluoro- 2- (2- methoxyphenyl) acetamide
At 0 DEG C, to methanol (50mL) solution that fluoro- 2- (2- methoxyphenyl) ethyl acetate of 2,2- bis- (3.0g) is housed Middle addition concentrated ammonia liquor (20mL) stirs this reaction solution 5 hours at 0 DEG C.Reaction solution is concentrated under reduced pressure and removes organic solvent, then 100mL cold water is added, is extracted with ethyl acetate, extract liquor extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, Filtrate concentration, purifies titled by residue with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1: 1 (V: V)) It closes object (2.0g).
Step 3:2,2- bis- fluoro- 2- (2- methoxyphenyl) acetonitrile
Fluoro- 2- (2- methoxyphenyl) acetamide of 2,2- bis- (2.0g) is dissolved in tetrahydrofuran (50mL), at 0 DEG C Triethylamine (3mL) and trifluoroacetic anhydride (2mL) is added.This reaction solution is stirred 1 hour at 0 DEG C, reaction solution is poured into ice water In (100mL).Mixed liquor is extracted with dichloromethane, and extract liquor extract liquor is washed with saturated common salt, and anhydrous sodium sulfate is dry, mistake Filter, filtrate are concentrated to give title compound (1.5g).
Step 4:2,2- bis- fluoro- 2- (2- methoxyphenyl) acetaldehyde
At 0 DEG C, into tetrahydrofuran (50mL) solution of fluoro- 2- (2- methoxyphenyl) acetonitrile of 2,2- bis- (1.5g) It is slowly added to lithium aluminium hydride reduction (0.4g), continues stirring 1 hour after being added dropwise at 0 DEG C.Then 10mL 1M hydrochloric acid is added dropwise Reaction, reaction solution are poured into cold water and are extracted with ethyl acetate, and extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, Filtrate concentration, purifies titled by residue with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=2: 1 (V: V)) It closes object (0.50g).
Fluoro- 2- hydroxyl -3- (2- methoxyphenyl) propionitrile of step 5:3,3- bis-
At 20 DEG C, slowly add to acetonitrile (10mL) solution of fluoro- 2- (2- methoxyphenyl) acetaldehyde of 2,2- bis- (0.50g) Enter triethylamine (1mL) and trimethylsilyl cyanide (0.5mL).It is stirred at room temperature after finishing 1 hour, reaction solution is poured into saturated ammonium chloride In aqueous solution, ethyl acetate extraction, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate concentration will be residual Object is stayed to purify to obtain title compound (0.40g) with silica gel column chromatography (eluent: petroleum ether: ethyl acetate=2: 1 (V: V)).
Fluoro- 2- hydroxyl -3- (2- methoxyphenyl) ethyl propionate of step 6:3,3- bis-
At 0 DEG C, the ethyl alcohol (10mL) to fluoro- 2- hydroxyl -3- (2- methoxyphenyl) propionitrile (0.40g) of 3,3- bis- is molten It is slowly continually fed into dry hydrogen chloride gas in liquid, and maintains stirring 5 hours.Reaction solution is poured into 100mL cold water, acetic acid Ethyl ester extraction, extract liquor are washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue silicagel column color Spectrometry (eluent: petroleum ether: ethyl acetate=4: 1 (V: V)) purifies to obtain title compound (0.20g).
1H NMR (400MHz, CDCl3) δ 7.39 (dd, J=7.6Hz, 1.6Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 6.91 (t, J=7.6Hz, 1H), 6.88 (d, J=7.6Hz, 1H), 4.94-5.03 (m, 1H), 3.79-4.16 (m, 2H), 3.81 (s, 3H), 3.29 (d, J=7.2Hz, 1H), 1.05 (t, J=7.2Hz, 3H).
The chloro- 5- of intermediate 10:4- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- The synthesis of (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine
Referring to page 31 and page 42 in patent WO2016/207226 of synthetic method synthesising target compound.
1H NMR (400MHz, DMSO-d6) δ 8.93 (s, 1H), 7.25 (d, J=8.8Hz, 1H), 7.17 (d, J= 8.4Hz, 1H), 5.92 (dd, J=6.8Hz, 3.6Hz, 1H), 5.69 (t, J=3.2Hz, 1H), 4.24-4.26 (m, 2H), 2.80-3.30 (m, 10H), 2.73 (s, 3H), 2.04 (s, 3H).
The chloro- 5- of intermediate 11:4- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- The synthesis of (furans -2- base) thieno [2,3-d] pyrimidine
Referring in patent WO2015/97123 page 192 of synthetic method synthesising target compound.
The chloro- 5- of intermediate 12:4- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- The synthesis of (4- fluorophenyl) thieno [2,3-d] pyrimidine
By the chloro- 5- of 4- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- iodo thieno [2,3-d] pyrimidine (the synthetic method synthesis referring in patent WO2015/97123 page 191) (563mg), 4- fluorobenzoic boric acid The mixture of (140mg), tetra-triphenylphosphine palladium (11mg) and cesium carbonate (65mg) are dissolved in the dioxane in glass tube sealing together In (20mL) and water (10mL), it is heated to 90 DEG C under nitrogen protection, reaction solution is cooled to room temperature after 3 hours and pours into ice water In, it is extracted with dichloromethane, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue Title compound (100mg) is purified to obtain with thin-layered chromatography (solvent: methylene chloride: methanol=10: 1 (V: V)).
Intermediate 13:(R) -2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) first Oxygroup) phenyl) methyl butyrate synthesis:
Intermediate 14:(S) -2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) first Oxygroup) phenyl) methyl butyrate synthesis:
Step 1:(R) -2- ((R) -2- methoxyl group -2- phenylacetyl oxygroup) -3- methyl -3- (2- ((1- (2,2,2- tri- Fluoro ethyl) -1H- pyrazoles -5- base) base) methoxyl group) phenyl) methyl butyrate and (S) -2- ((R) -2- methoxyl group -2- phenylacetyl Oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) base) methoxyl group) phenyl) methyl butyrate
At 0 DEG C, (R)-(-)-α-methoxyphenylacetic acid (1.66g) is dissolved in 50mL methylene chloride, under stirring successively 5 drop DMF and oxalyl chloride (2.54g) is added.This reaction solution is warmed to room temperature stirring 1 hour.(R) -2- is concentrated under reduced pressure in reaction solution Methoxyl group -2- phenylacetyl chlorine.Intermediate 1 (1.93g) is dissolved in the dry pyridine of 50mL, is slowly added at room temperature above-mentioned Acyl chlorides simultaneously continues stirring 1 hour.It is concentrated under reduced pressure, is extracted with ethyl acetate after residue diluted with water, extract liquor uses dilute salt respectively Sour (2M) and saturated common salt water washing.Organic phase is dried, filtered with anhydrous sodium sulfate, filtrate concentration, by residue silicagel column Chromatography (eluent: petroleum ether: ethyl acetate=10: 1 (V: V)) purifies (R) -2- ((R) -2- methoxyl group -2- phenylacetyl Oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) base) methoxyl group) phenyl) methyl butyrate (0.90g)；
1H NMR (400MHz, CDCl3) δ 7.56 (d, J=2.0Hz, 1H), 7.23-7.31 (m, 7H), 6.99 (t, J= 8.8Hz, 1H), 6.92 (d, J=8.8Hz, 1H), 6.41 (d, J=1.6Hz, 1H), 5.85 (s, 1H), 5.07 (d, J= 11.6Hz, 1H), 4.99 (d, J=11.6Hz, 1H), 4.76-4.88 (m, 2H), 4.67 (s, 1H), 3.42 (s, 3H), 3.36 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H).
(S) -2- ((R) -2- methoxyl group -2- phenylacetyl oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) - 1H- pyrazoles -5- base) base) methoxyl group) phenyl) methyl butyrate (0.80g).
1H NMR (400MHz, CDCl3) δ 7.57 (d, J=2.0Hz, 1H), 7.13-7.27 (m, 7H), 6.91 (t, J= 8.8Hz, 1H), 6.81 (d, J=8.8Hz, 1H), 6.37 (d, J=1.6Hz, 1H), 5.80 (s, 1H), 4.98 (d, J= 12.4Hz, 1H), 4.75-4.86 (m, 3H), 4.73 (s, 1H), 3.52 (s, 3H), 3.33 (s, 3H), 1.35 (s, 3H), 1.17 (s, 3H).
Step 2:(R) -2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) methyl butyrate and (S) -2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) methyl butyrate
At 0 DEG C, (R) -2- ((R) -2- methoxyl group -2- phenylacetyl oxygroup) -3- methyl -3- that step 1 is obtained (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) base) methoxyl group) phenyl) methyl butyrate (0.90g) is dissolved in 30mL first In alcohol, it is slowly added to sodium methoxide powder (100mg) and continues to stir 1h.Reaction solution is poured into saturated aqueous ammonium chloride, second Acetoacetic ester extraction, extract liquor saturated common salt water washing, anhydrous sodium sulfate dry, filter, filtrate concentration, by residue silica gel Column chromatography (eluent: petroleum ether: ethyl acetate=5: 1 (V: V)) purifies (R) -2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate (0.50g).
1H NMR (400MHz, CDCl3) δ 7.61 (d, J=1.6Hz, 1H), 7.23-7.28 (m, 2H), 6.87- 7.01 (m, 2H), 6.46 (d, J=2.0Hz, 1H), 5.16 (s, 2H), 4.82-4.88 (m, 3H), 3.50 (s, 3H), 2.78 (d, J= 7.6Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H).
Referring to aforesaid operations, (S) -2- ((R) -2- methoxyl group -2- phenylacetyl oxygroup) -3- methyl-is hydrolyzed with sodium methoxide 3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) base) methoxyl group) phenyl) methyl butyrate (0.80g) obtains (S) - 2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate (0.40g)。
1H NMR (400MHz, CDCl3) δ 7.61 (d, J=1.6Hz, 1H), 7.23-7.28 (m, 2H), 6.87- 7.01 (m, 2H), 6.46 (d, J=2.0Hz, 1H), 5.16 (s, 2H), 4.82-4.88 (m, 3H), 3.50 (s, 3H), 2.78 (d, J= 7.6Hz, 1H), 1.41 (s, 3H), 1.35 (s, 3H).
Intermediate 15:(R) -2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) cyclopropyl) and ethyl acetate synthesis:
Intermediate 16:(S) -2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) cyclopropyl) and ethyl acetate synthesis:
Step 1:(R) -2- methoxyl group -2- phenylacetic acid ((R) -2- ethyoxyl -2- oxo -1- (1- (2- ((1- (2,2,2- Trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl)) ethyl ester and (S) -2- methoxyl group -2- phenylacetic acid ((R) - 2- ethyoxyl -2- oxo -1- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl Base)) ethyl ester
One synthetic method with reference to the step of intermediate 13 and intermediate 14 replaces intermediate 1 to obtain (R) -2- with intermediate 5 Methoxyl group -2- phenylacetic acid ((R) -2- ethyoxyl -2- oxo -1- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) cyclopropyl)) ethyl ester (0.40g)；
1H NMR (400MHz, CDCl3) δ 7.55 (d, J=2.0Hz, 1H), 7.24-7.36 (m, 7H), 6.90- 6.96 (m, 2H), 6.40 (d, J=2.0Hz, 1H), 5.12 (s, 2H), 5.02 (s, 1H), 4.88 (q, J=8.4Hz, 2H), 4.71 (s, 1H), 3.79-3.92 (m, 2H), 3.38 (s, 3H), 1.10-1.13 (m, 1H), 0.99-1.03 (m, 1H), 0.93 (t, J= 7.2Hz, 3H), 0.80-0.83 (m, 2H).
(S) -2- methoxyl group -2- phenylacetic acid ((R) -2- ethyoxyl -2- oxo -1- (1- (2- ((1- (2,2,2- trifluoro second Base) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl)) ethyl ester (0.30g).
1H NMR (400MHz, CDCl3) δ 7.55 (d, J=1.6Hz, 1H), 7.32-7.36 (m, 5H), 7.20- 7.25 (m, 1H), 7.04 (dd, J=7.6Hz, 1.6Hz, 1H), 6.83-6.88 (m, 2H), 6.37 (d, J=2.0Hz, 1H), 5.11 (d, J =12.8Hz, 1H), 5.06 (d, J=12.8Hz, 1H), 5.07 (s, 1H), 4.80-4.87 (m, 2H), 4.78 (s, 1H), 3.86-4.23 (m, 2H), 3.36 (s, 3H), 1.04 (t, J=7.2Hz, 3H), 0.92-0.94 (m, 2H), 0.72- 0.76 (m, 1H), 0.65-0.68 (m, 1H).
Step 2:(R) -2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) benzene Base) cyclopropyl) ethyl acetate and (S) -2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) cyclopropyl) ethyl acetate
Two synthetic methods hydrolyze (R) -2- methoxyl group -2- with sodium ethoxide respectively with reference to the step of intermediate 13 and intermediate 14 Phenylacetic acid ((R) -2- ethyoxyl -2- oxo -1- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) Phenyl) cyclopropyl)) ethyl ester (0.40g) and (S) -2- methoxyl group -2- phenylacetic acid ((R) -2- ethyoxyl -2- oxo -1- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl)) ethyl ester (0.30g) obtains (R) -2- hydroxyl Base -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) ethyl acetate (0.30g)；
1H NMR (400MHz, CDCl3) δ 7.59 (d, J=2.0Hz, 1H), 7.23-7.29 (m, 2H), 6.94- 6.98 (m, 2H), 6.44 (d, J=1.6Hz, 1H), 5.16 (s, 2H), 4.90-5.09 (m, 2H), 4.03-4.11 (m, 1H), 3.90-3.98 (m, 2H), 2.98 (d, J=7.6Hz, 1H), 1.19-1.26 (m, 1H), 1.12 (t, J=7.6Hz, 3H), 0.99-1.03 (m, 1H), 0.80-0.85 (m, 2H).
(S) -2- hydroxyl -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ring Propyl) ethyl acetate (0.20g)；
1H NMR (400MHz, CDCl3) δ 7.59 (d, J=2.0Hz, 1H), 7.23-7.29 (m, 2H), 6.94- 6.98 (m, 2H), 6.44 (d, J=1.6Hz, 1H), 5.16 (s, 2H), 4.90-5.09 (m, 2H), 4.03-4.11 (m, 1H), 3.90-3.98 (m, 2H), 2.98 (d, J=7.6Hz, 1H), 1.19-1.26 (m, 1H), 1.12 (t, J=7.6Hz, 3H), 0.99-1.03 (m, 1H), 0.80-0.85 (m, 2H).
Intermediate 17:(R) -2- hydroxyl -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) Cyclopropyl) ethyl acetate synthesis:
Step 1:(2- (2- methoxyphenyl) pyrimidine-4-yl) methylmethanesulfonate ester
According to the method for 5 step 1 of intermediate implement that title compound is made.
Step 2:1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) second -1- ketone
According to the method for 5 step 2 of intermediate implement that title compound is made.
Step 3:3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -3- methyl oxirane -2- Carboxylic acid, ethyl ester
According to the method for 5 step 3 of intermediate implement that title compound is made.
Step 4:2- hydroxyl -3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) butyl- 3- olefin(e) acid second Ester
According to the method for 5 step 4 of intermediate implement that title compound is made.
Step 5:2- hydroxyl -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) cyclopropyl) Ethyl acetate
According to the method for 5 step 5 of intermediate implement that title compound is made.
Step 6:(R) (((((2- (2- methoxyphenyl) is phonetic by 2- by 1- by (R) -2- ethyoxyl -1- for -2- methoxyl group -2- phenylacetic acid Pyridine -4- base) methoxyl group) phenyl) cyclopropyl) -2- oxo) ethyl ester
According to the method for 13 step 1 of intermediate implement that title compound is made.
Step 7:(R) -2- hydroxyl -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) cyclopropyl Base) ethyl acetate
According to the method for 13 step 2 of intermediate implement that title compound is made.
Intermediate 18:(R) -2- hydroxyl -3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -3- The synthesis of methylbutanoic acid methyl esters:
Step 1:2- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -2 methyl propanal
According to the method for 1 step 9 of intermediate implement that title compound is made.
Step 2:2- hydroxyl -3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -3- methylbutyronitrile
According to the method for 1 step 10 of intermediate implement that title compound is made.
Step 3:(2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -3 Methylbutanoic acid
According to the method for 1 step 11 of intermediate implement that title compound is made.
Step 4:2- hydroxyl -3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -3 Methylbutanoic acid Methyl esters
According to the method for 1 step 12 of intermediate implement that title compound is made.
Step 5:(R) (((2- (2- methoxyphenyl) is phonetic by 2- by -2- ((R) -2- methoxyl group -2- phenylacetyl oxygroup) -3- Pyridine -4- base) methoxyl group) phenyl) -3 Methylbutanoic acid methyl esters
According to the method for 13 step 1 of intermediate implement that title compound is made.
Step 6:(R) -2- hydroxyl -3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) -3- methyl Methyl butyrate
According to the method for 13 step 2 of intermediate implement that title compound is made.
The synthesis of intermediate 19:2- amino -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
Step 1:2- azido -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
At 0 DEG C, to being slowly added dropwise in methylene chloride (15mL) solution of intermediate 2 (250mg) and triethylamine (202mg) Mesyl chloride (172mg) is warmed to room temperature after being added dropwise and continues to stir 1h.Reaction solution is poured into water, methylene chloride extraction Twice, extract liquor saturated common salt water washing, anhydrous sodium sulfate dry, filter, and filtrate is concentrated to get brown oil.By oily Object was dissolved in 5mL DMF and is added sodium azide (130mg), with room temperature reaction 12 hours.Reaction solution is poured into water, acetic acid Ethyl ester extraction, extract liquor are washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue silicagel column color Spectrometry (eluent: petroleum ether: ethyl acetate=2: 1 (V: V)) purifies to obtain title compound (190mg).
Step 2:2- amino -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
Obtained solid in step 1 is dissolved in the in the mixed solvent of THF (5mL) Yu water (5mL), adds triphenylphosphine (500mg) is then heated to reflux 2 hours and is cooled to room temperature.Reaction solution is poured into ice water, methylene chloride extraction, extract liquor is used Saturated common salt washing, anhydrous sodium sulfate dry, filter, filtrate concentration, by residue silica gel column chromatography (eluent: petroleum Ether: ethyl acetate=1: 1 (V: V)) purify to obtain intermediate 19 (102mg).
Embodiment 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) butyric acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) methyl butyrate
At 0 DEG C, to the chloro- 5- of 4- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine (110mg) (intermediate 12) and 2- hydroxy-3-methyl -3- (2- ((1- (2,2,2- Trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate (80mg) (intermediate 1) THF (10mL) solution in It is added sodium hydride (11mg), stirring 2 hours is warmed to room temperature after finishing.Reaction solution is poured into saturated aqueous ammonium chloride (50mL) In, methylene chloride extraction, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, and residue is used in filtrate concentration Thin-layered chromatography (solvent: methylene chloride: methanol=10: 1 (V: V)) purifies to obtain title compound (80mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) butyric acid
At room temperature, to 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- Fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) that lithium hydroxide is added in the solution in Isosorbide-5-Nitrae-dioxane and water (1: 1) (6mL) is solid for methyl butyrate Body (22mg) is stirred at room temperature 12 hours, reaction solution is poured into water, and adjusts pH to 3-4, methylene chloride extraction with dilute hydrochloric acid (2M) It takes, extract liquor is washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue thin-layered chromatography (exhibition Open agent: methylene chloride: methanol=4: 1 (V: V)) purifying, take the biggish isomers of polarity to obtain title compound (1.5mg).
1H NMR (400MHz, DMSO-d6) δ 8.61 (s, 1H), 7.52 (d, J=1.6Hz, 1H), 7.16-7.26 (m, 5H), 7.07 (d, J=8.4Hz, 1H), 6.96 (d, J=8.8Hz, 1H), 6.86-6.88 (m, 3H), 6.49 (s, 1H), 6.20 (s, 1H), 5.17-5.21 (m, 4H), 4.11-4.22 (m, 2H), 2.77 (t, J=5.2Hz, 2H), 2.32-2.64 (m, 8H), 2.24 (s, 3H), 2.20 (s, 3H), 1.01 (s, 3H), 0.81 (s, 3H).
Embodiment 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) first Oxygroup) phenyl) cyclopropyl) acetic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine -4- oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 1 is replaced with intermediate 5, obtains title compound (80mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine furan Mutter -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles - 5- yl) methoxyl group) phenyl) cyclopropyl) acetic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoro second Base) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) and ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- first Base piperazine -1- base) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain Title compound (1.91mg).
1H NMR (400MHz, CD3OD) δ 8.45 (s, 1H), 7.50 (d, J=2.0Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.24-7.28 (m, 2H), 7.12-7.16 (m, 2H), 6.99-7.05 (m, 3H), 6.76 (t, J=7.6Hz, 1H), 6.53 (d, J=1.6Hz, 1H), 6.46 (d, J=6.0Hz, 1H), 5.64 (s, 1H), 5.21-5.28 (m, 2H), 5.09- 5.17 (m, 2H), 4.30-4.36 (m, 2H), 3.10-3.20 (m, 4H), 3.03 (t, J=5.2Hz, 2H), 2.88-3.02 (m, 4H), 2.74 (s, 3H), 1.92 (s, 3H), 0.84-0.92 (m, 1H), 0.63-0.72 (m, 1H), 0.42-0.48 (m, 1H), 0.36-0.42 (m, 1H).
Embodiment 3:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) butyl- 3- olefin(e) acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) butyl- 3- olefin(e) acid ethyl ester
Referring to the method for step 1 in embodiment 1, intermediate 6 replaces intermediate 1, obtains title compound (24 mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) and thieno [2,3-d1 pyrimidine-4-yls) oxygroup) -3- (2- methoxyphenyl) butyl- 3- olefin(e) acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) butyl- 3- olefin(e) acid Ethyl ester replaces 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thiophene Pheno simultaneously [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain title compound (2.87mg).
1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H), 7.18-7.32 (m, 5H), 6.77-6.94 (m, 5H), 6.12 (s, 1H), 4.94 (s, 1H), 4.72 (s, 1H), 4.06-4.19 (m, 2H), 3.66 (s, 3H), 2.74 (t, J=6.0Hz, 2H), 2.33-2.60 (m, 8H), 2.28 (s, 3H), 2.19 (s, 3H).
Embodiment 4:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclopropyl) acetic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 2 replaces intermediate 1, obtains title compound (60 mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclobutyl) acetic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclopropyl Base) ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain title compound (20mg).
1H NMR (400MHz, DMSO-d6) δ 8.59 (s, 1H), 7.18-7.28 (m, 6H), 7.13 (td, J=8.8 Hz, 1.6Hz, 1H), 6.85 (d, J=7.6Hz, 1H), 6.66 (t, J=7.6Hz, 1H), 6.29 (dd, J=7.6Hz, 1.6Hz, 1H), 5.36 (s, 1H), 4.20-4.316 (m, 2H), 3.76 (s, 3H), 2.81 (t, J=5.2Hz, 2H), 2.49- 2.70 (m, 8H), 2.29 (s, 3H), 1.95 (s, 3H), 0.78-0.85 (m, 1H), 0.66-0.73 (m, 1H), 0.44-0.52 (m, 1H), 0.36-0.43 (m, 1H).
Embodiment 5:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclobutyl) acetic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclobutyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 3 replaces intermediate 1, obtains title compound (40 mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorobenzene Base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) cyclobutyl) acetic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- methoxyphenyl) ring fourth Base) ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain title compound (15mg).
1H NMR (400MHz, DMSO-d6) δ 8.66 (s, 1H), 7.18-7.21 (m, 5H), 7.06-7.10 (m, 2H), 6.85 (d, J=8.0Hz, 1H), 6.67 (t, J=7.2Hz, 1H), 6.39 (d, J=7.2Hz, 1H), 5.43-5.52 (m, 1H), 5.40 (d, J=4.0Hz, 1H), 4.89 (d, J=6.0Hz, 1H), 4.85 (s, 1H), 4.11-4.16 (m, 1H), 3.94-3.99 (m, 1H), 3.72 (s, 3H), 3.59-3.68 (m, 1H), 2.67 (t, J=5.2Hz, 2H), 2.38-2.58 (m, 8H), 2.27 (s, 3H), 2.13 (s, 3H), 1.96-2.08 (m, 2H).
Embodiment 6:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) -3 Methylbutanoic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) -3 Methylbutanoic acid ethyl ester
Referring to the method for step 1 in embodiment 1, intermediate 7 replaces intermediate 1, obtains title compound (30 mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) and thieno [2,3-d1 pyrimidine-4-yls) oxygroup) -3- (2- methoxyphenyl) -3 Methylbutanoic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methyl piperazine -1- base) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) -3- methyl fourth Acetoacetic ester replaces 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) Thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxy Base) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain title compound (5mg).
1H NMR (400MHz, DMSO-d6) δ 8.63 (s, 1H), 7.07-7.25 (m, 7H), 6.88 (d, J=8.0Hz, 1H), 6.76-6.82 (m, 2H), 6.20 (s, 1H), 4.22-4.26 (m, 1H), 4.11-4.17 (m, 1H), 3.74 (s, 3H), 2.79 (t, J=5.2Hz, 2H), 2.48-2.72 (m, 8H), 2.27 (s, 3H), 1.76 (s, 3H), 0.97 (s, 3H), 0.83 (s, 3H)。
Embodiment 7:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) -3 Methylbutanoic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) ethyl butyrate
Referring to the method for step 1 in embodiment 1, intermediate 8 replaces intermediate 1, obtains title compound (10 mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) butyric acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methyl piperazine -1- base) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- methoxyphenyl) ethyl butyrate Instead of 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) benzene Base) ethyl butyrate, take the biggish isomers of polarity to obtain title compound (2mg).
1H NMR (400MHz, DMSO-d6) δ 8.66 (s, 1H), 7.27-7.31 (m, 2H), 7.21 (t, J=8.8Hz, 2H), 7.09-7.15 (m, 2H), 7.05 (d, J=8.8Hz, 1H), 6.88 (d, J=8.0Hz, 1H), 6.71 (t, J=7.2 Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 5.38 (d, J=4.8Hz, 1H), 4.12-4.16 (m, 1H), 4.02-4.06 (m, 1H), 3.75 (s, 3H), 3.46-3.52 (m, 1H), 2.68 (t, J=5.6Hz, 2H), 2.33-2.58 (m, 8H), 2.22 (s, 3H), 2.09 (s, 3H), 0.85 (d, J=7.2Hz, 3H).
Embodiment 8:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- Fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3,3- bis- fluoro- 3- (2- methoxyphenyl) propionic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3,3- bis- fluoro- 3- (2- methoxyphenyl) ethyl propionate
Referring to the method for step 1 in embodiment 1, intermediate 9 replaces intermediate 1, obtains title compound (30 mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3,3- bis- fluoro- 3- (2- methoxyphenyl) propionic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methyl piperazine -1- base) second Oxygroup) phenyl) -6- (4- fluorophenyl) thieno [2,3-D] pyrimidine-4-yl) oxygroup) bis- fluoro- 3- (2- methoxybenzene of -3,3- Base) ethyl propionate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorine Phenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain title compound (5mg).
1H NMR (400MHz, DMSO-d6) δ 8.66 (s, 1H), 7.31-7.35 (m, 1H), 7.14-7.24 (m, 4H), 6.96 (d, J=8.0Hz, 1H), 6.78-6.83 (m, 2H), 6.72 (t, J=8.0Hz, 1H), 6.62 (t, J=8.0Hz, 1H), 6.04-6.11 (m, 1H), 4.10-4.20 (m, 2H), 3.70 (s, 3H), 2.84 (t, J=5.2Hz, 2H), 2.60-2.83 (m, 8H), 2.40 (s, 3H), 2.32 (s, 3H).
Embodiment 9:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine Furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) butyl- 3- olefin(e) acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine furan Mutter -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) 3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) butyl- 3- olefin(e) acid ethyl ester
Referring to the method for step 1 in embodiment 1, intermediate 4 replaces intermediate 1, and intermediate 10 replaces intermediate 12, must mark It inscribes compound (2.55mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine furan Mutter -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) butyl- 3- olefin(e) acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((1- (2,2,2- trifluoros Ethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) butyl- 3- olefin(e) acid ethyl ester replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- Methyl piperazine -1- base) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, obtains title compound (2.55mg)。
1H NMR (400MHz, CD3OD) δ 8.70 (s, 1H), 8.50 (s, 1H), 7.49 (s, 1H), 7.34 (d, J=1.6 Hz, 1H), 7.25-7.33 (m, 2H), 7.09 (t, J=8.0Hz, 2H), 6.89-6.96 (m, 2H), 6.32 (s, 1H), 6.19 (s, 1H), 5.63 (t, J=3.6Hz, 1H), 5.55 (dd, J=6.8Hz, 4.0Hz, 1H), 5.17 (s, 2H), 4.84-4.94 (m, 2H), 4.30 (t, J=4.8Hz, 2H), 2.90-3.300 (m, 10H), 2.83 (s, 3H), 1.93 (s, 3H).
Embodiment 10:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- Fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrrole Azoles -5- base) methoxyl group) phenyl) cyclopropyl) acetic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine furan Mutter -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles - 5- yl) methoxyl group) phenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 5 replaces intermediate 1, and intermediate 10 replaces intermediate 12, obtains Title compound (12mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine furan Mutter -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles - 5- yl) methoxyl group) phenyl) cyclopropyl) acetic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- Trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) and ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- first Base -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, takes polarity biggish Isomers obtains title compound (4.50mg).
1H NMR (400MHz, CD3OD) δ 8.43 (s, 1H), 7.51 (d, J=2.0Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 7.17 (td, J=7.6Hz, 1.6Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.84 (t, J=7.6Hz, 1H), 6.58 (dd, J=7.6Hz, 1.6Hz, 1H), 6.54 (d, J=1.6Hz, 1H), 5.63 (s, 1H), 5.60 (t, J=3.2Hz, 1H), 5.56 (dd, J=6.4Hz, 3.6Hz, 1H), 5.27 (d, J=13.2Hz, 1H), 5.24 (d, J =13.2Hz, 1H), 5.03-5.18 (m, 2H), 4.34-4.42 (m, 2H), 3.12-3.22 (m, 4H), 3.06 (t, J= 4.8Hz, 2H), 2.90-3.05 (m, 4H), 2.77 (s, 3H), 2.07 (s, 3H), 0.87-0.92 (m, 1H), 0.61-0.68 (m, 1H), 0.42-0.48 (m, 1H), 0.34-0.42 (m, 1H).
Embodiment 11:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (furan Mutter -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) cyclopropyl) acetic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (furans - 2- yl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 5 replaces intermediate 1, and intermediate 11 replaces intermediate 12, obtains Title compound (40mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (furans - 2- yl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) Methoxyl group) phenyl) cyclopropyl) acetic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoros Ethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) and ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, takes the biggish isomers of polarity Obtain title compound (1.91mg).
1H NMR (400MHz, CD3OD) δ 8.43 (s, 1H), 7.54 (d, J=1.6Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.03 (d, J= 8.4Hz, 1H), 6.86 (t, J=7.6Hz, 1H), 6.60 (d, J=7.2Hz, 1H), 6.54 (s, 1H), 6.38 (dd, J= 3.2Hz, 2.0Hz, 1H), 5.65 (s, 1H), 5.62 (d, J=7.2Hz, 1H), 5.30 (d, J=13.2Hz, 1H), 5.24 (d, J =13.2Hz, 1H), 5.07-5.17 (m, 2H), 4.32-4.47 (m, 2H), 3.12-3.30 (m, 4H), 3.08 (t, J= 5.2Hz, 2H), 2.90-3.07 (m, 4H), 2.80 (s, 3H), 2.05 (s, 3H), 0.84-0.93 (m, 1H), 0.61- 0.69 (m, 1H), 0.44-0.52 (m, 1H), 0.36-0.42 (m, 1H).
Embodiment 12:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (furan Mutter -2- base) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles - 5- yl) methoxyl group) phenyl) butyric acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (furans - 2- yl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) methyl butyrate
Referring to the method for step 1 in embodiment 1, intermediate 11 replaces intermediate 12, obtains title compound (60mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (furans - 2- yl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- Base) methoxyl group) phenyl) butyric acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) second Oxygroup) phenyl) -6- (furans -2- base) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoros Ethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methyl piperazine Piperazine -1- base) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, take the biggish isomers of polarity to obtain title Compound (15mg).
1H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 7.77 (s, 1H), 7.56 (d, J=2.0Hz, 1H), 7.17-7.25 (m, 3H), 7.09 (d, J=8.0Hz, 1H), 6.85-6.95 (m, 2H), 6.55 (s, 1H), 6.48-6.50 (m, 1H), 6.24 (s, 1H), 5.48 (d, J=3.2Hz, 1H), 5.18-5.25 (m, 4H), 4.22-4.36 (m, 2H), 2.85 (t, J =5.2Hz, 2H), 2.45-2.78 (m, 8H), 2.33 (s, 3H), 1.80 (s, 3H), 0.99 (s, 3H), 0.85 (s, 3H).
Embodiment 13:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- Fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) - 1H- pyrazoles -5- base) methoxyl group) phenyl) butyric acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine Furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- Pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate
Referring to the method for step 1 in embodiment 1, intermediate 10 replaces intermediate 12, obtains title compound (20mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine Furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- Pyrazoles -5- base) methoxyl group) phenyl) butyric acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methyl piperazine -1- base) second Oxygroup) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- methyl -3- (2- ((1- (2, 2,2- trifluoroethyls) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl - 3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, takes the biggish isomery of polarity Body obtains title compound (5mg).
1H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 7.56 (d, J=1.6Hz, 1H), 7.17-7.24 (m, 3H), 7.09 (d, J=8.0Hz, 1H), 6.93 (t, J=7.2Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6..55 (d, J= 1.6Hz, 1H), 6.24 (s, 1H), 5.85 (dd, J=7.2Hz, 3.6Hz, 1H), 5.51 (t, J=7.2Hz, 1H), 5.17- 5.25 (m, 4H), 4.21-4.33 (m, 2H), 2.83 (t, J=5.2Hz, 2H), 2.34-2.74 (m, 8H), 2.28 (s, 3H), 1.81 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H).
Embodiment 14:(2R) -2- (((5Sa) -5-- (3- chloro-2-methyl -4- (2- (4- methyl piperazine -1- base) ethoxy Base) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d1 pyrimidine-4-yls) oxygroup) -3- (2- ((1- (2,2,2- trifluoros Ethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) butyric acid
Step 1:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base)-6- (5- fluorine furans-2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup)-3- methyl-3- (2-((1- (2,2,2- tri- Fluoro ethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate
Referring to the method for step 1 in embodiment 1, intermediate 13 replaces intermediate 12, obtains title compound (20mg).
Step 2:(2R) -2- (((5Sa) -5-- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((1- (2,2,2- trifluoroethyl) - 1H- pyrazoles -5- base) methoxyl group) phenyl) butyric acid
Referring to the method for step 2 in embodiment 1, (2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methyl Piperazine -1- base) ethyoxyl) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- methyl - 3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) methyl butyrate replaces 2- ((5- (the chloro- 2- of 3- Methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygen Base) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, take pole The biggish isomers of property obtains title compound (3mg).
1H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 7.56 (d, J=1.6Hz, 1H), 7.17-7.24 (m, 3H), 7.09 (d, J=8.0Hz, 1H), 6.93 (t, J=7.2Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6..55 (d, J= 1.6Hz, 1H), 6.24 (s, 1H), 5.85 (dd, J=7.2Hz, 3.6Hz, 1H), 5.51 (t, J=7.2Hz, 1H), 5.17- 5.25 (m, 4H), 4.21-4.33 (m, 2H), 2.83 (t, J=5.2Hz, 2H), 2.34-2.74 (m, 8H), 2.28 (s, 3H), 1.81 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H).
Embodiment 15:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) Phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((1- (2,2,2- trifluoro second Base) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) acetic acid
Step 1:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- trifluoro second Base) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 15 replaces intermediate 1, and intermediate 10 replaces intermediate 12, obtains To title compound (10mg).
Step 2:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- trifluoro second Base) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) acetic acid
Referring to the method for step 2 in embodiment 1, (2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methyl Piperazine -1- base) ethyoxyl) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2 (- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) cyclopropyl) and ethyl acetate replace 2- ((5- (3- Chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine - 4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, it takes The biggish isomers of polarity obtains title compound (5mg).
1H NMR (400MHz, CD3OD) δ 8.43 (s, 1H), 7.51 (d, J=2.0Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 7.17 (td, J=7.6Hz, 1.6Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.84 (t, J=7.6Hz, 1H), 6.58 (dd, J=7.6Hz, 1.6Hz, 1H), 6.54 (d, J=1.6Hz, 1H), 5.63 (s, 1H), 5.60 (t, J=3.2Hz, 1H), 5.56 (dd, J=6.4Hz, 3.6Hz, 1H), 5.27 (d, J=13.2Hz, 1H), 5.24 (d, J =13.2Hz, 1H), 5.03-5.18 (m, 2H), 4.34-4.42 (m, 2H), 3.12-3.22 (m, 4H), 3.06 (t, J= 4.8Hz, 2H), 2.90-3.05 (m, 4H), 2.77 (s, 3H), 2.07 (s, 3H), 0.87-0.92 (m, 1H), 0.61-0.68 (m, 1H), 0.42-0.48 (m, 1H), 0.34-0.42 (m, 1H).
Embodiment 16:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- Fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) amino) -2- (1- (2- methoxyphenyl) cyclopropyl) acetic acid
Step 1:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine Furans -2- base) thieno [2,3-d] pyrimidine-4-yl) amino) -2- (1- (2- methoxyphenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 19 replaces intermediate 1, and intermediate 10 replaces intermediate 12, must mark It inscribes compound (20mg).
Step 2:2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (5- fluorine Furans -2- base) thieno [2,3-d] pyrimidine-4-yl) amino) -2- (1- (2- methoxyphenyl) cyclopropyl) acetic acid
Referring to the method for step 2 in embodiment 1,2- ((5- (3- chloro-2-methyl -4- (2- (4- methyl piperazine -1- base) second Oxygroup) phenyl) -6- (5- fluorine furans -2- base) thieno [2,3-d] pyrimidine-4-yl) amino) -2- (1- (2- methoxyphenyl) Cyclopropyl) ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- methyl -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles - 5- yl) methoxyl group) phenyl) ethyl butyrate, obtain title compound (5mg).
1H NMR (400MHz, DMSO-d6) δ 8.32 (s, 1H), 7.33-7.38 (m, 2H), 7.18 (t, J=8.0Hz, 1H), 6.89 (d, J=7.6Hz, 1H), 6.78 (t, J=8.0Hz, 1H), 6.48 (d, J=7.6Hz, 1H), 5.84 (dd, J= 6.8Hz, 3.6Hz, 1H), 5.62 (t, J=3.6Hz, 1H), 5.26 (d, J=8.4Hz, 1H), 4.71 (d, J=8.4Hz, 1H), 4.31-4.34 (m, 2H), 3.75 (s, 3H), 2.89-2.95 (m, 2H), 2.60-2.85 (m, 8H), 2.44 (s, 3H), 2.02 (s, 3H), 0.84-0.89 (m, 1H), 0.51-0.60 (m, 2H), 0.38-0.43 (m, 1H).
Embodiment 17:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) Phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((2- (2- methoxyphenyl) pyrimidine - 4- yl) methoxyl group) phenyl) -3 Methylbutanoic acid
Step 1:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((2- (2- methoxyphenyl) pyrimidine -4- Base) methoxyl group) phenyl) -3 Methylbutanoic acid methyl esters
Referring to the method for step 1 in embodiment 1, intermediate 1 is replaced with intermediate 18, obtains title compound (20mg).
Step 2:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((2- (2- methoxyphenyl) pyrimidine -4- Base) methoxyl group) phenyl) -3 Methylbutanoic acid
Referring to the method for step 2 in embodiment 1, with (2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- first Base piperazine -1- base) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -3- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) and -3 Methylbutanoic acid methyl esters replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- first Base -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, takes polarity biggish different Structure body obtains title compound (4mg).
1H NMR (400MHz, DMSO-d6) δ 8.80 (d, J=4.8Hz, 1H), 8.52 (s, 1H), 7.54 (d, J= 5.6Hz, 1H), 7.43-7.49 (m, 2H), 7.11-7.28 (m, 9H), 6.97-7.02 (m, 2H), 6.89 (d, J=4.0Hz, 1H), 6.44 (s, 1H), 5.25 (d, J=15.2Hz, 1H), 5.24 (d, J=15.2Hz, 1H), 4.26-4.28 (m, 1H), 4.16-4.19 (m, 1H), 3.77 (s, 3H), 2.60-2.90 (m, 10H), 2.44 (s, 3H), 1.76 (s, 3H), 1.07 (s, 3H), 0.99 (s, 3H).
Embodiment 18:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) Phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) ((((2- (2- methoxyphenyl) is phonetic by 2- by 1- by -2- Pyridine -4- base) methoxyl group) phenyl) cyclopropyl) acetic acid
Step 1:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine - 4- yl) methoxyl group) phenyl) cyclopropyl) ethyl acetate
Referring to the method for step 1 in embodiment 1, intermediate 1 is replaced with intermediate 17, obtains title compound (90mg).
Step 2:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine - 4- yl) methoxyl group) phenyl) cyclopropyl) acetic acid
Referring to the method for step 2 in embodiment 1, (2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methyl Piperazine -1- base) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) cyclopropyl) ethyl acetate replace 2- ((5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -4- oxygroup) -3- first Base -3- (2- ((1- (2,2,2- trifluoroethyl) -1H- pyrazoles -5- base) methoxyl group) phenyl) ethyl butyrate, takes polarity biggish different Structure body obtains title compound (45mg).
1H NMR (400MHz, CDCl3) δ 8.78 (d, J=5.6Hz, 1H), 8.44 (s, 1H), 7.98 (d, J=4.8 Hz, 1H), 7.66 (dd, J=7.6Hz, 1.6Hz, 1H), 7.40-7.45 (m, 2H), 7.02-7.14 (m, 5H), 6.89- 6.97 (m, 3H), 6.78 (d, J=8.0Hz, 1H), 6.74 (d, J=7.6Hz, 1H), 6.36 (d, J=7.6Hz, 1H), 5.78 (s, 1H), 5.22 (d, J=15.2Hz, 1H), 5.15 (d, J=15.2Hz, 1H), 4.32-4.39 (m, 2H), 3.85 (s, 3H), 2.61- 3.13 (m, 10H), 2.47 (s, 3H), 1.96 (s, 3H), 0.90-0.99 (m, 1H), 0.81-0.89 (m, 1H), 0.60-0.69 (m, 1H), 0.51-0.59 (m, 1H).
Embodiment 19:(R) -4- (2- (4- (4- (carboxyl (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxy Base) phenyl) cyclopropyl) methoxyl group) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -5- base) the chloro- 3- methylenedioxy phenoxy of -2- Base) ethyl)-1- methyl-1-((phosphonato) methyl) piperazine-1-
Step 1:(2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) benzene Base) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) -2- (1- (2- ((2- (2- methoxyphenyl) pyrimidine - 4- yl) methoxyl group) phenyl) cyclopropyl) acetic acid (4- methoxyl group) benzyl ester
At room temperature, to (2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) Phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) ((((2- (2- methoxyphenyl) is phonetic by 2- by 1- by -2- Pyridine -4- base) methoxyl group) phenyl) cyclopropyl) acetic acid (75mg), (4- methoxyl group) benzylalcohol (23mg) and triphenylphosphine (55mg) Toluene (10mL) solution in be added dropwise DIAD (37mg), risen to after finishing 50 DEG C stir 1 hour.Reaction solution is poured into water, second Acetoacetic ester extraction, extract liquor are washed with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, by residue silicagel column Chromatography (eluent: methylene chloride: methanol=15: 1 (V: V)) purifies to obtain title compound (60mg).
Step 2:(R) -4- (2- (the chloro- 4- of 2- (6- (4- fluorophenyl) -4- (2- ((4- methoxy-benzyl) oxygroup) -1- (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) cyclopropyl) -2- oxoethoxy) thieno [2,3- D] pyrimidine -5- base) -3- methylphenoxy) ethyl) -1- (((two tert-butoxy phosphoryls) oxygroup) methyl) -1- methyl piperazine - 1-
At room temperature, to (2R) -2- (((5Sa) -5- (3- chloro-2-methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) Phenyl) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine-4-yl) oxygroup) ((((2- (2- methoxyphenyl) is phonetic by 2- by 1- by -2- Pyridine -4- base) methoxyl group) phenyl) cyclopropyl) acetic acid (4- methoxyl group) benzyl ester (60mg), sodium iodide (26mg) and sodium bicarbonate Di-t-butyl chloromethyl phosphate (45mg) is added dropwise in acetone (10mL) solution of (15mg), is stirred at room temperature after finishing 1 hour.It will Reaction solution filtering, solid drying is directly used in reacts in next step.
Step 3:(R) -4- (2- (4- (4- (carboxyl (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) benzene Base) cyclopropyl) methoxyl group) -6- (4- fluorophenyl) thieno [2,3-d] pyrimidine -5- base) the chloro- 3- methylphenoxy of -2-) second Base)-1- methyl-1-((phosphonato) methyl) piperazine-1-
At room temperature, to (R) -4- (2- (the chloro- 4- of 2- (6- (4- fluorophenyl) -4- (2- ((4- methoxy-benzyl) oxygroup) -1- (1- (2- ((2- (2- methoxyphenyl) pyrimidine-4-yl) methoxyl group) phenyl) cyclopropyl) -2- oxoethoxy) thieno [2, 3-d] pyrimidine -5- base) -3- methylphenoxy) ethyl) -1- (((two tert-butoxy phosphoryls) oxygroup) methyl) -1- methyl piperazine Trifluoroacetic acid (3mL) is added dropwise in methylene chloride (4mL) solution of piperazine -1-, is stirred at room temperature after finishing 12 hours.Reaction solution is dense Contracting, residue is through preparing target compound 10 (mg) of post separation
1H NMR (400MHz, CD3OD) δ 8.80 (d, J=5.6Hz, 1H), 8.41 (s, 1H), 8.01 (d, J=5.2 Hz, 1H), 7.68 (dd, J=7.2Hz, 1.6Hz, 1H), 7.49 (td, J=8.0Hz, 1.2Hz, 1H), 7.33 (d, J=8.4Hz, 1H), 7.22-7.26 (m, 2H), 7.13-7.17 (m, 3H), 6.99-7.06 (m, 3H), 6.93 (d, J=8.4Hz, 1H), 6.77 (t, J=7.2Hz, 1H), 6.43 (dd, J=7.6Hz, 1.6Hz, 1H), 5.63 (s, 1H), 5.29 (d, J=15.6Hz, 1H), 5.22 (d, J=15.6Hz, 1H), 4.89 (d, J=8.4Hz, 2H), 4.32 (t, J=4.4Hz, 2H), 3.85 (s, 3H), 3.12-3.60 (m, 8H), 3.07-3.10 (m, 2H), 3.05 (s, 3H), 1.99 (s, 3H), 0.99-1.06 (m, 1H), 0.84- 0.92 (m, 1H), 0.56-0.71 (m, 2H)
Biological activity test
1. the external protein active of compound measures:
The protein active screening technique of Mcl-1 is established using fluorescence polarization method.The basic principle is that: small molecule chemical combination The small peptide (FITC-Noxa) of object and fluorophor FITC label competes its binding site with Mcl-1.As FITC-Noxa and greatly After molecular substance Mcl-1 is combined, fluorescent material FITC absorbs luminous energy after the irradiation of the blue polarised light (485nm) of single plane Excitation state is leapt to, ground state is then returned back to, and issues the polarized fluorescence (525nm) of single plane.On the contrary, if FITC-Noxa Fail in conjunction with macromolecular substances Mcl-1, it is fast that small molecule is rotated or turned over speed, and transmitting light will be gone partially relative to excitation optical plane Vibrationization.That is when compound it is emulative in conjunction with Mcl-1 after, FITC-Noxa will exist with free state, partially Vibration value reduces.Therefore, compound and the binding ability of Mcl-1 can reflect by the variation of polarization value.
Concrete operations are as follows: the compound storing liquid of 10mM being diluted to 1mM with DMSO first, carries out 3 with DMSO later Times gradient dilution.The compound of 4 μ L gradient dilutions is taken to be transferred to (PBS, pH 7.4 in 96 μ L reaction buffers；50mM NaCl； 0.01%NP40 and 2mM dithiothreitol dithio (DTT)), it is black that this further diluted compound is then added to the hole 384- Color round bottom plateIn, then add the protein solution containing 10nM Mcl-1 of 8 μ L reaction buffers preparation.Then Above-mentioned test mixture is rocked to incubation 30 minutes at 23 DEG C, adds the reaction buffering that 4 μ L contain 10nM FITC-Noxa later Liquid simultaneously continues incubation at room temperature 120 minutes.Polarization light value measurement is carried out at Ex 485/Em 530 by EnVision.Pass through number According to analysis software Prism processing data and obtain the IC50 value of the compound.
2. the cell-proliferation activity of compound measures:
Using the Cell of Promega companyDetection reagent establishes suspension cell Proliferation Ability screening side Method.
Human leukemia cell MV-411 and human myeloma cell NCI-H929 is with being supplemented with 10% (MV-411) and 20% (NCI-H929) fetal calf serumRPMI-1640Culture medium is cultivated, and condition of culture is 37 DEG C, 95% air and 5% CO2, be incubated at 25cm2 or 75cm2 plastic tissue culture vesselIn, one week secondary culture 2 ~3 times.
By cell respectively with the inoculation of the density of 8 × 103 cells/wells (MV-411) and 1 × 104 cells/well (NCI-H929) In 96- porocyte culture platesIn, 195 holes μ L/, and at 37 DEG C, 95% air and 5% CO2 in cultivated. Untested compound is added after 24 hours: compound being subjected to 3 times of gradient dilutions with DMSO since 10mM (being dissolved in DMSO), often A concentration takes 4 μ L to be added in the serum free medium of 96 μ L, and the compound after finally taking 5 μ L culture mediums to dilute is added to inoculation Have in the culture version of cell.Final concentration of the 0.1% of DMSO in cell culture fluid, the final concentration of test compound be 0.3nM~ 10μM.37 DEG C of above-mentioned cell are incubated 3 days.
After 3 days, cell viability measurement is carried out by Cell Titer-Blue (Promega) kit, finally by Prism program calculates the 503nhibiting concentration of compound on intracellular proliferation, i.e. IC50 value.
The biological data of selected part of compounds
It is analyzed according to selected compounds of the biological method as described herein to above-mentioned preparation.It is as the result is shown under Table:
Protein active data
Cytological data

Claims (10)

1. formula (I) compound or its pharmaceutically acceptable salt, solvate, isomers or prodrug,
Wherein,
X is O, NH or S；
R1Selected from H and 3-8 unit's heteroaryl, the heteroaryl is optionally by C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl or C3-8Cycloalkanes Base, C1-6Alkyl-O- or 6-10 member aryl replace, the C1-6Alkyl is optionally replaced by 1-3 halogen, and described 6-10 member aryl is optionally by 1-3 independently selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces；
A is singly-bound or double bond, and b is singly-bound；When a is singly-bound, R2And R3It is each independently selected from H, C1-6Alkyl or halogen, or Person R2、R33-6 member naphthenic base is formed together with the carbon atom being attached thereto；And R2And R3It cannot simultaneously be H；
When a is double bond, R3It is not present, R2For
R4It is each independently halogen, C1-6Alkyl, C1-6Alkyl-O- or cyano；
R5Selected from phenyl and 3-8 unit's heteroaryl, the phenyl and 3-8 unit's heteroaryl are optionally selected from halogen and C by 1-31-6Alkane The group of base replaces；
R6Selected from 3-8 circle heterocyclic ring base, the Heterocyclylalkyl is optionally by C1-6Alkyl ,-C1-6Alkylidene-O-P (=O) (OH)2、C1-6 Alkyl-O- replaces；
R7And R8It is each independently selected from H and C1-6Alkyl；
P and q is each independently 1,2,3,4,5 and 6；
M is 0,1,2,3 or 4.
2. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, isomers or prodrug, Middle R1Selected from H and 3-8 unit's heteroaryl, the heteroaryl is optionally by C1-6Alkyl, C1-6Alkyl-O- or 6-10 member aryl Replace, the C1-6Alkyl is optionally replaced by 1-3 halogen, and the 6-10 member aryl is optionally independent by 1-3 Ground is selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces.
3. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, isomers or prodrug, Middle R1Selected from H, pyrazolyl and pyrimidine radicals, the pyrazolyl and pyrimidine radicals are optionally by C1-6Alkyl, C1-6Alkyl-O- or 6-10 member aryl replaces, the C1-6Alkyl is optionally replaced by 1-3 halogen, and the 6-10 member aryl is optionally By 1-3 independently selected from C1-6Alkyl and C1-6The group of alkyl-O- replaces.
4. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, isomers or prodrug, In
When a is double bond, R3It is not present, R2ForWherein R7And R8For hydrogen.
5. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, isomers or prodrug, Middle R5Selected from phenyl and furyl, the phenyl and furyl are optionally selected from halogen and C by 1-31-6The group of alkyl takes Generation.
6. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, isomers or prodrug, Middle p is 1, q 2, m 0,1 or 2.
7. compound according to claim 1 or its pharmaceutically acceptable salt, solvate, isomers or prodrug, Described in compound be selected from:
8. a kind of pharmaceutical composition, it includes compound of formula I defined in the present invention or its pharmaceutically acceptable salts, solvation Object, isomers or prodrug and pharmaceutically acceptable carrier.
9. compound described in -7 or its pharmaceutically acceptable salt, solvate, isomers or prodrug according to claim 1 It is used to treat the purposes as caused by the MCL-1 albumen for over-expressing or lacking of proper care or in the drug of the disease aggravated in preparation.
10. compound described in -7 or its pharmaceutically acceptable salt, solvate, isomers or prodrug according to claim 1 It is used to treat bladder cancer, the cancer of the brain, breast cancer and uterine cancer, chronic lymphatic leukemia, colon cancer, cancer of the esophagus and liver in preparation Cancer, lymphoblast leukaemia, acute myeloid leukaemia, lymthoma, oophoroma, non-small cell lung cancer, Huppert's disease, urgency Purposes in the drug of property leukemic lymphoblastoid or myelodysplastic syndrome.
CN201810425784.0A 2017-11-23 2018-05-08 Mcl-1 selective depressant and its preparation and use Pending CN110452253A (en)

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CN201880075917.4A CN111372936B (en) 2017-11-23 2018-11-22 Mcl-1 selective inhibitors, their preparation and use

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